section name header

Info


A. Types of Agents (Abbreviated List) [1,2] navigator

  1. Alkylating Agents (see reference [2])
    1. Cyclophosphamide (Cytoxan®, Neosar®)
    2. Ifosfamide (Noxamide, Ifex®)
    3. Chlorambucil (Leukeran®)
    4. Melphalan (Alkeran®)
    5. Busulfan
    6. Thiotepa (Thioplex®)
    7. Procarbazine (Matulane®)
    8. Carmustine (BiCNU; Nitrogen Mustard)
    9. Lomustine (CCNU®)
    10. Dacarbazine (DTIC)
    11. Temozolomide (Temodar®) [3]
  2. DNA Cross Linking (Platinum)
    1. Cisplatin (Platinol®)
    2. Carboplatin (Paraplatin®)
    3. Oxaliplatin
  3. DNA Strand Breaking Agents
    1. Doxorubicin (Adriamycin®, Liposomal: Evacet®, Doxil®)
    2. Daunorubicin (Cerubidine®)
    3. Epirubicin (Ellence®, Pharmorubicin®)
    4. Idarubicin (Idamycin®)
    5. Bleomycin (Blenoxane®)
    6. Mitoxantrone (Novantrone®)
  4. DNA Topoisomerase Inhibitors
    1. Topoisomerase II inhibitors: Etoposide (VP16; VePesid®), Teniposide (VM26, Vumon®)
    2. Topoisomerase I inhibitors: Irinotecan (CPT-11; Camptosar®) Topotecan (Hycamtin®)
  5. Antimetabolites
    1. Methotrexate (MTX)
    2. 5-Fluorouracil (5-FU)
    3. 6-Mercaptopurine (6-MP) - purine (adenosine) analog
    4. 6-Thioguanine (6-TG) - purine (adenosine) analog, more toxic than 6-MP [25]
    5. Cytosine Arabinoside (AraC) - cytosine analog
    6. Hydroxyurea (Hydrea®) - blocks DNA synthesis, inhibition of ribonucleotide reductase
    7. Fluorodeoxyadenosine (2-FDA) - blocks DNA polymerase
    8. 2-Chlorodeoxyadenosine (CDA, cladribine, Leustatin®) [30]
    9. 2-Deoxycoformycin (Pentostatin)
    10. Asparaginase (Elspar®)
    11. Difluoromethylornithine (DFMO)
    12. Gemcitabine (Gemzar®)
    13. Capecitabine (Xeloda®)
  6. Tubulin Binding Agents
    1. Vincristine (Oncovin®)
    2. Vinblastine (Velban®)
    3. Vinorelbine (Navelbine)
    4. Paclitaxel (Taxol®)
    5. Docetaxel (Taxotere®)
    6. Ixabepilone (Ixempra®) [27]
  7. Glucocorticoids (Corticosteroids)
    1. Prednisone and prednisolone
    2. Methylprednisolone
    3. Dexamethasone
    4. Hydrocortisone
    5. These agents induce apoptosis in a variety of cell types, particularly leukocytes
  8. Hormonal Agents (see below)
    1. Tamoxifen (Nolvadex®), Raloxifene (Evista®)
    2. Leuprolide (Lupron®), Goserelin (Zoladex®)
    3. Megestrol acetate (Megace®), Provera
    4. Finasteride, Bicalutamide (Casodex®)
    5. Flutamide (Eulexin®)
    6. Retinoic acids
  9. Biological Response Modifiers
    1. Interferon Alfa (Roferon A®, Intron A®) [12]
    2. Interleukin 2 (Bioleukin®, Proleukin®, Aldesleukin) [12,13]
    3. Interferon beta (betaseron®, Avonex®)
    4. Interferon Gamma (Immuneron®) [14]
    5. Tumor Necrosis Factor (TNF)
    6. Interleukin 12
  10. Biotherapeutics
    1. Anti-Her2/neu antibodies (anti-her2 Abs; see below)
    2. Anti-CD20 Abs (bare Ab or radioactive)
    3. Anti-CD33 Abs (conjugates)
    4. Anti-EGF Receptor Abs [31]
    5. Antisense Olignonucleotides - antisense bcl-2 (augmerosen) appears promising [62]
  11. Angiogenesis Inhibitors [15]
    1. Antibody to VEGF (bevacizumab, Avastin®)
    2. Large number of experimental agents including angiostatin
    3. Synergistic activity with standard chemotherapy and radiotherapy in early studies
    4. Thalidomide and derivatives
  12. Proteasome inhibitors [11,17,18]
  13. Histone Deacetylase (HDAC) Inhibitors 14 DNA Demethylating Agents
  14. Optimal chemotherapies based on disease have been compiled [2]

