• Information
  1. List of Agents
  2. Asparaginase
  3. Capecitabine
  4. Chlorodeoxyadenosine
  5. Clofarabine
  6. Cytosine Arabinoside
  7. Deoxycoformycin
  8. Erlotinib
  9. Fludarabine
  10. 5-Fluorouracil
  11. Gefitinib
  12. Gemcitabine
  13. Hydroxyurea
  14. Imatinib
  15. Lapatinib
  16. Lenalidomide
  17. Methotrexate
  18. 6-Mercaptopurine
  19. Nelarabine
  20. Nilotinib
  21. Pemetrexed
  22. Sorafenib
  23. Sunitinib
  24. Temsirolimus
  25. Thalidomide

A. List of Agents [1]

1. Asparaginase (Elspar®) - toxic in lymphoblastic lymphocytes, not normal cells
2. Capecitabine (Xeloda®) - oral 5-FU prodrug, for resistant metastatic breast cancer
3. 2-Chlorodeoxyadenosine (CDA, cladribine, Leustatin®)
4. Clofarabine (Clolar®) - purine nucleoside antimetabolite
5. Cytosine Arabinoside (AraC) - cytosine analog
6. 2-Deoxycoformycin (Pentostatin) - blocks adenosine deaminase, toxic in lymphocytes
7. Difluoromethylornithine (DFMO) - inhibits polyamine biosynthesis
8. Fludarabine (2-FDA, Fludara®) - toxic in lymphocytes; blocks DNA polymerase
9. 5-Fluorouracil (5-FU) - thymidine analog
10. Gefitinib (Iressa®) - EGF-R1 small molecule (kinase) inhibitor
11. Gemcitabine (Gemzar®) - 2',2'-difluorodeoxycytidine, inhibits DNA chain elongation
12. Hydroxyurea (Hydrea®) - blocks DNA synthesis, inhibition of ribonucleotide reductase
13. Imatinib (Gleevec®) - blocks bcr-abl and other protein tyrosine kinases
14. Lapatinib - blocks EGF-R1 and EGF-R2 (HER2) small molecule inhibitor
15. Lenalidomide (Revlimid®) - thalidomide analog, active in MDS, myeloma
16. Methotrexate (MTX) - blocks dihydrofolate reductase and binds certain enzymes
17. 6-Mercaptopurine (6-MP) - purine (adenosine) analog
18. Pemetrexed (Alimta®) - blocks multiple enzymes in folate metabolism
19. Temsirolimus
20. Thalidomide (Thalomid®) - blocks TNFa, anti-angiogenic activities
21. Monoclonal Antibodies (MAb)
    1. Bevacizumab (Avastin®) - MAb to vascular endothelial growth factor (anti-VEGF Ab)
    2. Cetuximab (Erbitux®) - MAb to epidermal growth factor receptor 1 (EGF-R1)
    3. Panitumumab (Vectibix®) - recombinant human EGF-R (IgG2 kappa) mAb for colorectal Ca
    4. Rituximab (Rituxan®) - mAb to CD20, mainly on B cells, for lymphomas, autoimmunity
    5. Trastuzumab (Herceptin®) - MAb blocks EGF-R2 (HER2/neu), for breast cancer

B. Asparaginase (Elspar®)

1. Depletes cellular stores of L-asparigine
2. Toxic in lymphoblastic lymphocytes, not normal lymphocytes or other cells
3. Utility: childhood acute lymphoblastic leukemia (ALL)
4. Toxicity
   1. Nausea and vomiting, Fever and chills, Headache, Hypersensitivity; analphylaxis
   2. Abomdinal pain, Hyperglycemia, CNS depression or hyperexcitability
   3. Acute hemorrhagic pancreatitis, coagulation defects or thrombosis
   4. Renal damage, Hepatic damage

C. Capecitabine (Xeloda®) [2]

1. Oral 5-FU prodrug activated by cytidine deaminase
2. Utility
   1. Third line metastatic breast cancer
   2. First line metastatic colon cancer (equivalent efficacy to 5-FU intravenous)
   3. Combination with docetaxel (Taxotere®) approved in breast cancer
   4. Capecitabine (oral) is at least as effective as 5FU/LV as adjuvant therapy of Stage III CRC with improved disease free survival and fewer side effects [3]
3. Toxicity
   1. High rates of hand-foot syndrome (palmer-plantar dysesthesia, ~16%)
   2. Some nausea and vomiting
   3. Diarrhea and stomatitis typically less than 5-FU
   4. Dermatitis
   5. Bone marrow depression
   6. Hyperbilirubinemia
   7. Ocular irritation and corneal depositis
4. Dose is 2000-2500 mg/m2/d; doses >1800mg/m2/d are poorly tolerated

