TABLE 192-1 -- KARNOFSKY AND ZUBROD PERFORMANCE SCORE SCALES
KARNOFSKY PERFORMANCE STATUS SCALE | |
Value | Level of Functional Capacity |
100 | Normal, no complaints, no evidence of disease |
90 | Able to carry on normal activity, minor signs or symptoms of disease |
80 | Normal activity with effort, some signs or symptoms of disease |
70 | Cares for self, unable to carry on normal activity or to do active work |
60 | Requires occasional assistance but is able to care for most needs |
50 | Requires considerable assistance and frequent medical care |
40 | Disabled, requires special care and assistance |
30 | Severely disabled, hospitalization is indicated although death is not imminent |
20 | Hospitalization is necessary, very sick, active supportive treatment necessary |
10 | Moribund, fatal processes progressing rapidly |
0 | Dead |
EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG, ZUBROD) PERFORMANCE SCALE | |
Performance Status | Definition |
0 | Asymptomatic |
1 | Symptomatic; fully ambulatory |
2 | Symptomatic; in bed <50% of day |
3 | Symptomatic; in bed >50% of day |
4 | Bedridden |
TABLE 192-2 -- EXAMPLES OF TIMING OF CHEMOTHERAPY
Adjuvant Therapy | Neoadjuvant Therapy | Organ-Sparing Therapy | Combination Chemotherapy |
Stage I and II breast cancer | Stage III breast cancer | Anal cancer | Metastatic solid tumors[*] |
Stage III colorectal cancer | Larynx cancer | Hematologic malignancies | |
Stage III melanoma | Esophageal cancer | ||
Stage I–III lung cancer |
* | Usually palliative. |
TABLE 192-3 -- HORMONAL THERAPY
Corticosteroids | |
Prednisone Dexamethasone (Decadron) | |
Androgens | |
Halotestin | |
Estrogens | |
Diethylstilbestrol (DES) | |
Antiandrogens | |
Bicalutamide (Casodex) Flutamide (Eulexin) Nilutamide (Nilandron) | |
Antiestrogens | |
Tamoxifen (Nolvadex) Toremifene (Fareston) | |
Progestational agents | |
Medroxyprogesterone acetate (Megace) | |
Luteinizing hormone–releasing hormone analogues | |
Leuprolide (Lupron) Goserelin (Zoladex) | |
Aromatase inhibitors | |
Anastrazole (Arimidex) Exemestane (Aromasin) Letrozole (Femara) | |
Estrogen receptor antagonist | |
Fulvestrant (Faslodex) | |
TABLE 192-4 -- IMMUNOTHERAPY
Interferon-alfa (Intron A, Roferon) Interleukin-2 (Proleukin) |
TABLE 192-5 -- MOLECULARLY TARGETED AGENTS AND MONOCLONAL ANTIBODIES
MOLECULARLY TARGETED AGENTS | |
Imatinib (Gleevec) Erlotinib (Tarceva) EGFR TKI Antiangiogenesis agents | |
Bevacizumab (Avastin) VEGF inhibitor Thalidomide (Thalomid) Lenalidomide (Revlimid) | |
Multikinase inhibitor | |
Sorafenib (Nexavar) Scinitinib (Sutent) | |
Bortezomib (Velcade)-proteasome inhibitor | |
MONOCLONAL ANTIBODIES | |
Trastuzumab (Herceptin) Rituximab (Rituxan) Gemtuzumab ozogamicin (Mylotarg) Alemtuzumab (CamPath) Cetuximab, C-225 (Erbitux) Tositumomab Iodine 131 (Bexxar) Ibritumomab tiuxetan Y 90 (Zevalin) | |
EGFR = epidermal growth factor receptor; VEGF = vascular endothelial growth factor. |
TABLE 192-6 -- CHEMOTHERAPEUTIC AGENTS
Agent | Class | Action | Excretion | Unique Side Effects | Drug Interactions | Indications |
ALKYLATING AGENTS | ||||||
Busulfan (Myleran) | Bifunctional alkylating agent | Interacts with thiol groups of proteins and nucleic acids, forming DNA cross-links; cell cycle nonspecific | Metabolized in liver, excreted by kidneys | Hepatotoxicity (veno-occlusive disease), pulmonary fibrosis, cataracts, skin darkening (pseudo-Addison's syndrome) | None | Chronic granulocytic leukemia, preparative regimens for stem cell transplantation |
Carboplatin (Paraplatin) | Platinum coordination compound | Produces interstrand DNA cross-links, similar to those with bifunctional alkylating agents; cell cycle nonspecific | Renal | Nephrotoxicity, ototoxicity, neuropathy, hypomagnesemia, hypersensitivity reactions, hepatotoxicity | Avoid other nephrotoxic or ototoxic drugs | Ovarian cancer, testicular cancer, lung cancer, head and neck cancer, breast cancer |
Carmustine (BCNU, BiCNU) | Nitrosourea | Alkylates DNA and RNA; cell cycle nonspecific | Hepatic biotransformation, renal excretion | Delayed and cumulative myelosuppression, pulmonary toxicity (dose-related), hepatotoxicity, nephrotoxicity, cutaneous toxicity | None | Brain tumors, Hodgkin's and non-Hodgkin's lymphomas, myeloma |
Chlorambucil (Leukeran) | Bifunctional alkylating agent | Formation of interstrand DNA cross-links with resultant inactivation of DNA; cell cycle nonspecific | Hepatic biotransformation, renal excretion | Hepatotoxicity, pulmonary toxicity | None | CLL, Waldenstr?m's macroglobulinemia, Hodgkin's and non-Hodgkin's lymphomas, myeloproliferative disorders, ovarian cancer |
