VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• CISplatin

Chemical Name:

• ( SP -4-2)-Diamminedichloroplatinum

Molecular Formula:

• Cl₂H₆N₂Pt

Cisplatin is a platinum-containing antineoplastic agent.1,7,13

Cisplatin is often used as a component of combination chemotherapeutic regimens because of its relative lack of hematologic toxicity.64,73

Testicular Cancer

Cisplatin is used as a component of various chemotherapeutic regimens for the treatment of metastatic testicular tumors, including nonseminomatous testicular carcinoma, seminoma testis, and extragonadal germ-cell tumors, in patients who have already received appropriate surgery and/or radiation therapy.1,63,403

Nonseminomatous Testicular Carcinoma

In the treatment of disseminated nonseminomatous testicular carcinoma (stage III), cisplatin is one of the most active single agents;13,64,79 however, combination chemotherapy for induction of remissions is superior to single-agent therapy.64,65,66,67,68,69,70,71,72,73,79 Various regimens have been used in combination therapy, and comparative efficacy is continually being evaluated.64,65,66,67,68,69,70,71,72,73,74,75,76,77,380 Most clinicians use cisplatin in combination with other antineoplastic agents as initial therapy in patients with stage III or unresectable stage II nonseminomatous testicular carcinoma;64,65,66,67,68,69,70,71,72,73,74,75,76,77,403 if the patient has persistent, localized tumor following chemotherapy, the residual tumor is removed surgically,64,65,66,67,68,71,72,73,74,75,76,77 and if the residual disease contains malignant elements, additional chemotherapy is administered.64,74,75,76,77,80

Cisplatin has been used in combination with bleomycin and vinblastine, with or without other antineoplastic agents, for the induction of remissions.64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,403 Cisplatin also has been used in combination with bleomycin and etoposide for the treatment of disseminated disease.63,335,403,406,407,408,409,410,411,412 These chemotherapy regimens usually produce a complete remission in 60-70% of patients with disseminated disease;65,66,67,68,69,70,71,72,73,74,75,76,77,403 response rates generally are higher in patients with minimal stage III disease65,69,70,73,74,77 and less advanced disease70,73 and lower in patients with advanced stage III disease.65,69,70,73,74,77 An additional 10-20% of patients can attain a complete remission following surgical removal of localized residual disease after chemotherapy-induced partial remissions.65,66,67,71,72,73,75,76 Most patients who attain a complete remission remain disease free, and those patients who have continuous disease-free remission for longer than 2 years generally are considered cured.64,73 Maintenance chemotherapy does not appear to be necessary following the attainment of a complete remission.64,71,77,78 Although not clearly established,64,71,73 patients with embryonal carcinoma may have a better response to chemotherapy than do patients with choriocarcinoma or teratocarcinoma.77,79

For the initial treatment of advanced nonseminomatous testicular carcinoma, most clinicians recommend regimens containing cisplatin and bleomycin, in combination with etoposide rather than vinblastine, particularly because of the reduced neuromuscular toxicity and evidence suggesting greater efficacy in poor-risk patients.403,406,407,408,409,411,412 In addition, while a regimen of etoposide, cisplatin, and bleomycin appears to be as effective overall as a regimen of vinblastine, cisplatin, and bleomycin, the etoposide-containing regimen may be more effective than the vinblastine-containing regimen in a subgroup of patients with advanced disease (i.e., high tumor load).408 However, the best combination or sequential therapy in the treatment of advanced nonseminomatous testicular tumors has not been established, and comparative efficacy is continually being evaluated.411

A regimen of cisplatin, ifosfamide with mesna, and either vinblastine or etoposide has induced complete responses in 20-45% of patients who previously received other cisplatin-based chemotherapy regimens,403,502,503,504,505 and is considered by most clinicians to be the standard initial salvage (i.e., second-line) regimen in patients with recurrent testicular cancer.63,403,507 Patients with minimal or moderate disease have a more favorable outcome with this salvage regimen than those with extensive disease.403,503 In a clinical study in patients with recurrent germ cell tumors (who had previously received at least 2 cisplatin-based chemotherapy regimens and were considered to have cisplatin-responsive disease), a regimen of cisplatin, ifosfamide, and either vinblastine or etoposide resulted in disease-free status in 36% of patients (with or without surgery) and median duration of disease control ranged from 3 to more than 42 weeks, median survival was 53 weeks, and 20% of patients had survival of 2 years or longer.503,567 In patients with refractory disease, high-dose chemotherapy with autologous bone marrow transplant (ABMT) or peripheral stem cell rescue may produce durable complete remissions in some patients.403,507,508 Patients with progressive tumors during initial or salvage therapy and those with refractory mediastinal germ cell tumors generally appear to benefit less from high-dose chemotherapy and ABMT or peripheral stem cell rescue than those whose disease relapses after a response.403 Salvage surgery also may be considered for certain highly selected patients (e.g., those with chemorefractory disease confined to a single site).403

The role of chemotherapy in the treatment of stage I and resectable stage II nonseminomatous testicular carcinoma has not been clearly established.64,71,73,81,82 Although most patients with stage I disease are cured by surgery alone, cisplatin-containing combination chemotherapy regimens have been used successfully to induce complete remissions in a limited number of these patients whose disease relapsed following surgical treatment.71,73,95 Cisplatin-containing combination chemotherapy regimens have also been used successfully as an adjuvant to surgery (orchiectomy and retroperitoneal lymphadenectomy) to induce complete remissions in patients with resectable stage II disease.71,73,398 Although the precise role of chemotherapy as an adjuvant to surgery in the treatment of stage II disease remains to be clearly established,64,73,81,403 such therapy with cisplatin-containing combination regimens is effective in preventing tumor recurrence in patients with such disease.81,82,372,398,403 When surgery, follow-up, and chemotherapy are optimal in patients with stage II disease who have no postoperative evidence of residual or recurrent disease, including absence of elevated tumor markers, cure rates appear to be similar whether cisplatin-containing chemotherapy is administered as an adjuvant to surgery (i.e., beginning postoperatively) or is withheld and used to treat relapse in closely monitored patients.398,403 In patients with residual gross disease or residual elevated tumor markers following retroperitoneal lymphadenopathy, some clinicians recommend that all such patients receive cisplatin-containing combination chemotherapy.64

Seminoma Testis

Cisplatin-containing combination chemotherapy regimens have been used successfully in the treatment of disseminated seminoma testis,65,67,71,74,77,83,84,373,382,403,413 with complete remission rates comparable to those in patients with disseminated nonseminomatous disease.71,74,77,83,413 Further evaluation is needed to determine the optimum therapy.64,84

Extragonadal Germ-Cell Tumors

Although data are limited and some reports indicate a low response rate,64,87 cisplatin-containing combination chemotherapy regimens (followed by surgery when feasible) have reportedly been successful in the treatment of advanced extragonadal germ-cell tumors,88,89,90 with complete remission rates comparable to those in patients with nonseminomatous tumors of similar advanced stages.88,89 Cisplatin-containing combination chemotherapy regimens have also been reported to be successful in a few cases for the treatment of extragonadal endodermal sinus tumor (yolk-sac carcinoma) in males,91,92 although this tumor is generally considered poorly responsive to chemotherapy.93

Ovarian Cancer

Cisplatin is used alone or in combination therapy for the treatment of ovarian cancer.1,509

Adjuvant Therapy for Early-stage Ovarian Epithelial Cancer

Platinum-based therapy has been used for adjuvant treatment following surgery in early-stage ovarian epithelial cancer†.509(See Uses: Ovarian Cancer: Adjuvant Therapy for Early-stage Ovarian Epithelial Cancer in Carboplatin 10:00.)

First-line Therapy for Advanced Ovarian Epithelial Cancer

A platinum-containing agent in combination with paclitaxel is a preferred regimen for the treatment of advanced ovarian epithelial cancer.63,509 The best combination or sequential therapy with multiple agents in the treatment of advanced ovarian tumors has not been established, and comparative efficacy is continually being evaluated.509

Combination chemotherapy regimens containing platinum are associated with higher response rates and improved survival compared with non-platinum-containing regimens as first-line treatment for advanced ovarian cancer.96,218,509 The benefit of cisplatin used in combination therapy rather than as monotherapy has not been fully established.218,219,509 In a large randomized trial, cisplatin combined with paclitaxel produced higher response rates than paclitaxel alone and similar response rates but less toxicity than cisplatin alone; median survival did not differ among the groups.219

Carboplatin versus Cisplatin

Randomized trials have demonstrated that carboplatin is as effective as but less toxic than cisplatin when used in combination with either paclitaxel757,758 or cyclophosphamide for the initial treatment of advanced ovarian cancer.521,522 Carboplatin in combination with paclitaxel currently is a preferred regimen for the initial treatment of advanced ovarian epithelial cancer.63,509 (See Uses: Ovarian Cancer: First-line Therapy for Advanced Ovarian Epithelial Cancer in Carboplatin 10:00.)

Platinum-Containing Agent with Paclitaxel Versus Platinum-containing Agent with Cyclophosphamide

The combination of IV cisplatin and IV paclitaxel has been used for the initial treatment of advanced epithelial ovarian carcinoma,219,509,512,514,515,516,517,518,577,578,641 and evidence from randomized trials indicates that this combination is superior to combined cisplatin and cyclophosphamide for initial treatment.509,517,641 In a comparative study of patients with suboptimally debulked (greater than 1 cm residual tumor mass) stage III or IV ovarian cancer who had no prior chemotherapy, combined therapy with paclitaxel and cisplatin produced higher rates of overall objective response (73 versus 60%), increased disease-free survival (median: 18 versus 13 months), and increased overall survival (median: 38 versus 24 months) compared with a combined regimen of cisplatin and cyclophosphamide.517 A higher frequency of neutropenia, fever, alopecia, and allergic reactions was observed in patients receiving cisplatin and paclitaxel compared with those receiving cisplatin and cyclophosphamide.517 In another randomized trial, higher rates of overall and complete response (59 versus 45% and 41 versus 27%, respectively) and prolonged median overall survival (36 versus 26 months) were observed in patients receiving paclitaxel and cisplatin versus cyclophosphamide and cisplatin for advanced epithelial ovarian cancer.641 At a follow-up of 6.5 years, the survival benefit associated with the cisplatin and paclitaxel regimen in both randomized trials has been maintained.759

Intraperitoneal Cisplatin and Paclitaxel

Combined IV and intraperitoneal therapy with IV paclitaxel, intraperitoneal cisplatin, and intraperitoneal paclitaxel† has been used for the treatment of optimally debulked stage III epithelial ovarian cancer.10001

The National Cancer Institute (NCI) recommends use of a combined IV and intraperitoneal regimen for eligible patients with advanced epithelial ovarian cancer because of a substantial survival benefit.10005 Based on clinical trials, NCI recommends that use of a regimen containing intraperitoneal cisplatin (100 mg/m²) and a taxane (either IV only or IV plus intraperitoneal) should be strongly considered following primary surgery in patients with optimally debulked stage III epithelial ovarian cancer.10001,10005 Although an optimal intraperitoneal chemotherapy regimen has not been established,10005 favorable results were observed following sequential administration of IV paclitaxel, intraperitoneal cisplatin, and intraperitoneal paclitaxel in the Gynecologic Oncology Group (GOG)-172 study.10001

In this randomized phase 3 trial (GOG-172), 429 patients with previously untreated stage III epithelial ovarian cancer or primary peritoneal cancer, with no residual mass exceeding 1 cm in diameter following surgery, received either combined IV and intraperitoneal therapy or IV therapy.10001 All patients enrolled in this study had good baseline GOG performance status (0-2) and adequate bone marrow, renal, and hepatic function.10001 Most patients (88%) had ovarian cancer, and serous adenocarcinoma was the most common histologic type (79% of patients).10001 The primary end points of the study were progression-free survival and overall survival.10001 Combined IV and intraperitoneal therapy consisted of IV paclitaxel 135 mg/m² by 24-hour infusion on day 1, followed by intraperitoneal cisplatin 100 mg/m² on day 2 and intraperitoneal paclitaxel 60 mg/m² on day 8.10001 IV therapy consisted of IV paclitaxel 135 mg/m² by 24-hour infusion on day 1 followed by IV cisplatin 75 mg/m² on day 2.10001 Both regimens were repeated every 21 days for up to 6 cycles.10001 Patients who received combined IV and intraperitoneal therapy had longer median progression-free (23.8 versus 18.3 months) and overall (65.6 versus 49.7 months) survival compared with patients who received IV therapy.10001

Most (83%) of the patients receiving IV therapy completed 6 cycles of their assigned chemotherapy regimen; however, only 42% of patients receiving combined IV and intraperitoneal therapy completed 6 cycles of assigned chemotherapy; patients who could not complete the intraperitoneal regimen received IV therapy for the remaining treatment cycles.10001 The most common reason for discontinuance of intraperitoneal therapy was catheter-related complications.10001 Grade 3 or 4 leukopenia (76 versus 64%), GI effects (46 versus 24%), metabolic effects (27 versus 7%), fatigue (18 versus 4%), neurologic effects (19 versus 9%), infection (16 versus 6%), thrombocytopenia (12 versus 4%), and pain (11 versus 1%) occurred more frequently in patients receiving combined IV and intraperitoneal therapy than in those receiving IV therapy.10001 Although patients receiving combined IV and intraperitoneal therapy reported less improvement in abdominal discomfort before cycle 4, improvement in abdominal discomfort was similar in both treatment groups 1 year after completion of therapy.10002,10010 Among patients who received combined IV and intraperitoneal therapy, quality of life was worse during and shortly after completion of therapy (before cycle 4 and at 3-6 weeks following therapy) compared with those who received IV therapy.10001,10002 Quality-of-life scores were similar for the groups at 1 year after completion of treatment, except for greater persistence of moderate paresthesias in patients receiving combined IV and intraperitoneal therapy.10001,10002,10005

Retrospective review of baseline data (patient and disease characteristics) from two phase 3 clinical trials (including GOG-172) for patients receiving intraperitoneal therapy for optimally debulked stage III epithelial ovarian cancer suggested that extent of residual tumor mass, histology, and age were important predictors of survival in such patients.10004 Patients with clear cell histology appeared to derive less benefit from intraperitoneal therapy compared with those with serous histology (hazard ratio for progression-free and overall survival of 2.66 and 3.88, respectively).10004 In addition, each additional year of age was associated with a 1% increase in the risk of death.10004 Although patients enrolled in the studies had optimally debulked (1 cm or less residual tumor mass) disease, survival was greater in patients with only microscopic residual disease.10004

Retrospective analysis of data from patients receiving a modified IV and intraperitoneal regimen suggests that a reduced dosage of intraperitoneal cisplatin administered in conjunction with a shortened IV paclitaxel infusion time may result in less toxicity and produce a survival benefit similar to that reported in the GOG-172 study (67 months versus 65.6 months reported in GOG-172).10001,10008 The modified IV and intraperitoneal regimen consisted of IV paclitaxel 135 mg/m² by 3-hour infusion on day 1, followed by intraperitoneal cisplatin 75 mg/m² on day 2 and intraperitoneal paclitaxel 60 mg/m² on day 8 of each 21-day cycle.10008 Most patients (80%) completed 4 or more cycles of therapy and 55% completed 6 cycles.10008 The frequency of grade 3 or 4 neutropenia (12%), GI effects (8%), metabolic effects (5%), neurologic effects (6%), infection (2%), fatigue (2%), and thrombocytopenia (0%) in this series of patients receiving the modified IV and intraperitoneal regimen appeared to be lower than toxicity rates reported in the GOG-172 study.10008 By shortening the infusion time for IV paclitaxel to 3 hours, the modified regimen also may provide an outpatient alternative to inpatient administration over 24 hours.10008,10012 However, randomized controlled trials are needed to establish comparative safety and efficacy of this modified regimen.10008 The modified IV and intraperitoneal schedule containing the lower intraperitoneal cisplatin dosage and the 3-hour IV paclitaxel infusion also has been studied in conjunction with a third cytotoxic drug, but with evidence of excessive toxicity.10013,10014

Based on current evidence, combined IV and intraperitoneal therapy with IV paclitaxel, intraperitoneal cisplatin, and intraperitoneal paclitaxel is recommended (accepted) for use as initial adjuvant treatment of optimally debulked stage III epithelial ovarian cancer in patients with good performance status (GOG performance status of 0-2).10012

Second-line Therapy for Advanced Ovarian Epithelial Cancer

Either cisplatin or carboplatin can be used when retreatment is indicated in patients with platinum-sensitive disease who relapse; however, some clinicians suggest that carboplatin may be preferred because it is associated with a more favorable toxicity profile than cisplatin.489,509 Although some patients who failed to respond to cisplatin or had a response of only short duration have responded to carboplatin,495,520 nonplatinum-based regimens (e.g., paclitaxel) generally are preferred for retreatment of patients with platinum-resistant disease.489,509,512,514 Responses to cisplatin also have been observed in patients with disease resistant to initial treatment with paclitaxel monotherapy.361,642

Dosage and Other Therapeutic Considerations

While some evidence indicates that dose intensity (i.e., amount of platinum per unit time) is an important factor in achieving optimum results in patients with stage III or IV ovarian carcinoma, other evidence suggests that total platinum dose or duration of exposure is a more important factor in improving progression-free survival in responding patients.513,565 However, no improvement in response appears to occur with increased dose intensity or increased total dose once a certain threshold is reached.361,639,640 Although optimum duration of chemotherapy has not been clearly defined, there currently is no evidence of improved response and/or survival when the duration of drug administration exceeds 6 cycles.513,524,525 Despite the fact that platinum-containing combination chemotherapy regimens are associated with high response rates, no regimen has been found that is sufficiently active to prevent disease progression and/or recurrence in most women with stage III or IV ovarian carcinoma. 521,523

Other therapeutic techniques, such as interval debulking surgery, may improve survival in patients with advanced ovarian carcinoma.509,579 In a randomized study involving patients with residual lesions (greater than 1 cm) following primary surgery for advanced ovarian cancer (stages IIB through IV) who responded to cisplatin-based induction chemotherapy, those who received interval debulking surgery accompanied by subsequent chemotherapy had improved survival compared with those who received chemotherapy alone.579

Ovarian Germ Cell Tumors

Cisplatin-containing chemotherapy regimens are used in the treatment of ovarian germ-cell tumors, including endodermal sinus tumors.63,122,123,124,374,385,401,415,582 Combination chemotherapy with cisplatin, bleomycin, and etoposide currently is a regimen of choice for the adjuvant therapy of ovarian germ-cell tumors.63,415,582

Bladder Cancer

Cisplatin is used widely in the treatment of muscle-invasive and advanced bladder cancer. Approximately 20-25% of patients with bladder cancer are initially diagnosed with invasive tumors.584 Radical cystectomy is the standard therapy for muscle-invasive bladder cancer;584,585,591,593,594 however, because of the high rate of metastasis following local therapy, combined modality treatment including chemotherapy (neoadjuvant or adjuvant), radiation therapy, and surgery is being evaluated for the management of invasive disease and also has been used to allow bladder preservation in selected patients.584,585,588,590,594,600,607,608,610,612,621,622 Combination chemotherapy alone or as an adjunct to local therapy with surgery and/or radiation therapy is used for the palliative and occasionally curative treatment of locally advanced (unresectable) or metastatic bladder cancer.556,584,585,587

Over 90% of bladder tumors are transitional cell carcinomas originating from the uroepithelium.584,585,587 Other histologic types of bladder cancer, such as squamous cell carcinoma (6-8%) and adenocarcinoma (2%), are associated with greater resistance to treatment and a more aggressive pattern of local spread than transitional cell carcinoma.585,587 Bladder carcinoma is clinically staged according to the TNM classification.584,585,587 Major prognostic factors in patients with carcinoma of the bladder include the depth of tumor invasion into the bladder wall and the degree of differentiation or grade of the tumor.584,585

Muscle-invasive Bladder Carcinoma

Overview

Choice of therapy in muscle-invasive cancer must be individualized according to prognostic factors, the patient's medical condition, expected benefits and risks of therapy, and patient preference.585,588,589,590 Important prognostic factors used to guide selection of therapy for invasive bladder cancer include stage of tumor, particularly whether the tumor is organ-confined (stage 2 or T3a) or not organ-confined (stage T3b, 4, 4a, or 4b); presence of lymph node involvement, and lymphatic or vascular invasion of the tumor.584,588

There is a 30-50% risk of nodal or distant metastases in patients with muscle-invasive bladder carcinoma.584,588,591,592 Radical cystectomy (i.e., removal of the bladder, prostate, and seminal vesicles in men or removal of the bladder, uterus, fallopian tubes, ovaries, and upper vagina in women) with pelvic lymphadenectomy is considered standard therapy in the US; depending on the location of the tumor, partial cystectomy rarely may be adequate in some patients.584,585,591,593,594 A retrospective analysis demonstrated that radical cystectomy with urinary diversion is well tolerated and effective for the definitive treatment of muscle-invasive bladder cancer in geriatric patients (70 years of age or older) in good health (i.e., good cardiac performance and absence of cardiovascular or pulmonary problems) in comparison with younger patients (younger than 70 years).399

Rarely, transurethral resection (TUR) alone has been effective in selected patients with a small (less than 2 cm), solitary papillary tumor that is minimally invasive into muscle and is not associated with carcinoma in situ, a palpable mass, or hydronephrosis;584,585,591 however, in the treatment of muscle-invasive bladder carcinoma, TUR more often is used to debulk tumors prior to the administration of systemic therapy with chemotherapy and/or radiation therapy in selected patients receiving combined modality treatment with bladder preservation.593,595 Some clinicians perform a second TUR in selected patients to further reduce tumor burden or to pursue findings (e.g., progression of disease, absence of residual tumor) that may influence treatment strategy.127