D. Chlorodeoxyadenosine (CDA, cladribine, Leustatin®) [4]

1. Deoxyadenosine analog
2. Inhibits action of ribonucleotide reductase and DNA polymerase alpha
3. Utility
   1. First line therapy hairy cell leukemia (HCL)
   2. In HCL, initial complete response ~85% with 7 day infusion (0.1mg/kg/d)
   3. Remission in >80% of patients after 1 year (~12% partial response)
4. Toxicity
   1. Fever (acute)
   2. Bone marrow depression
   3. Peripheral neuropathy at high doses
   4. Side effects include mild marrow suppression and thrombocytopenia and fever
   5. Less side effects with increased efficacy compared to pentostatin

E. Clofarabine (Clolar®, Evoltra®)

1. Purine nucleoside analog, antimetabolite
2. Inhibits ribonucleotide reductase and acts as chain terminator
3. Approved for acute lymphoblastic leukemia (ALL) relapsed after at least 2 prior therapies
4. Given intravenously over 2 hours daily for 5 consecutive days
5. Repeat every 2-6 weeks based on organ function, blood count recovery
6. Bone marrow suppression is major problem, some liver function abnormalities

F. Cytosine Arabinoside (AraC, Cytarabine, Cytosar®)

1. Toxic to white blood cells, mainly myelogenous lineage
2. Cytosine analog, recognized as analog of 2'-deoxycytidine
3. Utility: first line with anthracyclines in AML, also used in ALL, NHL, accellerated CML
4. Toxicity
   1. Nausea, vomiting, anaphylactoid hypersensitivity, respiratory distress (high dose)
   2. Bone marrow depression
   3. Conjunctivitis, oral ulceration, fever
   4. Hepatic damage, central and peripheral neurotoxicity (high doses)
   5. Rhabdomyolysis, rash
   6. Pancreatitis when used with asparaginase

G. Deoxycoformycin (Pentostatin, Nipent®) [4]

1. Blocks adenosine deaminase, leads to excess dATP and dADP, toxic in lymphocytes
2. Used in hairy cell leukemia
3. Toxicity
   1. Nausea, vomiting
   2. Rash, keratoconjunctivitis
   3. Nephrotoxicity, Hepatoxicity
   4. Bone marrow depression
   5. CNS depression
   6. Respiratory failure

H. Erlotinib (OSI-774, Tarceva®) [6,7,8,51]

1. Potent anti-EGF-R1 agent, 150mg po qd, FDA approved for NSCLC and pancreatic cancer
2. Pivotal study in Stage IIIB/IV NSCLC performance status 0-3, fater 1-2 prior regimens
3. Erlotinib increased survival by 2 months following first relapse from 4.7 to 6.7 months
4. Median response duration 7.9 months
5. Highest responses in women, Asians, never-smokers, adenocarcinoma pathology
6. Likely more active than gefitinib, and should be used in earlier stage disease
7. Presence of mutations in EGF-R increases likelihood of response to, but not survival with, erlotinib [9]
8. Neither erlotinib nor gefitinib showed activity in combination with chemotherapy in NSCLC
9. Improved mortality when used in first line pancreatic cancer with gemcitabine
10. Main side effects are acne-like rash and some diarrhea, mainly at higher doses

I. Fludarabine (2-FDA, Fludara®)

1. Actively toxic to lymphocytes; blocks DNA polymerase
2. First line (alone or combination) for chronic lymphocytic leukemia (CLL)
3. Toxicities
   1. Nausea, vomiting
   2. Bone marrow depression, immunosuppression
   3. CNS effects, visual disturbances
   4. Renal damage at high dose
   5. Pulmonary infiltrates