Cisplatin (Platinol) | Platinum coordination compound | Produces interstrand DNA cross-links similar to bifunctional alkylating agents; cell cycle nonspecific | Renal | Nephrotoxicity, ototoxicity, neuropathy, hypomagnesemia, hypersensitivity reactions, hemolytic anemia, SIADH | Avoid other nephrotoxic or ototoxic drugs | Testicular cancer, other germ cell tumors, ovarian cancer, bladder cancer, prostate cancer, lung cancer, sarcomas, cervical cancer, endometrial cancer, gastric cancer, breast cancer, adrenal cancer, head and neck cancer |
Cyclophosphamide (Cytoxan, Neosar) | Alkylating agent of the nitrogen mustard type | Cross-linking of DNA and RNA, inhibits protein synthesis; cell cycle nonspecific | Hepatic biotransformation with renal excretion | Hemorrhagic cystitis, SIADH | Phenobarbital increases rate of metabolism and leukopenia; cyclophosphamide potentiates the effects of succinylcholine and may increase oral anticoagulant activity | Breast cancer, ovarian cancer, Hodgkin's and non-Hodgkin's lymphomas, leukemias, neuroblastoma, retinoblastoma, other sarcomas, bladder cancer, lung cancer, cervical cancer, endometrial cancer, prostate cancer, osteogenic sarcoma, Wilms' tumor |
Dacarbazine (DTIC-Dome) | Nonclassic alkylating agent | Inhibits DNA and RNA synthesis via formation of carbonium ions; cell cycle nonspecific | Hepatic biotransformation, renal excretion | Pain on injection, flulike syndrome, hepatic veno-occlusive disease, photosensitivity | Heparin, lidocaine, hydrocortisone, phenytoin, phenobarbital, interleukin-2 | Melanoma, Hodgkin's disease, sarcomas |
Ifosfamide (Ifex) | Alkylating agent of the nitrogen mustard type | Alkylated metabolites interact with DNA; cell cycle nonspecific | Hepatic biotransformation, renal elimination | Hemorrhagic cystitis, nephrotoxicity, CNS toxicity | None | Germ cell tumors, sarcomas, non-Hodgkin's lymphomas, cervical cancer, Ewing's sarcoma, lung cancer |
Lomustine (CCNU, CeeNU) | Nitrosourea | Alkylates DNA and RNA, inhibits DNA synthesis; cell cycle nonspecific | Hepatic biotransformation, renal excretion | Delayed and cumulative myelosuppression, pulmonary toxicity (dose-related), hepatotoxicity, nephrotoxicity | Cimetidine enhances toxicity | Brain tumors, Hodgkin's disease, multiple myeloma, GI cancers |
Mechlorethamine, nitrogen mustard (Mustargen) | Bifunctional alkylating agent | Cross-links strands of DNA and RNA, inhibits protein synthesis; cell cycle nonspecific | Rapidly deactivated in body fluids and tissues | Extravasation | None | Hodgkin's disease, intracavitary treatment of effusions; topically for mycosis fungoides |
Melphalan (Alkeran) | Alkylating agent of nitrogen mustard type | Forms interstrand, intrastrand, or DNA protein cross-links; cell cycle nonspecific | Deactivated in body fluids and tissues, renal elimination 50% | Pulmonary toxicity | Cimetidine decreases oral bioavailability; cyclosporine enhances risk of renal toxicity | Multiple myeloma, breast cancer, ovarian cancer, rhabdomyosarcoma, bone marrow ablation for stem cell transplantation |
Mitomycin (Mutamycin) | Antitumor antibiotic | Acts as a bifunctional alkylating agent, inhibiting DNA synthesis; cell cycle nonspecific, but most active in G and S phases | Hepatic biotransformation, renal elimination | Cumulative myelosuppression, extravasation, renal toxicity, pulmonary toxicity, cardiac toxicity, hemolytic-uremic syndrome | Prior treatment with vinca alkaloids may predispose to pulmonary toxicity; if used with doxorubicin, may potentiate cardiotoxicity | Gastric cancer, pancreatic cancer, anal cancer, lung cancer, head and neck cancer, cervical cancer |
Oxaliplatin (Eloxatin) | Platinum coordination compound | Produces interstrand DNA cross-links similar to bifunctional alkylating agents; cell cycle nonspecific | Renal | Nephrotoxicity, neurotoxicity (worse with cold), allergic reactions | Avoid other nephrotoxic drugs, incompatible with 5-fluorouracil | Colorectal cancer |
Procarbazine (Matulane) | Nonclassic alkylating agent and an MAO inhibitor | Unknown; metabolism produces highly active free radicals that may alkylate and methylate DNA; cell cycle specific, S phase | Renal 70% after hepatic biotransformation | Disulfiram (Antabuse)–like side effects with alcohol ingestion; patients should avoid foods containing tyramine due to the drug's MAO inhibitory effects; central and peripheral neurotoxicity, hepatotoxicity, pulmonary toxicity | >100, including alcohol, antihistamines, anticoagulants, anticonvulsants, hypoglycemics, certain antihypertensives, caffeine-containing preparations, narcotics, methyldopa, metrizamide, sympathomimetics, tyramine or other high pressor amine-containing foods | Hodgkin's disease, brain tumors |