The addition of preoperative radiation has not been shown to affect overall survival in patients undergoing radical cystectomy for muscle-invasive bladder cancer and is not standard care in the US;584,585,591,596 however, limited evidence from a matched analysis suggests that preoperative radiation therapy may reduce the rate of local recurrence in patients with T3b tumors.584,597 Although overall survival in patients receiving sole treatment with radiation for invasive disease is inferior to that obtained with radical cystectomy, treatment with radiation therapy alone with external beam radiation may be considered in patients who refuse or are unable to tolerate surgery.556,584,585,591 Treatment with radiation therapy followed by salvage cystectomy does not appear to adversely affect survival or rate of metastasis compared with immediate cystectomy in patients with muscle-invasive bladder cancer.584,585,598,599

Despite treatment with radical cystectomy, 50% of patients with muscle-invasive bladder cancer will develop metastases within 18 months.590,593,600 Because of the high rates of metastasis following local therapy with cystectomy and/or radiation therapy, the addition of chemotherapy to the treatment regimen for muscle-invasive bladder cancer is being investigated.584,585,588,590,600 Randomized trials are being conducted to determine the benefit of chemotherapy (adjuvant or neoadjuvant) added to cystectomy or used in conjunction with radiation therapy for muscle-invasive bladder carcinoma;585,590 studies to date have shown no effect on overall survival.128,584,588,590,601,602,603,604,605,606 Combined modality therapy with combination chemotherapy, radiation therapy, and conservative surgery (aggressive transurethral resection or partial cystectomy) has been used to allow organ preservation in selected patients with muscle-invasive bladder cancer;129,584,594,595,607,608,609,610 however, the effect on survival with use of organ-sparing treatment versus standard therapy with radical cystectomy is not known.584,593,595,611

Neoadjuvant or Adjuvant Chemotherapy

In patients with muscle-invasive bladder cancer, chemotherapy has been given prior to (i.e., as neoadjuvant therapy) or following (i.e., as adjuvant therapy) local treatment with surgery and/or radiation therapy.128,584,588,591,600,602 The benefit of adjuvant or neoadjuvant chemotherapy has not been established, and use of chemotherapy as a component of therapy currently is considered investigational in the treatment of muscle-invasive bladder cancer.128,130,133,556,588,590,591,600,602

Although no survival benefit has been conclusively demonstrated with the use of adjuvant chemotherapy,133,584,588,602,603,605,606 some experts recommend systemic therapy following either cystectomy or aggressive transurethral resection in patients with adverse prognostic factors (e.g., stage T3b or greater, node-positive disease, lymphatic or vascular invasion of the tumor).133,584,588,600,602 Use of adjuvant chemotherapy may be unnecessary or excessive treatment, particularly in patients with muscle-invasive bladder cancer that is organ-confined (e.g., stage T2 or T3a) and node-negative.133,556,602

Trials evaluating the use of single chemotherapeutic agents as adjuvant therapy have not shown any benefit,584,591 and combination regimens consisting of cisplatin, methotrexate, and vinblastine with or without doxorubicin (abbreviated as M-VAC or CMV, respectively) currently are used for the adjuvant treatment of muscle-invasive bladder cancer.591,605,606 Combination chemotherapy used as adjuvant treatment has been demonstrated to delay progression of disease and decrease local recurrence of tumor in patients with muscle-invasive bladder cancer.605,606 When chemotherapy is administered in the adjuvant setting, it is recommended that a minimum of 4 cycles (at full doses) be given;133,584 however, the optimal dose, schedule, and number of courses for adjuvant chemotherapy in the treatment of muscle-invasive bladder carcinoma has not been determined.133,602 Additional study in randomized trials is needed to determine the benefit of adjuvant chemotherapy for invasive bladder cancer.133,588,591,600,602

Single-agent cisplatin or cisplatin-containing combination chemotherapy has been used as neoadjuvant therapy preceding cystectomy and/or radiation therapy or as concurrent therapy with definitive or preoperative radiation therapy in patients with muscle-invasive bladder cancer.128,604,612,614,615,616,617,618,638 The addition of neoadjuvant chemotherapy to local treatment appears to cause regression of existing tumor, decrease local recurrence of tumor, and increase time to relapse of disease in patients with muscle-invasive bladder cancer;602,604,612,613,614,615 however, no effect on overall survival has been conclusively demonstrated.128,584,602,604,614,615,616 Results of a pooled analysis that mostly included randomized trials of single-agent cisplatin did not demonstrate a difference in survival with the addition of chemotherapy (neoadjuvant or concurrent) in patients undergoing cystectomy and/or radiation therapy for muscle-invasive bladder cancer;601 however, based on experience with treatment of advanced bladder cancer, single-agent cisplatin is considered less effective than combination cisplatin-based chemotherapy.556,601,625,627

Results from large randomized trials of neoadjuvant therapy with cisplatin-based combination regimens (e.g., cisplatin, methotrexate, and vinblastine; cisplatin and doxorubicin) have not shown a survival benefit in patients with muscle-invasive bladder cancer.128,617 Subgroup analysis suggests a possible effect of neoadjuvant chemotherapy on overall survival in patients with cancers of histologic grade G3 or stage T3 or T4a disease,128,617 and further randomized trials may identify prognostic factors that allow selection of a subgroup of patients with locally advanced bladder cancer who are likely to benefit from neoadjuvant chemotherapy. 128,602 Because a conclusive survival benefit has not been shown, routine use of neoadjuvant therapy with combination chemotherapy regimens (e.g., cisplatin, methotrexate, and vinblastine with or without doxorubicin) for muscle-invasive bladder cancer is not recommended, and such therapy is considered investigational.128,130,556 Longer periods of follow-up in ongoing randomized trials are needed to establish the benefit (if any) of neoadjuvant chemotherapy in patients undergoing cystectomy and/or radiation therapy for muscle-invasive bladder cancer.130,133,614,617,618

The effect of sequence of therapy when chemotherapy is used in conjunction with local treatment (i.e., cystectomy and/or radiation therapy) for invasive bladder cancer is not known.619 Interim analysis of a randomized trial of patients with stage T3b or T4a tumors receiving either adjuvant or neoadjuvant chemotherapy did not detect any difference in survival.619 Further study is needed to establish the benefit of adding chemotherapy (adjuvant or neoadjuvant) to cystectomy and/or radiation therapy for the treatment of muscle-invasive bladder cancer.130,133,584,588,600,601,602

Neoadjuvant chemotherapy for muscle-invasive bladder cancer typically is administered IV.591 In a limited number of patients with muscle-invasive bladder cancer, neoadjuvant chemotherapy has been administered intra-arterially;590,620 however, this method of administration is associated with substantial toxicity, and the comparative efficacy of intra-arterial chemotherapy versus IV chemotherapy for the neoadjuvant treatment of muscle-invasive bladder cancer is not known.590,591,620

Combined Modality Therapy with Bladder Preservation

Single-agent cisplatin or cisplatin-containing combination chemotherapy (e.g., cisplatin with methotrexate and vinblastine [CMV]) has been used in conjunction with radiation therapy and conservative surgery as a bladder-sparing approach for the treatment of selected patients with muscle-invasive bladder cancer.129,594,607,608,610,612,621,622 Clinical trials are under way to investigate whether bladder preservation is a reasonable goal in patients with small-volume, organ-confined (stage T2 or T3a) disease when total eradication of the tumor can be achieved;556,585,588,595,600,623 patients with bulky tumors, tumors with overexpression of p53 nuclear protein, nontransitional or mixed histology carcinoma, hydronephrosis, and/or ureteral obstruction are at high risk for relapse of invasive bladder tumor and generally are not good candidates for clinical trials of organ-preserving therapy.129,594,595,607,624

Following aggressive transurethral resection (TUR), use of chemotherapy with radiation therapy appears to produce survival rates comparable to those reported for radical cystectomy in patients with muscle-invasive bladder cancer.594,611,621,622 In one case series, patients with muscle-invasive bladder cancer (stages T2 through T4, node-negative disease) underwent TUR followed by combination chemotherapy with cisplatin, methotrexate, and vinblastine (CMV) and then radiation therapy with concurrent cisplatin therapy.607 At 5 years, the overall survival rate was 52%, and 43% of all patients who entered the study had survived with a functioning bladder.611 However, in a randomized trial of patients with muscle-invasive bladder cancer (stages T2 through T4, node-negative disease) undergoing aggressive TUR followed by radiation therapy with concurrent cisplatin therapy, with or without the addition of neoadjuvant combination chemotherapy with cisplatin, methotrexate, and vinblastine (CMV) preceding concurrent chemoradiation therapy, neoadjuvant chemotherapy caused substantial toxicity (particularly severe neutropenia and sepsis) and did not provide additional benefit in rate of overall survival (48 versus 49%), rate of survival with a functioning bladder (36 versus 40%), or rate of distant metastases (33 versus 39%).129 Combination chemotherapy with cisplatin, methotrexate, vinblastine, and doxorubicin (M-VAC) followed by partial cystectomy also has been used as an organ-preserving approach to the treatment of muscle-invasive bladder cancer.609 Response to induction chemotherapy and/or radiation therapy confirmed by cystoscopy and/or bladder biopsy is an important predictor of survival in patients with muscle-invasive bladder cancer.595,608,613,622

Bladder preservation is attempted only in patients with disease that responds to induction chemotherapy and/or radiation therapy.593,594,607,608,609,610 Patients with disease that does not demonstrate a complete response to chemotherapy and/or radiation therapy are immediately referred for radical cystectomy;129,593,595,607,608,610 further study is needed to determine whether delay of cystectomy adversely affects outcome in such patients.556,595,622 All patients who receive organ-sparing therapy must be carefully monitored for tumor recurrence and/or occurrence of new tumors; local therapy (e.g., intravesical instillation) and/or cystectomy eventually is required in some patients.588,593,595,600,609 Combined modality treatment with conservative surgery and radiation therapy with concurrent cisplatin-containing chemotherapy may be a reasonable alternative in patients with muscle-invasive bladder cancer who refuse or are unable to tolerate radical cystectomy, and clinical trials are under way to investigate this approach;556,585,611 however, unless randomized trials demonstrate that survival is comparable to that achieved with radical cystectomy, organ-preserving treatment cannot be routinely recommended in patients with muscle-invasive bladder cancer.133,556,584,607

Advanced Bladder Carcinoma

Combination chemotherapy is used alone or as an adjunct to local therapy with surgery and/or radiation therapy for the palliative treatment of advanced (unresectable) or metastatic bladder carcinoma.584,585,587 The prognosis for patients with advanced or metastatic bladder cancer generally is poor, particularly in patients with bony or hepatic metastases.587,625 Although complete response to combination chemotherapy has been observed in some patients with metastatic bladder cancer,585,591,625,629,632 median survival with current treatment is only 12 months.587,626

Combination Cisplatin-based Chemotherapy

Cisplatin-based combination chemotherapy regimens (e.g., cisplatin, methotrexate, and vinblastine with or without doxorubicin, abbreviated as M-VAC or CMV, respectively; cisplatin and gemcitabine) currently are used for the palliative treatment of advanced or metastatic bladder cancer.63,134,556,584,585,626 In patients with metastatic bladder cancer, the potential benefit must be weighed against the substantial toxicity associated with aggressive chemotherapy.584,587 The activity of new agents and optimal regimens for the treatment of advanced or metastatic bladder cancer are continually being evaluated.587,626

Combination cisplatin-based therapy is superior to single-agent cisplatin,625,627 and combination chemotherapy regimens consisting of 3 or 4 drugs are considered standard therapy for patients with metastatic bladder cancer.63,588,591,594 Overall response rates with cisplatin-based combination regimens range from 40-70%, with complete responses rates of 10-20%.134,584,627,629,632

In randomized trials, patients with advanced or metastatic bladder cancer receiving combination chemotherapy with cisplatin, methotrexate, vinblastine, and doxorubicin (M-VAC) had higher response rates and more prolonged survival compared with single-agent cisplatin625,627 or combination therapy with cisplatin, doxorubicin, and cyclophosphamide.630 The use of M-VAC also is associated with greater toxicity than single-agent cisplatin, particularly leukopenia, mucositis, granulocytopenia, and drug-related mortality.627 At 6 years of follow-up, patients receiving M-VAC have more prolonged survival than those receiving cisplatin, but despite the superior efficacy of this regimen, only 3.7% of patients receiving M-VAC are alive and continuously disease-free.625

Combination therapy with cisplatin and gemcitabine is an alternative to M-VAC for the treatment of advanced or metastatic bladder cancer.134,556 In a large randomized trial of patients receiving either M-VAC or cisplatin and gemcitabine for the treatment of advanced or metastatic bladder cancer, overall median survival (14.8 versus 13.8 months, respectively), median time to progressive disease (7.4 months for each regimen), and response rates (38 versus 44%, respectively, using intent-to-treat analysis) were similar.134 Prophylactic hematopoietic agents (growth factors) were not administered to either group; grade 3 or 4 neutropenia, neutropenic sepsis, grade 3 or 4 mucositis, and alopecia occurred more frequently in patients receiving M-VAC whereas grade 3 or 4 anemia or grade 3 or 4 thrombocytopenia were observed more often in patients receiving cisplatin and gemcitabine.134

Patients receiving combination chemotherapy with cisplatin, methotrexate, and vinblastine (CMV) had a higher rate of survival at 1 year (29 versus 16%) but experienced more toxicity than those receiving methotrexate and vinblastine for advanced or metastatic bladder cancer.631 The comparative efficacy of M-VAC and CMV has not been investigated in randomized trials; some clinicians favor M-VAC as the established regimen of choice for the treatment of advanced or metastatic bladder cancer63,584,591,626 whereas others prefer CMV because of decreased toxicity associated with this regimen.63,556 Because of the cardiac toxicity associated with doxorubicin, CMV generally is preferable to M-VAC in patients with cardiac dysfunction.584 Non-transitional cell bladder cancers are less sensitive to standard cisplatin-based chemotherapy regimens than is transitional cell bladder carcinoma,587,632 and most clinicians recommend that standard regimens such as M-VAC or CMV not be used in patients with metastatic adenocarcinoma or squamous cell carcinoma of the bladder.556,587

Because of the substantial toxicity and poor survival associated with current regimens, optimal therapy for advanced bladder cancer continually is being evaluated and all eligible candidates should be considered for entry into clinical trials;556,585 randomized trials are under way to compare the efficacy and toxicity of M-VAC with other regimens (e.g., paclitaxel and carboplatin) for the treatment of advanced or metastatic bladder cancer.135,585

Dosage Considerations

The usual dosage schedule for the M-VAC regimen is a monthly cycle consisting of IV cisplatin 70 mg/m² (administered on day 2), IV methotrexate 30 mg/m² (administered on days 1, 15, and 22), IV vinblastine 3 mg/m² (administered on days 2, 15, and 22), and IV doxorubicin 30 mg/m² (administered on day 2).134,584,632

Higher doses of cisplatin are administered in the CMV regimen.584,629 The usual dosage schedule for the CMV regimen is a 21-day cycle consisting of IV cisplatin 100 mg/m² (administered on day 2), IV methotrexate 30 mg/m² (administered on days 1 and 8), and IV vinblastine 4 mg/m² (administered on days 1 and 8).584,629

Escalated doses in the M-VAC regimen with concomitant administration of hematopoietic therapy (GM-CSF or G-CSF) have been used in patients with advanced urothelial carcinoma.136,584,626,633,634 In a randomized, phase III trial, a higher rate of complete response but no difference in overall survival was observed in patients receiving high-dose M-VAC with G-CSF versus classic M-VAC alone (without G-CSF) for advanced bladder cancer.136

Treatment with cisplatin-based regimens should be discontinued if objective response is not observed following 2 or 3 cycles of therapy.584 Although the optimal duration of therapy has not been fully determined, some experts recommend 4-6 cycles of therapy as tolerated for patients showing clinical response; additional cycles of therapy do not appear to improve outcome.556,584 Surgical resection, when indicated, generally is considered after 4 cycles of therapy; additional cycles of chemotherapy following surgery have not been shown to provide benefit.556,584

Administration of cisplatin in divided doses may be necessary in patients with renal impairment receiving cisplatin-based regimens for the treatment of advanced bladder cancer.584

Adverse Effects and Other Considerations

Substantial toxicity, including myelosuppression and mucositis, is associated with use of the M-VAC regimen in patients with advanced or metastatic bladder cancer.626,632 The administration of hematopoietic agents (e.g., G-CSF, GM-CSF) has been used to reduce the incidence and severity of myelosuppression in patients receiving M-VAC for advanced bladder cancer.136,636,637 Prophylactic use of G-CSF should be strongly considered in patients receiving M-VAC.136,556

Carboplatin has been substituted as a less toxic alternative to cisplatin in some patients receiving combination chemotherapy for advanced bladder cancer.584,635 Inadequate dosing of carboplatin may have contributed to its lesser efficacy compared with cisplatin in earlier studies of platinum-based regimens for the treatment of advanced or metastatic bladder cancer.556,584,591,635 Combination therapy with paclitaxel followed by carboplatin is being investigated as an active regimen in patients with advanced bladder cancer, including patients with abnormal renal function.63,137,138,585

Head and Neck Cancer

Cisplatin is commonly used in combination with fluorouracil for the palliative treatment of recurrent or metastatic head and neck cancer†.63,527,673,674 Combination therapy with cisplatin, methotrexate, bleomycin, and vincristine also has been used for the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck.675 Methotrexate alone also may be used for the treatment of recurrent or metastatic head and neck cancer, particularly in patients who cannot tolerate aggressive chemotherapy.63,672

Cisplatin-containing combination therapy is superior to single-agent therapy in producing higher response rates; however, no effect on overall survival has been demonstrated.526,673,674,675,676 In a randomized study, patients with recurrent or metastatic squamous cell carcinoma of the head and neck who received cisplatin and fluorouracil, carboplatin and fluorouracil, or methotrexate alone had objective response rates of 32, 21, and 10%, respectively.673 Although the objective response rate achieved with cisplatin and fluorouracil was greater than that observed with methotrexate alone, combination chemotherapy was associated with increased toxicity (particularly hematologic and renal toxicity), and no difference in survival was observed.673 Patients receiving cisplatin and fluorouracil for advanced head and neck cancer had a higher response rate and delayed progression of disease but no difference in survival compared with those receiving either cisplatin or fluorouracil alone.674 In another randomized trial, patients receiving cisplatin, methotrexate, bleomycin, and vincristine for recurrent or metastatic head and neck cancer had higher rates of complete response than those receiving cisplatin and fluorouracil; although both combination regimens produced a higher rate of objective response than cisplatin alone, no difference in survival was detected among the treatment groups.675

Cisplatin has been administered concurrently with radiation therapy for the palliative treatment of head and neck cancer in patients with locally advanced disease that is unresectable.145,153,672 The use of cisplatin-containing chemotherapy administered concurrently with radiation therapy is being investigated as an approach to resectable disease in cases where surgical resection would lead to functional deficit.145,156 Cisplatin also has been used in combination with docetaxel and fluorouracil as induction therapy prior to radiotherapy or chemoradiotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck.765,766 (See Uses: Head and Neck Cancer, in Docetaxel 10:00.)

In males younger than 50 years of age with metastatic squamous neck cancer who have a poorly differentiated tumor, an occult primary tumor, and elevated β-human chorionic gonadotropin (β-hCG) and α-fetoprotein (AFP), chemotherapy with a platinum-containing regimen should be considered because these tumors may respond to such therapy in a manner similar to extragonadal germ cell malignancies.515,528

Cervical Cancer

Cisplatin is used, alone63,685,687 or in combination therapy,63,684,686,687,688 concurrently with radiation therapy for the treatment of invasive cervical cancer† (FIGO stages IB2 through IVA cervical cancer684,685,687,688 or FIGO stage IA2, IB, or IIA cervical cancer with poor prognostic factors, such as metastatic disease in pelvic lymph nodes, parametrial disease, or positive surgical margins,686 identified at the time of primary surgery).683,684,685,686,687,688,690,697 Cisplatin also is used in the treatment of metastatic or recurrent cervical cancer†.63,174,175,181,184,690,691,692

Overview

About 13,000-16,000 new cases of invasive cervical cancer and 5,000 deaths from this disease occur in the US each year.173,689,690,691,693 The most common histologic types of cervical cancer are squamous cell carcinoma (approximately 80-90%) and adenocarcinoma (approximately 10-20%); adenosquamous carcinoma and small cell carcinoma of the cervix occur less frequently, and other types of cancers of the cervix are relatively rare.174,690,691,732 The principal risk factor for the development of preinvasive cervical lesions or invasive cervical cancer is infection with certain subtypes of human papilloma virus (HPV).690,692,694,699

Procedures routinely used to determine the clinical stage of cervical cancer include physical examination, radiologic studies, and cervical biopsy; although they are not included in the process of clinical staging, imaging procedures, such as computed tomography (CT) or magnetic resonance imaging (MRI), and/or lymphangiography with fine-needle aspiration may be used to establish the extent of invasive disease.692,693 HIV testing should be considered, particularly in younger (less than 50 years of age), at-risk patients diagnosed with invasive cervical cancer, because of the higher prevalence of HIV infection, often asymptomatic, in these women compared with women in the general population.693,728,732 Prognostic factors for cervical cancer include the stage of disease, the volume and grade of tumor, histologic type, spread of disease to pelvic or para-aortic lymph nodes, and vascular invasion.690,710 Controversy exists regarding whether adenocarcinoma of the cervix carries a worse prognosis than squamous cell carcinoma of the cervix, and most treatment recommendations for cervical cancer are based on experience in patients with squamous cell carcinoma.690,711 The clinical staging system established by the Federation Internationale de Gynecologie et d'Obstetrique (FIGO) is commonly used to classify cervical cancer.690

The earliest stage of invasive cervical cancer (FIGO stage IA1) may be treated surgically.690,691,692,693 Other early-stage, small-volume cervical cancer (FIGO stage IA2, IB1, or IIA) may be treated initially with surgery or radiation therapy.690,691,692,693,700 According to the findings from randomized trials, strong consideration should be given to the concurrent administration of cisplatin-based chemotherapy to prolong overall survival and progression-free survival in women who require postoperative radiation therapy for the treatment of stage IA2, IB1, or IIA cervical cancer with poor prognostic factors identified at the time of primary surgery683,686,690 or in women who require primary radiation therapy for the treatment of stage IB1 or IIA cervical cancer with poor prognostic factors.683,684,690

For the initial treatment of early stages of cervical cancer, surgery is preferred for younger women who have concerns about preservation of the ovaries and avoidance of vaginal atrophy and stenosis; radiation therapy is advisable in women who have bulky disease, women who have disease with poor prognostic factors (e.g., metastasis to pelvic lymph nodes), or women who are not suitable candidates for surgery.690,691,693,700,701 Although randomized controlled studies are needed, some evidence suggests that survival may be prolonged in patients receiving primary treatment with surgery rather than radiation therapy for early stages of adenocarcinoma of the cervix.700,710 Patients initially treated with surgery may require postoperative radiation therapy to reduce the risk of local recurrence if tumor is present in the margins of the surgical specimen or has metastasized to pelvic or para-aortic lymph nodes.691,692 Because the combination of radical surgery and adjuvant radiation therapy increases both morbidity and the cost of treatment, careful staging and identification of prognostic factors are important in the selection of the optimal mode of initial treatment.692,700,701,702,732

Although controversy exists regarding the optimal treatment of stage IB2 cervical cancer, many experts prefer the use of primary radiation therapy.691,732 Initial treatment with radiation therapy generally is recommended in women with stages IIB through IVA cervical cancer.690,691 According to the findings from randomized trials, strong consideration should be given to the concurrent administration of cisplatin-based chemotherapy to prolong overall survival and progression-free survival in women receiving primary radiation therapy for the treatment of stage IB2683,685,690 or stages IIB through IVA cervical cancer.683,684,690 Results of randomized trials and pooled data from randomized trials did not demonstrate prolonged survival or improved local control of disease with use of neoadjuvant chemotherapy followed by radiation therapy in locally advanced cervical cancer;692,703,704,705,706,707,708,709 evidence from at least 2 randomized trials suggests that use of neoadjuvant chemotherapy may adversely affect survival in patients receiving radiation therapy for locally advanced cervical cancer.706,709

Palliative treatment with radiation and/or chemotherapy has been used in patients with metastatic or recurrent cervical cancer.690,691,692 The benefit of chemotherapy and/or radiation therapy versus best supportive care has not been established in patients with advanced cervical cancer.174

FIGO Stage IA1 Cervical Cancer

Chemotherapy currently is not usually recommended for FIGO stage IA1 cervical cancer.690,691,692,693,732 Instead, simple hysterectomy or cone biopsy are initial treatments of choice.690,691,692,693,732 The use of conservative surgical management of adenocarcinoma in situ of the uterine cervix with conization has not been established.692,712 Radiation therapy alone (intracavitary insertion only) may be used to treat stage IA1 disease in women who are not suitable candidates for surgery.690

FIGO Stage IA2 Cervical Cancer

In patients with FIGO stage IA2 cervical cancer, surgery or pelvic radiation therapy is the initial treatment of choice.690,692,693 Concurrent cisplatin-based chemotherapy may be strongly considered for certain women with this stage of the cancer.