J. 5-Fluorouracil (5-FU)

1. Thymidine analog with fluorine replacing the methyl group on thymidine
2. Also called methyldeoxyuridine, floxuridine
3. Utility
   1. Colon cancer: adjuvant and systemic therapy
   2. Squamous Cell Cancers: Head and Neck, Esophagus, Anus (Anorectal)
   3. Gastric Cancer
   4. Biliary tract cancer
   5. Carcinoid (usually with streptozocin)
4. Activity
   1. Conversion to two active metabolites:
   2. 5-fluoro-2'deoxyurine 5'-monophosphate inhibits thymidylate synthase
   3. Fluorouridine 5'-triphosphate affects RNA processing and function
5. Resistance
   1. Related primarily to overexpression of thymidylate synthase
   2. Catabolism to inactive metabolites by dihydropyrimidine dehydrogenase (DHPD)
   3. Increased levels of thymidylate phosphorylase also associated with resistance
   4. 5-FU is not removed from cells by the PGP-1 (mdr1) multidrug resistance pump
   5. Eniluracil, an inhibitor of DHPD, increases half-life of 5-FU [10]
6. Dosing
   1. Weekly 5-FU is better tolerated than daily continuous infusion x 5 days
   2. Given with leucovorin (folinic acid) to reduce toxicities

K. Gefitinib (Iressa®) [6,11,12,51]

1. Specific small-molecule inhibitor of epidermal growth factor receptor 1 (EGF-R1, HER-1)
   1. EGF is a growth factor for many NSCLC and other epithelial cancers [51]
   2. Overexpression of EGF-R1 is observed in a subset of NSCLC patients
   3. Activating (kinase-domain) mutations in EGF-R1 in primary tumors correlate with response to gefitinib [13]
2. Response rates in 2nd-3rd line NSCLC 10-15% (single arm trials) [14]
   1. ~40% have improved symptoms and survival prolonged 2-4 months more than expected
   2. Did not improve survival or quality of life when used in first line NSCLC in combination with standard chemotherapy
   3. ~10% of primary NSCLC tumors have activating mutations of EGF-R1 and these may show the best response to gefitinib [15]
   4. Resistance to gefitinib due to mutations in EGF-R1 protein demonstrated [16]
   5. No improvement in survival when combined with best supportive care in 2nd or 3rd line NSCLC versus best supportive care alone [17]
   6. Some potential benefit in Asian patients and never-smokers with advanced NSCLC [17]
3. Side Effects
   1. Main side effects are acne-like rash (primarily at 500mg qd, not at 250mg qd)
   2. Diarrhea increased at 500mg qd
   3. Increased risk of severe acute interstitial pneumonia [18]
   4. Overall very well tolerated
4. Approved as single agent for relapsed NSCLC (not in combination with chemotherapy)

L. Gemcitabine (Gemzar®) [19]

1. Deoxycytidine (dCTP) Analog: 2',2'-difluorodeoxycytidine
   1. Structurally similar to cytarabine (ara-C) with different in vitro activities
   2. Activation through phosphorylation to 2'-2'-difluorodeoxycytidine-triphosphate (dFdC-TP)
   3. dFdC-TP inhibits DNA synthesis via several different mechanisms of action
   4. dFdC-TP inhibits ribonucleotide reductase
   5. dFdC-TP is incorporated into DNA which leads to chain termination
2. Broad spectrum of activity
3. Mechanisms of Resistance
   1. Appears related to loss of ability to phosphorylate the drug to active metabolite
   2. Also with increased levels of cellular dCTP (the normal deoxynucleotide)
4. Approved Uses
   1. First line in locally advanced or metastatic pancreatic cancer
   2. Second line in non-small cell lung cancer (NSCLC)
5. Other Activities
   1. Utility of gemcitabine in a wide range of malignancies
   2. Breast cancer
   3. Bladder cancer
   4. Ovarian cancer
6. Usual Dosing
   1. Usually given as 1000mg/m2 weekly for three weeks in a row
   2. Rest period of 1 week
7. Major Side Effects
   1. Thrombocytopenia
   2. Nausea, Vomiting, Fatigue
   3. Transaminase Elevations (AST and ALT)
   4. Peripheral Neuropathy
   5. Edema
   6. Pulmonary toxicity

M. Hydroxyurea (Hydrea®)

1. Blocks DNA synthesis, inhibition of ribonucleotide reductase
2. Utility
   1. Tumor lysis for cell reduction in acute leukemias, CML (chronic, accellerated)
   2. Sickle cell anemia
   3. HIV infection
3. Toxities
   1. Nausea, vomiting, bone marrow depression, stomatitis, dysuria, alopecia
   2. Rare neurological disturbances
   3. Pulmonary infiltrates