Streptozocin (Zanosar) | Nitrosourea | Inhibits DNA synthesis | Renal | Cumulative, dose-related renal toxicity, hepatotoxicity, glucose intolerance | None | Islet cell carcinoma of the pancreas, carcinoid tumors |
Temozolomide (Temodar) | Nonclassic alkylating agent | Inhibits DNA and RNA synthesis via formation of carbonium ions; cell cycle nonspecific | Hepatic biotransformation, renal excretion | Photosensitivity | None | Melanoma, brain tumors |
DIFFERENTIATING AGENTS | ||||||
All-Trans retinoic acid (TRA) | Retinoid | Induces differentiation and/or inhibition of clonogenicity | Conjugation to glucuronic acid with subsequent biliary excretion and enterohepatic circulation | Mucocutaneous toxicity, ocular toxicity, musculoskeletal toxicity, neurologic toxicity, hepatotoxicity, lipid toxicity | None | Acute progranulocytic leukemia |
Arsenic trioxide (Trisenox) | Natural product | Induces differentiation of acute progranulocytic leukemia cells | Hepatic metabolism, excreted in urine | Prolonged QT interval, acute progranulocytic leukemia differentiation syndrome, leukocytosis, peripheral neuropathy | Medications that increase the QT interval, such as antiarrhythmics and amphotericin | Acute progranulocytic leukemia |
ENZYMES | ||||||
Asparaginase (Elspar) | Enzyme | Hydrolyzes 1-asparaginine to aspartic acid and ammonia, resulting in a cellular deficiency of 1-asparaginine; sensitive tumor cells lack asparagine synthetase; interferes with protein, DNA, and RNA synthesis; cell cycle specific for G1 phase of cell division | Metabolized in liver | Hypersensitivity reactions, inhibitory effects on protein synthesis with resultant decreases in hepatic synthesis of coagulation factors, pancreatitis, hyperglycemia, CNS depression, hepatotoxicity | Abolishes effects of methotrexate on malignant cells; concurrent vincristine may enhance the hyperglycemic effects of asparaginase and may increase risk of neuropathy | Acute lymphoblastic leukemia |
ANTIMETABOLITES | ||||||
5-Azacitidine (Vidaza) | Antimetabolite, a pyrimidine nucleoside analogue of cytidine | Causes hypomethylation of DNA and direct cytotoxicity on abnormal hematopoietic cells | Hepatic metabolism, excreted in urine | Renal toxicity, low serum bicarbonate levels | None | Myelodysplasia |
Capecitabine (Xeloda) | Antimetabolite of the pyrimidine analogue type | Fluoropyrimidine carbamate prodrug form of 5-fluorouracil; given orally; inactive as itself; inhibits DNA and RNA synthesis; cell cycle specific, S phase | Hepatic catabolism | Hand and foot syndrome, angina | Warfarin potentiation, phenytoin, antacids, leucovorin, thymidine | Breast cancer, colorectal cancer |
Cladribine (Leustatin), 2-chloro-2-deoxy-D-adenosine | Antimetabolite | Purine nucleoside analogue, inhibits both DNA synthesis and repair | Uncertain | Bone marrow suppression, fever, paralysis, and/or acute renal failure when used at very high doses for bone marrow transplantation | None known | Hairy cell leukemia |
Cytarabine (Cytosar-U, Tarabine PFS) | Antimetabolite | Activated to cytarabine triphosphate in tissues, inhibits DNA synthesis; cell cycle specific, S phase | Deaminated in blood and tissues | Pancreatitis; with high doses, cerebral dysfunction, GI damage, hepatotoxicity, pulmonary edema, corneal damage, “Ara-C syndrome” | With high-dose cyclophosphamide, may increase cardiotoxicity | Acute granulocytic leukemia and its variants, non-Hodgkin's lymphoma, myelodysplasia[*] |
Fludarabine phosphate (Fludara) | Antimetabolite of the purine type | 2-Fluoro-ara-ATP inhibits DNA synthesis by inhibition of ribonucleotide reductase and the DNA polymerases; cell cycle specific, S phase | Renal | Neurologic, pulmonary toxicity | None | CLL |
Fluorouracil (5-FU, Adrucil) | Antimetabolite of the pyrimidine analogue type | Inhibits DNA and RNA synthesis; cell cycle specific, S phase | Respiratory, small renal elimination | Cerebellar ataxia, myocardial ischemia | None | Breast cancer, GI cancers, head and neck cancer, bladder cancer, ovarian cancer, endometrial cancer, effusions |
Floxuridine (FUDR) | Antimetabolite of the pyrimidine analogue type | Inhibits DNA and RNA synthesis; cell cycle specific, S phase | Respiratory, small renal elimination | Cerebellar ataxia, myocardial ischemia, hepatotoxicity | Leucovorin enhances activity and toxicity; thymidine rescues toxic effects | Intra-arterial therapy for hepatic malignancies |