Primary surgical treatment for FIGO stage IA2 cervical cancer generally consists of radical hysterectomy with pelvic lymph node dissection.690,692,693 The use of conservative surgical management with cone biopsy alone is not established as an appropriate treatment option for stage IA2 cervical cancer.690,732,737,738 Postoperative radiation therapy is required in women with stage IA2 cervical cancer with poor prognostic factors (i.e., metastatic disease in pelvic lymph nodes, parametrial disease, positive surgical margins) identified at the time of primary surgery.690 According to the findings from randomized trials, strong consideration should be given to the concurrent administration of cisplatin-based chemotherapy in women who require postoperative radiation therapy for the treatment of stage IA2 cervical cancer with poor prognostic factors.683,686,690,732

Primary radiation therapy for FIGO stage IA2 cervical cancer consists of intracavitary brachytherapy with or without external-beam radiation therapy.690,692,693,732

FIGO Stage IB1 or IIA Cervical Cancer

In patients with FIGO stage IB1 or IIA cervical cancer, the use of surgery or pelvic radiation therapy as initial treatment appears to produce equivalent results. Concurrent cisplatin-based chemotherapy may be strongly considered for certain women with this stage of the cancer.690,691,692,700

Primary surgical treatment for FIGO stage IB1 or IIA cervical cancer generally consists of radical hysterectomy with pelvic lymph node dissection (with or without para-aortic lymph node dissection); depending on the extent of vaginal involvement in patients with stage IIA disease, a more extensive upper vaginectomy also is performed.690,691,692,693,700,732 Postoperative radiation therapy is required in women with stage IB1 or IIA cervical cancer with poor prognostic factors (i.e., metastatic disease in pelvic or para-aortic lymph nodes, parametrial disease, or positive surgical margins) identified at the time of primary surgery.690 According to the findings from randomized trials, strong consideration should be given to the concurrent administration of cisplatin-based chemotherapy in women who require postoperative radiation therapy for the treatment of stage IB1 or IIA cervical cancer with poor prognostic factors.683,686,690,732

Primary radiation therapy for stage IB1 or IIA cervical cancer consists of a combination of external-beam radiation and intracavitary implants.690,691,692,693,700 Some evidence suggests that the use of prophylactic radiation of the para-aortic nodes may prolong overall survival in patients receiving pelvic radiation therapy for bulky stage IIA cervical cancer.692,696 According to the findings from randomized trials, strong consideration should be given to the concurrent administration of cisplatin-based chemotherapy in women who require primary radiation therapy for the treatment of stage IB1 or IIA cervical cancer with poor prognostic factors.683,684,690,732

FIGO Stage IB2 Cervical Cancer

The treatment of stage IB2 cervical cancer is controversial, and numerous methods have been used including surgery alone, radiation therapy alone, surgery with adjuvant radiation therapy, radiation therapy with adjuvant surgery, and neoadjuvant chemotherapy and surgery.690,691,692,693,700,732,736

Many experts currently prefer initial treatment with pelvic radiation therapy consisting of a combination of external-beam radiation and intracavitary implants for bulky stage IB cervical tumors.685,691,732 According to the findings from randomized trials, strong consideration should be given to the concurrent administration of cisplatin-based chemotherapy in women receiving primary radiation therapy for the treatment of stage IB2 cervical cancer.683,684,685,690 Some evidence suggests that the use of prophylactic radiation of the para-aortic nodes may prolong overall survival in patients receiving pelvic radiation therapy for stage IB2 cervical cancer.692,696 Although it does not improve survival and many experts discourage its routine practice,685,692,732 extrafascial hysterectomy has been performed following primary radiation therapy for stage IB2 cervical tumors to reduce the risk of recurrence of central pelvic disease.685,691,693 In a randomized controlled trial, the addition of neoadjuvant chemotherapy did not improve control of local disease or prolong disease-free survival in patients receiving radiation therapy for invasive cervical cancer, including those with bulky stage IB tumors.704

Primary surgery for bulky stage IB cervical cancer consists of radical hysterectomy with pelvic node and para-aortic lymph node dissection.690,692,693 The addition of adjuvant radiation therapy to primary surgery increases morbidity in patients with stage IB cervical cancer, including those with bulky tumors,700 and routine use of this combination is not advised in such patients.692,702 Long-term follow-up from a randomized controlled trial involving patients with stage IB squamous carcinoma of the cervix suggests that the addition of neoadjuvant cisplatin-containing chemotherapy reduces tumor volume, improves tumor operability, and consequently prolongs survival and disease-free survival in patients receiving surgery and adjuvant pelvic radiation therapy for bulky tumors.736

FIGO Stages IIB-IVA Cervical Cancer

Because of high rates of local relapse, extensive locoregional disease (FIGO stages IIB through IVA) generally is treated with pelvic radiation therapy consisting of external-beam radiation therapy and brachytherapy.683,690,691,692,693 According to the findings from randomized trials, strong consideration should be given to the concurrent administration of cisplatin-based chemotherapy in women receiving radiation therapy for the treatment of stages IIB through IVA cervical cancer.683,684,690 Some evidence suggests that the use of prophylactic radiation of the para-aortic nodes may prolong overall survival in patients receiving pelvic radiation therapy for stage IIB cervical cancer.692,696

FIGO Stage IVB Cervical Cancer

Patients with distant metastases (FIGO stage IVB) may receive chemotherapy for control of systemic disease; such patients also may benefit from palliative treatment with radiation therapy for symptoms from pelvic disease and/or distant metastases.690,691,692 The benefit of chemotherapy and/or radiation therapy versus best supportive care has not been established in patients with metastatic cervical cancer.174

Recurrent Cervical Cancer

Depending on the initial treatment of cervical cancer, local recurrence of disease is treated with the treatment modality the patient did not previously receive.690,691,692 Radiation therapy can prolong survival and improve local control of disease in patients with locally recurrent cervical cancer following hysterectomy.692,693 In patients with local recurrence of disease following primary radiation therapy for cervical cancer, the overall survival rate following pelvic exenteration is 30-60%.690,691,692,693

Most patients with recurrent cervical cancer have disease at local and distant sites.691 Palliative treatment with chemotherapy may be considered in patients with recurrent cervical cancer, but responses to treatment typically are short-lived.691,692 Radiation therapy may be useful in the palliation of symptoms in such patients,692 although many patients are symptomatic from recurrence of disease in a previously irradiated field where additional radiation may be contraindicated.732 The benefit of palliative chemotherapy versus best supportive care has not been established in patients with recurrent cervical cancer.174,732

Treatment of Cervical Cancer during Pregnancy

Treatment for preinvasive cervical lesions (i.e., CIN 2, CIN 3, cervical carcinoma in situ) in pregnant women may be delayed and followed up with reevaluation in the postpartum period, but expert colposcopy and cervical biopsy should be performed promptly to confirm the absence of invasive disease.690,693,716 Diagnostic cone biopsy should be performed when microinvasive or invasive cervical carcinoma is suspected; cone biopsy is associated with substantial morbidity, such as excessive blood loss and increased risk of miscarriage, in pregnant women.693

Most patients with cervical cancer during pregnancy are diagnosed with early-stage disease.717,718,719 The prognosis of early-stage cervical cancer appears to be similar in pregnant and nonpregnant women receiving standard treatment.718,719,720,721 Although surgery and radiation therapy are equally effective for the treatment of early-stage cervical cancer, surgical treatment is preferred in pregnant women because it allows preservation of ovarian and sexual function in this younger patient population.717,718,721

The choice and timing of treatment of invasive cervical cancer during pregnancy depend on the stage of disease, duration of the pregnancy (i.e., gestational age of the fetus) at the time of diagnosis, risk to the mother and the fetus, and the wishes of the patient.690,693,722,723,724,725 The treatment of invasive cervical cancer diagnosed before fetal maturity (less than 20 weeks' gestation) is controversial; although many experts traditionally have recommended immediate treatment (according to stage of disease) with loss of the pregnancy,690,717,721,722,732 some clinicians support longer delays in treatment for patients with early-stage, nonbulky cervical tumors who desire completion of the pregnancy.724,725,732 If invasive cervical cancer is detected later in pregnancy when the fetus is viable (generally at greater than 20 weeks' gestation), planned delay of treatment is offered to appropriate candidates (according to stage and extent of disease, histology, and lesion size) who are placed under close surveillance for progression of disease, and delivery of the fetus by cesarean section is followed by surgery or radiation therapy for invasive cervical cancer according to the stage of disease.693,717,721,722 Most experts agree that planned delay of treatment to improve fetal viability is a reasonable option in women with early-stage cervical cancer (FIGO stage IA or IB1) detected in the third trimester or late second trimester of pregnancy.690,692,693,718,722,723,724,725,726,732

Treatment of Cervical Cancer in HIV-infected Women

The prevalence of cervical squamous intraepithelial lesions and HPV infection with oncogenic genotypes is high among women with human immunodeficiency virus (HIV) infection,727,728 and the US Centers for Disease Control and Prevention (CDC) has designated invasive cervical cancer in HIV-positive women as an acquired immunodeficiency syndrome (AIDS)-defining illness.728 Some evidence suggests that antiretroviral therapy (triple-drug therapy including an HIV protease inhibitor) may reduce the prevalence and/or lower the grade of cervical lesions in HIV-infected women despite the persistence of HPV infection.727 Women with HIV infection who are diagnosed with invasive cervical cancer often have more aggressive and advanced disease with a poorer prognosis.690,728 The same standard treatment for preinvasive cervical lesions or invasive cervical cancer used in non-HIV-infected women generally is recommended in HIV-infected women, but response to treatment may be poor; close surveillance is required, and repetitive treatment of cervical intraepithelial neoplasia (CIN) may be necessary in HIV-infected women to prevent progression of disease.728,732 Evidence from a phase III, nonblinded, randomized trial indicates that the recurrence rate of CIN is reduced and time to recurrence is prolonged in women with HIV infection receiving adjunctive therapy with vaginal fluorouracil† versus observation only following excisional or ablative treatment of high-grade cervical dysplasia (i.e., CIN 2 or 3).741

Concurrent Chemotherapy and Radiation Therapy for Invasive Cervical Cancer

Results from 3 large randomized, controlled, phase III trials at 3 years or more of follow-up show that the addition of cisplatin-based chemotherapy given concurrently with radiation therapy decreases the risk of death by 40-50% in women receiving primary radiation therapy for FIGO stages IB2 through IVA cervical cancer684,685 and in women receiving postoperative radiation therapy for FIGO stage IA2, IB, or IIA cervical cancer with poor prognostic factors (i.e., metastatic disease in pelvic lymph nodes, parametrial disease, positive surgical margins)686 identified at the time of primary surgery.683,697 Results from 2 other large randomized trials show that in patients receiving concomitant chemotherapy and radiation therapy for FIGO stages IIB through IVA cervical cancer, risk of death is decreased by about 30-40% among those receiving cisplatin-containing versus non-cisplatin-containing chemotherapeutic regimens.683,687,688,697

Because of the findings from these randomized trials, NCI recommends that strong consideration be given to the concurrent administration of cisplatin-based chemotherapy in women who require radiation therapy for the treatment of cervical cancer. 683 Substitution of carboplatin for cisplatin is not recommended because of the lack of evidence supporting comparable efficacy of this agent for cervical cancer.687,732 Further study is needed to establish the magnitude of benefit when chemotherapy is given concurrently with optimal-dose radiation therapy in patients with locally advanced cervical cancer.689

Clinical Trials

In addition to its cytotoxic effects, chemotherapy is believed to have a synergistic antineoplastic effect with radiation therapy by mechanisms that include increased sensitivity of tumor to radiation and inhibition of the repair of sublethal damage to tumor induced by radiation.687,689,698 The current recommendation for concurrent cisplatin-containing chemotherapy and radiation therapy in women with invasive cervical cancer (FIGO stage IB2 through IVA disease or FIGO stage IA2, IB, or IIA disease with poor prognostic factors) is based principally on the findings from 5 large, randomized trials (3 randomized trials showing prolonged survival with the concurrent use of chemotherapy and radiation therapy versus radiation therapy alone and 2 randomized trials showing the superiority of cisplatin-containing regimens versus non-cisplatin-containing regimens for concurrent use with radiation therapy).683,684,685,686,687,688,690

In a randomized trial of 403 patients (386 evaluable patients) with advanced squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix confined to the pelvis (FIGO stages IIB through IVA or FIGO stage IB or IIA with a tumor diameter of at least 5 cm or involvement of the pelvic lymph nodes), the estimated overall rate of survival at 5 years (calculated at a median follow-up of 43 months) was higher (73 versus 58%) among those receiving concurrent chemotherapy (with cisplatin and fluorouracil) and pelvic radiation therapy than among those receiving radiation therapy alone (consisting of pelvic radiation therapy and irradiation of the para-aortic lymph nodes).684 The estimated rate of disease-free survival at 5 years was 67% among patients who received combined therapy with chemotherapy and radiation and 40% among those who received radiation therapy alone.684 According to stage of disease, overall survival was prolonged with the addition of chemotherapy to radiation therapy in patients with FIGO stage IB, IIA, or IIB cervical cancer but not in patients with stage III or IVA disease; however, the study was not designed to test for differences in survival within these subgroups.684,732 The rates of distant or locoregional metastases were lower among patients receiving combined modality treatment (14 versus 33% and 19 versus 35%, respectively); a higher rate of reversible adverse hematologic effects was observed in patients receiving combined chemotherapy and radiation therapy, but the severity of late adverse effects was similar between the groups.684

In a randomized trial of 374 patients (369 evaluable patients) with bulky or barrel-shaped stage IB (i.e., FIGO stage IB2) squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix, higher rates of overall survival (83 versus 74% at 3 years) and progression-free survival were observed at 4 years in those receiving concurrent chemotherapy (with cisplatin) and radiation therapy with adjuvant hysterectomy than in those receiving radiation therapy with adjuvant hysterectomy.685,698 The relative risks of progression of disease and death among women receiving combined chemotherapy and radiation therapy were 0.51 and 0.54, respectively, compared with those receiving radiation therapy alone.685 Higher frequencies of adverse hematologic effects (21 versus 2%) and adverse GI effects (14 versus 5%) were observed in patients receiving combined chemotherapy and radiation therapy than in those receiving radiation therapy alone.685

At a median follow-up of 42 months in a randomized trial of 268 patients (243 evaluable patients) with clinical stage IA2, IB, or IIA cervical cancer initially treated with radical hysterectomy and pelvic node dissection, higher rates of overall survival (estimated 4-year survival of 81 versus 71%) and progression-free survival (estimated 4-year progression-free survival of 80 versus 63%) were observed in those receiving concurrent chemotherapy (with cisplatin and fluorouracil) and pelvic radiation therapy versus pelvic radiation therapy alone for high risk factors, such as positive pelvic lymph nodes, positive surgical margins, and/or microscopic involvement of the parametrium, identified at the time of primary surgery.686,698

Optimal chemotherapy regimens for the treatment of invasive cervical cancer have not been established.684,689,698 Current evidence from large, randomized, phase III trials indicates that cisplatin is a drug of choice for chemotherapy to be used concomitantly with radiation therapy for locally advanced cervical cancer.687,688 Cisplatin may be used alone685,687 or in combination therapy (e.g., cisplatin and fluorouracil)684,686,687,688 as an adjunct to radiation therapy in patients with locally advanced cervical cancer; however, results from at least one randomized trial suggest that cisplatin alone is as effective but less toxic than cisplatin-containing combination regimens for concomitant use with radiation therapy.687,689 Improvement in survival with the combination of chemotherapy and radiation therapy in patients with locally advanced cervical cancer has been observed only with concurrent administration of chemotherapy.684,685,686,689 Analysis of pooled data from several randomized trials did not demonstrate prolonged survival or improved local control of disease with use of neoadjuvant chemotherapy followed by radiation therapy in locally advanced cervical cancer.689,692,703

In a randomized trial of 575 patients (526 evaluable patients) receiving concurrent chemotherapy and radiation therapy for stage IIB, III, or IVA squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix without involvement of the para-aortic lymph nodes, follow-up at a median duration of 35 months showed higher rates of survival and progression-free survival among those receiving cisplatin alone or a combination regimen of cisplatin, fluorouracil, and hydroxyurea than among those receiving hydroxyurea alone.687 The rates of progression-free survival at 24 months were 67, 64, and 47% in patients receiving radiation therapy and concomitant chemotherapy with cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone, respectively.687 Relative risk of death was 0.61 or 0.58 in those receiving cisplatin alone or combination therapy with cisplatin, fluorouracil, and hydroxyurea, respectively, compared with those receiving hydroxyurea alone.687 The rate of local recurrences was lower in patients receiving radiation therapy with cisplatin or cisplatin-containing combination therapy (19 and 20%, respectively) than in those receiving radiation therapy with hydroxyurea alone (30%); the rate of distant metastases (i.e., lung metastases) also was lower in patients receiving radiation therapy with cisplatin alone or radiation therapy with cisplatin in combination chemotherapy (3 and 4%, respectively) than in those receiving radiation therapy with hydroxyurea alone (10%).687 Compared with patients receiving either cisplatin or hydroxyurea alone, the frequency of moderate or severe leukopenia was more than double and the frequency of moderate or severe granulocytopenia was approximately double in patients receiving the 3-drug regimen (cisplatin, fluorouracil, and hydroxyurea).687

In a randomized trial of 388 patients (368 evaluable patients) receiving concomitant chemotherapy and radiation therapy for FIGO stage IIB, III, or IVA squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the cervix without involvement of the para-aortic lymph nodes, follow-up at a median duration of 8.7 years showed higher rates of survival (55 versus 43%) and progression-free survival in those receiving cisplatin and fluorouracil than in those receiving hydroxyurea alone.688 Relative risk of progression of disease or death was 0.79 and relative risk of death was 0.74 in those receiving cisplatin and fluorouracil compared with those receiving hydroxyurea.688 Severe (grade 3) or life-threatening (grade 4) leukopenia occurred less frequently in patients receiving combination therapy with cisplatin and fluorouracil (4%) than in those receiving hydroxyurea alone (24%).688

The results of these randomized trials suggest that agents other than hydroxyurea, particularly cisplatin (alone or in combination with other agents), are preferred for concurrent use with radiation therapy in the treatment of locally advanced cervical cancer.687,688,689,732 Fluorouracil is used in combination with cisplatin for concurrent chemotherapy and radiation therapy in patients with locally advanced cervical cancer,684,686,687,688 but randomized controlled studies are needed to determine if this combination regimen is superior to cisplatin alone.684,689,732,742 Although carboplatin often is used as a less toxic substitute for cisplatin, current evidence supports the use of cisplatin-containing chemotherapy given concurrently with radiation therapy in patients with locally advanced cervical cancer, and similar benefit with carboplatin-containing chemotherapy cannot be assumed.687,732 Additional comparative studies are needed to determine the optimal chemotherapy regimens and schedules to be used concurrently with radiation therapy for the treatment of locally advanced cervical cancer.689,698,732,742

Chemotherapy for Metastatic or Recurrent Cervical Cancer

Cisplatin is used in the palliative treatment of metastatic or recurrent squamous cell carcinoma of the cervix†.63,175,181,184,690 The drug is considered one of the most active agents in the treatment of cervical neoplasms.175 Response rates of 18-31% have been reported with use of cisplatin as a single agent in advanced cervical cancer.175,184,692

Cisplatin also has been used as a component of various combination chemotherapeutic regimens (e.g., bleomycin, cisplatin and ifosfamide [BIP]; bleomycin, cisplatin, mitomycin, and vincristine [BOMP]) for the treatment of metastatic or recurrent cervical cancer.63,177,179,180,181 Limited evidence from a small randomized trial of patients with advanced cervical cancer suggests that cisplatin-based chemotherapy is superior to hydroxyurea, which has minimal activity as a single agent in the treatment of metastatic or recurrent cervical cancer.185,732 Combination regimens have not been consistently shown to be superior to the use of single agents, such as cisplatin, one of the most active drugs in the treatment of metastatic or recurrent cervical cancer.174,691,692,732 Although relatively high response rates have been reported with cisplatin-containing combination chemotherapy regimens, these regimens generally are more toxic and do not appear to be superior to cisplatin alone in the treatment of metastatic or recurrent cervical cancer.178,179,181,732 For example, high objective response rates have been observed with the combination regimen of bleomycin, ifosfamide, and cisplatin in women with metastatic or recurrent cervical cancer,179,180 but toxicity is greater and survival is not improved in women receiving the combination regimen rather than cisplatin alone.179 Similarly, higher response rates and prolonged progression-free survival but greater toxicity and no difference in overall survival has been observed with use of the combination of cisplatin and ifosfamide (with mesna) compared with cisplatin alone in patients with metastatic or recurrent squamous cell carcinoma of the cervix.178

Because of its lesser toxicity, carboplatin may be considered as an alternative to the parent compound cisplatin, particularly in patients with nephrotoxicity or neurotoxicity caused by advanced cervical tumor who are not suitable candidates for cisplatin therapy;176,182,183 however, randomized controlled trials comparing carboplatin and cisplatin have not been performed to date,176,732 and because of superior response rates and lesser hematologic toxicity, most experts consider cisplatin the current drug of choice in the treatment of advanced cervical cancer, particularly in patients who have received radiation therapy.182,732

Various single agents and combination regimens for the treatment of advanced cervical cancer have been evaluated mostly in phase II studies, and optimal treatment has not been established.174,690,691,732 In addition, the benefit of chemotherapy versus best supportive care has not been studied in patients with metastatic or recurrent cervical cancer.174 Because the prognosis of patients with advanced cervical cancer remains poor and optimal therapy has not been established, all such patients may be considered for enrollment in clinical trials investigating new agents or combination regimens.174,690,691,732 The use of cisplatin with other agents (e.g., paclitaxel,220,690,714 gemcitabine,221,690 fluorouracil,713,739,740 vinorelbine715 ) or in other combination regimens (e.g., cisplatin, methotrexate, vinblastine, and doxorubicin [MVAC]731 ) is being evaluated in patients with metastatic or recurrent cervical cancer.