N. Imatinib (STI-571, Gleevec®) [20,21,22]

1. Specific Tyrosine Kinase Inhibitor
   1. Competitive inhibitor of oncogenic bcr-abl tyrosine kinase
   2. Also blocks platelet derived growth factor receptor (PDGF-R)
   3. Inhibits c-kit (stem cell factor receptor) tyrosine kinase
2. Dosing
   1. Orally active, recommended dose 400mg once daily [21]
   2. Recommended first line therapy in chronic phase chronic myelogenous leukemia (CML)
   3. Also shows efficacy in gastrointestinal stromal tumors (PDGF dependent)
3. Chronic Myeloid Leukemia (CML) [22,23]
   1. Imatinib is superior first line therapy versus high dose IFNa + low dose cytarabine [23]
   2. Dose is 400mg/d
   3. Remarkable efficacy in first line and interferon alpha (IFNa) relapsed CML
   4. Major molecular responses in 57% of patients with complete cytogenic remissions [11]
   5. At 5 years, 87% of of CML patients had complete cytogenetic responses, 7% showed progressive disease, ~90% survival; drug well tolerated [59]
   6. Also shows some efficacy in blast phase of CML and in bcr-abl+ ALL
4. Gastrointestinal Stromal Tumors (GIST) [22,24]
   1. Partial response (>50% shrinkage) rates ~55% in patients with metastatic GIST [22]
   2. 5% complete + 47% partial resopnses, 32% stable disease in metastatic GIST [12, 43]
   3. Dose 400mg bid for GIST induces more rapid remissions than 400mg qd
   4. Progression free survival >2 years with metastatic GIST
5. Hypereosinophilic Syndrome (HES) [25]
   1. Persistent eosinophilia without recognized cause
   2. Often progresses to eosinophilic or other leukemia
   3. Four of 5 patients with HES responded to 100mg qd
6. Systemic Mast Cell Disease [26]
   1. Activating mutations in c-kit receptor implicated in mast cell disease
   2. 50% response in 10 patients with systmic mast cell disease (100mg or 400mg qd dose)
   3. 2 patients had complete clinical and histological remission
   4. Patients with c-kit mutations did not respond to the treatment
7. Also active in chronic myeloproliferative diseases with rearranged platelet derived growth factor receptor ß gene (chromosome 12p13) [27]
8. Generally Well Tolerated
   1. Nausea (55%), vomiting (~30%), edema (~55%), diarrhea (~35%)
   2. Muscle cramps, rash
   3. Edema has been problematic, with pleural effusion, ascities, pulmonary edema in 5%
   4. Neutropenia and thrombocytopenia common
   5. About 5% have increases in hepatic transaminase levels; discontinued in 0.5%
   6. Unusual cause of hypophosphatemia; low or normal 1,25 VitD3 with elevated PTH levels [28]
   7. May block bone remodeling (likely both formation and resorption) in some patients [28]

O. Lapatinib (Tykerb®) [29,50]

1. Orally active EGF-R1 and EGF-R2 (HER2/neu) inhibitor
2. Binds to and inhibits kinase domains of these receptor tyrosine kinases
3. Activity in trastuzumab (Herceptin®) resistant breast cancer
4. Increased progression free-survival when combined with capcitabine by 4 months, versus capcitabine alone in relapsed HER2+ breast cancer
5. Crosses blood-brain barrier so has potential activity in brain metastases
6. Dosing
   1. Approved in combination with capcitabine (oral) for resistant Stage IV breast cancer
   2. Dose is 1250mg po qd (every day of 21 day cycle) combined with capcitabine
   3. Capcitabine dosing is 1000mg/m2 bid days 1-14 of 21 day cycle
7. Side Effects
   1. Most commonly rash, diarrhea, nausea, fatigue
   2. Increased diarrhea and dyspepsia
   3. Increased palmpar-plantar erythrodysesthesia
   4. Overall generally well tolerated

P. Lenalidomide (Revlimid®) [30,31]

1. Thalidomide derivative approved for myeloma and myelodysplastic syndrome (MDS)
2. MDS [30,32,33]
   1. Approved for MDS with anemia (chr 5q- MDS)
   2. Dose is 10mg qd for 21 (or 28) days of 28 day cycle
   3. Clear benefit in ~55% of erythropoietin refractory anemias
   4. Cytogenic complete remissions in ~35% of patients with 5q- MDS
   5. Reduces RBC transfusion dependence in >80% of patients with 5q- MDS
3. Multiple Myeloma [31,34]
   1. Always combined with dexamethasone in myeloma
   2. Standard of care front line therapy is lenalidomide with dexamethasone
   3. This combination provides >90% responses front-line
   4. May be followed by bone marrow transplant
   5. Also shows excellent therapy in relapsed myeloma
4. Side Effects
   1. Main side effects are neutropenia and thrombocytopenia
   2. Diarrhea, rash, pruritus and fatigue also common
   3. Combination with chemotherapy associated with increased venous thromboembolic risk

