309Chemotherapy

ONE LETTER AND COMBINATION CHEMOTHERAPY ABBREVIATIONS

      A: dactinomycin/actinomycin D

      ABVD: adriamycin/doxorubicin, bleomycin, vinblastine, dacarbazine

      AcFucy: dactinomycin, 5-FU, cyclophosphamide

      AI: aromatase inhibitor

      B: bleomycin

      BEP: bleomycin, etoposide, cisplatin

      C: cyclophosphamide

      CDDP: cisplatin; cis-diamminedichloroplatinum

      CHOPP-R: cyclophosphamide, hydroxyurea, vincristine, procarbazine, prednisone, rituximab

      CMFV: cyclophosphamide, methotrexate, 5-FU, vinblastine

      D: doxorubicin

      E: etoposide, VP-16

      Epi: epirubicin

      F: 5-FU

      H: hydroxyurea

      L: chlorambucil

      Lev: levamisole

      L-PAM: L-phenylalanine mustard

      M: methotrexate

      MAC: methotrexate, dactinomycin, cyclophosphamide or chlorambucil

      MMC: mitomycin

      MOPP: nitrogen mustard, vincristine, procarbazine, prednisone

      MVPP: nitrogen mustard, vinblastine, procarbazine, prednisone

      O: oncovin/vincristine

      P: cisplatin

      Pr: prednisolone

      T: tamoxifen

      TVPP: thiotepa, vinblastine, procarbazine, prednisone

      V: vinblastine

      VAC: vincristine, doxorubicin cyclophosphamide

      VBM: vinblastine, bleomycin, methotrexate

      VBP: vinblastine, bleomycin, cisplatin

      VDC: vincristine, doxorubicin, cyclophosphamide

310CHEMOTHERAPY DEFINITIONS

•   Dose: amount of chemotherapy administered

•   Intensity: the amount of drug administered over time

•   Schedule: time interval for delivery of chemotherapy

•   Chemotherapy cycle: one treatment of single or combination agents in the full course of therapy

•   Chemotherapy course: sequence of cycles for treatment

•   Planning of treatment: must take into consideration tumor type, extent of disease, patient’s comorbidities including renal function, age, social and emotional function, or if therapy is primary or salvage

DELIVERY

Routes are intravenous (IV), intramuscular (IM), per oral (PO), intraperitoneal (IP), or regional. Most chemotherapy is administered systemically, by IV. It can be given regionally to primary tumors or their metastasis. IP chemotherapy is administration of chemotherapy directly into the abdominopelvic cavity. Regional chemotherapy can be used to treat solitary organ lesions, like liver metastasis. This occurs by obstruction of the outflow tract for a limited amount of time so that the chemotherapy can penetrate the tumor mass directly. It can also be directly administered to a cavity such as for pleural or pericardial lesions.

METABOLISM

•   Pro-drugs can be bio-transformed into active metabolites. This includes cyclophosphamide. It is important to know those drugs that are activated by the liver because IP administration may have no effect.

•   Excretion: hepatobiliary or renal excretion are the main routes of excretion. Drugs can be metabolized to pro-drugs, to inactive states, remain unchanged, or accumulate in body tissues.

PRINCIPLES OF CHEMOTHERAPY TUMOR KILL

The patient needs two cycles after resolution of tumor markers and/or no evidence of disease with complete clinical remission (CCR) to eliminate microscopic systemic disease.

CHEMOTHERAPY REGIMENS

•   Primary: chemotherapy is the initial treatment.

•   Adjuvant: chemotherapy is used following primary treatment with surgery or radiation therapy (XRT).

•   Neoadjuvant: chemotherapy is used for initial treatment to be followed by surgery, XRT, or a combination of therapies.

•   Secondary: any chemotherapy regimen given after primary chemotherapy.

•   Salvage: chemotherapy is used in the treatment of recurrent or persistent disease after previous chemotherapy.

•   Consolidation: chemotherapy that is continued/used for a defined interval after primary or adjuvant chemotherapy to decrease the chance of cancer recurrence in patients with CCR. This is usually a short duration of treatment (4–6 more cycles).

•   Maintenance: chemotherapy that is continued/used after primary or adjuvant chemotherapy for an indefinite interval to decrease the chance of cancer recurrence in patients with CCR. This is usually of a longer duration than consolidation therapy until progression or toxicity. Some protocols specify 18 cycles or 22 months after primary adjuvant therapy.

