VA Class:AN900

AHFS Class:

• Antineoplastic Agents 10:00

Generic Name(s):

• CARBOplatin

Carboplatin is a platinum-containing antineoplastic agent.1,2,3,4,5,6,92,93

While the relative efficacy of carboplatin and cisplatin in the treatment of specific malignancies remains to be more fully elucidated, the drugs appear to have similar efficacy in platinum-responsive ovarian tumors,1,5,9,10,11,12,60,137,184,185 lung cancers,18,29,121,137 and certain head and neck cancers,17,137 but carboplatin is less effective than cisplatin in certain testicular cancers.24,78,137,193 Carboplatin and cisplatin are associated with different toxicity profiles1,2,3,4,5,8,9,10,11,12,68 and carboplatin may be effective in patients with platinum-responsive tumors who are unable to tolerate cisplatin because of renal impairment, refractory nausea, hearing impairment, or neuropathy.4,40,137 It has been suggested that while carboplatin may be preferred in patients with renal failure or patients at high risk for ototoxicity or neurotoxicity,4,10 cisplatin may be preferred in patients who have decreased bone marrow reserve or a high risk of sepsis, or who require anticoagulation therapy.10,137

Ovarian Cancer

Carboplatin is used alone or in combination therapy for the treatment of ovarian cancer.1,9,29

First-line Therapy for Advanced Ovarian Epithelial Cancer

Combination Chemotherapy

Carboplatin in combination with paclitaxel† is a preferred regimen for the initial treatment of advanced ovarian epithelial cancer.9,29 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.9

Carboplatin versus Cisplatin: Randomized trials have demonstrated that carboplatin is as effective as but less toxic than cisplatin when used in combination with either paclitaxel184,185 or cyclophosphamide10,11 for the initial treatment of advanced ovarian cancer. Further study is needed to determine optimal dosing for carboplatin.186

Carboplatin has been substituted for cisplatin in combination therapy with paclitaxel.145,184,185 In randomized trials in advanced ovarian cancer, carboplatin was as effective as cisplatin when combined with paclitaxel but was better tolerated.184,185

In a randomized trial designed to establish noninferiority of the studied carboplatin-containing regimen, 792 women with small-volume stage III ovarian cancer (i.e., no tumor nodule greater than 1 cm in diameter following the initial surgery) received either carboplatin/paclitaxel or cisplatin/paclitaxel.184 The treatment regimens consisted of carboplatin at the dose required to obtain an area under the plasma concentration-time curve (AUC) of 7.5 mg/mL per minute (using the Calvert formula in which creatinine clearance, calculated using the Jellife formula, was substituted for GFR) and paclitaxel 175 mg/m² as a 3-hour IV infusion; or cisplatin 75 mg/m² IV administered at 1 mg per minute and paclitaxel 135 mg/m² as a 24-hour continuous IV infusion every 3 weeks for a total of six courses.184 Based on median overall survival and median progression-free survival, carboplatin with paclitaxel was as effective as cisplatin with paclitaxel for small-volume stage III ovarian epithelial cancer.184 Grade 2 to 4 thrombocytopenia and grade 1 to 2 pain occurred more frequently in patients receiving the carboplatin regimen, whereas leukopenia and GI, renal (genitourinary), and metabolic toxicities (e.g., hypomagnesemia or abnormal electrolytes) occurred more frequently in patients receiving the cisplatin regimen.184 Grade 2 to 4 neurologic toxicity, mainly peripheral neuropathy, occurred with similar frequency (about 30%) in both groups.184

In another randomized trial designed to establish noninferiority of carboplatin, 798 women with FIGO stage IIb-IV ovarian cancer received either carboplatin/paclitaxel or cisplatin/paclitaxel.185 The treatment regimens consisted of paclitaxel 185 mg/m² administered IV over 3 hours followed by carboplatin at the dose required to obtain an AUC of 6 mg/mL per minute (using the Calvert formula in which GFR was estimated using the Jellife formula) administered IV over 30-60 minutes; or paclitaxel 185 mg/m² administered IV over 3 hours followed by cisplatin 75 mg/m² administered IV over 30 minutes.185 Regardless of calculated doses, the maximal absolute doses administered for each drug were paclitaxel 400 mg, carboplatin 880 mg, and cisplatin 165 mg.185 Based on the proportion of patients without disease progression at 2 years, median overall survival, and median progression-free survival, carboplatin with paclitaxel was as effective as cisplatin with paclitaxel for FIGO stage IIa-IV ovarian epithelial cancer.185 Grade 3 or 4 hematologic toxicity and grade 3 or 4 non-neutropenic infections occurred more frequently in patients receiving the carboplatin regimen, whereas certain grade 3 or 4 nonhematologic toxicities, including nausea, vomiting, and peripheral sensory neuropathy, occurred more frequently in patients receiving the cisplatin regimen.185

Carboplatin also has been substituted for cisplatin in combination therapy with cyclophosphamide.10,11 In randomized trials comparing the use of carboplatin versus cisplatin in combination with cyclophosphamide for advanced ovarian cancer, similar efficacy was observed but carboplatin appeared to have a more favorable therapeutic index than cisplatin.10,11

Because carboplatin is as effective as cisplatin in combination regimens for advanced ovarian cancer, it is preferred except in patients who are unable to tolerate carboplatin (e.g., those who have decreased bone marrow reserve, a high risk of sepsis, or imperative need for anticoagulation therapy).137,167

Platinum-containing Agent with Paclitaxel Versus Platinum-containing Agent with Cyclophosphamide: Evidence from randomized trials indicates that combined therapy with a platinum-containing agent and paclitaxel is superior to therapy with cyclophosphamide and a platinum-containing agent for the initial treatment of advanced epithelial ovarian carcinoma and therefore is the preferred regimen.9,29,60,137,139,147 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 cisplatin and paclitaxel 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.139 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.139 In another randomized trial, a higher rate of complete response and prolonged overall survival was observed in patients receiving paclitaxel and cisplatin versus cyclophosphamide and cisplatin for advanced epithelial ovarian cancer.147 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.183

Carboplatin and Docetaxel: Carboplatin in combination with docetaxel† has been used for the first-line treatment of ovarian cancer.196 In a phase III randomized trial, response rates, progression-free survival, and 2-year survival rates were similar in patients receiving docetaxel and carboplatin versus paclitaxel and carboplatin for stage Ic-IV epithelial ovarian cancer or primary peritoneal cancer.196 Severe or life-threatening neutropenia and neutropenic complications occurred more frequently in patients receiving docetaxel and carboplatin, whereas neurotoxicity was more common in patients receiving paclitaxel and carboplatin.196

Monotherapy

Carboplatin also has been used as a single agent in the first-line treatment of advanced ovarian cancer†.9,29 However, the specific role of carboplatin monotherapy for this advanced cancer remains to be established.137

In a large randomized trial known as the ICON3 (International Collaborative Ovarian Neoplasm 3) trial, 2074 patients with invasive ovarian cancer were randomly assigned to receive carboplatin alone, carboplatin and paclitaxel, or cyclophosphamide/doxorubicin/cisplatin (also known as CAP).187 About 95% of the patients were randomly assigned to a control group (carboplatin alone or CAP) or the standard regimen (carboplatin and paclitaxel) on a 2:1 basis favoring the control group.187 Patients enrolled in the study had invasive ovarian cancer that was FIGO stage I (9%), FIGO stage II (11%), FIGO stage III (64%), or FIGO stage IV (16%).187 Treatment regimens consisted of carboplatin at the dose required to obtain an AUC of 5-6 mg/mL per minute; paclitaxel 175 mg/m² IV over 3 hours followed by carboplatin (at the same dose used for carboplatin monotherapy); or cyclophosphamide 500 mg/m², doxorubicin 50 mg/m², and cisplatin 50 mg/m².187 At least 80% of the patients received 6 cycles of chemotherapy, and approximately one-third of patients receiving a control regimen (carboplatin alone or CAP) received taxane-based therapy as second-line treatment upon progression of disease.187

At a median follow-up of 4.25 years, median overall survival and median progression-free survival were similar among the treatment groups.187 Alopecia, fever, and sensory neuropathy occurred more frequently in patients receiving carboplatin combined with paclitaxel than in those receiving carboplatin alone.187 Sensory neuropathy also occurred more frequently in patients receiving carboplatin and paclitaxel than in those receiving CAP.187 Fever occurred more frequently in patients receiving CAP than in those receiving carboplatin and paclitaxel.187

The combination regimen of carboplatin plus paclitaxel generally remains preferred for the initial treatment of advanced ovarian cancer.9,29,191,192 However, because of the comparable efficacy and lesser toxicity demonstrated in this randomized trial, some clinicians consider single-agent carboplatin a reasonable option for the first-line treatment of advanced ovarian cancer.29,137,187

Second-line Therapy for Advanced Ovarian Epithelial Cancer

Combination Chemotherapy

Carboplatin is being studied for use in combination regimens for the second-line treatment of advanced ovarian epithelial cancer†.9 Most experience to date has been with platinum-based regimens that included paclitaxel.9

Combined analysis of data from 2 randomized trials in which a total of 802 patients with platinum-responsive ovarian cancer received either paclitaxel with platinum-based chemotherapy or conventional platinum-based chemotherapy for relapsed disease suggested a survival benefit associated with combination therapy.188 The median age of the patients was 59-60 years, and 75% of the patients did not experience relapse of ovarian cancer until at least 12 months following prior therapy.188 About 92% of patients had received only 1 prior line of treatment, and prior therapy included a taxane in only 43% of patients.188 Inclusion criteria and treatment regimens differed among the 3 protocols used in the 2 randomized trials.188

In all 3 protocols, courses of treatment were administered every 3 weeks.188 Treatment regimens included carboplatin alone in 71% of patients receiving a platinum-based regimen alone and paclitaxel combined with carboplatin in 80% of patients receiving combination therapy.188 Dosages for the agents were paclitaxel 175 mg/m² or 185 mg/m² administered as a 3-hour IV infusion; cisplatin 75 mg/m² as monotherapy or 50 mg/m² in combination; carboplatin at the dose required to obtain a minimum AUC of 5-6 mg/mL per minute.188