Q. Methotrexate (MTX)

1. Blocks dihydrofolate reductase (DHFR) and binds certain enzymes
   1. Leads to accumulation of cellular folates in inactive oxidized form
   2. Thymidylate and purine nucleotide synthesis are then inhibited
2. MTX is Polyglutamated Intracellularly
   1. These metabolites are toxic, directly inhibit thymidylate synthetase
   2. These polyglutamates also have an extended half life
3. Utility
   1. High Grade and Burkitt Non-Hodgkin's Lymphoma (systemic and/or intrathecal)
   2. Central nervous system lymphoma
   3. Acute lymphocytic leukemia: CNS prophylaxis (intrathecal)
   4. Systemic therapy for bladder cancer (MVAC)
   5. Osteosarcoma
   6. Choriocarcinoma
   7. Previously used in breast cancer therapy (CMF), but not usually recommended now
   8. Lower doses used as first line disease modifying therapy for rheumatoid arthritis (RA)
4. Toxicities
   1. Mucositis - diarrhea, pain, bleeding
   2. Myelosuppression
   3. Nausea and vomiting
   4. Renal tubular injury
   5. Acute and chronic liver toxicity
   6. Acute pneumonitis (hypersensitivity reaction)
   7. Neurotoxicity in ~30% of patients receiving intrathecal MTX
5. Reduce dose for renal impairment

R. 6-Mercaptopurine (6-MP)

1. Purine (adenosine) analog
2. Treatment of childhood ALL
3. Metabolized by TPMT (thiopurine methyltransferase) [35]
   1. This is a polymorphic enzyme
   2. ~5% of children are homozygous null mutants and can have severe 6-MP toxicity
   3. Children with ALL heterozygous for TPMT have reduced minimum residual disease
4. Toxicities
   1. Nausea, vomiting, diarrhea, bone marrow depression
   2. Cholestasis and rare hepatic necrosis
   3. Oral and intestinal ulcers
   4. Pancreatitis

S. Nelarabine (Arranon®) [36]

1. Prodrug of deoxyguanosine analog 9-ß-D-arabinofuranosylguanine (ara-G)
2. FDA approved for T-ALL third line therapy
3. Complete response in 18% with 20.6 week median survival in adults
4. Complete response in 23% with 13 week median survival in children
5. Cytopenias, headache, somnolence, neurotoxicity can occur
6. Neurotoxicity can be fatal is dose limited: paresthesia, ataxia, confusion, seizure, coma

T. Nilotinib (Tasigna®) [52]

1. Orally active competitive inhibitor of BCR-ABL (binds in ATP site)
2. Approved for CML for patients resistant to or intolerant of imatinib
3. Active in majority of imatinib-resistant CML cell lines
4. For 33 blastic-phase CML patients, hematologic response in 13, cytogenic response in 9
5. Of 46 accclerated phase CML patients, 33 had hematologic and 22 cytogenetic responses
6. Myelosuppression, rash, and transient indirect hyperbilirubinemia were main side effects
7. Most patients intolerant of imatinib appear to tolerate nilotinib
8. Fluid retention is only rare with nilotinib; QT prolongation does occur and should be watched

U. Pemetrexed (Alimta®) [37]

1. Antimetabolite inhibits several enzymes involved in folate metabolism:
   1. Dihydrofolate reductase
   2. Thymidylate synthase
   3. Glycinamide ribonucleotide formyltransferase
2. FDA approved for combination with cisplatin (Platinol®) in malignant pleural mesothelioma
   1. Median survival of combination 12.1 months versus 9.3 months with cisplatin alone
   2. Response rate single agent pemetrexed 14% with 10.7 month median survival
3. Toxicities
   1. Myelosuppression
   2. Rash
   3. Fatigue
   4. Mouth sores
   5. Nausea and diarrhea
4. Vitamin B12 1000µg IM q9 weeks and folic acid 350-1000µg po qd reduce toxicities
5. Dexamethasone 4mg bid x 3 days is begun the day before treatment to reduce rash
6. Being evaluated in other solid tumor malignancies
7. Dose is 500mg/m2 IV over 10 minutes q3 weeks
   1. Do not use in patients with creatinine clearance <45mL/min
   2. Do not use with drugs that reduce renal function