Non-small Cell Lung Cancer

Overview

Cisplatin is used as a component of various chemotherapeutic regimens for advanced non-small cell lung cancer†.63,529,665 Non-small cell lung cancer, which includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma, accounts for approximately 80% of all lung cancers; the prognosis for this neoplasm is poor with a 5-year survival of less than 10% in patients with advanced disease.530,658

Cisplatin-containing chemotherapy is used for the treatment of advanced non-small cell lung cancer.63,529,665 A small survival benefit has been demonstrated for the use of platinum-based (cisplatin) chemotherapy alone or combined with radiation therapy in selected patients with unresectable, locally advanced or metastatic non-small cell lung cancer who have a good performance status.529,530,646,647,648,649,650,651,652,653,654,655,671 Analysis of pooled data from individual patients enrolled in published and unpublished randomized trials530 or from published randomized trials646 indicates a 13% reduction in risk of death and an absolute increase in survival rate of 4% at 2 years for cisplatin-based chemotherapy combined with radiation therapy compared with radiation therapy alone in the treatment of unresectable, locally advanced non-small cell lung cancer.530,646,647,648,649,650,651,652,671 The optimal timing of chemotherapy used in conjunction with radiation therapy (sequential, concurrent, or alternating) has not been established.646,665 Analysis of pooled data from individual patients enrolled in published and unpublished randomized trials530 indicates that the addition of cisplatin-containing chemotherapy to supportive care in patients with advanced non-small cell lung cancer provides a small survival advantage (i.e., absolute increase in survival rate of approximately 10% at 1 year or increased median survival of about 1.5 months).529,530,653,654,655 Results from two small randomized trials suggest that the administration of cisplatin-containing chemotherapy preceding surgery prolongs survival in patients with resectable, locally advanced non-small cell lung cancer although further study is needed to confirm these findings.656,657,665

Because many patients with earlier stages of disease treatable with surgical resection subsequently develop metastases, the use of adjuvant chemotherapy and/or radiotherapy is being investigated.529 Current evidence does not show improvement in survival with radiation therapy658 and/or chemotherapy506,529,530,647 administered following surgery in patients with resectable non-small cell lung cancer. Although limited by the inclusion of mostly studies involving now-obsolete equipment,660 analysis of pooled data from individual patients enrolled in published and unpublished randomized trials659 indicates that postoperative treatment with conventional radiation therapy reduces local recurrence of disease but adversely affects survival in patients with completely resected stage I and II non-small cell lung cancer. The effect of postoperative radiation therapy in patients with later stages of non-small cell lung cancer (e.g., stage IIIA with N2) has not been established.659 Differing regimens of radiation therapy (e.g., accelerated versus conventional radiation therapy) also are being investigated.661,662

Combination Chemotherapy for Advanced Non-small Cell Lung Cancer

Platinum-based chemotherapy regimens currently are preferred for the treatment of non-small cell lung cancer.63,530,665 A detrimental effect on survival has been observed for patients with non-small cell lung cancer receiving treatment based on alkylating agents, such as busulfan and cyclophosphamide, and such regimens are not recommended.530,665 Currently preferred regimens for the treatment of advanced non-small cell lung cancer include the combination of cisplatin with another agent, such as paclitaxel,63,187,529,665,666 vinorelbine,63,529,665,667 gemcitabine,63,187,529,669,670 or docetaxel.187,529

In randomized trials, patients with advanced non-small cell lung cancer receiving cisplatin combined with paclitaxel666 or gemcitabine670 had higher response rates and similar median survival compared with those receiving combination therapy with cisplatin and etoposide; consequently, paclitaxel-containing regimens63,529,665,666,668 or other platinum-based regimens63,529,665,670 currently are preferred in the treatment of patients with advanced non-small cell lung cancer. (See Uses: Non-small Cell Lung Carcinoma in Paclitaxel 10:00 or Gemcitabine 10:00.) Cisplatin combined with gemcitabine is associated with improved survival (estimated median survival of 9.1 versus 7.6 months) and higher response rates (30 versus 11%) compared with cisplatin alone in patients with advanced non-small cell lung cancer.669 Patients with stage IIIB or IV non-small cell lung carcinoma receiving cisplatin and vinorelbine had a longer median survival, higher survival rate at 1 year, a longer median progression-free survival, and higher response rate than those receiving cisplatin alone.667 (See Uses: Non-small Cell Lung Carcinoma in Vinorelbine 10:00.)

Use of chemotherapy for the treatment of advanced non-small cell lung cancer generally is advised only in patients with good performance status (ECOG performance status of 0 or 1, and 2 in selected patients) and evaluable lesions so that treatment can be discontinued if the disease does not respond.647,665 The decision to use chemotherapy must be individualized according to several factors, including patient preference, toxicity, survival benefit, quality of life, and cost of treatment.529,530,646,647,654,655,665 Once the decision is made to use chemotherapy, treatment should begin promptly to allow for optimal response in patients receiving chemotherapy combined with radiation therapy for unresectable stage III disease and to allow treatment before deterioration of performance status in patients with stage IV disease.665 Although the optimal duration of chemotherapy has not been fully established, treatment with 2-8 cycles generally is advised in patients with stage IV or unresectable stage III non-small cell lung cancer; periodic imaging studies are used to monitor response and determine whether to continue treatment.665

Cisplatin, an active agent in the treatment of non-small cell lung carcinoma, produces an objective response in about 10-20% of patients,186,188,667,669 No single chemotherapy regimen currently can be recommended as superior in the treatment of non-small cell lung cancer.529,530,663 Analysis of pooled data from published randomized trials664 involving patients with advanced non-small cell lung cancer indicates higher response rates and a small increase in survival rates at 6 months and 1 year but greater toxicity in patients receiving combination chemotherapy versus single-agent chemotherapy. A large randomized trial showed a higher response rate but no difference in median survival in patients receiving combination therapy with cisplatin and paclitaxel for advanced non-small cell lung cancer compared with those receiving high-dose cisplatin alone.188

Various chemotherapy regimens used alone or in combination with other treatment modalities, such as radiation therapy, are continually being evaluated for the treatment of advanced non-small cell lung cancer.529,530,662 Because current treatment is not satisfactory for almost all patients with non-small cell lung cancer except selected patients with early-stage, resectable disease, all patients may be considered for enrollment in clinical trials at the time of diagnosis.529

Small Cell Lung Cancer

Cisplatin is used in combination chemotherapy for the treatment of small cell lung cancer†.63,533 Combination chemotherapy regimens are superior to single-agent therapy for the treatment of small cell lung cancer and moderately intensive drug doses are superior to doses that produce minimal toxicity.533 Various regimens have been used in combination therapy, and many 2- to 4-drug combination regimens, including cisplatin-containing regimens, have produced response rates of 65-90 or 70-85% and complete response rates of 45-75 or 20-30% in patients with limited-stage or extensive-stage disease, respectively; however, comparative efficacy is continually being evaluated.533,535,536,537,538 While efficacy of the various available regimens is continually being evaluated, combination chemotherapy containing cisplatin and etoposide currently is considered a preferred regimen for the treatment of small cell lung carcinoma.63,515,533 Combination therapy with cisplatin and etoposide used in combined modality treatment with concurrent thoracic irradiation that is administered early in the course of treatment is a preferred regimen for limited-stage small cell lung cancer.533,583 Cisplatin in conjunction with etoposide also is used in the treatment of extensive-stage small cell lung cancer.63,533

In a randomized study, patients with previously untreated extensive-stage small cell lung cancer receiving combination therapy with cisplatin and etoposide (PE); cyclophosphamide, doxorubicin, and vincristine (CAV); or an alternation of these regimens (PE/CAV) had similar objective response rates, complete response rates, and median survival; because of a higher frequency of severe thrombocytopenia associated with the alternation of regimens, therapy with PE/CAV generally is not recommended.677,678 Cisplatin in combination with etoposide and ifosfamide with mesna is used as an alternative regimen for the treatment of small cell lung cancer.63,678 Second-line therapy with combination regimens (e.g., cisplatin and etoposide) or single agents (e.g., paclitaxel, topotecan) may be of some value for the treatment of small cell lung cancer refractory to other chemotherapy regimens (particularly when relapse occurs more than 6 months following completion of initial treatment).63,533

Although optimum duration of chemotherapy has not been clearly defined, additional improvement in survival has not been observed when the duration of drug administration exceeds 3-6 or 6 months in patients with limited-stage or extensive-stage small cell lung cancer, respectively.533 Because the current prognosis for small cell lung carcinoma is unsatisfactory regardless of stage and despite considerable diagnostic and therapeutic advances, all patients with this cancer are candidates for inclusion in clinical trials at the time of diagnosis.533

Malignant Pleural Mesothelioma

Cisplatin is used in combination with pemetrexed for the treatment of malignant pleural mesothelioma in patients who are not eligible for surgery.63,679(See Uses: Malignant Pleural Mesothelioma in Pemetrexed 10:00.)

Cisplatin alone202,203,679,680 or in combination with other agents (e.g., doxorubicin, mitomycin)204,681 is used in the palliative treatment of advanced malignant pleural mesothelioma†.202,203,204,679,680,681 Combination chemotherapy regimens are associated with greater toxicity and do not appear to prolong survival or improve control of symptoms in patients with unresectable malignant pleural mesothelioma.679,680,682

Esophageal Cancer

Cisplatin has been used alone569,576,644 and in combination therapy63,568,569,570,576,644 for the treatment of localized or advanced esophageal cancer†. Optimum therapy for esophageal cancer has not been established, and new therapies are continually being evaluated.568,569 Because the prognosis for most patients with esophageal cancer remains poor, all newly diagnosed patients should be considered for enrollment in clinical trials comparing various treatment modalities.361,568

Localized Esophageal Cancer

For the treatment of patients with localized esophageal cancer, combined modality treatment consisting of combination chemotherapy with cisplatin and fluorouracil and concurrent radiation therapy may be used prior to surgery (as neoadjuvant therapy) or as an alternative to surgery (i.e., in patients who are not considered suitable surgical candidates or in an attempt to avoid perioperative mortality [less than 10%] and to relieve dysphagia).568

Combined modality therapy consisting of combination chemotherapy with cisplatin and fluorouracil and concurrent radiation therapy is more effective than radiation therapy alone in patients with localized esophageal carcinoma.569,570,572 Patients with locally advanced esophageal cancer (most patients had squamous cell carcinoma) who received combined modality therapy with cisplatin and fluorouracil and concurrent radiation therapy had longer survival (12.5 versus 8.9 months) and higher survival rates (38 versus 10% at 24 months) than patients who received radiation therapy alone.570 Cisplatin 75 mg/m² (up to a maximum dose of 150 mg) was administered IV on day 1 and fluorouracil 1 g/m² (up to a maximum dose of 8 g) was administered by 96-hour continuous IV infusion on days 1-4 every 4 weeks during concurrent radiation therapy and every 3 weeks following the completion of radiation therapy.570,572 At 5 years, 26% of patients who received combined modality therapy were alive compared with none of the patients who received radiation therapy alone.572 In patients with localized esophageal cancer, particularly squamous cell carcinoma, who are not considered suitable candidates for surgery, combined modality treatment with cisplatin and fluorouracil and concurrent radiation therapy may be used as an alternative therapy.569,570,571,572 Although the comparative benefit of combined chemotherapy and radiation versus surgery has not been established, some experts recommend combined modality treatment with combination chemotherapy (e.g., cisplatin and fluorouracil) and concurrent radiation therapy with or without surgery as primary treatment for localized, resectable esophageal cancer.361,568,572

Because of high rates of distant metastasis or locoregional recurrence of disease in patients undergoing surgery for localized esophageal cancer, the addition of systemic therapy was proposed to provide early treatment of disseminated but undetected disease and to reduce the risk of recurrent locoregional disease.569,570 Neoadjuvant therapy may reduce tumor size and increase the chances of complete resection in patients with locally advanced esophageal cancer.569,575 Variable results have been observed in studies of induction therapy with cisplatin-based chemotherapy and concurrent radiation therapy followed by surgery in patients with squamous cancer or adenocarcinoma of the esophagus.568,573,574 In a large, randomized trial, surgery combined with preoperative and postoperative chemotherapy with cisplatin and fluorouracil did not improve survival compared with surgery alone in patients with localized, operable esophageal carcinoma.645 Combined modality treatment of esophageal cancer may be associated with substantial toxicity,569,570,572 and choice of therapy must be individualized.568 Histologic type also influences choice of therapy for esophageal carcinoma.568,575 Clinical trials for esophageal cancer have included mostly patients with squamous cell carcinomas, and surgical resection remains standard therapy for esophageal adenocarcinoma.568,575 Further study is needed to determine the role of neoadjuvant or adjuvant therapy in combination with surgery in the treatment of localized esophageal cancer.568,569

Advanced Esophageal Cancer

Combination therapy with cisplatin and fluorouracil is used for the palliative treatment of metastatic (local or distant) disease or recurrent or locally advanced disease that is not amenable to surgery or radiation therapy,63,568,570,576,644 and such combined therapy currently is considered a regimen of choice.63,568,644 Cisplatin also has been used alone in the palliative treatment of advanced esophageal cancer.569,576 Although higher response rates are achieved with cisplatin and fluorouracil than with cisplatin alone in patients with metastatic disease, no overall difference in survival has been observed.569,576 Combination therapy with cisplatin and other active agents for advanced esophageal cancer (e.g., paclitaxel) is being investigated.568,569,576

Biliary Tract Cancer

Cisplatin has been used in combination with gemcitabine for the treatment of unresectable locally advanced or metastatic biliary tract cancer† (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), including unresectable recurrent disease following surgical resection.761,763

Experts state that, in patients with biliary tract adenocarcinoma (the most common type of biliary tract cancer), chemotherapy can be recommended in individuals with unresectable locally advanced or metastatic disease and in those with recurrent disease following surgical resection.762 Chemotherapy is recommended in such individuals with good performance status (ECOG performance status of 0 or 1).762 However, in patients with poor performance status (ECOG performance status of 2 or 3) or insufficient biliary decompression, the benefits of chemotherapy are limited and use of alternative therapy for palliation of associated symptoms (e.g., pain) and improvement in quality of life is recommended.762

In a phase 3 trial in 410 patients with unresectable locally advanced or metastatic biliary tract carcinoma, including unresectable recurrent disease following surgical resection, patients who received cisplatin in combination with gemcitabine had longer median overall (11.7 versus 8.1 months) and progression-free (8 versus 5 months) survival, a higher 6-month progression-free survival rate (59.3 versus 42.5%), and higher rates of tumor control (complete or partial responses or stable disease) (81.4 versus 71.8%) compared with those who received gemcitabine alone.761 Only one patient in each treatment group achieved a complete response.761 Patients enrolled in the study generally had good baseline performance status (ECOG performance status of 0 or 1 in 88% of patients).761 Based on current evidence, combination therapy with cisplatin and gemcitabine is recommended (accepted) for use in the treatment of unresectable locally advanced or metastatic biliary tract cancer (intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer, or ampullary cancer), including unresectable recurrent disease following surgical resection, in patients with good performance status (ECOG performance status of 0 or 1).764

For further information on the treatment of unresectable locally advanced or metastatic biliary tract cancer, including use of combination therapy with cisplatin and gemcitabine, see Uses: Biliary Tract Cancer, in Gemcitabine 10:00.

Melanoma

Cisplatin and other platinum analogs, such as carboplatin, have minimal activity but substantial toxicity in metastatic melanoma†.745 Although cisplatin has been used in combination therapy (e.g., carmustine, cisplatin, dacarbazine, and tamoxifen) for the palliative treatment of metastatic melanoma,63,751,752 evidence suggests that the addition of cisplatin to dacarbazine-containing regimens increases toxicity but does not improve survival.748 Evidence from large, randomized trials has not established the superiority of combination regimens compared with dacarbazine alone,743,747,752 and dacarbazine monotherapy currently is a systemic treatment of choice for metastatic melanoma (see Uses: Melanoma in Dacarbazine 10:00 for an overview of therapy for melanoma).63,744,745,747,752 The use of cisplatin-containing chemotherapy in combination with biologic therapy using aldesleukin and interferon alfa is being investigated for the treatment of metastatic melanoma.63,746,749,750,752,753,754

Intra-arterial† infusions of cisplatin have been used in the treatment of regionally confined metastases from malignant melanoma.241 Cisplatin also has been used for hyperthermic isolated limb perfusion for recurrent melanoma of the extremity.755

Brain Tumors

Cisplatin has been used for the palliative treatment of various primary brain tumors†.63 Regimens that include cisplatin have been used principally in the treatment of medulloblastoma63,548 and germ cell tumors.63,545 Most primary brain tumors are treated with surgery and/or radiation therapy, but adjuvant chemotherapy may prolong survival in some tumor types and has increased disease-free survival in patients with medulloblastoma, certain germ cell tumors, and gliomas.540

Malignant Gliomas

Astrocytic Tumors

Cisplatin has been used as an adjunct for the treatment of astrocytic tumors†, such as anaplastic astrocytoma and glioblastoma multiforme.63 Although brief in duration, responses to high-dose IV cisplatin have been observed in patients with malignant glioma that recurred following previous chemotherapy with nitrosoureas.628 (For further discussion of the treatment of astrocytic tumors, see Uses: Brain Tumors in Carmustine 10:00.)