At a median follow-up of 3.5 years, median overall survival and median progression-free survival were prolonged in patients receiving paclitaxel and platinum-based chemotherapy versus platinum-based chemotherapy alone.188 Grade 2-4 neurologic toxicity (20 versus 1%) and alopecia (86 versus 25%) occurred more frequently in patients receiving combination therapy with paclitaxel and a platinum agent than in those receiving a platinum agent alone.188

Carboplatin also is being studied in combination with other agents for the treatment of relapsed ovarian cancer.9 In a phase III randomized trial, patients with platinum-responsive recurrent ovarian cancer receiving combination therapy with carboplatin and gemcitabine appear to have prolonged progression-free survival compared with those receiving carboplatin alone; combination therapy was associated with a higher frequency of grade 3 or 4 hematologic toxicity.189

Monotherapy

Carboplatin is used alone as second-line (salvage) therapy for the palliative treatment of patients with advanced ovarian carcinoma who have recurrence following an initial chemotherapy regimen, including ones that had cisplatin as a component.1,9 Either cisplatin or carboplatin can be used when retreatment is indicated in patients with platinum-responsive disease who relapse; however, some clinicians suggest that carboplatin may be preferred because it is associated with a more favorable toxicity profile than cisplatin.2

Although some patients who failed to respond to cisplatin or had a response of only short duration have responded to carboplatin,1,3 nonplatinum-based regimens generally are preferred for retreatment of patients with platinum-refractory disease.2,9,60,72

Adjuvant Therapy for Early-stage Ovarian Epithelial Cancer

Carboplatin also has been used alone or in combination therapy for the adjuvant treatment of early-stage ovarian cancer†.9 In 2 large randomized trials, patients receiving adjuvant therapy with single-agent or combination platinum-based therapy experienced prolonged overall survival and/or prolonged recurrence-free survival compared with patients undergoing observation (i.e., no adjuvant chemotherapy until chemotherapy was clinically indicated).179,180 However, evidence from one study (EORTC-ACTION trial) suggests that survival benefit may be limited to patients whose early-stage disease is associated with a poorer prognosis.137,179

In a large randomized trial known as the EORTC-ACTION trial (i.e., European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial), 448 patients who underwent appropriate surgery and had disease identified with surgical staging as any of the qualifying FIGO stages (i.e., stages Ia-Ib, grade II-III; all stages Ic and IIa; and all stages I-IIa with clear-cell epithelial cancer of the ovary) were randomly assigned to either adjuvant chemotherapy or observation.179 The median age of patients in the study was 54-55 years.179

Adjuvant chemotherapy consisted of at least 4 courses (but preferably 6 courses) of a platinum-based regimen following surgery.179 Platinum-based therapy included single-agent therapy or combination therapy with either carboplatin (at a required dose of 350 mg/m²) or cisplatin (at a required dose of 75 mg/m²).179 Most patients in the chemotherapy arm received cisplatin combined with cyclophosphamide (about half of the patients) or single-agent carboplatin (about one third of the patients).179

At a median follow-up of 5.5 years, patients receiving adjuvant chemotherapy had similar 5-year overall survival (85 versus 78%) and prolonged recurrence-free survival (76 versus 68%) compared with patients under observation.179 About 66% of the patients in the trial had undergone nonoptimal surgical staging, and completeness of surgical staging was identified as an independent prognostic factor.179 Optimal surgical staging of ovarian cancer minimizes the likelihood of undetected residual disease.179 Subgroup analysis showed that overall survival and recurrence-free survival were prolonged in patients with nonoptimally staged disease who received adjuvant chemotherapy, but not in patients with optimally staged disease who received adjuvant chemotherapy.179 The results of this analysis suggest that the observed benefit of adjuvant therapy may be limited to patients with inadequately staged epithelial ovarian cancer who are likely to have appreciable residual disease.179

In another large randomized trial known as the ICON1 (International Collaborative Ovarian Neoplasm 1) trial, 477 patients with early-stage ovarian cancer were randomly assigned to either adjuvant chemotherapy or observation.180 The adequacy of surgical staging was not monitored; 93% of the patients had FIGO stage I disease, and most patients had well differentiated (32%) or moderately differentiated (41%) tumors.180 The median age of patients in the study was 55 years.180

Recommended adjuvant chemotherapy following surgery consisted of 6 courses of a platinum-based regimen administered at 3-week intervals.180 Platinum-based therapy included either carboplatin or cisplatin, as single-agent therapy or in combination therapy (e.g., cyclophosphamide, doxorubicin, and cisplatin, also known as CAP).180 Using the Calvert formula, the recommended dose of carboplatin when used as a single agent was based on the dose required to obtain an area under the plasma concentration-time curve (AUC) of 5 mg/mL per minute; the recommended dose of carboplatin when used in combination was based on the dose required to obtain an AUC of 4 mg/mL per minute.180 The recommended dose of cisplatin when used as a single agent was 70 mg/m².180 The recommended doses for the CAP regimen were cyclophosphamide 500 mg/m², doxorubicin 50 mg/m², and cisplatin 50 mg/m².180

Of the 241 patients assigned to adjuvant chemotherapy, 197 patients received chemotherapy that was documented; among these patients, 171 (87%) received single-agent carboplatin, 21 (11%) received cisplatin-based combination therapy, 3 (2%) received carboplatin-based combination therapy, 1 (less than 1%) received single-agent cisplatin, and 1 (less than 1%) received an unspecified regimen.180 Among the patients receiving adjuvant chemotherapy, a total of 168 patients (85%) received all 6 cycles of chemotherapy but 65 patients required delayed doses or reduced dosage typically because of treatment toxicity.180

At a median follow-up of 4.25 years, patients receiving adjuvant chemotherapy had prolonged 5-year overall survival (79 versus 70%; hazard ratio: 0.66) and prolonged 5-year recurrence-free survival (73 versus 62%; hazard ratio: 0.65) compared with patients under observation.180

Interpretation of the results of each of the 2 randomized trials is limited by the small sample size; enrollment in both studies was stopped before the planned number of patients (i.e., at least 1000 patients in the ACTION trial and 2000 patients in the ICON1 trial) was accrued.179,180 Although the outcomes of the 2 randomized trials were similar, some important differences between the studies include the broader inclusion criteria and lack of strict surgical staging in the ICON1 trial.181,182 Combined analysis of the data from the ACTION and the ICON1 trials showed that at a median follow-up of at least 4 years, patients receiving adjuvant chemotherapy had prolonged 5-year overall survival (82 versus 74%; hazard ratio: 0.67) and prolonged 5-year recurrence-free survival (76 versus 65%; hazard ratio: 0.64) compared with patients under observation.181 Subgroup analyses of the combined data from the 2 trials according to age, tumor stage, histologic cell type, and cell differentiation did not identify any prognostic factor for the effect of adjuvant chemotherapy; subgroup analysis according to the completeness of surgical staging was not done because information about surgical staging was not collected in the ICON1 trial.181

In patients with FIGO stage Ia or Ib ovarian epithelial cancer, surgery alone generally is adequate.9 However, some prognostic factors, including grade III tumor, densely adherent tumor, or FIGO stage Ic disease, are associated with higher risk of recurrence of the disease, and additional treatment options may be considered.9 The results of these 2 randomized trials, individually or combined, suggest that adjuvant chemotherapy may benefit some patients with early-stage (FIGO stage I or II) ovarian epithelial cancer.179,180,181 However, further study is needed to differentiate patients with good-prognosis early-stage ovarian epithelial cancer who can be treated with surgery alone from patients with poor-prognosis early-stage disease who may benefit from surgery with immediate adjuvant chemotherapy.9,137,182 Various regimens were used for adjuvant chemotherapy in the 2 trials, and further study also is needed to compare the efficacy and toxicity of different regimens.137,182

Lung Cancer

Small Cell Lung Cancer

Carboplatin is used as a component of combination regimens for the treatment of small cell lung cancer†.3,4,18,19,20,29,75,76 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.18,22 Various regimens have been used in combination therapy and many 2- to 4-drug combination regimens, including carboplatin-containing regimens, have produced objective 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.18,19,20,22,75

Carboplatin-containing regimens are used in chemotherapy for extensive-stage small cell lung cancer and in combined modality treatment (i.e., combination chemotherapy with concurrent thoracic irradiation administered early in the course of treatment) for limited-stage disease.18,142 In the treatment of small cell lung cancer, carboplatin has been used in conjunction with etoposide with or without ifosfamide.3,18,19,20,22,29,75,76 In a randomized study, patients with small cell lung cancer receiving carboplatin and etoposide had similar response rates and median survival but less toxicity than those receiving cisplatin and etoposide.153

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.18 While efficacy of the various available regimens is continually being evaluated, combination chemotherapy regimens containing carboplatin and etoposide (with or without ifosfamide) currently are considered preferred18,29,137 or alternative29,137 regimens for the treatment of small cell lung carcinoma.

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.18

Non-small Cell Lung Cancer

Carboplatin is an active agent in non-small cell lung carcinoma†.121,137 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 metastatic or unresectable, locally advanced non-small cell lung cancer who have a good performance status.132,133

Carboplatin in combination with paclitaxel is used as an alternative to cisplatin-containing regimens in the treatment of advanced non-small cell lung cancer.29,132,137,152,177,178 Similar response rates and median survival were observed in a randomized trial in which patients received carboplatin and paclitaxel versus regimens of cisplatin in combination with paclitaxel, gemcitabine, or docetaxel for advanced non-small cell lung cancer.177 However, in another randomized trial, response rates were similar but median survival was shorter for patients receiving carboplatin and paclitaxel than for those receiving cisplatin and paclitaxel for advanced non-small cell lung cancer.152 In other randomized trials, response rates and median survival were similar in patients receiving either carboplatin and paclitaxel or cisplatin and vinorelbine for advanced non-small cell lung cancer; grade 3 peripheral neurotoxicity occurred more frequently in patients receiving paclitaxel and carboplatin whereas leukopenia/neutropenia and nausea and vomiting were more frequent in patients receiving vinorelbine and cisplatin.178,198

Carboplatin also is used as an alternative to cisplatin in combination with docetaxel for the treatment of advanced non-small cell lung cancer.29 In a randomized phase III trial comparing a platinum agent and docetaxel with cisplatin and vinorelbine for the treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer, patients receiving carboplatin and docetaxel had similar response rates and median survival as those receiving cisplatin and vinorelbine; higher response rates and a trend toward prolonged median survival were observed in patients receiving cisplatin and docetaxel compared with those receiving cisplatin and vinorelbine.197

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.132,133 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.132

Cervical Cancer

The role of carboplatin in the treatment of cervical cancer† remains to be established.157,166 (See Uses: Cervical Cancer in Cisplatin 10:00 for an overview of treatment for cervical cancer.)