PLATINUM SENSITIVITY/RESISTANCE IN HGSTOC OR OVARIAN GERM CELL TUMORS

Tumors are classified as platinum sensitive, resistant, or refractory.

•   Platinum sensitive: if the tumor recurs 6 or more months after the completion of primary platinum-based chemotherapy, it is said to be platinum sensitive.

•   Platinum resistant: if the tumor recurs within 6 months of primary platinum-based chemotherapy, it is considered platinum resistant.

•   Platinum refractory: if the tumor does not respond to initial platinum chemotherapy and growth continues during the primary treatment, it is considered platinum refractory.

•   For germ cell tumors, the time interval is different and resistance is specified at 6 weeks. Germ cell tumors are designated as refractory if no response is seen at 4 weeks of ongoing chemotherapy.

TOXICITY

•   Side effects from chemotherapy are graded according to severity. The most commonly affected organ systems are the gastrointestinal system, the hematopoietic system, and the integumentary system. Please refer to the common toxicity criteria (CTC) website for the full classification of toxicity grades. Management of toxicity due to chemotherapy is with a reduction in the total dose of drug per cycle, called a dose reduction. This is usually a 20% to 25% dose reduction, or a decrease in the area under the curve (AUC) by one level.

•   Cardiac toxicity mainly occurs with doxorubicin. A history and exam can diagnose congestive heart failure (CHF). Confirmation is with an echocardiogram or with a multigated acquisition (MUGA) scan.

•   Pulmonary toxicity has been seen mainly with bleomycin. A pre-treatment carbon monoxide spirometry diffusion capacity test (DLCO) is recommended. A 15% change in the forced expiratory volume (FEV) indicates toxicity. Pulmonary toxicity can also be determined clinically with an examination. Clinical symptoms such as rales, hypoinflation, or a lag in the inspiratory phase on exam, as well as dyspnea occur before a documented drop in FEV.

•   Secondary malignancies can occur after the administration of chemotherapeutic agents. The rate is about 1% to 2%. Leukemias can occur from alkylating agents, which include melphalan, the podophyllotoxins, etoposide, cyclophosphamide, and the platinum compounds. The development of leukemias is dose dependent (2 g for etoposide). The median latency is 4 years after chemotherapy for epithelial ovarian cancer (EOC), with an overall incidence of 0.17% (1).

312THE CELL CYCLE

•   The cell cycle is broken into interphase and mitosis. Interphase consists of the G1, S, and G2 phases. G1 is a variable period, where protein, RNA, and DNA repair occur. The cell can terminally differentiate or continue in the cell cycle from this phase. S phase is when new DNA is synthesized. The G2 phase occurs after the S phase and thus the cell contains two times the amount of DNA. This is a short phase. It is the variation in the length of the G1 phase that affects the proliferative behavior of cell populations.

•   Mitosis consists of five phases. Prophase, the first phase, is when chromosomes condense. Metaphase is when chromosomal division occurs. This is the most radiosensitive phase. Anaphase is when sister chromosomes move to opposite cell poles. Telophase demonstrates polarization of chromosomes and disassembly of the cytoskeleton occurs. Cytokinesis follows with division of the cell into separate daughter cells. Cell cycle times vary from 10 to 31 hours.

•   Masses are usually palpated at 10⁹ cells or 1 cm in size. The 1-cm size usually occurs after 30 doublings of one tumor cell.

GROWTH FRACTION

This consists of the fraction of cells in a tumor that is actively proliferating. This fraction ranges from 25% to 95%.

CELL DEATH

Cell death has been seen with some tumors. This has been documented in some breast cancers associated with febrile episodes (2) or when tumors outgrow their vascular supply.

LOG KILL

A constant fraction of cells are killed with each dose of therapy—not a constant number of cells. To achieve substantial tumor reduction, a repetitive insult has to be delivered to the tumor. Single-agent chemotherapy can be curative in this fashion, but is not as effective as multiagent chemotherapy. Multiagent chemotherapy uses different drugs that target separate cellular pathways. The effect can be additive or synergic.