B. Cytotoxic Drugs
[Figure] "Killing Potential of Chemotherapeutic Agents" navigator

  1. Goal is Killing of Neoplastic but not Normal Cells
    1. Antimetabolites usually not as effective (but fewer side effects) as alkylating agents
    2. Lymphocytes typically more susceptible to killing than other cell types
    3. May be related to lymphocytes' relative ease of undergoing apoptotic cell death
    4. Note that DNA strand breaks are repaired better by normal vs. neoplastic cells
    5. This difference is thought to be responsible for "selective" killing of tumor cells
  2. Tumor Burden
    [Figure] "Cell Kill and Drug Resistance"
    1. Ability to eradicate tumor also depends on number of tumor cells, called "tumor burden"
    2. Probably due to increased likelihood of generating drug resistant cells with high burden
    3. Individualized dosing to insure consistent drug exposure can improve outcomes [16]
  3. Combination Therapy
    1. Tumor cells usually generate drug resistance fairly rapidly
    2. Tumor recurrence is usually due to generation of drug resistant mutants
    3. Combination chemotherapy is designed to reduce ability of cells to generate mutants
    4. Specific combinations of drugs are used which target different growth mechanisms
    5. In addition, reduction in severe toxic effects can be achieved with combinations
    6. That is, individual drug doses can be lowered, efficacy maintained, toxicity reduced
    7. Addition of biological agents and/or immune therapy may further improve treatments
  4. High Dose Chemotherapy with Stem Cell Rescue
    1. Has been evaluated mainly in treatment of metastatic, recurrent breast cancer
    2. However, compared with 2 years of standard maintenance (CMF) therapy, high dose chemotherapy with stem cell rescue had reduced disease-free and overall survival [58]
    3. Review of only positive randomized trial showed major design and reporting flaws [59]
  5. Mechanisms of Chemotherapy Resistance
    1. Particular primary tumors often have specific chemotherapeutic sensitivities
    2. Recurrence of tumors is due to generation of resistance
    3. Many resistant tumors express pump proteins which pump out various toxins
    4. The best understood pump is mdr1, and at least 6 additional pump proteins are known
    5. Mdr1 (multidrug resistance protein 1) can be induced by mutant p53 proteins
    6. Increase systemic metabolism of anticancer agents can lead to drug failure [16]

C. Platinumsnavigator

  1. Derivatives of heavy metal platinum
  2. Intercalate into minor groove of DNA, causes platinum-DNA adducts, cross-link DNA strands
  3. DNA repair enzymes can remove these cross links and allow cells to recover [24]
  4. Carboplatin (Paraplatin®)
    1. Utility: Increasing use in many resistant cancers, ovarian, lung cancer, cervix
    2. Toxicity: nausea, vomiting, bone marrow depression, peripheral neuropathy
    3. Toxicity: hearing loss, hemolytic anemia, transient cortical blindness
  5. Cisplatin (Platinol®)
    1. Utility: Head and neck, upper GI, lung, neuroblastoma, osteosarcoma, testicular, cervix
    2. Toxicity: nausea, vomiting, diarrhea, renal damage, ototoxicity, bone marrow depression
    3. Toxicity: peripheral neuropathy, electrolyte disorders, hemolysis, Raynaud's, sterility
    4. Cisplatin adjuvant therapy for completely resected stages I-III lung cancer is beneficial with tumors that do not express ERCC1 (DNA excision repair enzyme) [24]
  6. Oxaliplatin (Eloxatin®) [15]
    1. Utility: colon cancer (approved in second line in combination with 5FU/LV)
    2. Utility: combination with 5FU/LV is superior to irinotecan combination in first line
    3. Toxicity: pharyngolaryngeal dysesthesias (stridor may occur), paresthesias
    4. Toxicity: nausea, vomiting, bone marrow depression, rare anaphylaxis
    5. Toxicity: chronic peripheral neuropathy (high rates), diarrhea