Concurrent Chemotherapy and Radiation Therapy for Invasive Cervical Cancer

Concurrent platinum (i.e., cisplatin)-containing chemotherapy and radiation therapy is recommended in women with invasive cervical cancer (FIGO stage IB2 through IVA disease or FIGO stage IA2, IB, or IIA disease with poor prognostic factors).154,155,156,157,158,159 Although carboplatin often is used as a less toxic substitute for cisplatin, current evidence supports the use of cisplatin in chemotherapy regimens given concurrently with radiation therapy in patients with locally advanced cervical cancer, and similar benefit with the use of carboplatin-containing chemotherapy cannot be assumed.157,166

Metastatic or Recurrent Cervical Cancer

Carboplatin is an active agent in the treatment of metastatic or recurrent cervical cancer†.29,163,164,165 Objective response rates of 15% have been reported with the use of carboplatin as a single agent for the treatment of metastatic or recurrent squamous cervical cancer.163,164 Because of its lesser toxicity, carboplatin may be considered as an alternative to cisplatin, particularly in patients with nephrotoxicity or neurotoxicity caused by advanced cervical tumor who are not suitable candidates for cisplatin therapy.163,164,165 However, randomized controlled trials comparing carboplatin and cisplatin have not been performed to date,165,166 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.163,166 Some experts suggest that study of higher dosages and various dosage schedules is needed to fully establish the activity of carboplatin in advanced cervical cancer.164,166

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.159,160,162,166 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.160,161,162,166 In addition, the benefit of chemotherapy versus best supportive care has not been studied in patients with metastatic or recurrent cervical cancer.162 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.159,160,162,166

Head and Neck Cancer

Carboplatin may be useful in the treatment of recurrent or metastatic squamous cell carcinoma of the head and neck†.3,4,5,15,16,17,29,41,128,135 Therapy that includes carboplatin has been suggested as one of several alternatives to various cisplatin-containing regimens for recurrent or metastatic squamous cell carcinoma of the head and neck, but experience with carboplatin is less extensive than with cisplatin.3,4,5,15,16,17,41,137 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.200 Median survival was similar among the groups.200 Combination chemotherapy was associated with increased toxicity (particularly hematologic toxicity for cisplatin and carboplatin and renal toxicity for cisplatin).200

In males younger than 50 years of age with metastatic squamous neck cancer who have a poorly differentiated tumor, an occult primary, 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.128,137 Although surgical resection, radiation therapy, or both are preferred therapy for the initial management of cancer of the head and neck, chemotherapy before or after surgery or radiation therapy can be considered for such tumors.16,135

Wilms' Tumor

Carboplatin has shown activity in the management of Wilms' tumor†.29,65 Second-line (salvage) therapy with ifosfamide, carboplatin, and etoposide may be considered for patients with recurrent tumors of unfavorable histology, abdominal recurrence after radiation therapy, or recurrence within 6 months of nephrectomy or after initial 3-drug combination chemotherapy (e.g., vincristine, dactinomycin, and doxorubicin); however, this regimen is associated with substantial hematologic toxicity.65 Cyclophosphamide and etoposide alternating with carboplatin and etoposide has been used as an induction regimen preceding surgery and then as maintenance chemotherapy for patients with high-risk, relapsed Wilms' tumor.65 Patients with recurrent disease failing to respond to such attempts with salvage therapy should be offered treatment under protocol conditions in ongoing clinical trials.65

Brain Tumors

Carboplatin has been used for the palliative treatment of various primary brain tumors†.3,29 Regimens that include carboplatin have been used principally in the treatment of germ cell tumors.29,169 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.129

Malignant Gliomas

Astrocytic Tumors

Carboplatin has shown activity in the treatment of progressive or recurrent low-grade gliomas in children†.29,56,57 Use of carboplatin in combination with vincristine for the treatment of progressive low-grade gliomas in children is being investigated.58,169

Responses to IV carboplatin have been observed in adults with recurrent gliomas, including those who had received previous chemotherapy with nitrosoureas.29,170,171

Medulloblastoma

Carboplatin has shown activity in the treatment of recurrent medulloblastoma†.56,130 The use of carboplatin in myeloablative chemotherapy regimens (e.g., carboplatin, thiotepa, and etoposide) with autologous bone marrow or stem cell rescue has been studied in a limited number of children with recurrent medulloblastoma.172,173 In children with newly diagnosed medulloblastoma, combination regimens containing carboplatin are being investigated for use as neoadjuvant therapy preceding radiation therapy174 or as a component of intensive chemotherapy accompanied by autologous bone marrow rescue to avoid the need for radiotherapy in young children.175 Further study is needed to compare the efficacy and toxicity of carboplatin versus cisplatin in the treatment of medulloblastoma.174 (For further discussion of the treatment of medulloblastoma, see Uses: Brain Tumors in Cisplatin 10:00.)

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†.29,169,176

Neuroblastoma

Carboplatin is used as a component of combination therapy for neuroblastoma†.26,29 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.26 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).26 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.26 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.26

Testicular Cancer

Randomized trials indicate that a cisplatin-based regimen (i.e., cisplatin/etoposide or cisplatin/etoposide/bleomycin) is more effective than a carboplatin-based regimen (i.e., carboplatin/etoposide or carboplatin/etoposide/bleomycin) in the initial treatment of good-prognosis metastatic nonseminomatous germ cell tumors, and treatment with a carboplatin regimen generally is reserved for patients who do not tolerate or who refuse cisplatin.24,78,137,193 Limited data suggest that high-dose carboplatin and etoposide may be effective in the treatment of relapsed or refractory germ cell tumors† in some patients.23,30,59 High-dose carboplatin and etoposide with autologous bone marrow transplant has been associated with complete remission in 10-20% of patients with cisplatin-resistant germ cell tumors.23,30,59 Even higher rates of durable complete response (exceeding 50%) have been observed when high-dose carboplatin and etoposide, followed by peripheral blood stem cell transplantation or autologous bone marrow transplantation, is used as initial salvage therapy in patients with relapsed testicular cancer.23,194

Bladder Cancer

Carboplatin has been substituted as a less toxic alternative to cisplatin in some patients receiving combination chemotherapy for advanced bladder cancer†.143,146 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.100,143,144,146

Combination therapy with paclitaxel followed by carboplatin is being investigated as a tolerable and active regimen in patients with advanced bladder cancer, including patients with abnormal renal function.97,131,168 In a phase III randomized trial, 80 patients received paclitaxel 225 mg/m² IV over 3 hours, followed by carboplatin (at the dose required to obtain an AUC of 6 mg/mL per minute) IV over 30 minutes, every 21 days, or the standard MVAC regimen (i.e., cisplatin, methotrexate, vinblastine, and doxorubicin) every 28 days, for a maximum of 6 treatment cycles.190 The response rates were similar; at a median follow-up of 2.7 years, patients receiving paclitaxel and carboplatin had similar median overall survival as patients receiving MVAC.190 Severe neutropenia occurred more frequently in patients receiving MVAC than in those receiving paclitaxel and carboplatin.190 Interpretation of the results is limited by the failure to meet the planned accrual of 330 patients in the trial.190

Retinoblastoma

Carboplatin has been used in combination with etoposide in a limited number of children† with recurrent or progressive retinoblastoma†.102,106 While regimens including doxorubicin, cyclophosphamide, and/or vincristine have been used, some clinicians consider carboplatin one of several alternative agents that can be used in children with extraocular retinoblastoma.29,102 Therapy with carboplatin in combination with etoposide has been associated with partial or complete responses in up to 85% of children with recurrent disease; the role of carboplatin-containing regimens as adjuvant therapy after enucleation or as neoadjuvant therapy of ocular tumors remains to be determined.102,106

Other Uses

Carboplatin has been used for the treatment of breast cancer†.199 In a phase III randomized trial, higher response rates and prolonged median progression-free survival were observed with the addition of carboplatin to trastuzumab and paclitaxel for the treatment of HER2-overexpressing metastatic breast cancer; grade 4 neutropenia occurred more frequently in patients receiving carboplatin with trastuzumab and paclitaxel.199

Carboplatin is being studied for use in the treatment of endometrial cancer†.195 A phase III randomized trial comparing carboplatin and paclitaxel versus doxorubicin, cisplatin, paclitaxel and filgrastim (G-CSF) for advanced or recurrent endometrial cancer is under way.195

Reconstitution and Administration

Carboplatin is administered by IV infusion.1 Infusions of the drug usually are administered IV over a period of 15 minutes or longer;1,2,4,10,13,25,27,42 carboplatin has been administered by continuous IV infusion over 24 hours.1,2,3 Unlike precautions required during cisplatin administration, pretreatment and posttreatment hydration and/or diuresis are not necessary when carboplatin is administered.1,10,11,24,27,37 Carboplatin also has been administered intraperitoneally†.2,3,4,32,43,47 Needles, syringes, catheters, and IV administration sets that contain aluminum parts which may come in contact with carboplatin should not be used for preparation or administration of the drug.1 (See Chemistry and Stability: Stability.) The usual precautions for handling and preparing cytotoxic drugs should be observed when preparing or administering carboplatin.1

Commercially available carboplatin injection is a premixed aqueous solution containing 10 mg of carboplatin per mL.1 The manufacturer states that carboplatin aqueous solution may be further diluted with 0.9% sodium chloride injection or 5% dextrose injection to a concentration as low as 0.5 mg/mL.1 Prior to administration, carboplatin solutions should be inspected visually for particulate matter and discoloration.1

Dosage

Dosage of carboplatin must be based on the clinical, renal, and hematologic response and tolerance of the patient in order to obtain optimum therapeutic response with minimum adverse effects.1,10,11 While initial carboplatin dosage can be based on body surface area, dosage may be more accurately calculated using formula dosing methods based on the patient's renal function.1,81,82,83,84,85,93,107,108,137 Because renal function often is reduced in geriatric patients, the manufacturer recommends that dosing formulas incorporating estimates of glomerular filtration rate be used in geriatric patients to help minimize the risk of toxicity.1 (See Dosage: Individualization of Dosage.) The manufacturer recommends that carboplatin generally be given no more frequently than once every 4 weeks at usual dosage.1 A repeat course of carboplatin should not be administered until the patient's hematologic functions are within acceptable limits, and precautions must always be taken to treat a hypersensitivity reaction if it occurs .1 (See Cautions: Precautions and Contraindications.) When carboplatin is used as a component of a multiple-drug regimen, clinicians should consult published protocols for the dosage of each chemotherapeutic agent and the method and sequence of administration.