CELL-CYCLE NONSPECIFIC CHEMOTHERAPEUTIC AGENTS

These agents kill cells in all phases of the cell cycle.

CELL-CYCLE SPECIFIC AGENTS

These agents depend on the proliferative fraction of the tumor and a specific cell cycle phase. These agents are usually more effective against tumors with a high proliferative rate and a high growth fraction.

CELL GROWTH

Growth is usually demonstrated via a Gompertzian log tumor growth curve.

•   There are four phases to cell growth:

        Lag growth phase

        The log growth phase

313         Stable growth phase

        Death phase

MECHANISMS OF CYTOTOXICITY

Chemotherapeutic agents can target cellular DNA, proteins (such as enzymes, receptors, or the metabolic respiratory chain), and RNA.

MECHANISMS OF RESISTANCE

•   The Goldie–Coldman hypothesis is a mathematical model that predicts the probability of a tumor harboring drug-resistant clones. The number of drug-resistant clones depends on the mutation rate and the size of the tumor.

•   Documented mechanisms of drug resistance include as follows:

        The multidrug resistance protein-1 (MDR-1) and MDR-2 P-glycoproteins, which are components of the adenosine triphosphate (ATP)-binding cassette (ABC) transporters. These proteins transport drugs out of cells.

        Cells can decrease the entry of the drug into the cell via down regulation of cellular receptors.

        Metabolic inactivation of the drug can occur via up-regulation of the glutathione (GSH) sulfate and dihydrofolate reductase (DHFR) enzymes.

        There can be altered binding affinity of the drug to albumin or intracellular targets.

        Genomic change can occur via:

             Altered DNA repair mechanisms

             Gene point mutation

             Gene frameshift mutation

             Gene deletion

             Gene amplification

        Gatekeeping mutations: the initial genetic change that gives a single cell a selective growth advantage, allowing the subsequent acquisition of driver mutations, which alter the proliferation rate, invasion capability, cellular signaling, and DNA repair of a tumor.

        Passenger mutations: have no effect on the neoplastic process and accumulate with age.

PRIOR TO CHEMOTHERAPY ADMINISTRATION

The patient should have adequate laboratory values; these are considered to be:

•   White blood cell count (WBC) greater than 3 × 10³/mcL with an absolute neutrophil count (ANC) greater than 1.5 × 10³/mcL

•   Platelets greater than 100 × 10³/mcL

•   Normal liver function tests (LFTs)

•   Creatinine less than 2 mg/dL or creatinine clearance greater than 50 mL/min

•   Gynecologic Oncology Group (GOG) performance status of either 0, 1, or 2 with an estimated survival of more than 2 months

314CLASSES OF CHEMOTHERAPY AGENTS AND INDEPENDENT MECHANISMS OF ACTION

ALKYLATING AGENTS

These work by intercalating or cross-linking DNA—making DNA adducts. They are cell-cycle nonspecific.

•   Carboplatin (Paraplatin): a platinum compound. It is dosed with the following equation: carboplatin total dose (mg) = AUC × (GFR + 25). It can be given at an AUC of 7 as single agent or at an AUC of 5 to 6 in combination therapy. Its mechanism of action is intercalation with DNA and is administered via the IV or IP route. It is eliminated via the renal system. Its toxicities are primarily thrombocytopenia, hypersensitivity reactions, leukopenia, nausea, and vomiting. The platelet nadir is usually around 21 days. Secondary toxicities can include nephrotoxicity 7%, peripheral neuropathy 6%, and ototoxicity 1%. Vitamin B₆ can prevent some neurotoxicity. Hypersensitivity can occur in 25% of patients if more than six cycles are received. There is an increased risk of leukemia with a relative risk of 6.5. Amifostine can reduce the amount of thrombocytopenia at a dose of 910 mg/m².

•   Cisplatin (Platinol): a platinum compound that works by intercalating with DNA and creating G–G adducts. It is administered either IV or IP. It can be given as a single agent to radiosensitize certain tumors at 40 to 50 mg/m² weekly. It can be given as single-agent therapy at 50 to 100 mg/m², or at 75 mg/m² in combination with other drugs every 3 weeks. 90% is eliminated by the renal system and 10% by the hepatic/biliary system. Primary toxicities are leukopenia and anemia. Nephrotoxicity occurs in 21%, ototoxicity in 10%, and some patients have peripheral or autonomic neuropathy. Secondary toxicities are allergic reactions, low sodium (Na), potassium (K), calcium (Ca), and magnesium (Mg). The pancytopenia nadir occurs between 18 and 23 days. To reduce some nephrotoxicity, prehydrate with normal saline intravenous fluid (IVF) and consider mannitol diuresis with an additional 3 g of MgSO₄.