D. Taxanesnavigator

  1. Bind polymerized ß-tubulin in microtubules
  2. Prevent microtubule depolymerization
  3. Stabilize metaphase chromosomal structures and block metaphase to anaphase
  4. Paclitaxel (Taxol®) [4,5]
    1. Advanced ovarian cancer in combination with platinum
    2. Breast cancer, including combination with trastuzumab
    3. Kaposi's Sarcoma
    4. Formulated in polyoxyethylated castor oild (Cremophor®) which can cause hypersensitivity
    5. Severe hypersensitivity, likely due to Cremophor, in ~3% of paclitaxel recipients
    6. Toxicity: hypersensitivity reactions, bone marrow depression, peripheral neuropathy
    7. Toxicity: alopecia, myalgias, arthralgias, mucositis, uncommon cardiac toxicity
    8. Predmedication with antihistamines and glucocorticoids required
    9. Usual breast ca dose 175mg/m2 q3 weeks as 3-hour IV infusion
  5. Albumin-Bound Paclitaxel (Abraxane®) [5]
    1. Paclitaxel formulated bound to albumin
    2. FDA approved for second line chemotherapy in recurrent metastatic breast ca
    3. Dose is 260mg/m2 given as 30 minute infusion without predmedication
    4. Compared with paclitaxel-cremophor, had better response and longer progression time
    5. Time to progression 21 weeks in 2nd line breast ca
  6. Docetaxel (Taxotere®) [6]
    1. Advanced breast ca after failure of any prior chemotherapy
    2. Advanced NSCLC after failure of platinum-based chemotherapy
    3. Toxicity: Hypersensitivity reactions, nausea, vomiting, stomatitis, neutropenia
    4. Do not give if AST and/or ALT >1.5X ULN with Alk Phos >2.5X ULN
    5. Do not give if bilirubin abnormal
    6. Toxicity: Alopecia, fluid retention, peripheral neuropathy, cutaneous fibrosis
  7. Ixabepilone (Ixempra®) [27]
    1. Semisynthetic derivative of epothilone B
    2. Binds directly to ß-tubulin subunits on microtubules
    3. Suppresses dynamic instability of alpha-II and ß-III microtubules
    4. Like taxanes, blocks cell cycle in mitosis causing cell death
    5. Approved in combination with capecitabine for metastatic or locally advanced breast Ca
    6. Dosing is 40mg/m2 q3 weeks IV over 3 hours; dose adjust for liver dysfunction
    7. Toxicity: peripheral neuropathy, fatigue, asthenia, myalgia, alopecia, nausea, vomiting, stomatitis, diarrhea, palmar-plantar erythrodysesthesia; neutropenia dose dependent
    8. Premedicate all patients one hour prior to infusion with histamine H1 and H2 antagonists

E. Vinca Alkaloidsnavigator

  1. Block tubulin polymerization to microtubules
  2. Arrest cells in metaphase
  3. Vincristine (Oncovin®)
    1. Utility: brain, Ewing sarcoma, hepatoblastoma, Kaposi sarcoma, low grade NHL, myeloma
    2. Utility: rhabdomyosarcoma, pheochromocytoma
    3. Toxicity: tissue damage with extravasation, peripheral neuropathy, alopecia
    4. Toxicity: mild bone marrow depression, constipation, paralytic ileus, SIADH, jaw pain
  4. Vinblastine (Velban®)
    1. Utility: brain, Kaposi, testicular, melanoma
    2. Toxicity: nausea, vomiting, local reaction, bone marrow depression, alopecia
    3. Toxicity: peripheral neuropathy, stomatitis, jaw pain, muscle pain, paralytic ileus
  5. Vinorelbine (Navelbine) [7]
    1. Utility: NSCLC, breast, esophageal, Kaposi
    2. Toxicity: nausea, vomiting, injection site reactions, bone marrow depression, alopecia
    3. Toxicity: anorexia, stomatitis, asthenia, peripheral neuropathy, constipation