Because carboplatin is an antineoplastic agent of moderate emetic risk, antiemetic therapy is recommended.201 (See Cautions: GI Effects.)

Ovarian Cancer

For the treatment of advanced ovarian carcinoma (stage III and IV) in combination chemotherapy regimens (i.e., with cyclophosphamide), an initial IV carboplatin dose of 300 mg/m² can be used in adults.1,10,11 Subsequent dosage of the drug should be adjusted according to the patient's hematologic tolerance of the previous dose (e.g., as described below); doses should not be administered until the patient's hematologic function is within acceptable limits.1 Alternatively, carboplatin dosage can be calculated using formula dosing methods based on renal function. 1,81,82,83,84,85,93,107,108,137 (See Dosage: Individualization of Dosage.) A course of carboplatin consists of single doses administered once every 4 weeks (or longer if delayed for hematologic toxicity) for a total of 6 cycles.1,10,11,69,70,71

When carboplatin is used alone in the treatment of recurrent ovarian carcinoma, an initial dose of 360 mg/m² can be used, administering the drug once every 4 weeks (or longer if delayed for hematologic toxicity).1 Doses of carboplatin generally should not be repeated until the patient's hematologic function is within acceptable limits, adjusting dosage according to the patient's hematologic tolerance of the most recent dose (e.g., as described in the following paragraph).1,137

For patients who experience no hematologic toxicity (i.e., platelet counts greater than 100,000/mm³ and neutrophil counts greater than 2000/mm³) with the previous dose, dosage of carboplatin in single or combination therapy may be increased by 25%.1,10,11 In studies used to establish efficacy of carboplatin in combination with cyclophosphamide, dosage escalation above 25% of the initial dose was not evaluated.1,11 For patients who experience only mild to moderate hematologic toxicity (i.e., platelet counts of 50,000-100,000 mm³ or neutrophil counts of 500-2000/mm³, respectively) with the previous dose, dosage adjustment is not necessary in single agent or combination regimens.1,10,11 For patients who experience moderate to severe hematologic toxicity (e.g., platelet counts lower than 50,000 mm³ or neutrophil counts lower than 500/mm³, respectively) with the previous dose, the dosage of carboplatin in single agent or combination regimens should be reduced by 25%.1,10,11,137 In studies used to establish efficacy of carboplatin in stage III and IV ovarian carcinoma, carboplatin therapy was continued only at the investigator's discretion in patients who experienced hematologic toxicity following 2 dosage reductions (i.e., while receiving a carboplatin dosage equivalent to 50% of the initial dosage).11 Some authorities suggest that, rather than compromise carboplatin's efficacy by dosage reduction in patients who experience substantial hematologic toxicity, carboplatin therapy should be replaced with cisplatin (which is less myelosuppressive) therapy if possible.9 Whether concomitant hematopoietic agents (colony-stimulating factor) can obviate carboplatin dosage reduction in patients who experience substantial hematologic toxicity remains to be established.40,137

Other Neoplasms

Dosage of carboplatin used in the treatment of other malignant neoplasms† generally has been similar to that used in the treatment of ovarian carcinoma; however, various dosage schedules and regimens of carboplatin alone or in conjunction with other antineoplastic agents have been used.3,4,14,15,17,19,20,22,24,25,27,28,56,121 Clinicians should consult published protocols for dosages and the method and sequence of administration. In general, escalation of carboplatin dosages above 400 mg/m² results in substantial hematologic toxicity, but high-dose carboplatin (900-2000 mg/m²) has been used with colony-stimulating factors,40,67,121 autologous bone marrow rescue, and/or peripheral stem cell rescue.28,30,37,40,59,111,137

Individualization of Dosage

Several alternative methods for calculating initial carboplatin dosage have been suggested based on the patient's pretreatment renal function or pretreatment renal function and desired platelet nadir.1,38,81,82,83,84,85,93,107,108 These methods, compared with empiric dosage calculations based only on body surface area, compensate for patient variations in pretreatment renal function that may otherwise result in carboplatin underdosing (e.g., in patients with above average renal function) or overdosing (e.g., in patients with impaired renal function).1,81,82,83,84,85,93,107,108,121 The methods incorporate considerations about the direct relationship between renal clearance of carboplatin and glomerular filtration rate (GFR) over widely ranging renal function and about the predictive relationship between the area under the plasma concentration-time curve (AUC) of ultrafilterable platinum and the degree of subsequent thrombocytopenia and neutropenia.1,81,82,83,84,85,93,107,108

One commonly employed method for carboplatin dosage calculation in adults is the Calvert formula based on the patient's GFR (in mL/minute) and the target AUC (in mg/mL per minute).1,81,82,83,93,137 Using the Calvert formula, carboplatin dosage is calculated in mg, not mg/m2 .1 Because the predictability of this calculation has been established using chromic edetate Cr 51 (⁵¹Cr-EDTA) clearance to establish GFR,1,81,82,83,85,93 some clinicians have recommended that other methods for estimating creatinine clearance (e.g., Cockcroft-Gault equation, Jelliffe equation) not be substituted for this determination since carboplatin dosing based on such estimates may not be predictive.85 However, other clinicians have successfully employed such methods for estimating creatinine clearance because of their simplicity and/or unavailability of ⁵¹Cr-EDTA clearance, although they may not be as precisely predictive.121,137

Calvert Formula for Carboplatin Dosing:

total dose (mg) = target AUC (in mg/mL/min) × [GFR (in mL/min) + 25]

In studies used to derive the Calvert formula, the GFR was measured by ⁵¹Cr-EDTA, which correlates well with creatinine clearance.1,82,83,85,93 A target AUC of 5 (range: 4-6) mg/mL per minute appears to provide the most appropriate dosage range for use of carboplatin alone in patients previously treated with chemotherapeutic agents.1,82,83,93 Analysis of toxicity in previously treated patients receiving carboplatin alone indicates that substantial thrombocytopenia (grade 3 or 4 [platelet counts less than 50,000/ mm³]) occurs in 16% and leukopenia (grade 3 or 4 [leukocyte counts less than 200,000/ mm³]) occurs in 13% of patients with target AUCs of 4-5 mg/mL per minute.1 A higher incidence of myelotoxicity was reported in patients with target AUCs of 6-7 mg/mL per minute with thrombocytopenia (grade 3 or 4) occurring in 33% and leukopenia (grade 3 or 4) occurring in 34% of patients.1 For patients who previously did not receive chemotherapy, a target AUC of 7 (range: 6-8) mg/mL per minute has been recommended when carboplatin is used alone.82,83,93 Higher target AUCs (e.g., 7.5 mg/mL) also have been used (e.g., when carboplatin was used as a component of high-intensity dosing with paclitaxel and a hematopoietic agent for non-small cell lung carcinoma).121 Subsequent carboplatin dosage has been adjusted according to hematologic tolerance to the previous dose (e.g., reducing the dose by 25% for moderate to severe hematologic toxicity).121

The Calvert formula is not sufficiently accurate to determine carboplatin dosage for children or for adults with severe renal impairment (i.e., GFR less than 20 mL/minute); therefore, this formula should not be used in such patients.83 An alternative pediatric formula has been suggested, but specialized references should be consulted.83,93,119,120

Another method (the Chatelut or French formula) for carboplatin dosage calculation in adults that is simplified by not requiring determination of GFR has been suggested.84,85,93 While this method is more recent and therefore has not been employed as extensively as the Calvert method, it offers a means of estimating carboplatin clearance that relies only on patient age, gender, and serum creatinine concentration.84,85,93 Using the Chatelut formula, carboplatin dosage is calculated in mg, not mg/m2. 84,93

When carboplatin clearance is calculated as follows:

Carboplatin clearance (mL/min) =

[0.134 × wt] + [218 × wt × (1 - {0.00457 × age})] × [1 - {0.314 × gender}] ÷ serum creatinine (µmol/L) (where weight is in kg, age is in years, and gender is 0 for males and 1 for females)

This formula should not be used for calculating carboplatin dosage in pediatric patients or those undergoing hemodialysis.84

Dosage in Renal Impairment

Dosage of carboplatin should be reduced in patients with impaired renal function.3,5,38 Because patients with creatinine clearances less than 60 mL/minute are at increased risk of myelosuppression during carboplatin therapy, dosage in such patients should be adjusted according to the degree of renal impairment.1 When carboplatin is used alone in the treatment of recurrent ovarian carcinoma in patients with renal impairment, the manufacturer recommends that those with creatinine clearances of 41-59 mL/minute receive an initial dose of 250 mg/m² and those with creatinine clearances of 16-40 mL/minute receive an initial dose of 200 mg/m².1 The incidence of severe leukopenia, neutropenia, or thrombocytopenia in these patients at these dosages is about 25%.1 Subsequent carboplatin dosage should be adjusted according to the patient's hematologic tolerance to the previous dose.1 Although carboplatin has been used in a limited number of patients with creatinine clearances less than 15 mL/minute,38,39 the manufacturer states that experience in these patients is too limited to make dosage recommendations.1