•   Cyclophosphamide (Cytoxan): it is a pro-drug that is activated by liver metabolism and then the active drug intercalates with DNA. It is administered either IV or PO. It can be given as a single agent or in combination with other agents. The dosing is usually 10 to 50 mg/kg IV every 1 to 4 weeks or 600 to 1,000 mg/m² every 4 weeks. 85% is eliminated by the liver and 15% by the renal system. Primary toxicities include pancytopenia (this is the most marrow-suppressive drug), nausea, vomiting, and alopecia. Secondary toxicities are hemorrhagic cystitis from the acrolein metabolite, syndrome of inappropriate secretion of antidiuretic hormone (SIADH) if the dose is greater than 50 mg/kg, interstitial pneumonia, cardiomyopathy, and leukemia with a relative risk of 5.4 after 10 years. The nadir occurs at days 8 to 14. To diagnose hemorrhagic cystitis, obtain a urine analysis: confirmation is with gross hematuria or 20 red blood cells per high power field (RBC/HPF). Mesna should be coadministered to decrease the incidence of hemorrhagic cystitis. Methylene blue bladder irrigation can also decrease the complications of hemorrhagic cystitis.

•   Dacarbazine (DTIC): administered IV usually at a dose of 2 to 4.5 mg/kg/day for 5 to 10 days every 4 weeks. Elimination is via the renal system. Primary toxicities include pancytopenia, nausea, vomiting, and alopecia. Secondary toxicities include mucositis, stomatitis, myalgias, and hepatotoxicity. The nadir occurs 2 to 4 weeks after administration.

•   Ifosfamide (Ifex): also a pro-drug; it is activated by hepatic metabolism and is administered IV at a dose of 1.2 to 1.6 g/m²/day for 5 days every 3 to 4 weeks, 700 to 900 mg/m²/day for 5 days every 3 weeks, or 1,000 mg/m² on days 1 and 2 every 28 days as part of the ifosfamide–carboplatin–etoposide (ICE) protocol. Elimination is via the renal system for 73% of the drug. Primary toxicities are hemorrhagic cystitis, pancytopenia, nausea, vomiting, and alopecia. Secondary toxicities are nephrotoxicity, SIADH, and central nervous system (CNS) toxicity. CNS toxicity is increased with baseline dementia or a low serum albumin. The neurotoxin chloroacetaldehyde is a byproduct of this drug. The nadir is days 5 to 10 after administration and this drug also needs coadministration of mesna to decrease the incidence of hemorrhagic cystitis.

•   Melphalan (Alkeran): cross links DNA and can be administered IV, PO, or IP. Dosing occurs at 16 mg/m² IV every 2 weeks for four doses then at 4-week intervals, or 1 mg/kg IV every 4 weeks. The PO dose is 6 mg/day for 2 to 3 weeks followed by a 4-week holiday. There is 63 times greater exposure via the IP route. Elimination is 99% renal. Primary toxicity is pancytopenia with secondary toxicities to include nausea, vomiting, and leukemia (11.2% cumulative 10-year risk). The nadir occurs at days 28 to 35 and there is increased drug bioavailability if taken after fasting for 8 hours. Drug resistance is via increased intracellular glutathione S-transferase (GST), and buthionine sulfoximine (BSO) can reverse this resistance.

•   Temozolomide (Temodar): a triazene analog of dacarbazine with antineoplastic activity. As a cytotoxic alkylating agent, temozolomide is converted at physiologic pH to the short-lived active compound, monomethyl triazeno imidazole carboxamide (MTIC). The cytotoxicity of MTIC is due primarily to methylation of DNA at the O6 and N7 positions of guanine, resulting in inhibition of DNA replication. Unlike dacarbazine, which is metabolized to MTIC only in the liver, temozolomide is metabolized to MITC at all sites. Temozolomide is administered orally and penetrates well into the CNS. Dosing: varies by tumor protocol but commonly is calculated: BSA × 75 then rounded to the nearest 5 mg PO BID days 1 to 14. Another regimen is 150 mg/m² IV daily for 5 days of a 28 day cycle.