F. Topoisomerase I Inhibitorsnavigator

  1. Block topoisomerase I, leads to DNA strand breaks
  2. Irinotecan (CPT-11, Camptosar®) [8]
    1. Utility: colorectal, pancreatic, cervical
    2. Toxicity: nausea, vomiting, early and late diarrhea, fever, anorexia, stomatitis
    3. Toxicity: bone marrow depression, asthenia, alopecia, abdominal cramping and pain
    4. Deficiency of UGT1A1 enzyme (usually due to UGT1A1*28 homozygosity) associated with increased diarrhea and myelosuppression [22]
    5. Invader UGT1A1 Molecular Assay detects UGT1A1*28 allele; homozygous patients should receive reduced irinotecan doses [23]
  3. Topotecan (Hycamtin®) [9]
    1. Second line after platinum-based chemotherapy for ovarian cancer
    2. Slightly improved response rates versus paclitaxel in this population
    3. Second line for small cell lung cancer (SCLC), ovarian cancer, neuroblastoma
    4. Toxicity: Neutropenia, leukopenia, thrombocytopenia and anemia most common
    5. Toxicity: Nausea, vomiting, alopecia also common

G. Topoisomerase II Inhibitorsnavigator

  1. Block topoisomerase II, leads to DNA strand breaks
  2. Etoposide (VP16; VePesid®)
    1. Utility: SCLC, adrenocortical, gastric, NSCLC, osteosarcoma, Wilms, rhabdomyosarcoma
    2. Toxicity: nausea, vomiting, diarrhea, fever, hypotension, hypersensitivity
    3. Toxicity: bone marrow depression, rashes, alopecia, peripheral neuropathy, mucositis
  3. Teniposide (VM26, Vumon®)
    1. Utility: lung, lymphomas
    2. Toxicity: severe hypersensitivity, nausea, vomiting, diarrhea, phlebitis at infusion site
    3. Toxicity: bone marrow depression, alopecia, mucositis, rash, hepatitic toxicity
    4. Late leukemias have been reported

H. Anthracyclinesnavigator

  1. DNA strand breaking agents
  2. Doxorubicin (Adriamycin®)
    1. Utility: breast, Hodgkin's, NHL, biliary tract, carcinoid, endometrial, Ewing's, rhabdomyo
    2. Utility: hepatoblastoma, islet cell, Kaposi, ALL, thyroid, Wilms, soft tissue sarcoma
    3. Toxicity: nausea, vomiting, diarrhea, red urine (not hematuria), facial flushing
    4. Toxicity: anaphylactoid reactions, bone marrow depression, cardiotoxicity, alopecia
    5. Toxicity: stomatitis, anorexia, fever, chils, hand/foot dysesthesia, late leukemias
  3. Liposomal Doxorubicin (Doxil®)
    1. Utility: Kaposi
    2. Toxicity: better tolerated than non-liposomal: less nausea, vomiting, no red urine
    3. Toxicity: reduced cardiotoxicity, minimal alopecia, hand/foot dysesthesia
  4. Daunorubicin (Cerubidine®)
    1. Utility: AML, accellerated and blast phase CML
    2. Toxicity: nausea, vomiting, diarrhea, red urine (not hematuria), facial flush, arrhythmias
    3. Toxicity: anaphylactoid reactions, bone marrow depression, cardiotoxicity, alopecia
    4. Toxicity: stomatitis, anorexia, fever, chils, skin and nail pigmentation, photosensitivity
  5. Epirubicin (Ellence®, Pharmorubicin®) [10]
    1. Utility: breast, endometrial, soft tissue sarcoma
    2. Toxicity: red urine, neausea, vomiting, arrhythmias, anaphylactoid reactions, fatigue
    3. Toxicity: bone marrow depression, alopecia, paresthesias, late leukemia, cardiotoxicity
  6. Idarubicin (Idamycin®)
    1. Utility: AML, accellerated CML
    2. Toxicity: nausea, vomiting, bone marrow depression, alopecia, stomatitis
    3. Toxicity: myocardial toxicity, diarrhea
  7. Mitoxantrone (Novantrone®)
    1. Utility: androgen resistant prostate cancer, intermediate grade NHL
    2. Toxicity: nausea, vomiting, fever, phlebitis, blue-green sclera, blue-green urine pigment
    3. Toxicity: bone marrow depression, cardiotoxicity, alopecia, white hair, skin lesions
    4. Toxicity: hepatic damage, renal damage, stomatitis
    5. Also effective in progressive multiple sclerosis [14]