Hydroxyurea (Hydrea) | Antimetabolite | Inhibits ribonucleotide reductase, causing inhibition of DNA synthesis; cell cycle specific, S phase | Renal after hepatic biotransformation | Megaloblastosis | May enhance the effects of anti-HIV drugs | Myeloproliferative disorders, ovarian cancer, head and neck cancer, cervical cancer (with radiation therapy) |
Mercaptopurine (Purinethol, 6-MP) | Antimetabolite of the purine analogue type | Inhibits DNA synthesis; cell cycle specific, S phase | Metabolic alteration by xanthine oxidase, renal excretion | Hepatotoxicity, skin rashes | Dose must be reduced when used with allopurinol; concomitant methotrexate enhances bioavailability of 6-MP; inhibits Coumadin effects | Acute lymphoblastic leukemia |
Methotrexate (Folex, Mexate) | Antimetabolite of the folic acid analogue type | Inhibits DNA, RNA, thymidylate, and protein synthesis as a result of binding to dihydrofolate reductase; cell cycle specific, S phase | Renal | Hepatotoxicity, lung disease; in high doses, acute renal failure, acute neurologic dysfunction; avoid use with ascites, pleural effusions | Salicylates, NSAIDs, folic acid–containing vitamins, oral nonabsorbable broad-spectrum antibiotics, trimethoprim/sulfamethoxazole, other nephrotoxic drugs | Breast cancer, head and neck cancer, choriocarcinoma, acute lymphoblastic leukemia, non-Hodgkin's lymphomas, osteosarcoma, intrathecal treatment of meningeal leukemia, bladder cancer, lung cancer |
Pemetrexed (Alimta) | Antimetabolite of the folic acid analogue type | Inhibits thymidylate synthetase, dihydrofolate reductase, and de novo purine synthesis; cell cycle specific, S phase | Renal, after hepatic metabolism | Must be given with folic acid and vitamin B12; avoid use with ascites, pleural effusions | Salicylates, NSAIDs | Mesothelioma, breast cancer, lung cancer |
Pentostatin (Nipent) | Purine antagonist | Inhibits adenosine deaminase; also inhibits RNA synthesis | Renal | Fever, fatigue, rash, pain, hepatotoxicity, chronic immunosuppression | Enhances the effects of vidarabine, a purine nucleoside with antiviral activity; must not be given with fludarabine because of fatal pulmonary toxicity | Hairy cell leukemia, CLL |
Thioguanine (6-TG, Tabloid) | Antimetabolite of purine antagonist type | Purine antagonist; cell cycle specific, S phase | Hepatic transformation, renal excretion | Hepatotoxicity | None | Acute lymphocytic and granulocytic leukemia |
NONCOVALENT DNA-BINDING DRUGS | ||||||
Bleomycin (Blenoxane) | Antitumor antibiotic | Inhibition of DNA synthesis; most effective in G2 phase of cell division | Renal | Dose-related pulmonary fibrosis, hypersensitivity reactions, skin and mucocutaneous toxicity, including Raynaud's phenomenon (in combination with other agents), fever, chills; usually considered nonmyelosuppressive | Cisplatin may decrease renal clearance; high oxygen concentrations may enhance pulmonary toxicity, even after therapy | Testicular cancer and other germ cell tumors; Hodgkin's and non-Hodgkin's lymphomas; mycosis fungoides; squamous cell carcinomas of the head and neck, cervix, and vulva; pleural effusions |
Daunorubicin (Cerubidine) | Antitumor antibiotic | Binds to DNA by intercalation between base pairs and inhibits DNA and RNA synthesis by template disordering and steric obstruction; most active in S phase but not cell cycle phase specific | Hepatic biotransformation with 40% biliary excretion | Dose-related cardiotoxicity, extravasation, red urine | None | Acute granulocytic leukemia and its variants, acute lymphoblastic leukemia |
Doxorubicin (Adriamycin, Rubex) | Antitumor antibiotic | Binds to DNA by intercalation between base pairs and inhibits DNA and RNA synthesis by template disordering and steric obstruction; cell cycle specific, S phase | Hepatic biotransformation with 50% biliary excretion | Dose-related cardiotoxicity, extravasation, red urine | None | Acute granulocytic leukemia and its variants, acute lymphoblastic leukemia, breast cancer, bladder cancer, ovarian cancer, thyroid cancer, lung cancer, Hodgkin's and non-Hodgkin's lymphomas, sarcomas, gastric cancer, multiple myeloma, endometrial cancer, bladder cancer, prostate cancer, Wilms' tumor, neuroblastoma |
Idarubicin (Idamycin) | Anthracycline glycoside | Intercalates DNA and inhibits DNA synthesis, interacts with RNA polymerases, and inhibits topoisomerase II | Hepatic biotransformation, biliary | Dose-related cardiotoxicity, extravasation | None | Acute granulocytic leukemia and its variants |