•   Altretamine (Hexalen, Hexamethylmelamine): this is a pro-drug that is metabolically activated by the liver. It is important to not take supplements with B₁₂ because this inactivates the drug. It is administered PO at a dose of 260 mg/m²/day in four daily divided doses for 14 to 21 days every 4 weeks. 85% is eliminated via the renal system. Primary toxicities are pancytopenia, neuropathy, nausea, vomiting, and nephrotoxicity. Secondary toxicities include rash, neurotoxicity, and seizures. The nadir occurs at days 21 to 28.

ANTITUMOR ANTIBIOTICS

These agents intercalate with DNA, inhibit RNA synthesis, and interfere with DNA repair. They are cell-cycle nonspecific except for bleomycin.

•   Bleomycin (Blenoxane): complexes with iron to form an oxidase and produces free radicals. These free radicals produce DNA strand breaks in the G2 and M phases. It can be administered either IV, IM, or intracavitary for effusions. Dosing is calculated at 1 unit = 1 mg. The IV dose is bolused at 30 mg/week for 12 weeks, or 10 mg/m²/day for 4 days every 4 weeks. Do not exceed 400 mg total lifetime dose. For pleural effusions, 60 to 120 mg can be instilled into the cavity. 70% is eliminated by the kidneys. Primary toxicities are interstitial pneumonitis (10%), pulmonary fibrosis (1%), alopecia, mucositis, and nonneutropenic fever. Secondary toxicities are nausea, vomiting, pancytopenia, hyperpigmentation, and allergic reactions. The nadir occurs at day 12. Pulmonary toxicity occurs due to the iron free radicals targeting first the type I alveoli, followed by the type II alveoli. DLCO (carbon monoxide diffusion capacity spirometry) is the test to determine pulmonary toxicity. A 15% change from pre-treatment value signifies toxicity and thus the need to discontinue treatment. A CXR should be obtained prior to each course along with a DLCO, but it is important to rely on physical examination and patient symptoms. Risk factors for pulmonary toxicity are prior mediastinal irradiation, age greater than 70, and hyperoxia during surgical anesthesia. Steroid therapy may help with acute pneumonitis.

•   Doxorubicin (Adriamycin): inhibits the strand passing activity of topoisomerase-II and also intercalates with DNA. It is administered via IV and chelates with iron and copper. These heavy metal chelations contribute to the cardio toxicity of the drug. It is dosed at 60 to 75 mg/m² as a single agent or 40 to 60 mg/m² in combination every 3 to 4 weeks. Elimination is hepatobiliary for 40% of the drug. It is a vesicant. Primary toxicity is pancytopenia and secondary toxicities are XRT recall, cardiomyopathy, and palmar plantar erythema (PPE). To avoid PPE, consider treatment with vitamin B₆, avoid hot tubs and high friction activities. The nadir is at days 10 to 14. With a total dose greater than 500 mg/m², the patient has an 11% risk of cardiomyopathy. If the total dose is greater than 600 mg/m², there is a 30% risk. Dexrazoxane (Zinecard) is a cardioprotective agent. It is administered at a 10:1 ratio, but if there is renal compromise, it should be dose reduced (to a 5:1 ratio). Risk factors for development of cardiomyopathy are age greater than 70 years, prior cardiac disease, and prior mediastinal XRT. Pre-treatment tests include a baseline MUGA scan or echocardiogram, EKG, and a CXR. If symptoms present during treatment, obtain a MUGA scan or an echocardiogram.

•   Liposomal Doxorubicin (Doxil): the mechanism of action is similar to the nonliposomal form. It is given IV every 4 weeks at 40 to 50 mg/m². It is not a vesicant. The drug is found highly concentrated in tumor tissue (four times the serum amount). Toxicity is primarily pancytopenia. Secondary toxicity is palmar planter erythroddysesthesia (PPE).