Although carboplatin and cisplatin are both platinum-coordination compounds and have similar mechanism(s) of action, they have different toxicologic profiles, with carboplatin being better tolerated overall.1,2,3,4,5,9,10,11,40,60,68,72,92,93 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.1,2,3,4,5,10,11,53,66,67,93 The improved overall toxicity profile of carboplatin relative to cisplatin appears to result at least partly from the presence of a cyclobutane dicarboxylate ligand on carboplatin which results in a more stable compound; decreased reactivity with macromolecules and differences in renal handling appear to be important factors in this improvement.2,3,4,5,6,43,92,93 Differences in the toxicity and pharmacokinetic profiles of the drugs may be important determinants in the selection of carboplatin versus cisplatin for specific patients.4,9,10,92,93,98,99,100,101,137 In addition, differences in toxicity profile may make it possible to escalate carboplatin dosages beyond those usually recommended particularly when autologous bone marrow transplantation (ABMT), peripheral stem cell transplantation, and/or hematopoietic agents (colony-stimulating factors) are used concomitantly.28,30,40,66,67,92,93,110,111,121,137

Information on safety and efficacy of carboplatin has been obtained from clinical studies in patients with malignancy who received the drug alone1,13,53 or in conjunction with other antineoplastic agents (i.e., cyclophosphamide).1,10,11,24,25

Hematologic Effects

The major and dose-limiting adverse effect of carboplatin is bone marrow suppression, which is manifested as thrombocytopenia, leukopenia, neutropenia, and/or anemia and is more pronounced than that with cisplatin.1,3,4,10,11,27,28,53,56,66,67,79,80,93,121 Carboplatin-induced myelosuppression is dose related and appears to be most common and more severe in patients who have received prior antineoplastic therapy (especially cisplatin-containing regimens), those who are receiving concurrently or have received recently other myelosuppressive drugs or radiation therapy, and those who have renal impairment.1,3,38,53,66,67,82,83,84,85,93,101,121,137 The correlation between renal function and degree of thrombocytopenia and neutropenia is related to the pharmacokinetic characteristics of carboplatin and has resulted in the development of individualized dosing schedules based on glomerular filtration rate.38,82,83,84,85,93,101,102,121 (See Dosage: Individualization of Dosage, in Dosage and Administration.) Patients with poor performance status also appear to be at increased risk for severe leukopenia and thrombocytopenia during carboplatin therapy.1

At usual dosages, carboplatin-induced thrombocytopenia is more common and pronounced than leukopenia.53,82,93 Thrombocytopenia (platelet counts less than 100,000/mm³) occurred in about 60-70% of patients receiving usual dosages of carboplatin alone or in conjunction with cyclophosphamide in clinical trials; more severe thrombocytopenia (platelet counts less than 50,000/mm³) occurred in 22-41% of patients.1,10,11 Thrombocytopenia may be cumulative and occasionally require platelet transfusions.121 Leukopenia (leukocyte count less than 4000/mm³) was reported in up to 85-98% of patients receiving usual dosages of the drug alone or in conjunction with cyclophosphamide in clinical trials.1,10,11 Leukopenia was pronounced (leukocyte count less than 2000/mm³) in 15-26% of patients receiving usual dosages of carboplatin alone and in 68-76% of patients receiving the drug in conjunction with cyclophosphamide.1,10,11 In patients who received carboplatin alone, neutrophil counts less than 2000/mm³ occurred in 67% and neutrophil counts less than 1000/mm³ occurred in 16-21% of patients.1 When the drug was used in conjunction with cyclophosphamide, neutrophil counts less than 2000/mm³ occurred in 95-97% and counts less than 1000/mm³ occurred in up to 84% of patients.1,10,11 At high doses (i.e., 1.2 g/m² or greater), more than 90% of patients reportedly experience grade IV thrombocytopenia and neutropenia (platelet counts less than 25,000/mm³ and neutrophil counts less than 500/mm³, respectively), and decreases in hemoglobin concentrations of 3-3.5 g/dL.93,109

When carboplatin is administered alone, leukocyte and platelet nadirs generally occur 21 days (range: 14-28 days) following administration of the drug, and recovery of platelet counts (exceeding 100,000/mm³), leukocyte counts (exceeding 4000/mm³, and neutrophil counts (exceeding 2000/mm³) occurs within 28 days in 90, 67, and 74% of patients, respectively.1,53,93 In most patients, recovery generally is adequate to permit a repeat carboplatin dose 4 weeks after a previous dose.1,10,11,93 In clinical studies, at least one episode of infection occurred in 5% of patients receiving carboplatin alone and in 14-18% of patients receiving the drug in conjunction with cyclophosphamide.1,10,11

Anemia (hemoglobin less than 11 g/dL), which may be symptomatic (e.g., accompanied by asthenia), occurred in 71-91% of patients receiving usual dosages of carboplatin alone or in conjunction with cyclophosphamide in clinical trials, and anemia was severe (hemoglobin less than 8 g/dL) in 8-21% of such patients.1,10,11 The incidence of anemia appears to increase with increased exposure to carboplatin.1,93,121 Since anemia may be cumulative, transfusions may be needed during carboplatin therapy, particularly in patients receiving prolonged (e.g., more than 6 cycles) therapy.1,121,137 In clinical studies, bleeding was reported in 5-10% and transfusions were administered to 25-44% of patients.1,10

While hematologic toxicity associated with the standard dosages of carboplatin usually is not of sufficient magnitude to warrant routine administration of hematopoietic agents,60,137 autologous bone marrow transplant (ABMT), peripheral stem cell transplantation, and/or colony-stimulating factors (e.g., granulocyte colony-stimulating factor) have been used in patients receiving high-dose carboplatin or carboplatin in conjunction with other myelosuppressive therapy.28,30,40,66,67,93,110,111,121,137

GI Effects

Nausea and/or vomiting, which generally are mild to moderate in severity, have occurred in 65-94% of patients receiving carboplatin alone or in conjunction with cyclophosphamide.1,3,10,11,27,28,56,66,136 Carboplatin is classified as an antineoplastic agent of moderate emetic risk (i.e., incidence of emesis without antiemetics exceeds 30% but does not exceed 90%).201 Although nausea and/or vomiting occur in most patients receiving carboplatin, the drug is substantially less emetogenic and better tolerated than cisplatin.1,2,3,4,5,10,11,53,92,93,103,136,137,201 When carboplatin is used alone, nausea occurs in 10-15% and vomiting occurs in 65-81% of patients.1 Nausea and vomiting usually begin within 6-12 hours after administration of carboplatin and may persist up to 24 hours or longer;3,103 in some patients, vomiting may persist for up to 3 days.103 Delayed vomiting beginning 24 hours or longer after chemotherapy also has occurred in some patients.103 The incidence and severity of emesis may be reduced by pretreatment with antiemetics, although nausea and vomiting rarely may be refractory to antiemetic therapy.1,3,93,103,136 Carboplatin-induced acute vomiting episodes appear to be mediated by local GI and central mechanisms involving serotonin,93,94,95,136,137 and are most common in patients who have received prior emetogenic antineoplastic regimens (especially cisplatin-containing regimens) and in those who are receiving other emetogenic agents concurrently.1

There is some evidence that the incidence of nausea and vomiting is reduced when carboplatin is given as a 24-hour continuous IV infusion or administered IV in divided doses over 5 consecutive days rather than as a single IV infusion; however, efficacy of these administration schedules in the treatment of ovarian carcinoma has not been established.1 For the prevention of acute emesis, the American Society of Clinical Oncology (ASCO) currently recommends a 2-drug antiemetic regimen consisting of a 5-HT₃ serotonin receptor antagonist and dexamethasone given before the administration of carboplatin or other chemotherapy with moderate emetic risk.201 Delayed or anticipatory vomiting is more difficult to manage.136 For the prevention of delayed emesis, ASCO currently recommends single-agent therapy with dexamethasone or a 5-HT₃ serotonin receptor antagonist following the administration of carboplatin or other chemotherapy regimens with moderate emetic risk.201 Because anticipatory vomiting is a learned response conditioned by the severity and duration of previous emetic reactions to chemotherapy, optimal use of antiemetics for prevention of acute and delayed emesis during early courses of therapy is the most important means for preventing this effect; behavioral modification, hypnosis, and drug therapy (e.g., a benzodiazepine such as alprazolam or lorazepam [for anxiolytic, sedative, amnesic, and possibly antiemetic effects] with or without conventional antiemetics) also may be useful.136,201 For additional information on the mechanisms and management of nausea and vomiting induced by platinum compounds, see Cautions: GI Effects in Cisplatin 10:00.

Adverse GI effects other than nausea and vomiting have been reported in 21% of patients receiving carboplatin alone and in 40-50% of patients receiving carboplatin in conjunction with cyclophosphamide.1 When carboplatin is used alone, GI pain, diarrhea, and constipation have been reported in 6-17% of patients.1 Anorexia1 also has been reported in patients receiving carboplatin.