V. Sorafenib (Nexavar®) [38,39]

1. Multikinase inhibitor (oral) - inhibits VEGF and PDGF receptor kinases, other kinases
2. Blocks both tumor cell and vasculature targets
3. Overall and progression free survival improved versus placebo in advanced renal ca (RCC)
4. Superior to placebo for second line therapy for RCC (following IFNa failure)
5. Dose is 400mg po bid; may reduce to 400mg po qd if not tolerated
6. Rash, hypertension, fatigue, nausea, weight loss, neuropathy (pain)

W. Sunitinib (Sutent®) [40,41,42]

1. Multikinase inhibitor (oral) - inhibits VEGF and PDGF receptor kinases, other kinases
2. Blocks both tumor cell and angiogenic targets
3. Progression free and overall survival improved versus placebo in gastrointestinal stromal tumors (GIST) after disease progression or intolerance to imatinib (Gleevec®) [43]
4. Also approved for RCC based on objective resopnse rates [44]
5. Superior to IFNa in first line RCC therapy on progression free and overall response [42]
6. Cycles of 50mg po qd x 4 weeks, then 2 weeks off; maximum 87.5mg qd
7. Side Effects
   1. Fatigue, nausea, mucositis, stomatitis, skin discoloration, hypothyroidism, hepatitis
   2. Grade 3 neutropenia in ~10% of patients
   3. Frequent screening for hypothyoridism with TSH testing is recommended [45]
   4. Hypertension, left ventricular dysfunction, congestive heart failure (usually reversible) [5]

X. Temsirolimus (Torisel®) [46]

1. Inhibitor of mammalian target of rapamycin (mTOR) kinase
   1. Binds to FKBP-12, forming complex that inhibits mTOR signaling
   2. This leads to suppression of proteins that mediate progression through cell cycle
2. Temsirolimus 25mg IV weekly superior to IFNa or temsirolimus+IFNa in untreated poor prognosis metastatic RCC with overall survival 10.9, 7.3, 8.4 months respectively [46]
3. Rash, peripheral edema, hyperglycemia, hyperlipidemia with temsirolimus

Y. Thalidomide (Thalomid®) [47,48]

1. Activities
   1. Anti-inflammatory and immunomodulatory activities
   2. Stimulates Th1 cytokines: interferon gamma (IFNg), interleukin (IL)-12
   3. Stimulates production of tumor necrosis factor alpha (TNFa) by monocytes
   4. Inhibits angiogenesis
   5. Stimulates CD4+ and CD8+ lymphocytes; increases IL-2R expression
2. Utility
   1. Efficacy in various cancers and resistant autoimmune cases
   2. Responses in ~30% of patients with refractory multiple myeloma
   3. Approved for treatment of multiple myeloma and lepromatous leprosy (ENL reaction)
   4. Also used in myelofibrosis, myelodysplastic syndromes
   5. Reduces mucocutaneous lesions in Behcet's Syndrome
   6. Graft versus host disease (GVHD)
3. Dose
   1. Initiate at 50mg po qd
   2. For multiple myeloma, 50-400mg po qd (200mg is probably maximal dose)
   3. For erythema nodosum leprosum (ENL) 100-300mg po qd
   4. For aphthous ulcers, 50-300mg po qd
   5. Treatment continues until conditions subside or progresses
4. Side Effects [48]
   1. Severe teratogenicity
   2. Drowsiness and sedation - most common
   3. Abdominal Pain/Bloating, Constipation - very common
   4. Peripheral Neuropathy - mainly sensory
   5. Orthostatic Hypothension
   6. Dry mouth and/or skin also occur
   7. Thromboembolic Disease
5. Due to high teratogenicity, registration with manufacturer required by physicians
6. Peripheral Neuropathy
   1. Mainly sensory, painful
   2. Occurs in 30-50% of persons with >6 months of use
   3. Appears to be independent of dose but increases with duration of use
   4. Includes "pins and needles", leg cramps, foot pain
   5. EMG/NCS should be done at baseline and every 6 months or 10grams thereafter
   6. Decrease in sensory amplitudes by >40% should prompt discontinuation of drug
7. Thromboembolic Disease [48,49]
   1. Deep vein thrombosis, pulmonary embolism
   2. Incidence with thalidomide alone ~5%
   3. Incidence substantially increased with chemotherapy, particularly doxorubicin
8. Combination with glucocorticoids may also exacerbate side effects

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