The use of cisplatin and carmustine as adjuvant and/or neoadjuvant therapy in conjunction with radiation therapy for the treatment of high-grade gliomas† is being investigated.695 In a large randomized trial, cisplatin and carmustine administered by continuous IV infusion prior to postoperative radiation therapy in patients with newly diagnosed glioblastoma multiforme did not increase survival and was associated with greater toxicity than standard adjuvant therapy consisting of IV carmustine administered concurrently with radiation therapy.733

Medulloblastoma

Cisplatin is used in combination with lomustine and vincristine as adjuvant therapy following surgical resection and radiation therapy for the treatment of medulloblastoma†, the most common malignant childhood brain tumor.63,546 Such adjuvant chemotherapy is associated with improved progression-free survival in patients with poor prognostic factors (i.e., younger than 3 years of age, metastatic disease and/or subtotal resection with >1.5 cm³ of residual disease and/or nonposterior fossa location), but the role of adjuvant chemotherapy in children with average-risk medulloblastoma has not been established.546,548

The use of adjuvant chemotherapy coupled with reduced-dose radiation therapy in children with average-risk medulloblastoma (i.e., older than 3 years of age, total or near-total resection with <1.5 cm³ of residual disease, no dissemination) is being investigated.547,548 Because of the debilitating effects of radiation on growth and neurologic development, the use of postoperative chemotherapy (e.g., induction therapy with cyclophosphamide and vincristine followed by cisplatin and etoposide, with or without bone marrow rescue) to delay, modify, or possibly avoid the need for radiation therapy in children younger than 3-6 years of age is being studied.209,210,548

Cisplatin is an active agent in the treatment of recurrent medulloblastoma in children;211,212 response to chemotherapy is observed in more than 50% of patients with disease that recurs following treatment with surgery and radiation therapy, but long-term control of the disease is rare.548

Oligodendroglioma

Cisplatin also has been used, alone or in combination with other agents (e.g., cisplatin and etoposide) as salvage therapy for recurrent oligodendroglioma†, a uniquely chemosensitive form of glioma.63,213

Intracranial Germ Cell Tumors

Combination therapy with a platinum-containing agent (i.e., cisplatin or carboplatin) and etoposide is used in the treatment of intracranial germ cell tumors†.63,214,545 Other combination chemotherapy regimens (e.g., cisplatin, vinblastine, bleomycin) also have been used.214,545 The role of adjuvant chemotherapy in addition to radiation therapy for the treatment of such tumors remains to be established.545

Intra-arterial Therapy

Intra-arterial† administration of cisplatin, alone or in combination with other agents, has been investigated in the treatment of newly diagnosed or recurrent gliomas; severe adverse effects, including renal, otologic, neurologic, and retinal toxicity, have been reported in patients receiving such therapy, and the role of intra-arterial cisplatin in the treatment of primary brain tumors has not been established.195,196,197,198,199,201

Neuroblastoma

Cisplatin is used as a component of combination therapy for high-risk neuroblastoma†.63,541 Combination chemotherapy with moderate doses of carboplatin, cyclophosphamide, doxorubicin, and etoposide is used in conjunction with surgery (with or without radiation therapy) for the treatment of neuroblastoma in patients with intermediate-risk tumors or, in some cases, low-risk tumors.541 Although surgery alone typically is adequate for the treatment of low-risk tumors, combination chemotherapy is administered if surgical resection is incomplete (less than 50% of the primary tumor is resected) or if life-threatening or organ-threatening symptomatic disease is present (e.g., spinal cord compression).541 In patients with high-risk tumors, aggressive chemotherapy using higher doses of these drugs and additional drugs (e.g., ifosfamide, high-dose cisplatin, vincristine) is used.541 If high-risk disease responds to the initial regimen of chemotherapy, further therapy consists of surgical resection of the primary tumor, myeloablative therapy and autologous stem cell transplantation (bone marrow transplantation or peripheral blood stem cell transplantation), and radiation therapy (radiation to the primary tumor site and sometimes total-body irradiation); following recovery, 6 months of therapy with oral 13- cis -retinoic acid (isotretinoin) is administered.541

Other Uses

Cisplatin is used in the treatment of adrenocortical cancer†, anal cancer†, GI carcinoid tumors†, choriocarcinoma†, endometrial cancer†, gastric cancer†, hepatoblastoma†, liver cancer†, certain types of non-Hodgkin's lymphoma†, osteosarcoma†, and soft-tissue sarcomas in adults†.63Cisplatin also is used in the treatment of penile cancer†,224,225 malignant thymoma†,235,236,237,238 and anaplastic thyroid cancer†.63,387 Cisplatin has been used in the treatment of rhabdoid tumor of the kidney†, a highly malignant form of childhood kidney cancer.552 The drug also has shown some activity in the palliative treatment of advanced medullary thyroid cancer†.387

Intra-arterial† infusions of cisplatin have been used with some success in the treatment of regionally confined malignancies,40,41,241,242 including osteogenic sarcomas.41,241,242 Cisplatin has also been administered intraperitoneally† alone42,43 or in conjunction with IV sodium thiosulfate42 in patients with various tumors (e.g., adenocarcinoma of the breast, carcinoid, mesothelioma) that were associated with malignant ascites and/or were confined to the peritoneal cavity. (See also Intraperitoneal Cisplatin and Paclitaxel under Ovarian Cancer: First-line Therapy for Advanced Ovarian Epithelial Cancer, in Uses.)

Reconstitution and Administration

Cisplatin is administered by IV infusion.1 The drug has also been administered intra-arterially†40,41,132,139,241,242 and intraperitoneally†.42,43,346,476,10001,10008 Needles, syringes, catheters, or IV administration sets that contain aluminum parts which may come in contact with cisplatin should not be used for preparation or administration of the drug.1,12 (See Chemistry and Stability: Stability.)

The manufacturer recommends that protective gloves be used during handling of commercially available cisplatin injection and during preparation of cisplatin solutions,1 since skin reactions associated with accidental exposure to the drug may occur.1 If cisplatin solution comes in contact with the skin or mucosa, the affected area should be washed with soap and water (skin) or flushed with water (mucosa) immediately and thoroughly.1 Rarely, adverse local effects have occurred following extravasation of cisplatin during administration.1,100,322,323,482 (See Cautions: Local Effects.)

Patients should be adequately hydrated before and for 24 hours after administration of cisplatin1 to ensure good urinary output and minimize nephrotoxicity.1,243,245,251,256,343,344 (See Cautions: Renal and Electrolyte Effects.) Various regimens of IV hydration, with or without mannitol and/or furosemide diuresis, and various rates of administration of cisplatin have been employed.28,38,243,245,251,256,257,258,259,260,261,263,264,265 The clinician should consult published protocols for information related to specific regimens.245,256,257,258,259,260,261 The manufacturer and many clinicians recommend IV infusion of 1-2 L of fluid over 8-12 hours prior to administration of the drug.1,67,245,252,344 In adults, unless contraindicated, IV fluids are usually administered alone or with mannitol and/or furosemide at an initial rate sufficient to maintain hydration and a diuresis of 150-400 mL/hour during and for at least 4-6 hours after administration of cisplatin,245,251,252,256,343,344 and then a diuresis of 100-200 mL or more per hour for the next 18-24 hours65,251,252,343,344 or until vomiting stops and oral fluids are tolerated.343 Patients must be closely monitored for fluid and serum electrolyte disturbances.1,245,251 (See Cautions: Renal and Electrolyte Effects.) Potassium chloride is often added (e.g., 10-20 mEq/L) to IV fluids infused during and/or following administration of cisplatin to replace losses and prevent deficiencies.245,259,344

IV Infusion

For IV infusion, the manufacturer recommends that the required dose of cisplatin (as the commercially available injection) be diluted in 2 L of 5% dextrose and 0.33 or 0.45% sodium chloride injection containing 18.75 g of mannitol per liter (i.e., 37.5 g in 2 L), and infused IV over 6-8 hours.1 Various other methods of dilution and/or rates of administration are used, and the clinician should consult published protocols for information related to specific regimens.65,243,247,252,256,257,258,259,261 IV infusions over 15 minutes to 2 hours are commonly employed and have been used with minimal adverse renal effects.65,243,247,252,256,257,258,261 Continuous 24-hour38 or 5-day263,264,265 IV infusions of the drug have also been used. While cisplatin has been administered by rapid IV injection (e.g., over 1-5 minutes),25,27,259,290 such rapid administration may be associated with increased nephrotoxicity243 or ototoxicity290 compared with slower IV infusion of the drug.

Intra-arterial Infusion

For intra-arterial† infusion, cisplatin has been administered via an appropriately placed catheter using a controlled-infusion device.41,241,242 The cisplatin dose has generally been diluted in 0.9% sodium chloride injection (300 mL for doses less than 300 mg and 450 mL for doses greater than 300 mg) containing small amounts of heparin sodium (e.g., 3000 units)41,241,242 and infused over 2-4 hours (range 1-24 hours).40,41,241,242

Intraperitoneal Instillation

For intraperitoneal† administration in the Gynecologic Oncology Group (GOG)-172 study in patients with advanced epithelial ovarian cancer, the cisplatin dose was diluted in 2 L of 0.9% sodium chloride solution that was warmed to 37°C and administered as rapidly as possible through a surgically implanted peritoneal catheter.10001,10005,10015 Following peritoneal infusion, patients were asked to roll into a different position every 15 minutes for the next 2 hours to disperse the drug throughout the peritoneal cavity.10005,10015 In this study, the paclitaxel dose was diluted in a liter of saline solution that was warmed to 37°C and infused through the intraperitoneal catheter, followed by intraperitoneal infusion of an additional liter of warmed saline solution.10005,10015 Some clinicians have recommended that intraperitoneal chemotherapeutic agents be mixed in 1 L of 0.9% sodium chloride solution warmed to 37°C and administered by gravity flow as rapidly as possible; after infusion and in the absence of pain, an additional 1 L of 0.9% sodium chloride solution may be administered to ensure adequate distribution within the peritoneal cavity.10011

Cisplatin also has been diluted in 2 L of lactated Ringer's injection and administered by gravity flow over 10-12 minutes; after a 15- to 20-minute dwell, the peritoneal cavity was drained as completely as possible.346 Alternatively, the cisplatin dose has been diluted in 500 mL of 0.9% sodium chloride solution and administered by gravity flow over 15-20 minutes; after 24 hours, paracentesis was begun.43 There is some evidence that the risk of systemic anaphylactoid reactions may be increased when doses of 100 mg/m² are administered relatively rapidly into the peritoneal cavity; therefore, some clinicians have recommended that intraperitoneal administration of such doses be over 45 minutes or longer.476

Various implanted access ports and connecting catheters have been used for intraperitoneal administration of chemotherapeutic agents.10017 The intraperitoneal catheter may be placed at the time of primary (cytoreductive) surgery as long as contamination of the peritoneal cavity has not occurred.10015,10017 Timing of placement of the intraperitoneal catheter (at the time of primary surgery versus delayed insertion) does not appear to affect tolerance of intraperitoneal therapy or treatment completion rates.10015,10017 The intraperitoneal catheter should be removed as soon as intraperitoneal therapy is completed to avoid catheter-related complications.10011,10015 Further study is needed to optimize techniques for intraperitoneal therapy to minimize the risk of complications (e.g., infection, catheter obstruction, catheter retraction, bowel perforation, pain, leakage, port access problems).10005,10015,10016,10017 Specialized sources should be consulted for guidance on how to administer intraperitoneal therapy.10005,10016

Supportive therapy should include hydration and antiemetic therapy for the intraperitoneal infusion of cisplatin.10005,10015

Dosage

Dosage of cisplatin must be based on the clinical, renal, hematologic, and otic response and tolerance of the patient in order to obtain optimum therapeutic results with minimum adverse effects.1,13,245,276 The clinician should consult published protocols for the dosage of cisplatin and other chemotherapeutic agents and the method and sequence of administration. At the usual dosage, courses of cisplatin therapy should not be given more frequently than once every 3-4 weeks.1 A repeat course of cisplatin should not be administered until the patient's renal, hematologic, and otic functions are within acceptable limits, and precautions must always be taken to treat an anaphylactoid reaction if it occurs .1 (See Cautions: Precautions and Contraindications.)

Inadvertent substitution of cisplatin for carboplatin can result in potentially fatal overdosage.419,420,421,422 Therefore, care should be taken to ensure that such mix-ups do not occur.1,419,420,421,422 In addition, care should be taken to avoid prescribing practices by clinicians that fail to differentiate between daily doses of cisplatin and a total cisplatin dosage used in one course of therapy.1 To minimize the risk of overdosage, the manufacturer recommends that an alerting mechanism be instituted to verify any prescription or order for cisplatin doses exceeding 100 mg/m² per course.1 IV dosages exceeding 100 mg/m² per course once every 3-4 weeks are rarely used.1 Other safeguard procedures to minimize the risk of accidental overdosage of cisplatin (e.g., overdosage resulting from inadvertent administration of the drug when carboplatin was intended) also should be considered.1,419,420,421,422

Because cisplatin is considered an antineoplastic agent of high emetic risk, antiemetic therapy for the prevention of acute and delayed emesis is recommended.760(See Emetogenic Effects in Cautions: GI Effects.)

Testicular Cancer

For remission induction in the treatment of metastatic testicular neoplasms, the usual dosage of cisplatin in combination chemotherapy regimens (e.g., with bleomycin and etoposide) is 20 mg/m² IV daily for 5 consecutive days every 3 weeks for 3 or 4 courses of therapy.1,64,65,66,67,68,69,70,71,72,73,335,408 Randomized trials indicate that 3 cycles of therapy are sufficient for favorable-prognosis germ cell tumors since similar results are achieved with either 3 or 4 cycles of therapy in such patients.85,86 Use of high-dose cisplatin in combination chemotherapy for poor-risk germ cell tumors results in increased toxicity without additional clinical benefit.336

Ovarian Cancer

For the treatment of advanced ovarian carcinoma, a cisplatin dosage of 75 mg/m² IV once every 3 weeks has been used in combination therapy with paclitaxel.361,517 The usual dosage of cisplatin when used in combination with cyclophosphamide is 50-100 mg/m² IV once every 3-4 weeks.1,361 In combination therapy, cisplatin and cyclophosphamide are administered sequentially.1 When cisplatin is used as a single agent, the manufacturer's recommended dosage is 100 mg/m² IV once every 4 weeks,1 but some experts recommend dosages of 50-100 mg/m² IV once every 3 weeks,361 and dosages of 30-120 mg/m² IV once every 3-4 weeks have been used.97,98,101,102,103,104,105,383

Bladder Cancer

For the treatment of advanced bladder cancer, the usual dosage of cisplatin is 50-70 mg/m² IV once every 3-4 weeks, depending on the extent of prior radiation therapy and/or chemotherapy.1 For patients who have been extensively pretreated, the recommended initial dosage is 50 mg/m² IV once every 4 weeks.1 For additional information, see Advanced Bladder Carcinoma: Dosage Considerations, under Uses: Bladder Cancer.

Head and Neck Cancer

When used alone in the treatment of recurrent or advanced head and neck cancer†, cisplatin has been given in a dosage of 80-120 mg/m² IV once every 3 weeks38,143,144,147,149 or 50 mg/m² IV on the first and eighth days of every 4 weeks.143,148 In combination chemotherapy regimens, the usual dose of cisplatin has generally been 50-120 mg/m² IV, with the frequency of administration depending on the specific regimen employed.144,146,149,150,151,152,154,155,157,158,160,161,162,163,164,165,166,167,168,169,170 When used as induction chemotherapy in combination with docetaxel and fluorouracil, cisplatin 75-100 mg/m² has been administered IV once every 3 weeks.765,766 (See Head and Neck Cancer under Dosage and Administration: Dosage, in Docetaxel 10:00.)

Cervical Cancer

Invasive Cervical Cancer

For the treatment of invasive cervical cancer† (FIGO stages IB2 through IVA or FIGO stages I through IIA with poor prognostic factors), cisplatin doses of 40-75 mg/m² have been given concurrently with radiation therapy.684,685,686,687 Weekly685,729 or daily684,730 infusions of cisplatin have been used concomitantly with radiation therapy in patients with invasive cervical cancer. When used alone for the treatment of invasive cervical cancer, cisplatin 40 mg/m² IV once weekly has been administered concurrently with radiation therapy up to a maximum of 6 doses.685,687 When used in combination chemotherapy regimens (e.g., cisplatin and fluorouracil) for the treatment of invasive cervical cancer, cisplatin 50-75 mg/m² has been administered IV concurrently with radiation therapy according to various dosage schedules.684,686,687 Various regimens, doses, and dosage schedules have been used for concurrent cisplatin-based chemotherapy and radiation therapy, and the optimal treatment for locally advanced cervical cancer has not been established.683,732,742

Metastatic or Recurrent Cervical Cancer

For the treatment of metastatic or recurrent cervical carcinoma†, the usual dosage of cisplatin used alone or in combination therapy is 50 mg/m² IV once every 3 weeks up to a maximum of 6 courses.175,178,180,181 Higher dosages of cisplatin (e.g., 100 mg/m² IV once every 3 weeks) produce higher response rates in patients with advanced cervical cancer, but duration of response, survival, and progression-free survival are similar to those observed with the usual dosage, and toxicity is greater.175

Non-small Cell Lung Cancer

When used in combination chemotherapy for the treatment of non-small cell lung carcinoma†, cisplatin typically has been given in a dosage of 75-100 mg/m² IV once every 3-4 weeks depending on the specific regimen used.666,667,669,670

Esophageal Cancer

When used alone in the treatment of advanced esophageal cancer†, cisplatin has been given in a dosage of 50-120 mg/m² IV once every 3-4 weeks.576 In combination chemotherapy regimens for esophageal cancer, the usual dosage of cisplatin is 75-100 mg/m² IV once every 3-4 weeks.361,570,572,576

Biliary Tract Cancer

When cisplatin has been used in combination with gemcitabine for the treatment of unresectable locally advanced or metastatic biliary tract cancer† in adults, including treatment of unresectable recurrent disease following surgical resection, cisplatin 25 mg/m² has been administered by 1-hour IV infusion on days 1 and 8 of each 21-day cycle, and gemcitabine 1 g/m² has been administered by 30-minute IV infusion on days 1 and 8 after cisplatin administration.761,763 Treatment has been continued for 24 weeks (8 cycles of therapy) in the absence of disease progression or unacceptable toxicity.761,763

Intra-arterial Dosage

When cisplatin has been administered intra-arterially† for the treatment of regionally confined malignancies, including advanced bladder cancer,132,139 metastases from malignant melanoma,241 and osteogenic sarcomas,41,241,242 a dose of 75-150 mg/m² at intervals ranging from 2-5 weeks for at least 1-4 courses of therapy has been used.41,132,241,242

Intraperitoneal Dosage

For the management of intraperitoneal tumors (e.g., advanced ovarian carcinoma, carcinoid, mesothelioma) that are confined to the peritoneal cavity and/or are associated with malignant ascites, cisplatin has been administered intraperitoneally† in doses of 60-100 mg/m².43,476,10001

When combined therapy with intraperitoneal cisplatin and IV and intraperitoneal paclitaxel† has been used for the initial adjuvant treatment of optimally debulked stage III epithelial ovarian cancer, IV paclitaxel 135 mg/m² by 24-hour infusion on day 1, followed by intraperitoneal cisplatin 100 mg/m² on day 2 and intraperitoneal paclitaxel 60 mg/m² on day 8, has been administered every 21 days for up to 6 cycles.10001 Modified IV and intraperitoneal regimens are being investigated.10008,10012,10013,10014 (See Uses: Ovarian Cancer.)

Pediatric Dosage

Pediatric dosage of cisplatin has not been fully established.34,205,206,207,208 For the treatment of osteogenic sarcoma† or neuroblastoma†, cisplatin has been given in a dosage of 90 mg/m² IV once every 3 weeks or 30 mg/m² IV once weekly.34 For the treatment of recurrent brain tumors†, cisplatin has been given in a dosage of 60 mg/m² IV once daily for 2 consecutive days every 3-4 weeks.208,212

Dosage in Renal Impairment

Cisplatin therapy is contraindicated in patients with preexisting renal impairment.1 Because cisplatin-induced renal toxicity may become more prolonged and severe with repeated doses of the drug, the manufacturer states that cisplatin therapy should be resumed only when the patient has recovered normal renal function.1 (See Cautions: Precautions and Contraindications.)