Mucositis (i.e., oral ulceration) has been reported in 1% of patients receiving carboplatin alone and in 6-10% of patients receiving the drug in conjunction with cyclophosphamide.1

Nervous System Effects

Carboplatin-containing regimens are associated with a lower incidence of, and less severe, neurotoxicity than cisplatin-containing regimens.1,10,11,92,93 Neurotoxicity associated with carboplatin usually is characterized by peripheral neuropathies, which generally are sensory in nature (e.g., paresthesia).1,10,11,93 Peripheral neuropathies have occurred in 4-6% of patients receiving carboplatin alone and in 13-16% of patients receiving the drug in conjunction with cyclophosphamide.1,10,11,93 Carboplatin-induced peripheral neuropathy appears to be more common in patients older than 65 years of age than in younger adults.1 In addition, carboplatin-induced peripheral neuropathies appear to be cumulative occurring most commonly in patients receiving prolonged therapy and/or those who have received prior cisplatin therapy;1,93,121 in some cases, the neurotoxicity may be a delayed effect of cisplatin rather than secondary to carboplatin.93 Patients with preexisting cisplatin-induced peripheral neurotoxicity generally do not experience additional neurologic deterioration during carboplatin therapy.1

Adverse sensory effects, including otic and ocular effects (see Cautions: Otic and Ocular Effects) and taste abnormalities, have been reported in up to 13% of patients receiving usual dosages of carboplatin.1,87,93,111 Central neurotoxicity has been reported in 5% of patients receiving carboplatin alone and in 23-28% of patients receiving carboplatin in conjunction with cyclophosphamide.1 It has been suggested that central neurotoxicity in many of these patients may have been related to concomitant antiemetic therapy.1 Fatigue was one of the most common nonhematologic effects reported in patients receiving carboplatin concomitantly with paclitaxel.121

Otic and Ocular Effects

Ototoxicity1,87,93,111 has been reported in 12-13% of patients receiving usual dosages of carboplatin in conjunction with cyclophosphamide.1 When carboplatin has been used alone, ototoxicity and adverse sensory effects have been reported in only 1% of patients.1 While carboplatin is associated with a low incidence of hearing loss at usual dosages,1,87,93,111 ototoxicity may be dose-limiting at carboplatin doses of 2 g/m² or greater.93,110 The risk of ototoxicity also may be increased by concomitantly administered ototoxic drugs (e.g., aminoglycosides, furosemide, ifosfamide).93,111 (See Drug Interactions: Other Drugs.) Clinically important hearing loss has occurred in pediatric patients receiving carboplatin at higher than recommended doses in combination with other ototoxic agents.1

Other adverse sensory effects, including visual abnormalities, have been reported in 4-6% of patients receiving usual dosages of carboplatin in conjunction with cyclophosphamide.1 Loss of vision (which can be complete for light and colors) has been reported rarely in patients receiving carboplatin doses higher than those usually recommended; improvement and/or total recovery of vision occurred within weeks after the drug was discontinued.1,31

Renal and Electrolyte Effects

Mild and transient elevations of serum creatinine and BUN concentrations have occurred in 6-22% of patients receiving carboplatin alone or in conjunction with cyclophosphamide.1,10,11 Acute renal failure has been reported rarely.32,53 Nephrotoxicity is less common and severe than that associated with cisplatin, and concomitant IV hydration and diuresis generally are not necessary with carboplatin.1,10,11,24,27,37,92,93 As a result, administration regimens and monitoring requirements with carboplatin generally are less complex, and outpatient therapy is easier to accomplish.24,27,37,92 However, the risk of carboplatin-induced nephrotoxicity (e.g., impaired creatinine clearance) becomes more prominent at relatively high dosages.40,93,109,110 Animal studies indicate that carboplatin's reduced nephrotoxic potential relative to cisplatin may relate to differences in renal handling of the drugs and reactivity with macroglobulins;93 differences in risk do not appear to correlate with renal platinum concentrations.93,112

Carboplatin may cause electrolyte abnormalities, principally hyponatremia, hypokalemia, hypocalcemia, and/or hypomagnesemia.1,34,87 Such electrolyte changes, unlike those reported with cisplatin, usually are not symptomatic and do not require administration of supplemental electrolytes.1 Hyponatremia, hypocalcemia, and hypokalemia have been reported in 10-47% and hypomagnesemia has been reported in 29-62% of patients receiving carboplatin alone or in conjunction with cyclophosphamide.1,10,11

Hepatic Effects

Mild and usually transient elevations of serum alkaline phosphatase, aspartate aminotransferase (AST, SGOT), or bilirubin concentrations have been reported in 24-37, 15-23, or 5% of patients, respectively, receiving carboplatin alone or in conjunction with cyclophosphamide.1 Substantial abnormalities in liver function test results have been reported in a few patients receiving high doses of carboplatin (more than 4 times higher than the usually recommended dosage) and autologous bone marrow transplantation.1

Sensitivity Reactions

Allergic reactions10,33,55,56,61,62,90,91,104,105 have been reported in 2% of patients receiving carboplatin alone and in 10-12% of patients receiving carboplatin in conjunction with other antineoplastic agents.1 Allergic reactions associated with carboplatin are similar in nature and severity to those associated with other platinum-containing antineoplastic agents (e.g., cisplatin)1,33,55,61,93,104,105 and have included anaphylaxis1,10,33,56,61,62,91,143 and anaphylactoid reactions.1 Although allergic reactions usually have occurred following multiple courses of platinum-containing therapy,33,55,56,61,62,91,93,143 such reactions can occur with the initial dose.93,137,143 The risk of allergic reactions, including anaphylaxis, is increased in patients who previously have received treatment with platinum-containing agents.1 Rash, perioral tingling, urticaria, erythema, pruritus, bronchospasm, hypotension, and hypoxia have occurred within a few minutes after IV administration of carboplatin in patients who previously received a platinum-containing antineoplastic agent.1,10,33,61,90,91 Exfoliative dermatitis has been reported rarely.55

In many cases, allergic reactions appear to be immediate type I IgE-mediated hypersensitivity reactions,33,61,62,90,91,104,137,143 although some reactions may result from direct, nonimmunologic histamine release.104,137,143 In addition, some reactions may have been secondary to mannitol (which was present in the previous formulation) hypersensitivity96 rather than to carboplatin.134 Hypersensitivity reactions may be alleviated by IV epinephrine, corticosteroids, and/or antihistamines;1,33,55,61,93,143 in some cases, continued therapy with carboplatin may be possible with prophylactic corticosteroid and antihistamine therapy.33,61,93,104,105,143 While the manufacturer states that carboplatin is contraindicated in patients with a history of sensitivity reactions to other platinum-containing compounds,1 switching to cisplatin may be tolerated by some, but not all, patients who have experienced hypersensitivity reactions to carboplatin61,91,137 and vice versa.137

Other Adverse Effects

Although alopecia is uncommon in patients receiving carboplatin alone, occurring in about 2-3% of such patients, it occurs in 43-50% of patients receiving carboplatin in conjunction with cyclophosphamide.1,11 In patients receiving concurrent cyclophosphamide, the frequency and severity of alopecia was attributed to the cyclophosphamide dosage.1,11

Pain, most likely related to tumor size, has been reported in 36-54% of patients receiving carboplatin in conjunction with cyclophosphamide.1 In addition, asthenia, presumably secondary to carboplatin-induced anemia, has occurred in 40-43% of patients receiving carboplatin in conjunction with cyclophosphamide.1 Malaise1 also has been reported in patients receiving the drug. Adverse respiratory and genitourinary effects have occurred in 2-6% of patients receiving carboplatin alone and in 8-12% of patients receiving the drug in conjunction with cyclophosphamide.1 Hemolytic uremic syndrome has occurred rarely.1,35 Myalgias/arthralgias were one of the most common nonhematologic adverse effects reported in patients receiving carboplatin concomitantly with paclitaxel; these effects were cumulative with repeated cycles.121

Although not attributed to antineoplastic therapy, adverse cardiovascular effects, including cardiac failure, embolism, and cerebrovascular accident, have been reported in up to 23% of patients receiving carboplatin.1 Fatalities associated with cardiovascular events occurred in less than 1% of patients receiving the drug.1 Hypertension1 also has been reported in patients receiving carboplatin.

Precautions and Contraindications

Carboplatin is a highly toxic drug with a low therapeutic index, and a therapeutic response is not likely to occur without some evidence of toxicity.1,10,11 The drug should be used under the supervision of physicians experienced in therapy with cytotoxic agents.1 In addition, the manufacturer states that carboplatin should be used only when adequate treatment facilities for appropriate management of therapy and complications are readily available.1

Patients receiving carboplatin should be observed closely for possible hypersensitivity reactions, and appropriate equipment for maintenance of an adequate airway and other supportive measures and agents for the treatment of such reactions (e.g., antihistamines, epinephrine, oxygen, corticosteroids) should be readily available whenever carboplatin is administered.1,61 Patients with prior exposure to other platinum-containing agents are at increased risk for carboplatin-induced allergic reactions, including anaphylaxis.1 The manufacturer states that carboplatin is contraindicated in patients with a history of sensitivity reactions to the drug or other platinum-containing compounds (e.g., cisplatin);1 however, cross-sensitivity is not absolute, and occasionally with appropriate precautions patients sensitive to one platinum-containing compound have tolerated another.61,91,137 Exposure (e.g., industrial) to platinum-containing compounds can cause asthma and immediate and delayed hypersensitivity reactions,33,36,93 and the possibility that patients with a history of such exposure may be cross-sensitive to carboplatin should be considered.36

The emetogenic potential of carboplatin should be considered.1,2,3,4,5,10,11,53,103 (See Cautions: GI Effects.) The neurotoxic potential of the drug also should be considered, particularly in geriatric patients older than 65 years of age and patients previously treated with cisplatin.1 (See Cautions: Nervous System Effects.) Vision loss is possible in patients receiving carboplatin, particularly at high doses.1 (See Cautions: Otic and Ocular Effects.)

Because patients who receive myelosuppressive drugs experience an increased frequency of infection and/or bleeding, hematologic status must be carefully monitored.1,121 While the hematologic toxicity of carboplatin usually is moderate and reversible, severe myelosuppression may occur in patients who received prior antineoplastic therapy (especially cisplatin-containing regimens), those who are receiving concurrently or have received recently other myelosuppressive drugs or radiation therapy, and those with renal impairment.1,93,137 To monitor for the occurrence of carboplatin-induced bone marrow suppression, the manufacturer recommends that peripheral blood counts be performed at frequent intervals in all patients receiving the drug.1 In studies used to establish efficacy of carboplatin, peripheral blood counts were determined weekly.1,10,11 Carboplatin usually should not be administered to patients with severe bone marrow depression or substantial bleeding.1 Pretreatment platelet counts and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.1 In patients who experience myelosuppression following a dose of carboplatin, the manufacturer recommends that subsequent cycles of the drug be withheld until neutrophil counts exceed 2000/mm/³ and platelet counts exceed 100,000/mm³.1 Treatment of severe hematologic toxicity may consist of supportive care, anti-infective agents for complicating infections, blood product transfusions, autologous bone marrow rescue, peripheral stem cell transplantation, and hematopoietic agents (colony-stimulating factors).1,30,40,93,121,137

Because patients with renal impairment are at risk for severe bone marrow depression, renal function must be monitored carefully in patients receiving carboplatin.1,40,82,83,84,85,93 Creatinine clearance appears to most accurately reflect kidney function in patients receiving the drug.1,40,82,83,84,85,93 Although carboplatin has a low nephrotoxic potential, concomitant administration of an aminoglycoside has been associated with an increased risk of nephrotoxicity and/or ototoxicity.1 The possibility that carboplatin's nephrotoxicity may be potentiated by other nephrotoxic drugs also should be considered.1 (See Drug Interactions: Other Drugs.)