Mitoxantrone (Novantrone) | Antitumor antibiotic | Binds to DNA by intercalation between base pairs and a nonintercalative electrostatic interaction, resulting in inhibition of DNA and RNA synthesis; not cell cycle specific, but most active in late S phase | Hepatic biotransformation with biliary/fecal excretion | Dose-related cardiotoxicity, extravasation, blue-green urine | None | Prostate cancer, acute myelogenous leukemia and its variants, breast cancer, non-Hodgkin's lymphomas |
INHIBITORS OF CHROMATIN FUNCTION | ||||||
Docetaxel (Taxotere) | Mitotic spindle poison | Unique mitotic spindle inhibitor; cell cycle specific, M phase | Hepatic metabolism, biliary | Hypersensitivity reactions, fluid retention syndrome, nail discoloration, neuropathy, arthralgias | Inhibitors or activators of the liver cytochrome P-450 CYP34A enzyme system may affect metabolism | Breast cancer, prostate cancer, lung cancer, ovarian cancer, esophageal cancer, gastric cancer, head and neck cancer, bladder cancer |
Etoposide (VP-16, VePesid) | Epipodophyllotoxin | Inhibits DNA synthesis; cell cycle dependent and phase specific, with maximum effect in S and G2 phases | Hepatic biotransformation, then renal elimination | Allergic reactions, hepatotoxicity, CNS toxicity, hypotension | None | Testicular cancer, lung cancer, Hodgkin's and non-Hodgkin's lymphomas, choriocarcinoma, Ewing's sarcoma, acute granulocytic leukemia |
Irinotecan (Camptosar) | Topoisomerase I inhibitor | Binds to the topoisomerase I–DNA complex and prevents relegation of these single-strand breaks | Metabolized in the liver | Early and late diarrhea may be severe | None | Colorectal cancer, small cell lung cancer |
Paclitaxel (Taxol) | Mitotic spindle poison | Unique mitotic spindle inhibitor; cell cycle specific, M phase | Hepatic metabolism, biliary | Hypersensitivity reactions, neuropathy, arthralgias, cardiotoxicity | Enhanced myelosuppression with doxorubicin | Lung cancer, ovarian cancer, breast cancer, esophageal cancer, gastric cancer, head and neck cancer |
Paclitaxel protein-bound particles (Abraxane) | Mitotic spindle poison | Unique mitotic spindle inhibitor; cell cycle specific, M phase | Hepatic metabolism, biliary | Hypersensitivity reactions, neuropathy, arthralgias/myalgias, cardiotoxicity | Enhanced myelosuppression with doxorubicin | Metastatic breast cancer |
Topotecan (Hycamtin) | Topoisomerase I inhibitor | Binds to the topoisomerase I–DNA complex and prevents relegation of these single-strand breaks | Excreted unchanged in urine | — | None | Relapsed ovarian cancer, small cell lung cancer |
Vinblastine (Velban) | Vinca alkaloid | Blocks mitosis by arresting cells in metaphase; cell cycle specific, M phase | Biliary/fecal | Extravasation, neurotoxicity | None | Testicular cancer, breast cancer, choriocarcinoma, Hodgkin's and non-Hodgkin's lymphomas, Kaposi's sarcoma, bladder cancer, neuroblastoma, renal carcinoma |
Vincristine (Oncovin) | Vinca alkaloid | Blocks mitosis by arresting cells in metaphase; cell cycle specific, M phase | Biliary/fecal | Extravasation, neurotoxicity, constipation, SIADH | Concurrent use with 1-asparaginase may increase neurotoxicity | Acute lymphocytic leukemia, neuroblastoma, Wilms' tumor, Hodgkin's and non-Hodgkin's lymphomas, rhabdomyosarcoma, Ewing's sarcoma, breast cancer, small cell lung cancer, multiple myeloma |
Vinorelbine (Navelbine) | Vinca alkaloid | Inhibits tubulin polymerization, disrupting formation of microtubule assembly during mitosis; cell cycle specific, M phase | Biliary/fecal | Extravasation, neurotoxicity, constipation, SIADH | Drugs metabolized by liver P-450 system, phenytoin | Non–small cell lung cancer, breast cancer, non-Hodgkin's lymphomas |
HORMONAL AGENTS | ||||||
Anastrozole (Arimidex) | Nonsteroidal aromatase inhibitor | Inhibits the synthesis of estrogens by inhibiting the conversion of adrenal estrogens to estrogens | Metabolized in the liver | Hot flashes, arthralgias | None | Adjuvant and metastatic breast cancer in postmenopausal women |
Bicalutamide (Casodex) | Nonsteroidal antiandrogen | Binds to androgen receptors in prostate | Hepatic metabolism | Worsening bone pain, gynecomastia, hot flashes | None | Prostate cancer (usually in conjunction with LHRH antagonist) |
Dexamethasone (Decadron) | Corticosteroid | Multiple | Renal excretion of inactive metabolites | Cushingoid appearance, hyperglycemia, fluid retention, osteoporosis, muscular weakness, peptic ulcer disease, cataracts, psychosis, aseptic necrosis | Efficacy impaired by phenytoin | Acute lymphoblastic leukemia, Hodgkin's and non-Hodgkin's lymphomas, CLL, multiple myeloma, Waldenstr?m's macroglobulinemia, for treatment of cerebral edema, hypercalcemia, lymphangitic metastases, and as an antiemetic |