I. Bortezomib (PS-341, Velcade®) [11,17,18]navigator

  1. Intracellular 26S Proteasome [16,26]
    1. Proteasome responsible for intracellular protein degradation
    2. Proteasome also degrades cell cycle regulatory proteins (cyclins, others)
    3. Proteasome degrades I-kB, an inhibitor of nuclear factor kappa B (NFkB)
    4. NFkB stimulates inflammatory cytokine production and is anti-apoptotic
    5. High NFkB levels associated with chemotherapy resistance
    6. Blocking proteasomes prevents cell cycle progression and NFkB activation
  2. Bortezomib is a reversible inhibitor of the proteasome
  3. Bortezomib is directly toxic to many tumor cells, but spares most normal cells
  4. Multiple Myeloma [17,18]
    1. Response rate ~30% in highly refractory patients (4-5 prior lines of therapy)
    2. Disease control (response or stabilization) in ~70% of refractory patients
    3. Response rate 38% in relapsed and refractory myeloma
    4. Superior to dexamethasone for relapsed myeloma (mortality and other clinical benefits)
    5. May be very effective at first relapse as well as in refractory disease
    6. FDA approved for relapsed and refractory myeloma and for second line myeloma
  5. Side Effects [17,18]
    1. Generally well tolerated with diarrhea, fatigue, thrombocytopenia
    2. MInimal leukopenia or anemia; minimal neutropenia
    3. Peripheral neuropathy may be exacerbated, primarily with prior thalidomide therapy
    4. Dose should be reduced or drug stopped with peripheral neuropathy
    5. Peripheral neuropathy generally reversible
    6. COX-2 inhibitors and/or vitamin B6 50mg qd may reduce peripheral neuropathy
  6. Dosing
    1. Dose is 1.0-1.3mg/m2 twice weekly for 2 out of 3 weeks (one cycle) for myleoma
    2. May also be given 1.3-1.6mg/m2 once weekly for 4 of 5 weeks in solid tumors
    3. For NHL, dose is up to 1.5mg/m2 twice weekly for 2 of 3 weeks
    4. Maintenance weekly therapy after 8 cyclces of induction therapy
  7. Combinations
    1. For myeloma, may be combined with thalidomide, liposomal doxorubicin, or dexamethasone
    2. Ongoing studies combined with platinums, taxanes, gemcitabine, doxorubicin, others
    3. Combinations with other agents can provide 80-90% response rates

J. Vorinostat (Zolinza®)navigator

  1. Oral HDAC inhibitor
  2. Histones and Gene Expression [28]
    1. Core histones (H2A, H2B, H3, H4) may be acetylated or methylated or phosphorylated
    2. Nonacetylated histones associated with tightly wrapped, poorly transcribed DNA
    3. Acetylation of histones (on lysines and/or arginines) associated with transcriptional activation
    4. Deacetylation of histones leads to inhibition of gene expression
    5. Histone deacetylases (HDAC) are responsible for deacetylation of histones
    6. Inhibition of HDAC increases gene expression, including genes involved cell growth
  3. Exactly which genes are inactivated due to HDAC inhibitors is not clear
  4. In multicenter open-label study, 400mg/day vorinostat in patients with advanced CTCL lead to an overall response rate of ~30%

K. DNA Demethylating Agents [28]navigator

  1. Azacitidine (Vidaza®) [29]
    1. Pyridimidine nucleoside analog of cytidine
    2. DNA demethylating agent which stimulates certain gene expression
    3. Dose is 75mg/m2 sc once/d x 7 days, repeated every 4 weeks x 4 cycles
    4. Overall ~23% response rates, with 6 month increased median survival
    5. Unclear if superior to decitabine
  2. Decitabine (Dacogen®) [29]
    1. Pyridimidine nucleoside analog of cytidine, DNA demethylating agent
    2. Standard dose is 50mg/m2 IV over 3 hours, q8 hours x 3 days
    3. Repeat dosing every 6 weeks, for minimum of 4 cycles
    4. Overall response rate 17% (9% complete response)
    5. Duration of response 10.3 months but no increase in overall survival
    6. Lower doses given for longer durations and shorter intervals had 34% response rate