Cisplatin is a highly toxic drug, and generally is more poorly tolerated overall compared with carboplatin, another platinum-coordination compound.440,489,490,493,495,496,509,512,514,518,520,521,522,550 While the major dose-limiting adverse effects associated with cisplatin therapy include nonhematologic toxicities such as nephrotoxicity, ototoxicity, neurotoxicity, and emesis, the major dose-limiting adverse effects associated with carboplatin therapy are hematologic toxicities such as thrombocytopenia and leukopenia.440,489,490,495,496,520,521,522,532,551,553 Differences in the toxicity and pharmacokinetic profiles of the drugs may be important determinants in the selection of cisplatin versus carboplatin for specific patients.440,493,496,509,515,521,554,555,557,591

Renal and Electrolyte Effects

Renal Effects

Nephrotoxicity, which is dose related and can be severe, may occur in patients receiving cisplatin1,243,244,245,246 and is more common and severe than that associated with carboplatin.440,493,521,522,542,549,566 Geriatric patients may be at increased risk for nephrotoxicity associated with cisplatin therapy.1,756 (See Cautions: Geriatric Precautions.) When cisplatin formerly was administered without concomitant IV hydration and diuresis, nephrotoxicity was clearly cumulative and was the major dose-limiting adverse effect.1,243,244,245 Renal toxicity has occurred in 28-36% of patients receiving a single dose of cisplatin 50 mg/m².1 Renal toxicity is manifested by an increase in serum creatinine, BUN, serum uric acid, and/or a decrease in creatinine clearance1,243,244,245,246 and glomerular filtration rate.247,339

Cisplatin-induced renal impairment has been associated with renal tubular damage as evidenced by renal pathologic changes246,248 and by increased urinary excretion of β₂-microglobulin249 and enzymes such as N -acetyl-β-glucosaminidase (NAG),249 leucine aminopeptidase (LAP),249 and β-glucuronidase.250 Focal acute tubular necrosis may occur,246 with tubular degeneration,246,248 interstitial edema246 and fibrosis,248 dilation of convoluted tubules,246 and cast formation.246 Both proximal246,248,249 and distal246,248 tubules are affected, but glomeruli appear intact.246,248 While the exact mechanism(s) is not known, renal toxicity may be caused by the positively charged products of cisplatin that are formed in vivo.251,252

If renal toxicity occurs in patients receiving cisplatin, it generally appears during the second week after administration of the drug;1,246 with high-dose regimens, it may occur within several days.246 Renal insufficiency is usually mild to moderate and reversible with usual doses of the drug;13,243,244,245 however, high13,243,244,245 or repeated doses1,13,390 can increase the severity1,13,244,390 and duration1,244 of renal impairment and may produce irreversible renal insufficiency (sometimes fatal).13,243,244,245 The risk and degree of renal impairment may be increased by concomitant use of other nephrotoxic drugs.245,248,251,253,254,255 (See Drug Interactions: Nephrotoxic Drugs.) There is some evidence that cisplatin-induced renal impairment is not age dependent and that nephrotoxic effects may actually be less severe in patients with a single functional kidney.376

Regimens of IV hydration, diuresis, and 6- to 8-hour infusions of cisplatin are used to decrease the incidence and severity of nephrotoxicity1,28,243,245,256(see Dosage and Administration: Reconstitution and Administration), possibly by decreasing renal and urinary concentrations of the drug or its platinum-containing product(s).251 While several regimens have been shown to be very effective in reducing and minimizing renal toxicity,256,257,258,259 the most effective regimen remains to be established.243,251 The value of diuretics in minimizing nephrotoxicity is not clearly defined,13,28,244,251,260,261 and hydration alone may be equally effective.65,251 There is some evidence that intensive IV hydration with 0.9% sodium chloride injection and administration of cisplatin in 3% sodium chloride injection may substantially reduce the risk of nephrotoxicity, possibly by providing a chloride concentration that minimizes the formation and renal tubular concentration of nephrotoxic product(s) of the drug.252 Use of prophylactic amifostine (ethiofos), a phosphorylated sulfhydryl compound, reduces the incidence and severity of cisplatin-induced nephrotoxicity in patients with advanced ovarian cancer.581 (See Amifostine 92:56.) There is also some evidence that concurrent administration of IV sodium thiosulfate with cisplatin may reduce the risk of nephrotoxicity,42,369 but further studies are needed to determine whether the therapeutic efficacy of cisplatin is also affected;370 although the exact mechanism in preventing nephrotoxicity is not known, sodium thiosulfate may be concentrated in renal tubules, where it could react covalently with cisplatin to form an inactive compound and thereby protect the kidneys.42,370

The effect of the rate of administration of cisplatin on the incidence and severity of nephrotoxicity has not been fully elucidated.243,262 While there is some evidence that 6- to 8-hour infusions are less nephrotoxic than rapid IV administration,243 infusions over 15 minutes to 2 hours are commonly employed and have been used with minimal adverse renal effects.65,243,247,252,256,257,258,261 Continuous 24-hour38 or 5-day263,264,265 IV infusions of the drug have generally not been associated with a reduction in renal toxicity compared with shorter periods of drug administration;38,262,263,264,265 while there is some evidence that continuous 5-day IV infusions with IV hydration and diuresis may be employed with minimal adverse renal effects,375 a relative therapeutic advantage has not been established.262,375

The value of plasma platinum concentrations for predicting or monitoring nephrotoxicity has not been defined, but there is some evidence that patients who eventually develop cisplatin-induced renal toxicity may have elevated plasma platinum concentrations early in the course of 24-hour IV infusions of the drug.266

Recovery of renal function generally occurs within 2-4 weeks after administration of cisplatin,244,246,256 but may be delayed or rarely not occur.244 The long-term effects of the drug on renal function are not fully known.245,248,267 In patients who received cisplatin without concomitant hydration and diuresis, decreases in creatinine clearance have been reported to persist for up to 1-2 years after discontinuance of the drug.113,248 While subclinical renal impairment (which may be detected only by measurement of creatinine clearance) may develop and persist even when regimens of hydration and diuresis are employed,245,248,252,267,339 the evidence to date suggests that clinically important chronic renal failure or cumulative, delayed nephrotoxicity does not occur following discontinuance of therapy with usual doses of the drug (total cumulative doses of about 300-700 mg/m²) and regimens of hydration and diuresis.245,267

Hypomagnesemia and Other Electrolyte Effects

Cisplatin may cause serious electrolyte disturbances,251,268,269,270,271 principally hypomagnesemia,1,251,268,269,270,271,272,273,342,390 hypocalcemia,1,268,269,271,342,390 and hypokalemia;1,271 hypophosphatemia1,271 may also occur, and hyponatremia1,274,342 has occurred in some patients receiving cisplatin-containing combination chemotherapy. The disturbances in serum electrolytes have been associated principally with cisplatin-induced renal tubular dysfunction.1,251,268,269,270,271,272,390 The drug markedly increases urinary excretion of magnesium251,268,270,271,272,273,276,390 and calcium;342 urinary excretion of potassium,271,272 zinc,272 copper,272 and amino acids342 is also increased. Although the exact mechanism(s) is not known, the renal tubular dysfunction caused by cisplatin may result from a specific drug-induced membrane or transport-system defect.251

Hypomagnesemia and hypocalcemia may develop during cisplatin therapy or following discontinuance of the drug;268,269,270,271,273,390 although these electrolyte disturbances may occur within several days after an initial dose of the drug,268,269,342 hypomagnesemia usually develops within 3-4 weeks after therapy is initiated268,269,270,273 and appears to increase in severity with progressive courses of treatment.390 Children may be particularly susceptible to the development of cisplatin-induced hypomagnesemia.269 Hypomagnesemia and/or hypocalcemia may become symptomatic, with muscle irritability268 or cramps,270 clonus,271 tremor,270 carpopedal spasm,269,271 and/or tetany.1,269,271 Generally, these manifestations are managed and normal serum electrolyte concentrations may be restored by administration (usually parenteral)268,269,270,271,390 of appropriate supplemental electrolytes and discontinuance of the drug;1,268,269,270,271 however, hypomagnesemia may persist for several months to years after cisplatin therapy is discontinued268,270,390 and, in some patients, has persisted for longer than 3 years.270 The long-term effects of the drug on renal tubular dysfunction remain to be fully evaluated.251,270,342 The severity of hypomagnesemia has been associated with an increased risk of subsequently developing Raynaud's phenomenon,390 but a causal relationship has not been clearly established.1,390 (See Cautions: Cardiovascular Effects.)

Methods of preventing cisplatin-induced hypomagnesemia and optimum management of persistent hypomagnesemia have not been fully established.269,270,273,275,390 In patients with advanced ovarian cancer, use of prophylactic amifostine reduces the incidence and severity of cisplatin-induced hypomagnesemia.581 (See Amifostine 92:56.) Although not universally recommended,251 prophylactic administration of magnesium supplements during cisplatin therapy to patients without renal insufficiency has been suggested.272,275 Specific dosage recommendations have not been established, but some clinicians have given 3 g of magnesium sulfate IV during a 6-hour IV infusion of cisplatin in each course of therapy with the drug,275 or 1 g of magnesium sulfate IV daily for 5 days with each 5-day course of cisplatin when the serum magnesium concentration was less than 1.2 mEq/L.357 However, some data indicate that hypomagnesemia may develop despite replacement therapy.273 The value of oral magnesium supplements in the management of asymptomatic cisplatin-induced hypomagnesemia has not been established;270 chronic oral magnesium supplements do not appear to increase serum magnesium concentrations or hasten the resolution of such hypomagnesemia.270,390 It is also uncertain whether continuous administration of oral magnesium supplements is of value in preventing the development of symptomatic hypomagnesemia;269,270 however, to minimize the risk of recurrent, symptomatic episodes, adequate magnesium intake is generally recommended in patients who become symptomatic.251,270

GI Effects

Emetogenic Effects

Cisplatin, one of the most emetogenic antineoplastic agents, induces marked nausea and vomiting in virtually all patients.1,245,276,440,441,442,445,446,447,448,449,450,462,468,469,470 Because of its universal emetogenic potential, cisplatin is classified as an antineoplastic agent of high emetic risk (i.e., incidence of emesis exceeds 90% if no antiemetic agents are administered).760 In the absence of effective antiemetic therapy, patients develop an average of 10-12 vomiting episodes within the first 24 hours after an initial dose.440,462,468 Although cisplatin-induced nausea and vomiting generally are self-limited and seldom life-threatening, they occasionally are severe enough to require discontinuance of the drug.1,276,468 In addition, of all the adverse effects of cisplatin, patients often are most fearful of the emetogenic effects and may develop anticipatory nausea and vomiting440,462,468 and/or refuse further therapy with the drug.259,276,440,462

Nausea and vomiting, which appear to be mediated via local GI stimulation of central mechanisms,245,440,441,442,445,446,447,448,462,468,469,470 generally begin within 1-6 (usually 2-3) hours after administration of cisplatin; this early period of emesis after a dose is the most severe and generally persists for about 8 hours with repeating emetic episodes but may persist up to 24 hours or longer.1,101,276,440,441,462 Various degrees of nausea, vomiting, and anorexia may persist for up to 5-10 days.1,101,259,276 Delayed nausea and vomiting beginning or persisting 24 hours or longer (although occasionally beginning 16-20 hours) following chemotherapy has occurred in patients who had attained complete emetic control on the day of cisplatin therapy.1,440,441,445,449,450,451,458,459,462,468 The incidence and severity of cisplatin-induced nausea and vomiting appear to be increased in females, in young patients, and in patients receiving the drug in high doses, by rapid infusion, and/or in combination with other emetogenic drugs such as anthracyclines (e.g., doxorubicin); patients with a history of chronic heavy alcohol use appear to experience less frequent and severe emetogenic effects.440,450,462,468

Mechanism

The role of serotonin as a mediator of acute cisplatin-induced emesis has been strongly suggested by the temporal relationship between the emetogenic action of the drug and the release (e.g., from GI enterochromaffin cells) of serotonin (e.g., as reflected by increases in plasma and urine concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA)] as well as by the clinical efficacy of antiemetic agents that act as inhibitors of the type 3 (5-HT₃) serotonin receptor (e.g., dolasetron, granisetron, ondansetron, palonosetron, tropisetron [not commercially available in the US]).440,441,442,449,459,460,461,462,467,468,469,470 In addition, the severity of emetogenic activity and degree of serotonin release appear to be dose related441 and increased with repeated cisplatin courses.441 Studies in animals have shown that cisplatin-induced emesis can be prevented completely by ablation of the area postrema (the locus of the chemoreceptor trigger zone [CTZ]) or depletion of serotonin from this area; in addition, high levels of 5-HT₃ receptors have been demonstrated in this area, and direct injection of 5-HT₃ receptor antagonists into the area postrema also can prevent cisplatin-induced emesis.442,467,469 Therefore, current evidence suggests that the emetogenic action of cisplatin may be initiated by degenerative changes in the GI tract (e.g., small intestine) induced by the drug and associated increases in endogenous serotonin release; serotonin then stimulates vagal and splanchnic nerve receptors that project to the medullary vomiting (emetic) center of the brain and also appears to stimulate 5-HT₃ receptors in the area postrema.440,441,442,462,467,468,469 Thus, 5-HT₃ receptor antagonists appear to prevent or ameliorate acute cisplatin-induced emesis by inhibiting visceral (from the GI tract) afferent stimulation of the vomiting center probably indirectly at the level of the area postrema and by directly inhibiting serotonin activity within the area postrema and CTZ.440,441,442,462,467,468,469,470

Alternative mechanisms appear to be principally responsible for delayed nausea and vomiting induced by cisplatin, since similar temporal relationships between serotonin and emesis beyond the first day after a dose have not been established, and inhibitors of 5-HT₃ receptors do not appear to be effective alone in preventing or ameliorating delayed effects.440,441,445,458,459,462,468,469,470 Antagonists at substance P/neurokinin 1 (NK₁) receptors represent another class of antiemetic agents.760 The binding of the tachykinin substance P to NK₁ receptors in the GI tract and the brainstem emetic center appears to cause emesis.760 Substance P/NK₁ receptor antagonists, such as aprepitant, block the binding of substance P and therefore prevent acute and delayed emesis.760 (See Aprepitant 56:22.92.) Anticipatory vomiting is a learned response conditioned by the severity and duration of previous emetic reactions to chemotherapy.462,468

Management

There is some evidence that the incidence and/or severity of nausea and vomiting may be reduced with 5-day continuous IV infusions of cisplatin compared with rapid, intermittent IV administration.263,264,265,375,440

For the prevention of acute emesis, the American Society of Clinical Oncology (ASCO) currently recommends a 3-drug antiemetic regimen consisting of a type 3 serotonin receptor antagonist, dexamethasone, and aprepitant given before the administration of cisplatin or other chemotherapy regimens with high emetic risk.760(See Aprepitant 56:22.92.) Currently available selective 5-HT₃ receptor antagonists (e.g., dolasetron, granisetron, ondansetron, palonosetron, or tropisetron [not commercially available in the US], are comparably effective in preventing acute chemotherapy-induced nausea and vomiting.453,459,460,461,760 (For additional information, see the individual monographs for 5-HT₃ receptor antagonists in 56:22.20.)

For the prevention of delayed emesis, ASCO currently recommends a 2-drug regimen of dexamethasone and aprepitant following the administration of cisplatin or other chemotherapy associated with high emetic risk.760

Antiemetic agents with a lower therapeutic index (i.e., less efficacious and generally associated with more frequent adverse effects), including cannabinoids (e.g., dronabinol, nabilone), metoclopramide, butyrophenones, and phenothiazines, are not considered by ASCO to be appropriate first-line antiemetics for chemotherapy of high emetic risk; these drugs should be reserved for patients with refractory emesis or unacceptable toxicity from first-line agents.760 Although antihistamines (e.g., diphenhydramine) and benzodiazepines (e.g., alprazolam, lorazepam) may be useful as adjunctive antiemetic agents, they should not be used as monotherapy.760

Aggressive antiemetic therapy for the prevention of acute and delayed emesis during early courses of emetogenic chemotherapy is the best way to prevent anticipatory nausea and vomiting; behavioral modification and hypnosis also may be useful.468,760 Although evidence is lacking, many clinicians also find benzodiazepines useful in the management of anticipatory emesis.760

Other GI Effects

Diarrhea also has occurred in patients receiving cisplatin.1,34,107

Otic Effects

Ototoxicity, manifested as tinnitus, with or without clinical hearing loss,1,276,287,288,289,290,291,292,358,440 and occasional deafness,1,276,290,291 may occur in patients receiving cisplatin1,276,287,288,289,290,291,292,358 and may be more severe in children than in adults.1,289 Rarely, temporary unilateral otalgia and recruitment have also occurred.290

Tinnitus has occurred in about 9% of patients receiving cisplatin and is usually reversible;276 it is not clear whether tinnitus is dose related.276 The most common cisplatin-induced hearing changes are audiogram abnormalities, which occur in about 24% of patients receiving usual doses of the drug,276 but high-frequency loss on audiograms has been reported in up to 74-100% of patients receiving cumulative doses of 200 mg/m² or more.440 Audiogram abnormalities usually appear within 4 days after administration of the drug, consist of at least a 15-dB loss in pure-tone threshold, and are principally bilateral but can be unilateral.276,440 Cisplatin-induced audiogram abnormalities are dose related (increasing with higher single doses290,377,440 and total cumulative dosage) and cumulative;1,276,287,288,289,290,358,377,440 there is also some evidence that audiogram abnormalities may occur more frequently when the drug is administered by rapid IV injection compared with infusion over 1-3 hours290,377 or 24 hours.377 The audiogram abnormalities appear to be most severe in older adults288 and in children, especially young children.289 Although not clearly established,276,287 patients with preexisting hearing impairment may be more susceptible to cisplatin-induced ototoxicity.358 The long-term effects have not been fully determined, but the audiogram abnormalities generally appear to be irreversible;276,289,291,440 however, partial or complete recovery has been reported.358,440

Cisplatin-induced audiogram abnormalities are most common and usually most severe in the high frequency range (4000-8000 Hz);1,276,287,288,289,290,440 however, audiogram abnormalities may occur at frequencies up to 20,000 Hz,359 and with increasing cumulative dosage, abnormalities may become evident at lower frequencies (1000-4000 Hz) and result in clinical hearing loss.288,289,290,291,292,358,440 About 6% of patients receiving the drug have developed clinical hearing loss, manifested as decreased hearing acuity.276,440 Although audiogram abnormalities and clinical hearing loss usually develop gradually,276,287,290 rapid-onset clinical hearing loss has occurred rarely.291 Rarely, deafness after the initial dose of cisplatin has been reported.1 Clinically important hearing loss may occasionally require dosage reduction or discontinuance of cisplatin therapy.276,290,358

Although the exact mechanism of cisplatin-induced ototoxicity is not known, the drug has been shown to cause loss of hair cells of the organum spirale in animals and there are limited data to suggest that a similar effect occurs in humans.293,440 Electrophysiologic studies have shown the site of principal damage to be the apical stereocilia on the hair cell surface.440 The possibility that concomitant administration of other potentially ototoxic drugs (e.g., aminoglycosides) may increase the risk of ototoxicity in patients receiving cisplatin should be considered.276,294,440 (See Drug Interactions: Ototoxic Drugs.) In addition, ototoxicity may be enhanced in patients with prior or simultaneous cranial irradiation.1

Rarely, cisplatin has been reported to cause vestibular ototoxicity,1,295,296 manifested as vertigo295 or vestibular dysfunction.296 Although data are limited, cisplatin-induced vestibular ototoxicity may increase with increasing cumulative dosage296 and may be most likely to occur in patients with preexisting vestibular dysfunction.295,296

Nervous System Effects

Neurotoxicity produced by cisplatin usually is characterized by peripheral neuropathies,1,101,276,297,298,299,300,301,302,303,304,444 which are generally sensory in nature (e.g., paresthesias of the upper and lower extremities)101,276,297,298,299,300,301,444 but can also include motor (especially gait) difficulties;101,276,297,299,300,302,472 reduced or absent deep-tendon reflexes101,297,298,300,304 and leg weakness300,301 may also occur. A myasthenic-like syndrome characterized by ptosis and proximal muscle weakness also has been associated with cisplatin.305 Geriatric patients may be at increased risk for peripheral neuropathy associated with cisplatin therapy.1,756 (See Cautions: Geriatric Precautions.) Cisplatin-containing regimens are associated with a higher incidence of, and more severe, neurotoxicity than carboplatin-containing regimens,440,493,521,522 and neurotoxic effects of cisplatin have become the principal dose-limiting toxicity of the drug subsequent to institution of more effective means of controlling renal and GI toxicities.440,444,544

Cisplatin-induced peripheral neuropathies occur infrequently with usual doses of the drug and usually only with prolonged therapy (4-7 months) or high cumulative doses;1,276,297,298,299,300,301,302,303,304,486,488 however, neurologic manifestations have been reported after a single dose of the drug,1 and some evidence suggests that both cumulative-dose intensity and single-dose intensity may be risk factors in the development of neurotoxicity.486 Manifestations of cisplatin-induced neuropathy usually develop during treatment; rarely, neurologic manifestations may occur 3-8 weeks or longer after the last dose of cisplatin.1,444,474,488

The incidence of peripheral neuropathy may be increased when cisplatin is administered concurrently with other potentially neurotoxic agents (e.g., altretamine, paclitaxel, vincristine).245,487 Peripheral nerve damage caused by cisplatin has been documented by sensory and motor nerve conduction studies.298,299,300,303,444 Sural nerve biopsies from patients with cisplatin-induced paresthesias of the upper and lower extremities and gait disturbances have shown microscopic features consistent with a segmented demyelination pattern of peripheral nerve injury;302 loss of axons may also be present.301 In one case of cisplatin neurotoxicity, the spinal cord showed loss of myelinated fibers and gliosis of the dorsal columns at autopsy.304 Muscle cramps, defined as localized, painful, involuntary skeletal muscle contractions of sudden onset and short duration, have been reported and usually occurred in patients with symptomatic peripheral neuropathy who received relatively high cumulative doses of cisplatin.1

Lhermitte's sign (a sensation during neck flexion resembling electric shock) often is present with cisplatin-induced neuropathy.1,394,444The occurrence of Lhermitte's sign may be particularly likely to coincide with the onset of peripheral neuropathy.394 Lhermitte's sign has persisted for 2-8 months.394 As the neuropathy progresses, the sense of joint position also becomes impaired,444 and severely affected patients may become markedly impaired by sensory ataxia.444 Temperature and pain sensations remain relatively preserved.444

Dorsal column myelopathy1 and autonomic neuropathy1,395 have occurred in some patients receiving cisplatin. Transient partial (focal)101,306,471 or tonic-clonic (grand mal)48,126,306 seizures have also occurred in some patients receiving the drug.1,48,97,101,126,276,306 Other manifestations of focal neurologic deficits induced by the drug have included cortical blindness and aphasia with seizures or with homonymous hemianopia.471 Other reported adverse nervous system effects include slurred speech,101 loss of taste,1,276 memory loss,276 and intention tremor.276 Postmortem findings of leukoencephalopathy also have been reported.475

If manifestations of neuropathy occur, cisplatin therapy should immediately be discontinued; however, neuropathy may worsen even after discontinuance of the drug.1,488 Peripheral neuropathy may be irreversible in some patients1,297 but has been partially or completely reversible in others following discontinuance of cisplatin therapy.97,101,297,298,299,300

Management

The role, if any, of neurotrophic peptides (e.g., Org 2766, an analog of corticotropin devoid of glucocorticoid activity) or other drugs on neurotoxic effects of cisplatin remains to be more fully elucidated.443,440,444,448,473,474,483,484,485 There is limited evidence from a study in women receiving cisplatin (75 mg/m² every 3 weeks) and cyclophosphamide (750 mg/m² every 3 weeks) for ovarian cancer that Org 2766 (1 mg/m² administered subcutaneously before and after each cycle of chemotherapy) can prevent or attenuate cisplatin-induced neuropathy, as determined by effects on the threshold value for vibration perception, without apparently affecting the cytotoxic effects of the drugs adversely; fewer neurologic manifestations relative to placebo also were observed in patients receiving Org 2766.443,474 However, the drug does not appear to prevent delayed neurotoxic effects several months after discontinuance of cisplatin and Org 2766 therapy;440,474 therefore, it has been suggested that continued therapy with this drug may be necessary for up to several months after discontinuance of cisplatin.474 Although the mechanism of possible neuroprotection by Org 2766 is unclear, the drug is a melanocortin and has been postulated to trigger or facilitate peripheral-nerve repair.443,444,483 Amifostine (ethiofos), a phosphorylated sulfhydryl compound,444,448,473 and glutathione, another sulfhydryl compound,484,485 also have exhibited neuroprotective effects. In a randomized study of patients with advanced ovarian cancer, the incidence and severity of cisplatin-induced neurotoxicity appeared to be reduced in patients who received prophylactic amifostine.581 Additional study and experience are needed to determine the usefulness of potential neuroprotectant compounds in patients receiving cisplatin.443,444,448,473,474