Diethylstilbestrol (DES) | Estrogen | Stimulation of autocrine growth factors | Renal | Feminization in men, fluid retention, thromboembolic phenomena, induction of endometrial cancer | None | Breast cancer, prostate cancer |
Estradiol | Estrogen | Stimulation of autocrine growth factors | Renal | Feminization in men, fluid retention, thromboembolic phenomena, induction of endometrial cancer | None | Breast cancer, prostate cancer |
Estramustine (Emcyt) | Phosphorylated combination of estradiol and nitrogen mustard | Inhibits microtubule structure and function; cell cycle specific, M-phase | Biliary/fecal | Feminization, fluid retention | None | Prostate cancer |
Estrogens (Conjugated or esterified) | Estrogen | Stimulation of autocrine growth factors, inhibition of pituitary secretion of LH, resulting in decreased serum testosterone concentration | Primarily renal | Feminization in men, fluid retention, thromboembolic phenomena, induction of endometrial cancer | None | Breast cancer, prostate cancer |
Exemestane (Aromasin) | Steroidal aromatase inhibitor | Permanently binds to and irreversibly inhibits aromatase, inhibits the synthesis of estrogens by inhibiting the conversion of adrenal estrogens to estrogens | Metabolized in the liver | Hot flashes, arthralgias | None | Metastatic breast cancer in postmenopausal women |
Fluoxymesterone (Halotestin) | Androgen | Suppresses GnRh, LH, and FSH through a negative feedback mechanism involving the hypothalamus and anterior pituitary | Renal | Masculinization in women, hepatotoxicity | May increase anticoagulant effects of Coumadin; decreased blood glucose, resulting in potential for hypoglycemia in diabetics | Breast cancer |
Flutamide (Eulexin) | Antiandrogen | Inhibition of androgen uptake and/or inhibition of nuclear binding of androgen in target tissues; its interference with testosterone at the cellular level complements the “medical castration” produced by LHRH analogues | Renal | Worsening bone pain, hot flashes, gynecomastia | None | Prostate cancer (usually in conjunction with LHRH antagonist) |
Fulvestrant (Faslodex) | Estrogen receptor antagonist | Competitively binds to the estrogen receptor and down-regulates the estrogen receptor protein in breast cancer cells | Cleared by hepatobiliary route | Arthralgias | None | Recurrent breast cancer in postmenopausal women |
Goserelin (Zoladex) | Synthetic decapeptide analogue of LHRH | Suppresses pituitary gonadotrophins, with fall of serum testosterone into castrate range | Metabolism | Worsening bone pain, hot flashes | None | Breast cancer, prostate cancer |
Letrozole (Femara) | Nonsteroidal competitive inhibitor of aromatase | Inhibits synthesis of estrogens by inhibiting the conversion of adrenal estrogens to estrogens | Metabolized in the liver | Hot flashes, arthralgias | None | Adjuvant and metastatic breast cancer in postmenopausal women |
Leuprolide (Lupron, Lupron Depot) | Synthetic LHRH analogue | Suppresses secretion of GnRh, with a resultant fall in testosterone secretion, producing a “medical castration” | Metabolized in liver | Increased bone pain, hot flashes, thromboembolic phenomena | None | Prostatic cancer, breast cancer |
Medroxyprogesterone (Provera, Depo-Provera) | Progestational drug | Inhibition of pituitary gonadotropin production with resultant decrease in estrogen secretion | Renal | Weight gain, thromboembolic phenomena, fetal hazard | None | Breast cancer, endometrial cancer |
Megestrol acetate (Megace) | Progestational drug | Inhibition of pituitary gonadotrophin production, with resultant decrease in estrogen secretion | Renal | Weight gain, thromboembolic phenomena, fetal hazard | None | Breast cancer, endometrial cancer |
Nilutamide (Nilandron) | Nonsteroidal antiandrogen | Binds to androgen receptors in prostate, inhibiting androgen uptake and binding in the nucleus | Hepatic metabolism | Worsening bone pain, gynecomastia, hot flashes, visual disturbances, interstitial pneumonitis | Increased warfarin effect; inhibits liver cytochrome P-450 system; increased risk of alcohol intolerance | Prostate cancer (usually in conjunction with LHRH antagonist) |
Octreotide (Sandostatin) | Synthetic octapeptide analogue of somatostatin | Suppresses secretion of serotonin and GI peptides; blocks carcinoid flush, decreases serum 5-HIAA, and controls other symptoms associated with the carcinoid syndrome | Renal | Hyper/hypoglycemia, hepatic dysfunction | None | Palliative treatment of carcinoid tumors and vasoactive intestinal peptide tumors (VIPomas) |