L. Hormonal Therapynavigator

  1. Usually leads to temporary cell killing with many cells becoming quiescent
  2. Quiescent tumor cells eventually use original hormone as growth factor
  3. Withdrawal of original hormonal therapy at this time can sometimes lead to a temporary reduction in tumor growth
  4. Estrogen Receptor (ER) Blockers (SERMs and others)
    1. Tamoxifen (Nolvadex®) - ER mixed agonist/antagonist with uterine stimulating effects
    2. Raloxifene (Evista®) - ER mixed agonist/antagonist with NO uterine stimulating effects
    3. Fulvestrant (Faslodex®) - pure, potent ER antagonist
    4. Toremifine (Fareston®) - direct antiestrogenic activty on breast; agonist on endometrium
  5. Aromatase Inhibitors
    1. Aromatase is the enzyme in the periphery which converts androgens to estrogens
    2. Anastrozole (Arimidex®)
    3. Letrozole (Femara®)
    4. Exemestane (Aromasin®)
    5. Vorozole (Rivizor®) - not yet FDA approved
  6. Progestins
    1. Medroxyprogesterone acetate (MPA, Provera®)
    2. Progesterones (megestrol acetate, Megace®) - increases appetite, weight gain
  7. Gonadotropin Releasing Hormone (GNRH) Analogs
    1. Induce "medical castration" by blocking FSH and LH secretion
    2. Leuprolide (Lupron®)
    3. Goserelin (Zoladex®)
  8. Androgen Receptor Blockers [13]
    1. Flutamide (Eulexin®)
    2. Bicalutamide (Casodex®)
    3. Nilutamide (Nilandron®)
  9. Finasteride - 5 alpha-reductase inhibition (enzyme needed for DHT formation)
  10. Retinoic Acids
    1. Tretinoin
    2. Isotretinoin

References navigator

  1. Cancer Chemotherapy. 1997. Med Let. 39(996):21 abstract
  2. Drugs of Choice for Cancer Chemotherapy. 2000. Med Let. 42(1087):83
  3. Temozolomide. 1999. Med Let. 41(1068):123 abstract
  4. Crown J and O'Leary M. 2000. Lancet. 355(9210):1176 abstract
  5. Paclitaxel Albumin Bound. 2005. Med Let. 47(1208):39 abstract
  6. Docetaxel. 1996. Med Let. 38(984):87 abstract
  7. Vinorelbine. 1995. Med Let. 37(955):72 abstract
  8. Irinotecan. 1997. Med Let. 39(992):8 abstract
  9. Topotecan. 1996. Med Let. 38(986):96 abstract
  10. Epirubicin. 2000. Med Let. 42(1071):12 abstract
  11. Bortezomib. 2003. Med Let. 45(1161):57 abstract
  12. Gefitinib (Iressa). 2002. Med Let. 44(1138):77 abstract
  13. Bicalutamide. 1995. Med Let. 37(955):72
  14. Hartung HP, Gonsette R, Konig N, et al. 2002. Lancet. 360(9350):2018 abstract
  15. Oxaliplatin. 2003. Med Let. 45(1148):7 abstract
  16. Mitchell BS. 2003. NEJM. 348(26):2597 abstract
  17. Richardson PG, Barlogie B, Berenson J, et al. 2003. NEJM. 348(26):2609 abstract
  18. Richardson PG, Sonneveld P, Schuster MW, et al. 2005. NEJM. 352(24):2487 abstract
  19. Meyer UA. 2000. Lancet. 356(9242):1667 abstract
  20. Invader UGT1A1 Molecular Assay. 2006. Med Let. 48(1234):39 abstract
  21. Olaussen KA, Dunant A, Fouret P, et al. 2006. NEJM. 355(10):983 abstract
  22. Vora A, Mitchell CD, Lennard L, et al. 2006. Lancet. 368(9544):1339 abstract
  23. Reinstein E and Ciechanover A. 2006. Ann Intern Med. 145(9):676 abstract
  24. Ixabepilone. 2008. Med Let. 50(1278):7 abstract
  25. Esteller M. 2008. NEJM. 358(11):1148 abstract
  26. Decitabine. 2006. Med Let. 48(1247):91 abstract
  27. Chlorodeoxyadenosine. 1992. Med Let. 34(879):87
  28. Ciardiello F and Tortora G. 2008. NEJM. 358(11):1160 abstract