Pediatric Precautions

The manufacturer states that safety and efficacy of carboplatin in children have not been established.1 Although experience is limited, carboplatin has been used in the treatment of germ cell tumors in adolescents 16 year of age or older,24 in the treatment of various brain tumors or neuroblastoma in children and adolescents 6 months to 19 years of age,26,27,28,56,62 and in the treatment of Wilms' tumor in children 2-15 years of age.66,79,80 Adverse effects reported to date in children are similar to those reported in adults and include hematologic toxicity (principally thrombocytopenia),27,28,56,66,79,80 adverse GI effects such as nausea and vomiting,27,28,56,66 and hypersensitivity reactions such as urticaria, facial swelling, abdominal pain, coryza, and cough.62 Hearing loss also has been reported in children receiving carboplatin. 1 (See Cautions: Otic and Ocular Effects.)

Geriatric Precautions

While the safety and efficacy of carboplatin in geriatric patients have not been established specifically, a substantial number of patients who received the drug in clinical trials as part of combination therapy for ovarian cancer were elderly (i.e., 36% were 65 years of age or older and 6% were 75 years of age or older).1,10,11 Age was not found to be a prognostic factor for survival in these studies.1

Severe thrombocytopenia associated with carboplatin therapy occurred more frequently in geriatric patients than in younger patients.1 In addition, carboplatin-induced peripheral neuropathy appears to be more common in adults older than 65 years of age than in younger patients.1 Among a total of 1942 patients (21% of whom were 65 years of age or older) receiving carboplatin monotherapy for different tumor types, a similar incidence of adverse effects was observed in older and younger patients; other clinical experience has not revealed age-related differences among patients receiving the drug.1 However, the possibility of greater sensitivity of some older patients and increased risk for other effects of carboplatin related to age cannot be ruled out.1

Because dosage of carboplatin generally is based on the clinical and hematologic response, renal function, and tolerance of the patient, the fact that geriatric patients may have decreased renal function as well as decreased hematopoietic function should be considered.1,137 The manufacturer recommends that dosing formulas based on estimates of glomerular filtration rate be used to determine the appropriate dosage of carboplatin in geriatric patients.1

Mutagenicity and Carcinogenicity

Carboplatin is mutagenic in both in vitro and in vivo experimental models.1

Although the carcinogenic potential of carboplatin has not been fully studied, the manufacturer states that drugs with similar mechanisms of action and evidence of mutagenic effects have been reported to be carcinogenic.1 Secondary malignancies have been reported in patients receiving carboplatin in combination with other agents.1

Pregnancy, Fertility, and Lactation

Pregnancy

Carboplatin can cause fetal toxicity when administered to pregnant women,1 but potential benefits from use of the drug may be acceptable in certain conditions despite possible risks to the fetus.1,113,118 Carboplatin has been shown to be embryotoxic and teratogenic in rats.1 Reproductive studies in rats receiving carboplatin during organogenesis revealed evidence of embryotoxicity and teratogenicity.1 There are no adequate or controlled studies to date using carboplatin in pregnant women.1 Carboplatin should be used during pregnancy only in life-threatening situations or for disease for which safer drugs cannot be used or are ineffective.1,113,118 If the drug is administered during pregnancy or if the patient becomes pregnant while receiving carboplatin, the patient should be informed of the potential hazard to the fetus.1 Women of childbearing potential should be advised to avoid becoming pregnant during carboplatin therapy.1

Fertility

The effects of carboplatin on the gonads and fertility have not been fully determined.1,137

Lactation

It is not known whether carboplatin or its platinum-containing products are distributed into human milk.1 Because of the potential for serious adverse reactions to carboplatin in nursing infants if the drug were distributed into milk, nursing should be discontinued during carboplatin therapy.1

Myelosuppressive Therapy

Concomitant use of carboplatin and other myelosuppressive agents or radiation therapy may potentiate the hematologic toxicity of the other agents and vice versa.1,3,66,67,101 Patients receiving concurrently or who have received recently such therapy should be monitored carefully, and dosage of the drugs and time of administration should be managed to minimize additive toxic effects.1,93,137 In addition, the fact that use of carboplatin in individuals who have received prior antineoplastic therapy is associated with an increased risk of bone marrow suppression should be considered.1

Other Drugs

Concomitant administration of carboplatin and aminoglycosides results in an increased risk of nephrotoxicity and/or ototoxicity, and the drugs should be used concurrently with caution.1 Clinically important hearing loss has been reported in children receiving carboplatin at higher than recommended doses in combination with other ototoxic medications.1 The manufacturer states that the renal effects of other nephrotoxic drugs may be potentiated by carboplatin.1

Concomitant use of carboplatin and other emetogenic drugs or use of carboplatin in individuals who previously received emetogenic therapy is associated with an increased incidence of emesis.1

Acute Toxicity

Manifestations

Limited information is available on the acute toxicity of carboplatin.137 Overdosage of the drug would be expected to produce complications secondary to bone marrow suppression and/or hepatotoxicity.1,30,40 In addition, typical nonhematologic toxicity associated with platinum-containing antineoplastic agents (e.g., nephrotoxicity, neurotoxicity, ototoxicity) would be expected to become prominent with carboplatin overdosage.28,30,40,56,87,93,111,121 Carboplatin is substantially less toxic on a mg-for-mg basis than cisplatin,2,3,4,5,6,43 and inadvertent substitution of cisplatin (which usually is administered at substantially lower dosages) for carboplatin has resulted in massive cisplatin overdosage, including fatalities.114,115,116,117 (See Acute Toxicity in Cisplatin 10:00.)

Treatment

There currently is no established specific antidote for carboplatin overdosage.1 Management of overdosage currently consists principally in discontinuance of the drug and initiation of supportive measures appropriate for the type of toxicity observed.1 The use of colony-stimulating factors (CSFs), platelet transfusions, and/or red blood cell transfusions should be considered in patients experiencing substantial myelosuppression.30,40,106,137 Whether measures suggested for the management of cisplatin overdosage, including the possible merits of chemoprotectants,114,115,116,117 would be of benefit in the event of massive carboplatin overdosage remains to be established.137 (For additional information on acute toxicity associated with platinum compounds, see Acute Toxicity in Cisplatin 10:00.)

Although carboplatin is removed by hemodialysis,54,86 it is not known whether this procedure would enhance elimination of the drug following overdosage.137 Plasmapheresis has been used effectively in the management of cisplatin overdosage,114 and the possibility that it may be useful in the management of massive carboplatin overdosage should be considered.137

Pharmacology

The exact mechanism(s) of action of carboplatin has not been conclusively determined.2,3,4,5,6,7 Platinum-containing antineoplastic agents such as carboplatin and cisplatin appear to exert their effects by binding to DNA, thereby inhibiting DNA synthesis.2,3,4,5,6,7,92,93 The drugs are cycle-phase nonspecific.1,4 Carboplatin and cisplatin appear to act on tumor cells by the same general molecular mechanisms and, once bound to DNA, have virtually the same action.3,5,6,7 Although the principal mechanism of action of the drugs appears to be inhibition of DNA synthesis, other mechanisms also are involved in their antineoplastic activity.3,4,5,92,137

Carboplatin, like cisplatin, must undergo activation before antineoplastic activity occurs.1,2,3,4,5,6,7,92,93 The bidentate dicarboxylate ligands of carboplatin presumably are displaced by water (aquation), forming positively charged platinum complexes that react with nucleophilic sites on DNA.1,3,4,5,6,7,92 Although both carboplatin and cisplatin are activated by an initial aquation reaction,3,4,5,92 carboplatin is a more stable compound and is activated more slowly than cisplatin.1,3,4,5,6,7,92

Carboplatin produces predominantly DNA intrastrand interstrand cross-links rather than DNA-protein cross-links.1,3,4,5,6,7,93 The relative importance of intrastrand or interstrand DNA cross-linking in the antineoplastic activity of carboplatin remains to be clearly determined; however, interstrand cross-linking appears to correlate well with the cytotoxicity of the drug.2,3,4,5,6 Intrastrand cross-links result from the formation of adducts between the activated platinum complexes of the drug and (but not exclusively) the N-7 atom on guanine to produce 1,2-intrastrand links between adjacent guanosine molecules, between neighboring guanosine and adenosine molecules, or between neighboring guanosine molecules.2,5,92,122,137 Interstrand cross-linking within the DNA helix also occurs.2,5,92 The resultant interstrand intrastrand cross-links are stable bonds that do not dissociate easily.2,5,92 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.2,5,92

Higher concentrations of carboplatin than cisplatin are required to produce equivalent levels of DNA binding.1,3,4,5,6,7 In one in vitro study comparing the relative potency of the drugs in L1210 cells, carboplatin was 45 times less cytotoxic than cisplatin on a molar basis and peak levels of cross-linking occurred 6-12 hours later with carboplatin than with cisplatin.6 These differences are believed to result from the difference in rates of aquation or activation of the drugs.1,3,4,5 When the drugs are compared at concentrations that produce equivalent levels of DNA binding, however, both drugs induce equal numbers of drug-DNA cross-links, resulting in equivalent lesions and biologic activity.1,3,4,5,6,7 In various studies in mice, the antitumor activity of carboplatin was comparable to or slightly less than that of cisplatin.3