Hematologic Effects

The hematologic toxicity of cisplatin is usually moderate and reversible and affects all 3 blood lineages.13,245,276,440 Myelosuppression, which is manifested as leukopenia, thrombocytopenia, and anemia (a decrease in hemoglobin of greater than 2 g/dL), occurs in about 25-30% of patients receiving the drug.1,276 Geriatric patients may be at increased risk for myelosuppression associated with cisplatin therapy.1,756 (See Cautions: Geriatric Precautions.) Bone marrow suppression associated with cisplatin is less pronounced than that associated with carboplatin.440,495,496,521,522,551

Cisplatin-induced myelosuppression may be cumulative13,276 and may be more severe in patients previously treated with other antineoplastic agents or radiation therapy.245,276 Leukopenia and thrombocytopenia are dose related1,276 and more pronounced at doses exceeding 50 mg/m².1 Leukocyte and platelet nadirs generally occur 18-23 days (range: 7.2-45 days) following a single dose of cisplatin, with levels returning to pretreatment values in most patients within 39 days (range: 13-62 days).1,440 The incidence and severity of cisplatin-induced anemia are not clearly related to dose.276 The anemia is usually normochromic and normocytic38,97 and generally occurs over the same time course as leukopenia and thrombocytopenia;1,37,38 occasionally, the anemia may be severe, and patients may require transfusions.97,245,393

The etiology of cisplatin-induced anemia appears to be complex and several mechanisms may be involved.276,307,308,309,310,311 It has been suggested that anemia caused by cisplatin may result from a drug-induced decrease in erythropoietin276 or erythroid stem cells.310 There is also some evidence that both hemolysis and decreased erythropoiesis may contribute to the anemia.311 Rarely, cisplatin has reportedly caused hemolytic anemia;307,308,309 in a few of these cases, positive direct antiglobulin (Coombs') test results were observed,1,307,308 but it is not clear if this effect is immunologically mediated.307,308 Positive direct antiglobulin test results can apparently occur without evidence of hemolysis in patients receiving cisplatin.308,309

Sensitivity Reactions

Anaphylactoid reactions consisting principally of facial edema,1,276,313 flushing,276,312,440 bronchoconstriction,1 wheezing1,276 or respiratory difficulty (e.g., dyspnea),34,312,440 tachycardia,1,256,276,313 and hypotension1,2,276,312 have occurred within a few minutes after IV administration of cisplatin in patients who previously received the drug;1,256,276,312,313 diaphoresis,256 nasal stuffiness,440 rhinorrhea,313 conjunctivitis,313 generalized erythema,259,313 apprehension,313 and sensation of chest constriction313 also may occur. Anaphylactoid reactions also have occurred following intravesical†131 or intraperitoneal†476 administration of the drug. Cisplatin-induced anaphylactoid reactions usually have occurred only after multiple cycles (e.g, at least 5 doses) of the drug,245,312,313,440 but also can occur after the initial dose.440 The exact mechanism(s) is not known, but the reactions may be immune mediated in some patients.312 The reactions may be controlled by IV epinephrine, corticosteroids, and/or antihistamines as clinically indicated.1,34,126,259,276,312,313,440 Occasionally, patients who experienced anaphylactoid reactions reportedly have been safely retreated with cisplatin following pretreatment with corticosteroids256,276 and/or antihistamines;256,276,313,440 however, such prophylaxis is not uniformly effective in preventing recurrence.245,476,477

Rarely, urticarial or nonspecific maculopapular rashes,1,276,440 recurrent dermatitis,70 exfoliative dermatitis,477 and erythema70 have been reported in patients receiving cisplatin. In at least one patient, severe exfoliative dermatitis (diffuse erythroderma, desquamation, and eosinophilia) occurred after the second cycle of carboplatin and recurred with subsequent administration of cisplatin despite antihistamine and corticosteroid prophylaxis; with cisplatin, the dermatitis was associated with fever, facial edema, hypotension, tachycardia, and edema and cyanosis of the hands (as well as hypoesthesia and pain consistent with local ischemia).477

Ocular Effects

Optic neuritis1,298,304,314 (principally retrobulbar),298,314 papilledema,1,314 and cerebral (cortical) blindness1,48,315,471 have been reported infrequently in patients receiving recommended dosages of cisplatin. Improvement and/or total recovery usually occur after discontinuance of the drug.1,48,298,314 Corticosteroids, with or without mannitol, have been used in the management of these adverse ocular effects;1 however, the efficacy of such treatment has not been established.1

Cardiovascular Effects

Rarely, bradycardia,316 left bundle-branch block,276 and ST-T-wave changes with congestive heart failure276 have been associated with cisplatin therapy. Postural hypotension, which has been attributed to cisplatin-induced neurotoxicity, has also occurred.276 Hypertension, which persisted for up to 6 months and in some cases required treatment, has occurred following intra-arterial† infusion of the drug.317

Rarely, vascular toxicities have been associated with the use of cisplatin-containing combination chemotherapy.1,318,319,320,390,394,396,397 The adverse vascular effects are clinically heterogeneous1,396 and may include thrombotic microangiopathy,1,319 renovascular lesions,319 severe coronary artery disease,320,334 myocardial infarction,1,390,396,397 cerebrovascular accident,1,396 or cerebral arteritis.1 Various mechanisms have been suggested,1 including endothelial cell damage.319,396 Raynaud's phenomenon has also occurred in patients receiving bleomycin and vinblastine, with or without cisplatin.1,318,390,394 It has been suggested that cisplatin-induced hypomagnesemia may be an additional, although not essential, factor associated with its occurrence.1,390 (See Hypomagnesemia and Other Electrolyte Effects in Cautions: Renal and Electrolyte Effects.) The cause of Raynaud's phenomenon in these cases, however, is not clearly established and may involve the underlying disease or vascular compromise, bleomycin, vinblastine, hypomagnesemia, or some combination of these factors.1,390

Hepatic Effects

Mild and transient elevations of serum AST (SGOT),1,276 ALT (SGPT),276 and bilirubin1 concentrations may occur in patients receiving cisplatin. There has been one report of acute, reversible liver toxicity, manifested by transient elevations of serum bilirubin and hepatic enzymes, associated with cisplatin therapy.321

Local Effects

Rarely, local phlebitis has been associated with IV administration of cisplatin.100 There also have been rare reports of severe cellulitis with residual fibrosis322,482 and full-thickness skin necrosis323,482 following extravasation of the drug.1,482 Severity of local tissue toxicity appears to be related to the concentration of the cisplatin solution.1 Infusion of solutions with a cisplatin concentration exceeding 0.5 mg/mL may result in tissue cellulitis, fibrosis, and necrosis.1 Intra-arterial† infusion of cisplatin may result in local pain, edema, and erythema.241,242

Other Adverse Effects

Hyperuricemia may occur in patients receiving cisplatin,1,126,256 principally as a result of drug-induced nephrotoxicity.256 Hyperuricemia is more pronounced with doses greater than 50 mg/m², and peak serum concentrations of uric acid generally occur 3-5 days after administration of the drug.1 Allopurinol has been given to reduce serum uric acid concentrations.1,256

Elevated serum amylase concentrations have been reported infrequently in patients receiving cisplatin.1 Other adverse effects associated with cisplatin include mild alopecia1,100 or thinning of the hair,38 malaise,1 asthenia,1 hiccups,1 myalgia,100 pyrexia,324 and gingival platinum line.325 Although the exact mechanism(s) has not been determined, gynecomastia has occurred in some males with testicular carcinomas treated with cisplatin-containing combination chemotherapy;340,341 a direct causal relationship to cisplatin has not been established.340,341 Cisplatin has also been associated with the occurrence of syndrome of inappropriate antidiuretic hormone secretion (SIADH).1,237

Precautions and Contraindications

Cisplatin is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity.1,13,276 The drug must be used only under constant supervision by clinicians experienced in therapy with cytotoxic agents.1

Patients receiving cisplatin should be observed closely for possible anaphylactoid reactions, and appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of anaphylactoid reactions (e.g., antihistamines, epinephrine, oxygen, corticosteroids) should be readily available whenever cisplatin is administered.1 The manufacturer states that cisplatin is contraindicated in patients with a history of sensitivity reactions to the drug or other platinum-containing compounds;1 however, cross-sensitivity is not absolute, and occasionally with appropriate precautions patients sensitive to one platinum-containing compound have tolerated another.515,563,564 Exposure (e.g., industrial) to platinum-containing compounds can cause asthma and immediate and delayed hypersensitivity reactions,440,561,562 and the possibility that patients with a history of such exposure may be cross-sensitive to cisplatin should be considered.312

Renal, hematologic, otic, and neurologic function must be frequently and carefully monitored in patients receiving cisplatin;1,440 hepatic function should also be monitored periodically.1 Patients receiving the drug should be adequately hydrated, and serum electrolyte concentrations and fluid requirements carefully monitored;1,245,251,440 if serum electrolyte and/or fluid disturbances occur, appropriate treatment should be instituted.1,245,251,440

Cisplatin therapy is contraindicated in patients with preexisting renal impairment.1 The manufacturer recommends that serum magnesium, sodium, potassium, calcium, and creatinine concentrations and creatinine clearance and BUN be determined prior to beginning cisplatin therapy and prior to each additional course of therapy.1 While creatinine clearance appears to most accurately reflect the degree of renal insufficiency produced by the drug,244,245,251,339 some clinicians suggest that it is usually necessary to repeat measurement of creatinine clearance during cisplatin therapy only when the serum creatinine concentration increases by more than 33% over the baseline value.245 Since renal toxicity may become more prolonged and severe with repeated doses of cisplatin, the manufacturer states that another cisplatin dose should not be given until serum creatinine concentration is less than 1.5 mg/dL and/or BUN is less than 25 mg/dL.1 Cisplatin has been used successfully, however, in some patients with obstructive uropathy caused by tumors sensitive to the drug;252,328 in some of these patients, renal function improved following treatment with the drug.252,328 The drug has also been used successfully in some patients with a single functional kidney.376

The manufacturer recommends that peripheral blood cell counts be monitored weekly in patients receiving cisplatin;1 some clinicians suggest that blood counts can be monitored less frequently (e.g., every 2 weeks).361 While the hematologic toxicity of the drug is usually moderate and reversible, treatment of severe hematologic toxicity may consist of supportive therapy, anti-infectives for complicating infections, and blood product transfusions.13,245,276 The manufacturer states that a repeat dose of cisplatin should not be administered unless circulating blood elements are at an acceptable level (i.e., leukocyte count of at least 4000/mm³ and platelet count of at least 100,000/mm³).1 Fever and infection have been reported in patients with neutropenia.1 In the presence of cisplatin-induced hemolytic anemia, a further course of treatment may be accompanied by increased hemolysis, and the risk should be considered.1 The manufacturer states that cisplatin is contraindicated in patients with myelosuppression.1

Since cisplatin-induced ototoxicity is cumulative, the manufacturer recommends that audiometry be performed prior to initiating cisplatin therapy and prior to each additional course of therapy and that additional doses be withheld until audiometric determinations indicate that auditory acuity is within normal limits.1 Many clinicians believe that repeat audiograms are of limited value in the routine management of most patients receiving the drug276,290,440 and suggest that repeat audiometry be performed only when auditory symptoms occur290,440 or clinical hearing changes become apparent.290,440 Clinically important hearing changes may require dosage modification or discontinuance of therapy.276,290,358 The manufacturer states that cisplatin is contraindicated in patients with hearing impairment.1

Neurologic examinations should be performed regularly in patients receiving cisplatin, and the manufacturer recommends discontinuing therapy when symptoms of neurotoxicity first appear.1,440

Pediatric Precautions

Safety and efficacy of cisplatin in children have not been established.1,34,205,206,207,208 The drug has been used in the treatment of osteogenic sarcoma†, neuroblastoma†, and brain tumors† in children, but additional evaluation is needed.34,205,206,207,208 Some adverse effects (e.g., ototoxicity) appear to be more severe in children.1,289

Geriatric Precautions

While the safety and efficacy of cisplatin in geriatric patients have not been established specifically, data from 4 clinical trials involving a total of 1484 patients (29% of whom were older than 65 years of age) receiving cisplatin in combination with cyclophosphamide or paclitaxel for advanced ovarian cancer indicate that a higher incidence and greater severity of certain adverse effects may occur in older patients.1,756 Although age was not found to be a prognostic factor for survival in these studies, secondary analysis of data from one of these clinical trials demonstrated shorter survival in older patients compared with younger patients.1,756 Data from clinical trials involving the use of cisplatin in the treatment of metastatic testicular cancer or advanced bladder cancer are insufficient to determine whether elderly patients respond to the drug differently than younger patients.1,756

In all 4 clinical trials, severe neutropenia associated with cisplatin-containing chemotherapy occurred more frequently in geriatric patients than in younger patients; higher incidences of severe thrombocytopenia and leukopenia were observed in elderly patients receiving some cisplatin-containing regimens.1,756 A numerically higher incidence of peripheral neuropathy was observed in geriatric patients in 2 of the clinical trials, which evaluated nonhematologic toxicity according to age.756 Other clinical experience suggests that geriatric patients are at increased risk for myelosuppression, infectious complications, and nephrotoxicity associated with cisplatin therapy.1,756

Cisplatin is excreted mainly by the kidney and is contraindicated in patients with preexisting renal impairment.1,756 Because geriatric patients may have decreased renal function, careful dosage selection and monitoring of renal function are advised.1,756

Mutagenicity and Carcinogenicity

In vitro, cisplatin has been shown to be mutagenic in bacteria1,20,329 and has produced chromosomal aberrations in animal cells in tissue culture.1

Cisplatin has been shown to be carcinogenic in mice and rats.1,329 In studies in BD IX rats receiving intraperitoneal cisplatin at a dosage of 1 mg/kg body weight weekly for 3 weeks, 66% of the animals died within 450 days following the first application of the drug; approximately 40% of the deaths were related to malignancies (i.e., predominantly leukemias and 1 renal fibrosarcoma).1 Cisplatin-containing combination chemotherapy has been associated with the development of bladder cancer in a patient treated for nonseminomatous testicular carcinoma;330 however, other drugs and radiation therapy were used in this patient, and a direct causal relationship to cisplatin has not been established.330,331 Rarely, acute leukemia (e.g., lymphocytic, myeloid) has developed in patients receiving cisplatin therapy; in such patients, cisplatin generally has been given in combination with other leukemogenic agents and/or radiation.1,331,478,479,480,481

Pregnancy, Fertility, and Lactation

Pregnancy

Cisplatin and/or its platinum-containing products appear to cross the placenta.44 Cisplatin may cause fetal harm when administered to a pregnant woman,1,347,360 but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus.347,360 Cisplatin has been shown to be teratogenic in mice1,367 and embryotoxic in mice1,367,368 and rats.368 Cisplatin should be used during pregnancy only in life-threatening situations or severe disease for which safer drugs cannot be used or are ineffective.347,360 When the drug is administered during pregnancy or if the patient becomes pregnant while receiving the drug, the patient should be informed of the potential hazard to the fetus.1,347,360 Patients should be advised to avoid becoming pregnant during the period in which they are receiving cisplatin therapy.1

Fertility

The effects of cisplatin on the gonads and fertility have not been fully determined.332,333 Since the drug has produced testicular atrophy in animals13 and platinum is distributed in high concentration into testes,44,59 a risk of adverse testicular effects in humans exists. Although impairment of spermatogenesis is present in many males with testicular carcinomas prior to treatment, most males with these tumors become aspermic during and after treatment with cisplatin-containing combination chemotherapy;73,332,333 however, in some of these males, disease- and drug-induced impairment of spermatogenesis are apparently reversible.332,333 In one study in males with disseminated nonseminomatous testicular carcinoma treated with cisplatin, bleomycin, and vinblastine, with or without doxorubicin, 77% were initially oligospermic and 96% became aspermic within 2 months after initiation of therapy;333 however, there appears to be a high degree of reversibility as evidenced by a return of spermatogenesis with normal sperm counts 2-3 years after initiation of therapy.333 In addition, some of the males with recovery of spermatogenesis successfully impregnated their wives, resulting in 5 normal births, 3 ongoing pregnancies at the time of the study, and 1 spontaneous abortion.333 While recovery of spermatogenesis may occur,332,333 abnormal sperm may be present.332

Lactation

Cisplatin is distributed into milk.1 Because of the potential for serious adverse reactions to cisplatin in nursing infants, nursing should not be undertaken by women receiving the drug.1,347,360,361

Nephrotoxic Drugs

Cisplatin produces cumulative nephrotoxicity that is potentiated by aminoglycoside antibiotics.1,245,248,253,254,255 Concurrent administration of the drugs or administration of an aminoglycoside within 1-2 weeks after cisplatin therapy has been associated with an increased risk of nephrotoxicity245 and acute renal failure (sometimes severe).248,253,254 Aminoglycosides should be used with extreme caution, if at all, during or shortly after cisplatin therapy.245,248,251,253,254 Some clinicians suggest that the risk of this drug interaction may be reduced if the aminoglycoside is administered at least 2 weeks after cisplatin.245 Concomitant use of other potentially nephrotoxic drugs (e.g., amphotericin B) should probably also be avoided during cisplatin therapy.251,253,254

Ototoxic Drugs

Patients receiving cisplatin and other potentially ototoxic drugs such as aminoglycoside antibiotics or loop diuretics (e.g., ethacrynic acid, furosemide) concomitantly should be carefully monitored for signs of ototoxicity.276,294,440 A study in guinea pigs has shown that cisplatin and ethacrynic acid potentiate the ototoxic effects of each other.294

Antineoplastic Agents

Studies in animals200,362,365 and clinical trials in humans80,94,193,354,355,363,364,366 indicate that the antineoplastic activity of cisplatin and etoposide may be synergistic against some tumors. In mice implanted with P388200,362 or L1210200 leukemia or B16 melanoma,365 a combination of cisplatin and etoposide was shown to act synergistically in reducing the body burden of tumor cells and/or increasing survival. Response rates in humans receiving combination chemotherapy with cisplatin and etoposide suggest that the combination has synergistic antineoplastic activity against testicular carcinomas,80,94 small cell carcinoma of the lung,354,355,366 or non-small cell carcinoma of the lung.193,363,364 Studies in animals also indicate that the antineoplastic activity of cisplatin and some other antineoplastic agents (e.g., bleomycin, doxorubicin, fluorouracil, methotrexate, vinblastine, vincristine) is potentially synergistic.362

Limited data indicate that elimination of etoposide may be impaired in patients previously treated with cisplatin.378 In a randomized trial in patients with advanced ovarian cancer, response duration was adversely affected when pyroxidine was used in combination with altretamine (hexamethylmelamine) and cisplatin.1

Renally Excreted Drugs

Limited data suggest that cisplatin may alter the renal elimination of bleomycin337 and methotrexate,338 possibly as a result of cisplatin-induced nephrotoxicity.337 Although further documentation is needed, the possibility that cisplatin may affect the elimination of renally excreted drugs should be considered.347,361

Phenytoin

In patients receiving cisplatin and phenytoin, serum concentrations of phenytoin may be decreased,1,414 possibly as a result of decreased absorption and/or increased metabolism of phenytoin.414 In patients receiving cisplatin therapy, serum concentrations of phenytoin should be monitored and dosage adjustments made as necessary.414

Acute Toxicity

Manifestations

Overdosage of cisplatin may be fatal.1,420,421,422 In some cases, cisplatin overdosage resulted from inadvertent substitution of the drug for carboplatin;419,420,421 the latter drug is substantially less toxic than cisplatin and generally is administered at much higher dosages.419,420,421 Caution should be exercised to avoid inadvertent overdosage with cisplatin.1,419,420,421,422 (See Dosage and Administration: Dosage.)