Prednisone (Deltasone) | Corticosteroid | Multiple | Renal excretion of inactive metabolites | Cushingoid appearance, hyperglycemia, fluid retention, osteoporosis, muscular weakness, peptic ulcer disease, cataracts, psychosis, aseptic necrosis | Efficacy impaired by phenytoin | Acute lymphoblastic leukemia, Hodgkin's Hodgkin's and non-lymphomas, CLL, multiple myeloma, Waldenstr?m's macroglobulinemia, for treatment of cerebral edema, hypercalcemia, lymphangitic metastases, and as an antiemetic |
Tamoxifen (Nolvadex) | Nonsteroidal antiestrogen | Competes with estradiol for estrogen receptor protein | In feces, mainly as conjugates | Hot flashes, nausea/vomiting, vaginal bleeding or discharge, hypercalcemia, visual disturbances, thrombocytopenia, endometrial cancer, rare liver dysfunction | When used with coumarin anticoagulants a significant increase in anticoagulant effect may be seen | Adjuvant and metastatic breast cancer |
BIOLOGIC RESPONSE MODIFIERS | ||||||
Aldesleukin (Human Recombinant IL-2, Proleukin) | Lymphokine | Supports T-cell proliferation, augments natural killer cytotoxicity, induces lymphokine-activated killer (LAK) cell development, and participates in the activation of monocytes and B cells | Renal | Cardiovascular toxicity, nephrotoxicity, pulmonary toxicity, GI toxicity, endocrine toxicity, dermatologic complications, CNS toxicity, hematologic toxicity, fever and chills, infection, capillary leak syndrome | May potentiate effects of psychotropics, nephrotoxic drugs, and antihypertensive agents; corticosteroids may reduce effectiveness | Renal cancer, melanoma |
Erythropoietin (Aranesp, Epogen, Procrit)[†] | Hematopoietic growth factor | Stimulates division and differentiation of committed erythroid progenitors in the bone marrow | Metabolized in liver | Headache, hypertension, possible seizures, allergic reactions | None | Correction of anemia in chronic renal failure, azathioprine-treated HIV infection, myelodysplasia, multiple myeloma, chemotherapy-induced anemia |
Filgrastim (G-CSF, Neupogen) | Class II hematopoietic growth factor (acts on progenitor cells capable of forming only one differentiated cell type, the neutrophil) | CSFs bind to specific cell surface receptors and stimulate proliferation and differentiation | Metabolized in liver | Pain at site of subcutaneous injection, allergic reactions, arthralgias, bone pain | None | Decreases the incidence of infection after myelosuppressive chemotherapy, enhances myeloid engraftment after bone marrow transplantation, enhances peripheral progenitor cell yield |
Interferon-α (Intron-A, Roferon)[‡] | Interferon | Antiviral, antiproliferative, and immunomodulatory properties | Renal | Fever, flulike symptoms, cardiotoxicity, neurotoxicity | None | Hairy cell leukemia, Kaposi's sarcoma, renal cancer, non-Hodgkin's lymphoma |
Sargramostim (GM-CSF, Leukine, Prokine) | Class I hematopoietic growth factor (stimulates formation of granulocytes and macro-phages and is not lineage specific) | CSFs bind to specific cell surface receptors and stimulate proliferation and differentiation | Metabolized in liver | Fever, capillary leak syndrome, pain at site of subcutaneous injection, allergic reactions, arthralgias, bone pain | None | Decreases the incidence of infection after myelosuppressive chemotherapy, enhances myeloid engraftment after bone marrow transplantation, enhances peripheral progenitor cell yield |
TARGETED AGENTS | ||||||
Alemtuzumab (Campath) | Humanized monoclonal antibody | Targets CD52 antigen present on the surface of most normal lymphocytes and malignant B and T lymphocytes | Metabolism unclear | Hypersensitivity reactions, immunosuppressive | None | Relapsed B-cell CLL, T-cell prolymphocytic leukemia |
Bevacizumab (Avastin) | Recombinant humanized monoclonal antibody to VEGF; inhibits angiogenesis | Binds to all human forms of VEGF, preventing it from binding to its receptors, reducing blood vessel formation | Metabolized | Hemorrhage, hypertension, proteinuria, thrombophlebitis | SN-38 metabolite of irinotecan is higher with concurrent use | Metastatic colorectal cancer, lung cancer, breast cancer |
Bortezomib (Velcade) | Targeted agent | A reversible inhibitor of the 26S proteasome; inhibits the breakdown of ubiquinated intracellular proteins and disrupts the ubiquitin–proteasome pathway, eventually leading to apoptosis | Undergoes oxidative metabolism via cytochrome P-450 enzymes | Myelosuppression, peripheral neuropathy, asthenia, hypotension | Unknown | Relapsed multiple myeloma |