Further study is needed to elucidate more fully the extent of cross-resistance between cisplatin and carboplatin.2 Although some cisplatin-refractory tumors may respond to carboplatin, a high degree of cross-resistance appears to occur between the drugs.3,4,92 The mechanisms of cellular resistance to platinum-containing antineoplastic agents have not been fully elucidated,2,5,92 but studies using cisplatin indicate that 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.2,5,92,93 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.2,92,123,124,125 Increased repair of platinum complex-induced DNA adducts also has been demonstrated in certain resistant cell lines.2,92,126,127 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 has not been fully determined.2,92

Pharmacokinetics

The pharmacokinetics of carboplatin are complex and involve the parent compound as well as total platinum and ultrafilterable platinum.1,2,3,4,43 Total platinum consists of both protein-bound and nonprotein-bound platinum, while ultrafilterable platinum consists of carboplatin and nonprotein-bound carboplatin metabolites.2,43,44 Measurement of ultrafilterable platinum is commonly used in pharmacokinetic studies of carboplatin since only nonprotein-bound platinum or its platinum-containing products are cytotoxic.2,4,43,44,53

The pharmacokinetics of carboplatin have been studied principally in adults with various malignancies who received the drug IV either alone or in conjunction with other antineoplastic agents.3,4,5,43,44,45,46,47,48,49,53,54 The pharmacokinetics of the drug are similar to those of cisplatin; however, a smaller percentage of carboplatin's total platinum is protein-bound, carboplatin has a longer initial distribution half-life (t_½α), and carboplatin undergoes more extensive renal excretion.2,43

Absorption

Following IV infusion of a single dose of carboplatin in adults with malignancies, peak plasma concentrations of carboplatin, total platinum, and ultrafilterable platinum occur immediately.3,42,44,46 When a single carboplatin dose of 290-370 mg/m² is administered IV over 30-40 minutes in cancer patients with normal renal function, peak plasma concentrations of carboplatin, total platinum, and ultrafilterable platinum range from 84-140, 84-134, and 90-130 µmol/L, respectively;43,44 these plasma concentrations are essentially the same over the first 6 hours.44,45,46 Over a dosage range of 20-500 mg/m², peak plasma concentrations of carboplatin and free platinum and area under the plasma concentration-time curve (AUC) of the drug increase linearly with dose.1,3,43,45,46

Carboplatin is absorbed following intraperitoneal administration†, and peak concentrations of total platinum, free platinum, and carboplatin are attained within 2-4 hours following instillation.3,4,43,47 In a limited number of patients receiving intraperitoneal carboplatin dosages of 200-300 mg/m², approximately 65% of the dose was absorbed over a 4-hour dwell period.43,47 Although peak concentrations of ultrafilterable platinum in peritoneal fluid substantially exceed those achieved in plasma,3,43,47 penetration of platinum from the peritoneal cavity into tumor tissue is limited.43,50,51,52 While the clinical importance is unclear, data from studies in rats indicate that cisplatin is able to penetrate tumor tissue more effectively than carboplatin following intraperitoneal administration.43,51,52

Distribution

Following IV administration of carboplatin, platinum is widely distributed into body tissues and fluids, with highest concentrations in the kidney, liver, skin, and tumor tissue.3,43,44 Lower concentrations are found in fat and brain.3,43 Platinum also is distributed into erythrocytes, with maximum platinum concentrations of 2.5 µmol/L obtained 6 hours after IV infusion of a carboplatin dose of 290-370 mg/m².43,44 Following IV administration, the initial distribution half-lives of carboplatin, total platinum, and ultrafilterable platinum are essentially the same; the t_½α of carboplatin has been reported to be 1-2 hours.1,3,43,44 The volumes of distribution at steady-state of carboplatin, total platinum, and ultrafilterable platinum average 9-25, 23-117, and 10-20 L/m² respectively.43

In vitro studies indicate that carboplatin is not bound to plasma proteins, but degrades to platinum-containing products which rapidly bind to protein.45,49 In vivo, protein binding increases over time as the platinum-containing products of carboplatin become bound to tissue and plasma proteins.1,3,44,46,49,54 During the first 4 hours following IV administration of carboplatin, less than 24% of platinum is bound to plasma proteins; however, within 24 hours, 87% of platinum is protein-bound.46

It is not known whether carboplatin or its platinum-containing products cross the placenta or are distributed into milk.1

Elimination

Following IV administration of carboplatin, plasma concentrations of carboplatin and ultrafilterable platinum has been reported to decline in a biphasic manner, while plasma concentrations of total platinum reportedly decline in a triphasic manner.3,4,45,46,48,49 In adults with malignancy and normal renal function, plasma elimination half-lives (t_½β) of 2-3 hours have been reported for carboplatin and ultrafilterable platinum.1,43,44 A terminal elimination half-life (t_½γ) of 4-6 days has been reported for total platinum.43,44 Small amounts of total platinum can be detected in plasma 4 weeks after administration of carboplatin, indicating that the rate of elimination of total platinum may decrease with time.43

The mean elimination half-life of total platinum from erythrocytes reportedly is about 12 days following IV administration of the drug.43,44 Following intraperitoneal administration of carboplatin, the peritoneal elimination half-life of ultrafilterable platinum is about 4.2 hours.43

Renal clearance and total body clearance of platinum are reduced in patients with impaired renal function.3,4,38,54 In patients undergoing hemodialysis, the t_½β of total and ultrafilterable platinum is increased compared with values reported in individuals with normal renal function.43,54

The metabolic fate of carboplatin has not been completely elucidated.1,3,4,5,6,7,43 There is no evidence to date that the drug undergoes enzymatic biotransformation; the bidentate dicarboxylate ligands of carboplatin are believed to be displaced by water, forming positively charged platinum complexes that react with nucleophilic sites on DNA.1,3,4,5,6,7,43

Carboplatin and its platinum-containing product(s) are excreted principally in urine;1,3,4,43,44 there are insufficient data to date to determine whether intestinal secretion or fecal elimination occurs.1,43,54 Renal excretion predominantly occurs via glomerular filtration.1,3,43 The clearance of carboplatin is directly affected by the glomerular filtration rate (GFR), and this parameter of renal function often is decreased in geriatric patients.1 Dosing formulas that incorporate estimates of GFR to provide predictable areas under the plasma concentration-time curve (AUCs) for carboplatin should be used in geriatric patients to minimize the risk of toxicity.1 The relationship between GFR and AUC of ultrafilterable platinum has been used to develop several formulas for calculating carboplatin dosage.1,82,83,84,85,93,107,108 (See Dosage: Individualization of Dosage, in Dosage and Administration.) In patients with malignancy and normal renal function, about 65% of an IV dose of carboplatin is eliminated in urine within 12 hours and 71% is eliminated within 24 hours; a substantial portion of the amount excreted is unchanged carboplatin.1,3,43 Carboplatin (as ultrafilterable carboplatin) is removed extensively by hemodialysis.54,86

Chemistry and Stability

Chemistry

Carboplatin is a platinum-containing antineoplastic agent.1,2,3,4,5,6,92,93 Carboplatin, like cisplatin, is a platinum coordination compound composed of a platinum atom surrounded in a plane by 2 ammonia groups and 2 other ligands in the cis position; presence of the ammonia groups, the cis configuration, and neutrality in plasma are necessary for the activity of both drugs.2,5,43,92,93 However, the other 2 ligands in carboplatin are present in a bidentate dicarboxylate chelate ring structure rather than as 2 chloride atoms present in cisplatin.1,3,4,5,6,43 The cyclobutane dicarboxylate moiety has greater chemical stability than the chlorides contained in cisplatin and this difference results in a less reactive compound that is associated with reduced toxicity (e.g., nephrotoxicity) but with antineoplastic activity that may be comparable to or slightly less than that of cisplatin.2,3,4,5,6,43,92,93

Carboplatin occurs as a white to off-white crystalline powder.1,134 The drug has a solubility of 14 mg/mL in water and is insoluble in alcohol.1 A 1% solution of carboplatin has a pH of 5-7.1 Carboplatin is commercially available as a sterile, pyrogen-free, aqueous solution containing 10 mg of carboplatin per mL.1

Stability

Commercially available carboplatin aqueous solution in unopened vials is stable until the date indicated on the package when protected from light and stored as directed; the solution should be stored at 25°C, but may be exposed to temperatures ranging from 15-30°C.1 Carboplatin injection in multidose vials is stable for up to 14 days at 25°C.1

Carboplatin aqueous solution may be further diluted in 5% dextrose injection or 0.9% sodium chloride injection to concentrations as low as 0.5 mg/mL, and these dilutions are stable for 8 hours at 25°C; because there is no preservative in the formulation, the manufacturer states that unused portions of diluted carboplatin solution for infusion should be discarded 8 hours after preparation.1

Because some platinum coordination compounds (e.g., cisplatin) are unstable in certain sodium chloride solutions and because there is evidence that carboplatin dissolved in sodium chloride solutions is converted partially in vitro to cisplatin, it previously was suggested that these solutions not be used to dilute carboplatin.4,5,43,63 However, while the rate of carboplatin decomposition in 0.9% sodium chloride or 5% dextrose and 0.9% sodium chloride is greater than that in sterile water for injection (i.e., 4% loss in 7 days at 27°C), it still does not exceed 10% per day at room temperature (i.e., 4-5% loss in 24 hours at 25°C).42,63 In addition, while the process responsible for the loss of carboplatin potency in these solutions has not been fully characterized, a study using carboplatin solutions containing 1 mg/mL in 0.9% sodium chloride indicates that only a minimal amount of carboplatin (less than 0.7%) is converted to cisplatin within 24 hours at 25°C.42,64 Therefore, previous recommendations4,5,43 not to use sodium chloride solutions to dilute carboplatin no longer appear to be justified.42,64,137

Aluminum displaces platinum from the carboplatin molecule, resulting in the formation of a black precipitate and loss of potency.1 Carboplatin solutions should not be prepared or administered with needles, syringes, catheters, or IV administration sets containing aluminum parts that might come in contact with the drug.1

Additional Information

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

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