Acute overdosage with cisplatin may result in acute renal failure, ototoxicity that can progress to irreversible deafness, severe myelosuppression, intractable nausea and vomiting, and neuritis.1,419,420,421,424,425,426 Less commonly, hepatotoxicity (e.g., hepatic failure manifested as increased serum transaminase concentrations and elevations in clotting times, prothrombin time, and partial thromboplastin time), central neurotoxicity (e.g., manifested as generalized seizures and hallucinations), and ocular toxicity (e.g., manifested as visual changes such as blurring and altered color perception that are attributable to retinal damage, including retinal detachment) can occur.1,419,422 Other manifestations of neurotoxicity have included dysarthria, paresthesias, and impaired taste perception.426 Myelosuppression, nephrotoxicity, ocular toxicity, and neuropathy may be partially or totally reversible.419,425,426,440 However, ototoxicity (e.g., bilateral sensorineural hearing loss) often is irreversible419,426,440 and, in patients whose overdosage was not accompanied by IV hydration (e.g., when cisplatin inadvertently was given instead of carboplatin), renal failure also may be irreversible.419

Treatment

Although there currently is no established antidote for cisplatin overdosage,1 nucleophilic (reducing) sulfhydryl (thiol) compounds (e.g., glutathione, acetylcysteine, mesna) can inactivate cisplatin and act as chemoprotectants (e.g., protecting against nephrotoxicity).419,427,428,429,430,431,432,433,434,435,436,437,440,444,447,448 However, the potential benefits of such therapy in the management of cisplatin overdosage remain to be established, and many of these compounds would be of limited, if any, benefit if administration were delayed for several hours after cisplatin administration since most platinum would be protein bound and not in its reactive form.419,448 Theoretically offering potentially greater usefulness would be dithiocarbamates (e.g., dithiocarb [diethyldithiocarbamate, DDTC], amifostine [ethiofos]) since the drugs can react with platinum even after protein binding has occurred and can stimulate substantial biliary excretion of the metal.419,427,428,429,430,431,440,444,448 Since most experience to date with the effects of various chemoprotectants on cisplatin toxicity has been in animal or in vitro studies or in preliminary studies in humans, the role, if any, of these agents in treating cisplatin toxicity remains to be elucidated .419,427,428,429,430,431,432,433,434,435,436,437,444 The role, if any, of neurotrophic peptides (e.g., Org 2766, an analog of corticotropin devoid of glucocorticoid activity) on neurotoxic effects of cisplatin also remains to be elucidated .443,444,448

Management of cisplatin overdosage currently consists principally of discontinuance of the drug and general supportive measures to sustain the patient throughout any period of toxicity that may occur.1 Hemodialysis, even when initiated within 4 hours following overdosage of cisplatin, appears to have little effect on removing platinum from the body because of cisplatin's rapid and high degree of protein binding.1,419,423 However, limited evidence suggests that aggressive plasmapheresis may be useful in removing protein-bound platinum and thus ameliorating toxicity.419 Antiemetics that are recommended for the prevention of acute or delayed emesis associated with cisplatin (type 3 serotonin receptor antagonists, dexamethasone and aprepitant)760 may be useful for managing acute intractable nausea and vomiting.440,441,442,445,446,447,448,468 Hematopoietic agents (e.g., sargramostim [GM-CSF]) may be useful in managing myelosuppression,419 and hemodialysis may be required for the management of renal failure.419,426

Pharmacology

The exact mechanism(s) of action of cisplatin has not been conclusively determined,13,14,15 but the drug has biochemical properties similar to those of bifunctional alkylating agents.7,13,14,16,17,125 Platinum-containing antineoplastic agents appear to exert their effects by binding to DNA, thereby inhibiting DNA synthesis.13,14,15,17,18,19,20,125,440,489,490,491,492,493 Cisplatin is cycle-phase nonspecific.21,125 Although the principal mechanism of action of cisplatin appears to be inhibition of DNA synthesis, other mechanisms, possibly including enhancement of tumor immunogenicity, are involved in its antineoplastic activity.22

Neutrality of charge and the cis configuration are necessary for the cisplatin complex to exert antineoplastic activity.7,14,15,16 In the relatively high chloride concentration of plasma, the cisplatin complex is believed to be un-ionized, allowing passage of the drug through cell membranes.7,14 Intracellularly, in the presence of a low chloride concentration, the chloride ligands of the complex are displaced by water (aquation), resulting in formation of positively charged platinum complexes that are toxic and react with the nucleophilic sites on DNA.7,14,489,490,491,492,493 Cisplatin binds to DNA and inhibits DNA synthesis;13,14,15,17,18,19,20,440,489,490,491,492,493 protein and RNA synthesis also are inhibited but less extensively.19,21 The drug produces predominately DNA intrastrand and interstrand cross-links,14,15,17,20,125 with intrastrand cross-links resulting from the formation of adducts between activated platinum complexes of the drug and areas of specific base sequences;15,489,490,493,494 DNA-protein cross-links also are formed.20,490,493 The relative importance of intrastrand or interstrand DNA cross-links in the antineoplastic activity of cisplatin remains to be clearly determined;14,15,20 however, interstrand cross-linking appears to correlate well with the cytotoxicity of the drug.20 Interstrand cross-linking within the DNA helix also occurs.489,490,493 The resultant interstrand and intrastrand cross-links are stable bonds that do not dissociate easily.489,490,493 While the mechanism through which DNA adducts exert their cytotoxic effects has not been determined, limited evidence indicates that platinum adducts may inhibit DNA replication, transcription, and ultimately cell division.489,490,493

Cisplatin also has immunosuppressive,13 radiosensitizing,23,24,49 and antimicrobial properties.13

Further study is needed to elucidate more fully the extent of cross-resistance between cisplatin and carboplatin.489 Although some cisplatin-refractory tumors may respond to carboplatin, a high degree of cross-resistance appears to occur between the drugs.493,495,496 The mechanisms of cellular resistance to platinum-containing antineoplastic agents have not been fully elucidated,489,490,493 but resistance can be related to decreased cellular uptake of the drug or enhanced DNA repair and may be related to elevated cellular levels of sulfhydryl (thiol) compounds including glutathione or metallothionein.440,489,490,493 Glutathione appears to play an essential role in protecting cells from the effects of certain toxins including certain antineoplastic agents, and increased levels of this sulfhydryl compound have been demonstrated in certain cell lines resistant to cisplatin and other analogs.489,493,497,498,499 Increased repair of platinum complex-induced DNA adducts also has been demonstrated in certain resistant cell lines.489,493,500,501 The relative roles of these mechanisms of resistance and their relationship to treatment failure in patients who do not respond to platinum-containing antineoplastic agents have not been fully determined.489,493

Pharmacokinetics

The pharmacokinetics of cisplatin are complex and have been studied principally by using assays for elemental platinum26,28,29,30,31,33,34,36,37,38,39,40,41,43,44,46,47,48,49,52,54,56,57 or by using preparations of the drug containing radioactive platinum;25,45 only a few studies have used analytical methods capable of measuring intact cisplatin.27,32,53,391 Published studies on the pharmacokinetics of cisplatin have varied widely in the doses administered, the rate of administration, the use of IV hydration, and the concurrent use of diuretics;25,26,27,28,29,30,31,32,33,34,36,37,38,39,52 the effects of these factors, if any, on the pharmacokinetics of the drug and their clinical importance remain to be fully elucidated.26,27,28,30,31,32,36,38,52,141 The chemical identities of platinum-containing products of cisplatin that are formed in vivo have not been definitely determined.27,55 In addition, relationships between therapeutic activity or toxicity and plasma concentrations of cisplatin or platinum have not been clearly established;26,27,31,32,36,37 however, results of in vitro studies have suggested that only nonprotein-bound cisplatin or its platinum-containing products are cytotoxic.26,50

Absorption

Following rapid IV injection of cisplatin over 1-5 minutes25,27 or rapid IV infusion over 15 minutes30,31,386 or 1 hour,26,36 peak plasma drug27 and platinum25,26,27,30,31,36,386 concentrations occur immediately. Following rapid IV injection of a 50-mg/m² dose of cisplatin over 3-5 minutes to patients with normal renal function in one study, peak plasma concentrations of intact cisplatin, total platinum, and nonprotein-bound platinum averaged 2.3, 4.7, and 2.7 mcg/mL, respectively;27 after a 100-mg/m² dose, peak plasma concentrations averaged 3.3, 6.2, and 4.5 mcg/mL, respectively.27 Following rapid IV infusion of a 100-mg/m² dose of the drug over 15 minutes to patients with normal renal function in another study, peak plasma concentrations of nonprotein-bound platinum averaged 2.73 mcg/mL.31 Following 1-hour IV infusions of 50 and 70 mg/m² to patients with normal renal function, peak plasma total platinum concentrations of 2.26-2.4536 and 4.25-7.02 mcg/mL,26 respectively, have been reported.

When cisplatin is administered by IV infusion over 628,29,33,37 or 24 hours,38,141,386 plasma concentrations of total platinum increase gradually during the infusion and peak immediately following the end of the infusion.28,29,33,37,38,141,386 Following 6-hour IV infusions of 100 mg/m² to patients with normal renal function, peak plasma total and nonprotein-bound platinum concentrations ranging from 2.5-5.328,29,37 and 0.22-0.73 mcg/mL,30,31,37 respectively, have been reported. Following a 24-hour IV infusion of 80 mg/m² in one study, peak plasma total platinum concentrations ranged from 1.03-1.90 mcg/mL.38 When equal doses of cisplatin are administered by rapid IV infusion or infusion over 2-3 or 24 hours in patients with normal renal and hepatic function, the areas under the plasma nonprotein-bound platinum concentration-time curves (AUCs) appear to be equivalent.386

Concomitant IV administration of cisplatin and mannitol appeared to increase peak plasma concentrations of nonprotein-bound platinum in one study,31 but in another study mannitol appeared to have no effect on plasma concentrations of intact cisplatin, total platinum, or nonprotein-bound platinum.27 In one study comparing the effects of IV furosemide or mannitol on the pharmacokinetics of cisplatin, plasma concentrations of total platinum and nonprotein-bound platinum were similar following administration of either diuretic.28

Following intra-arterial† infusion of cisplatin, local tumor exposure to the drug is increased compared with IV administration as evidenced by increased plasma platinum concentrations in local veins draining the infused region compared with systemic veins40,41 and by increased AUCs calculated for local versus systemic exposure.40 Following local infusion, systemic plasma platinum concentrations are similar to those attained following IV administration of comparable doses of the drug.40,41 Local venous plasma platinum concentrations are reportedly lower following infusion of cisplatin into the hepatic artery compared with other arteries (e.g., brachial, femoral), suggesting that the drug is highly extracted by the liver.40

Cisplatin is rapidly and well absorbed systemically following intraperitoneal administration†,42,43,346 resulting in 50-100% of the degree of systemic exposure compared with IV administration when comparable doses are given;42 however, peak intraperitoneal fluid concentrations of nonprotein-bound platinum are greatly increased, and intraperitoneal exposure to nonprotein-bound platinum is increased by about 15- to 30-fold compared with IV administration.42,43

Distribution

Following IV administration of cisplatin, platinum is widely distributed into body fluids and tissues,44,45 with highest concentrations in the kidneys,1,44,59 liver,1,44,45,59 and prostate.1,44 Lower concentrations are found in the bladder,1,44 muscle,1,44,59 testes,1,44,59 pancreas,1,44,59 and spleen;1,44,59 platinum is also distributed into the small and large intestines,1,44,45,59 adrenals,1,44,59 heart,1,44,59 lungs,1,44,59 lymph nodes,59 thyroid,59 gallbladder,59 thymus,59 cerebrum,1,44,49 cerebellum,1,44,49 ovaries,44 and uterus.44 Platinum appears to accumulate in body tissues following administration of cisplatin33,36,44 and has been detected in many of these tissues for up to 6 months after the last dose of the drug.44 Platinum is also distributed minimally into leukocytes25 and erythrocytes.60,371,386

The volume of distribution of platinum in adults following IV administration of cisplatin has been reported to range from 20-80 L36,39,40,386 and averaged 41 L/m² in one study.40 Platinum is rapidly distributed into pleural effusions28 and ascitic fluid31,42,43 following IV administration of cisplatin. The manufacturer states that small amounts of platinum have been detected in the bile and large intestine following administration of cisplatin, but fecal excretion of platinum appears to be insignificant.1,29 Cisplatin is distributed into milk,1 and limited evidence indicates that the drug and/or its platinum-containing products cross the placenta.44

Although there is some evidence to the contrary,46,47,48 cisplatin and/or its platinum-containing products apparently do not readily penetrate the CNS.44,49,125 Following IV administration of cisplatin, platinum is distributed into intracerebral tumor tissue and edematous brain tissue adjacent to tumor;49 however, only low concentrations of platinum have been detected in healthy brain tissue.44,49 In one study in patients with brain tumors, platinum was barely or not detectable in CSF following IV administration of cisplatin,49 but, in other reports, platinum was detected in the CSF of patients with46,47 or without48 brain tumors following IV administration of the drug. When platinum has been detected in CSF, peak CSF platinum concentrations occurred within 30-60 minutes after IV administration of cisplatin46,47 and CSF platinum concentrations ranged from less than 5%46 to up to 100%48 of concurrent plasma concentrations.

Cisplatin does not undergo the instantaneous and reversible binding to plasma proteins that is characteristic of typical drug-protein binding.1 The platinum from cisplatin, but not cisplatin itself, is rapidly and extensively bound to tissue and plasma proteins,1,25,26,28,36,51 including albumin,1,36,51γ-globulins,1,36 and transferrin.1,36 Binding to tissue and plasma proteins appears to be essentially irreversible.51 Protein binding increases with time,25,26,50,51,54,141 and less than 2-10% of platinum in blood remains unbound several hours after IV administration of cisplatin.1,25,26,54

Elimination

Following rapid IV injection or infusion of cisplatin, plasma concentrations of intact cisplatin, total platinum, and nonprotein-bound platinum have generally been reported to decline in a monophasic,27 biphasic,25,26,29,36,39,46,141 and biphasic26,30,31,371,386 manner, respectively; however, some reports indicate that plasma concentrations of nonprotein-bound platinum decline in a monophasic manner27,36,386 and that plasma concentrations of total platinum may exhibit triphasic26,27,57,371 or quadraphasic386 elimination with a prolonged terminal phase.26,371,386 In adults with normal renal function, the following plasma elimination half-lives have been reported after rapid IV injection or infusion of cisplatin: intact cisplatin, about 20-30 minutes;27 total platinum, 8.1-49 minutes in the initial phase25,26,29,36,46,371,386 and 30.5-107 hours25,26,29,36,46 or possibly longer386 in the terminal phase;25,26,29,36,46,386 and nonprotein-bound platinum, 2.7-30 minutes in the initial phase26,31,371,386 and 32-53.5 minutes in the terminal phase.26,30,31,371,386 Concomitant administration of IV mannitol does not alter the terminal plasma half-life of nonprotein-bound platinum.31 Following 6-hour IV infusions of cisplatin in patients with normal renal function, a terminal plasma elimination half-life for total platinum of 73-290 hours has been reported.28,29,37 Some data suggest that the rate of elimination of total plasma platinum in patients with normal renal function may decrease with time.386 In one patient with acute oliguric renal failure requiring hemodialysis, the terminal plasma half-life of total platinum was approximately 10 days.58

In children with normal renal function, the serum elimination half-lives of total platinum reportedly average about 25 minutes in the initial phase and 44 hours in the terminal phase, and the serum elimination half-life of nonprotein-bound platinum averages 1.3 hours.34

Following IV administration of cisplatin, the elimination half-lives of total platinum from CSF and pleural effusion fluid are reportedly about 0.75-1.5 hours46,47 and 22 days,28 respectively. Following IV administration of the drug, a mean elimination half-life of total platinum from erythrocytes of about 30 hours has been reported, suggesting that cisplatin may increase the breakdown of erythrocytes.386 Following intraperitoneal administration of cisplatin, the peritoneal elimination half-lives of total platinum and nonprotein-bound platinum are about 33 hours43 and 1 hour,42,43 respectively.

The metabolic fate of cisplatin has not been completely elucidated.1,25,27,55 There is no evidence to date that the drug undergoes enzymatic biotransformation; the chloride ligands of the cisplatin complex are believed to be displaced by water, forming positively charged platinum complexes that react with nucleophilic sites.7,14 The chemical identities of platinum-containing products of the drug that are formed in vivo have not been definitely determined.27,55 Intact cisplatin25,53,55 and its platinum-containing product(s) are excreted principally in urine;1,25,26,28,29,30,31,36,52,55 fecal elimination1,29,45 of platinum appears to be insignificant.1 The presence of a secondary peak in plasma platinum concentration during the principal elimination phase of platinum has been reported, suggesting that cisplatin or its platinum-containing products may undergo enterohepatic circulation.36,39,40,371

Renal excretion appears to occur predominantly via glomerular filtration,26,54,141,391 but there is some evidence that secretion54,391 and possibly reabsorption391 of cisplatin or a platinum-containing product(s) also occurs. Following a 6-hour IV infusion of the drug, the renal clearance of total platinum decreases substantially to a relatively low, constant value about 6-12 hours after the end of the infusion;33 this appears to be consistent with a relatively high, initial renal clearance of intact cisplatin and nonprotein-bound platinum, followed by clearance of nonprotein-bound platinum-containing product(s).28,33,35,53,55 The urinary excretion of 2 platinum-containing compounds has been partially characterized.53,55 The first, a water-elutable compound believed to be intact cisplatin, represents most of the platinum initially excreted in urine but rapidly decreases to represent a very small fraction of excreted platinum.53,55 The second, a hydrochloric acid-elutable compound believed to be a positively charged complex formed by replacement of one of cisplatin's chloride ligands with water, initially represents a small fraction of platinum excreted in urine but rapidly increases to represent a large fraction of urinary platinum.55 A third, unidentified platinum-containing compound also appears to be excreted in urine.55

Following rapid IV injection or infusion of cisplatin in patients with normal renal function, approximately 15-50% of a dose is excreted in urine within 24-48 hours;25,26,29,30,31,36,52,386 most urinary excretion occurs within the first 4-6 hours following administration of the drug,25,26,28,31,36 apparently principally as intact cisplatin.25,53,55 Following IV infusion of the drug over 6 hours in patients with normal renal function, 24-hour urinary excretion has generally ranged from about 10-35%28,29,37,391 of a dose; however, in some reports as much as 65-80% of the dose administered was excreted within 24 hours.30,31 Concomitant IV administration of mannitol and a 15-minute or 6-hour IV infusion of cisplatin reportedly results in substantially decreased 24-hour urinary excretion of platinum.31 An average of 14% of the administered dose was excreted in urine within 24 hours in one study when cisplatin was given as a 24-hour IV infusion to patients with normal renal function.38 There is some evidence that the circadian timing of cisplatin administration has a pronounced effect on urinary platinum excretion, with evening administration of the drug resulting in greater urine output and lower peak urinary platinum concentrations than morning administration.56

The effects of renal impairment on the elimination of cisplatin and its platinum-containing products have not been fully evaluated;31,38,57,58,386 individuals with decreased renal function may have impaired elimination.38,58 There is also some evidence that patients with impaired renal function may have elevated plasma concentrations of nonprotein-bound platinum.31

Limited data indicate that cisplatin and/or its platinum-containing products are minimally removed by hemodialysis.57,58 In one patient, 4- to 5.5-hour periods of hemodialysis removed into the dialysate about 8% of individual doses of cisplatin given by IV infusion over 0.75-1.5 hours immediately prior to dialysis;57 about 3% of a dose was removed into the dialysate per period during periods of hemodialysis 24 and 48 hours after the first period.57

Chemistry and Stability

Chemistry

Cisplatin is a platinum-containing antineoplastic agent.1,7,13 The drug is an inorganic complex that contains a platinum atom surrounded in a plane by 2 chloride atoms and 2 ammonia molecules in the cis position.1,7,13,16 Cisplatin occurs as a yellow to orange crystalline powder and has a solubility of 1 mg/mL in water or in 0.9% sodium chloride solution.1

Commercially available cisplatin injection is a clear, colorless solution and contains hydrochloric acid and/or sodium hydroxide to adjust pH and sodium chloride.1 The commercially available injection has a pH of 3.7-6, an osmolality of about 285-286 mOsm/kg, and contains a sodium chloride concentration of 0.9%.1,400

Cisplatin powder for injection (no longer commercially available in the US; see Preparations) occurs as a white, lyophilized powder and contains sodium chloride and mannitol, and hydrochloric acid to adjust pH.2,125 Following reconstitution of the powder for injection with sterile water for injection as recommended (see Dosage and Administration: Reconstitution and Administration), solutions containing 1 mg of cisplatin per mL are clear and colorless125 and have a pH of 3.5-5.52 and sodium chloride and mannitol concentrations of 0.9 and 1%, respectively.2,125

Stability

Commercially available cisplatin injection should be protected from light.1,3,402 The injection should be stored at 15-25°C and refrigeration avoided (since precipitation of the drug may occur);1,4,5,402 however, if cisplatin injection is inadvertently refrigerated, the precipitate will dissolve at room temperature, without loss of potency.402 If freezing occurs, cisplatin injection may be thawed at room temperature until precipitate dissolves; the manufacturer states that the chemical or physical stability of the injection is not affected.402 When stored under recommended conditions, commercially available cisplatin injection is stable for 17 months following the date of manufacture;400 cisplatin injection remaining in the amber vial following initial entry is stable for 28 days when protected from light or for 7 days when stored under fluorescent room light.1 Cisplatin powder for injection should be stored at room temperature.125 Unopened vials of the powder for injection are stable for 2 years at room temperature (27°C).125

The manufacturer states that, when reconstituted as directed from cisplatin powder for injection, cisplatin solutions are stable for 20 hours when stored at 27°C.125 Following reconstitution of the powder for injection with bacteriostatic water for injection containing benzyl alcohol or parabens, cisplatin solutions containing 1 mg/mL are reportedly stable for at least 72 hours at 25°C.5 Reconstituted solutions of cisplatin removed from the amber vial should be protected from light if they are not to be used within 6 hours.392 Reconstituted solutions of cisplatin should be stored at room temperature and should not be refrigerated, since precipitation may occur;4,5,125 a precipitate reportedly forms within 1 hour when solutions containing 1 mg of cisplatin per mL of 0.9% sodium chloride injection are refrigerated (2-6°C).4 Redissolution of the precipitate may occur very slowly when the solution is warmed to room temperature,4 but such warming to effect redissolution is not recommended and cisplatin solutions containing a precipitate should be discarded.2

In aqueous solutions6,7 or solutions containing less than 0.2% sodium chloride,4,6 cisplatin is decomposed with displacement of chloride ions by water.4,6,7,8 Increasing the chloride concentration in the solvent4,6,7 up to 0.9%4,6 improves the stability of cisplatin in solution. The stability of cisplatin in various IV solutions and admixtures is reported as follows:

The stability of cisplatin in solution is reportedly not adversely affected by the presence of up to 5% mannitol;5,6 however, cisplatin-mannitol complexes may form after several days, and advanced preparation and storage of such admixtures should be avoided.61 Cisplatin solutions should generally not be diluted in sodium bicarbonate or other alkaline solutions because of enhanced decomposition of cisplatin;2,6 formation of a bright gold precipitate has occurred after admixture of 5% sodium bicarbonate and a cisplatin solution.6 Cisplatin may react covalently with sodium thiosulfate to form a pharmacologically inactive compound42,62 and may also react with sodium bisulfite.9 Specialized references should be consulted for specific stability and compatibility information.2

Aluminum displaces platinum from the cisplatin molecule,10,11,12 causing the formation of a black precipitate1,10,11,12 and loss of potency.1,12 Cisplatin solutions should not be prepared or administered with needles or IV administration sets containing aluminum parts that might come in contact with the drug.1,10,12 Stainless steel needles and plated brass hubs do not react with cisplatin within 24 hours.10

Additional Information

For further information on the handling of antineoplastic agents, see the ASHP Guidelines on Handling Hazardous Drugs at [Web].

1. Bristol-Myers Squibb. Platinol^®-AQ (cisplatin injection) prescribing information. Princeton, NJ; 2002 Nov.

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361. Reviewers' comments (personal observations)

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