•   Dactinomycin (Actinomycin D): the mechanism of action is DNA intercalation and it is administered IV. Dosing can be 9 to 13 mcg/kg IV per day for 5 days every 2 weeks or 1.25 mg/m² every 2 weeks for nonmetastatic gestational trophoblastic disease (GTD); 90% is eliminated via the hepatobiliary system. Primary toxicities are pancytopenia, nausea, vomiting, and mucositis. Secondary toxicity is alopecia. The nadir is days 7 to 10. The mode of resistance is via MDR P-glycoprotein.

•   Mitomycin C (Mutamycin): a pro-drug that crosslinks DNA. It is selectively activated by hypoxic cells. It is administered IV and dosed as a single agent at 10 to 20 mg/m² or in combination at 10 mg/m² every 6 to 8 weeks. Elimination is by the hepatobiliary system for 90% of the drug. Primary toxicity is pancytopenia and secondary toxicities are nausea, vomiting, nephrotoxicity, microangiopathic hemolytic anemia, hemolytic uremic syndrome (HUS), and multiorgan failure. The nadir is 4 to 6 weeks. There is cumulative myelosuppression so the total lifetime dose should be less than 60 mg/m².

•   Mitoxantrone (Novantrone): inhibits topoisomerase-II and is administered IV or IP at a dose of 12 to 14 mg/m² IV, or 10 mg/m² in 2 L of NS IP every 3 weeks. Elimination is hepatobiliary and primary toxicities are nausea, vomiting, diarrhea, and myelosuppression. The nadir is day 10. This drug may cause the “Smurf” syndrome and can turn the bowel and sclera blue.

•   Levamisole (Ergamisol): a synthetic imidazothiazole derivative initially used for helminthic infections. It is administered PO at a dose of 50 mg PO TID × 3 days per week, weekly for 1 year in combination with chemotherapy (5-fluorouracil [5-FU]). It is eliminated via the renal system. Primary toxicities are stomatitis, diarrhea, nausea, vomiting, and a metallic taste. Secondary toxicities are fever, chills, fatigue, myalgias, agranulocytosis, telangiectasia, seizures, edema, and chorea. The nadir is days 7 to 10. The tablets contain lactose: lactaid may be necessary in those with lactose intolerance.

ANTIMETABOLITES

These drugs antagonize folate, purines, pyrimidines, or ribonucleotide reductase. They therefore interfere with DNA synthesis. These agents are cell cycle specific for the S phase.

•   5-FU (Efudex): a pro-drug that is metabolized to FUDR. FUDR is a pyrimidine antimetabolite that inhibits thymidylate synthase and is incorporated into DNA and RNA. Administration is IV or topical. Dosing as a single agent is with a loading dose of 12 mg/kg (maximum of 800 mg) IV daily for 4 to 5 days, then after 28 days, a weekly maintenance dose of 200 to 250 mg/m² every other day for 4 days, every 4 weeks. It can also be dosed at 800 to 1,000 mg/m² IV daily for 4 days, repeated every 3 to 4 weeks. Oral dosing as capecitabine, of 15 to 20 mg/kg/day for 5 to 8 days can be used. Topical/vaginal application is given as a 5% cream; apply ½ vaginal applicator of 5% 5-FU (2.5 g) deep in the vagina at bedtime every 2 to 3 weeks. Elimination is 80% by the liver and 15% by the kidneys. Primary toxicities are granulocytopenia, thrombocytopenia, mucositis, nausea, vomiting, alopecia, and hyperpigmentation. Secondary toxicities are photosensitivity, cerebellar syndrome from the metabolite fluorocitrate, palmar plantar erythrodysesthesia (occurs in 42%–82% and can be reversed with vitamin B₆ dosed at 50 to 150 mg), and cardiotoxicity. The nadir is days 9 to 14. Patients with a genetic deficiency of DHFR should not receive this drug.

•   Capecitabine (Xeloda): a pro-drug that is metabolized to 5-FU. It is administered PO with a starting dose of 1,250 mg/m² administered as a divided BID dose. A reduced starting dose (950 mg/m² BID) is required for patients with a creatinine clearance equal to 30 to 50 mL/min. It is given for 14 days of a 21-day cycle. Elimination is renal and primary toxicities are diarrhea, nausea, and vomiting. Secondary toxicities are hand-and-foot syndrome, rash, dry skin, and fatigue. If the patient is taking warfarin concomitantly, frequent monitoring of the international normalized ratio (INR) is recommended.

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