Cetuximab (Erbitux) | Chimeric monoclonal antibody targeted against EGFR | Blocks growth factor from binding to EGFR, preventing cell signaling by tyrosine kinase phosphorylation | Metabolized | Hypersensitivity reactions, rash, diarrhea | None | Metastatic colorectal cancer |
Erlotinib (Tarceva) | Targeted agent | Inhibits the tyrosine kinase domain of the EGFR | Metabolized | Rash, diarrhea, interstitial lung disease | CYP3A4 induces and inhibitors may alter metabolism | Second-or third-line non–small cell lung cancer |
Gemtuzumab ozogamicin (Mylotarg) | Monoclonal antibody conjugated to a cytotoxic antibody, calicheamicin | Antibody binds to the CD33 antigen found on leukemia cells; when inside the cell, calicheamicin binds to DNA, causing double-strand breaks and cell death | Calicheamicin is metabolized to many metabolites | Hypersensitivity reactions, prolonged myelosuppression | None | Relapsed myeloid leukemia in patients >60 yr |
Imatinib (Gleevec) | Targeted agent; signal transduction inhibitor | Inhibits BCR-ABL tyrosine kinase | Hepatic metabolism, excreted in feces | Myelosuppression, hypophosphatemia, fluid retention | Drugs inhibiting/stimulating liver microsomal CYP3A4 enzyme | Chronic myelogenous leukemia, gastrointestinal stromal tumors (GIST) |
Lenalidomide (Revlimid, CC-5013) | Targeted agent | Induces apoptosis | Renal excretion | Neutropenia, thrombocytopenia, diarrhea, pruritus, rash, fatigue, leg cramps | Other myelosuppressive agents | Myelodysplasia, myeloma[?] |
Nexavar (Sorafenib, BAY 43-9006) | Targeted agent | Multikinase inhibitor, inhibits RAF kinase, VEGF, and PDGF receptors | Hepatic | Rash, hand and foot syndrome, fatigue, diarrhea, hair loss | CYP2C9 inducers, UGT1A1 pathway excreted agents (irinotecan) | Renal cell carcinoma |
Rituximab (Rituxan) | Chimeric anti-CD20 antibody | Targets CD20 antigen expressed on lymphocytes | Metabolized | Hypersensitivity reactions, lymphopenia | None | Relapsed low grade non-Hodgkin's lymphomas |
Thalidomide (Thalomid) | Immunomodulatory agent antigenic agent | Inhibits TNF-α, may inhibit angiogenesis through inhibition of bFGF and VEGF | Nonenzymatic hydrolysis | Teratogenicity, sedation, constipation, peripheral neuropathy, rash | Sedation enhanced with alcohol, other sedatives | Multiple myeloma |
Trastuzumab (Herceptin) | Recombinant humanized monoclonal antibody against Her-2/neu | Down regulates expression of ERBB2 pathways | Metabolized | Hypersensitivity reactions | Increased risk of cardiotoxicity when used with anthracyclines or taxanes | Metastatic or adjuvant Her-2/neu-positive breast cancer |
DRUGS TO OFFSET SIDE EFFECTS OF CHEMOTHERAPY | ||||||
Leucovorin (Folinic Acid, Citrovorum Factor, Wellcovorin) | Water-soluble folate vitamin | Increases general body pool of reduced folates | Metabolized in liver | None | In large amounts may counteract action of anticonvulsives | Prophylaxis and treatment of hematopoietic side effects of folic acid antagonists |
Mesna (Mesnex) | Synthetic sulfhydryl compound | Only metabolite, mesna disulfide, reacts chemically with urotoxic ifosfamide metabolites, resulting in their detoxification | Renal | Bad taste, diarrhea | None | Prophylaxis of cyclophosphamide/ifosfamide-induced hemorrhagic cystitis |
ATP = adenosine triphosphate; bFGF, basic fibroblast growth factor; CLL = chronic lymphocytic leukemia; CNS = central nervous system; CSF = colony-stimulating factor; EGFR = epidermal growth factor receptor; ERBB2 = Her-2/neu; FSH = follicle-stimulating hormone; G-CSF = granulocyte-colony stimulating factor; GM-CSF = granulocyte-monocyte colony stimulating factor; GI = gastrointestinal; GnRh = gonadotrophin-releasing hormone; 5-HIAA = 5-hydroxyindolacetic acid; HIV = human immunodeficiency virus; LH = luteinizing hormone; LHRH = luteinizing hormone–releasing hormone; MAO = monoamine oxidase; NSAIDs = nonsteroidal anti-inflammatory drugs; PDGF = platelet-derived growth factor; SIADH = syndrome of inappropriate secretion of antidiuretic hormone; TNF = tumor necrosis factor-α; VEGF = vascular endothelial growth factor. |
* | Note: An intrathecal formulation, DepoCyt, is used for the treatment of carcinomatous meningitis. |
† | Note: Dosing differs among agents. |
‡ | Note: Dosages differ between brands. |
? | Note: An analogue of thalidomide, a severe human teratogen. Restricted prescribing.  |
No hay comentarios:
Publicar un comentario