Principles of Chemotherapy

Ursula A. Matulonis

GENERAL PRINCIPLES

Chemotherapy agents are grouped into different categories based on mechanism of action. These categories include alkylating agents, antimicrotubule agents, plant alkaloids, antimetabolites, anthracyclines, topoisomerase inhibitors, and others.

In addition to tumor site and diagnosis, individual patient factors such as age, organ function, comorbidities, and residual toxicities from the receipt of prior therapies will all influence the choice of chemotherapy regimens. Dose adjustments should be made when appropriate depending on goals of treatment and previous treatments the patient may have received. Physicians prescribing anticancer agents should understand the goals of care for the individual patient (curative vs. palliative) as well as the metabolism and toxicities of the agents prescribed. Patients and their families should be educated about the expected toxicities and goals of therapy.

Tumor Growth

Tumor growth is a complicated intricate process governed by genetic abnormalities within the cell and the tumor’s interaction with its microenvironment. The understanding of cancer has accelerated significantly over the past decade, and Hanahan and Weinberg¹ have defined the distinguishing features of cancer detailing the following hallmarks in addition to genomic instability as an underlying premise of the make-up of cancer cells: promotion and sustaining proliferative signaling, evading growth suppressors, resisting cell death, allowing replicative immortality, induction of angiogenesis, and activating invasion and metastasis. The proliferation and growth control of normal cells are not well understood, but the mitogenic signaling of cancer cells is increasingly better understood. Cancer cells acquire the ability to proliferate unchecked by several different mechanisms: self-production of growth factor ligands; control of the tumor microenvironment by signaling local stromal cells, which in turn produce factors leading to cancer growth; overexpression or enhanced signaling of transmembrane receptors; and growth factor independence via constitutive activation of tyrosine kinases within the receptor and/or downstream signaling molecules.² Enabling characteristics of cancer cells that allow the above changes to occur include overall genomic instability and the cancer cell’s ability to avoid immune destruction.³

Cell Kinetics and Log Kill Hypothesis

Cell kinetics were originally described based on murine tumor models, but it is now accepted that most human solid tumors do not grow in an exponential manner. The log kill hypothesis was based on the L1210 murine leukemia model, which is a fast-growing leukemia where 100% of the cells are actively progressing through the cell cycle.⁴ Logarithmic kill hypothesis states that a given anticancer drug should kill a constant proportion or fraction of cells in contrast to a constant number of cells, and cell kill is proportional regardless of the bulk of tumor. For example, if a drug can lead to a 3 log kill of cancer cells and can reduce the cancer burden from 10⁹ to 10⁶, the same drug and dose can also reduce the tumor burden from 10⁶ to 10³.

However, solid tumors tend to follow the Gompertzian model of tumor growth because most solid tumors do not grow and expand exponentially.⁵ The Gompertzian model predicts that cell growth is faster at the start of the growth curve when a tumor is small compared to a larger tumor existing in the slower part of the growth curve, which thus has a lower growth fraction. The Gompertzian model also predicts that the sensitivity of a cancer to chemotherapy depends on where the tumor is in its growth phase and that growth decreases exponentially over time. Similarly, the log kill produced by chemotherapy is higher in small-volume tumors than large-volume tumors because of the differences in growth kinetics.

Drug Resistance

Resistance to chemotherapy ultimately occurs with all cancers except those that are curable. Multiple mechanisms exist, new mechanisms are being discovered, and overlapping mechanisms can occur simultaneously; tumor resistance to drug therapy results primarily from tumor growth and selection of existing resistant clones while sensitive cells are killed.^6,7 One of the original hypotheses explaining drug resistance is the Goldie and Coldman hypothesis reported initially in 1979, which served as the basis for drug regimens used in hematologic malignancies and more recently in gynecologic malignancies.⁸ The tenets of the Goldie and Coldman hypothesis include the following: Treatment should begin as soon as possible in order to treat the smallest amount and bulk of tumor, multiple non–cross-resistant agents should be used in order to avoid selection of resistant clones, and drugs should be used as often as possible and in doses that are higher than minimally cytotoxic doses. In clinical trials that test features of the Goldie and Coldman hypothesis, adjuvant breast cancer therapy has shown improvements in outcome by using this tenet, but in upfront treatment of ovarian cancer, the use of sequencing non–cross-resistant agents did not result in improved progression-free survival or overall survival.⁹ Examples of mechanisms of drug resistance include alteration of drug movement across the cell membrane with respect to both influx and efflux, increased repair of DNA to offset damage done by certain agents, defective apoptosis so cancer cells are not receptive to drug effects, alteration of drug targets such as topoisomerase II alteration by point mutation, deletions or overexpression, and other mechanisms. The mechanisms of resistance associated with specific agents are discussed within the individual drug descriptions.^6,10 Newly described drug resistance mechanisms include identification of secondary mutations that restore the wild-type BRCA reading frame, which is likely a mediator of acquired resistance to platinum-based chemotherapy.¹¹

Dose Intensity

The therapeutic selectivity of chemotherapy is dependent on the outcome of dose response between normal tissue and cancer tissue. Dose intensity is the amount of drug delivered per unit of time, and the dose intensity of each regimen is based on the time period during which the treatment is actually administered. Calculations can be made regarding the intended dose intensity as well as the actual dose intensity that the patient receives in total. By reducing the dose intensity to decrease toxicity, clinicians may compromise the predicted outcome of a patient, and therefore, it is mandatory that clinicians state up front the intended outcome of administering chemotherapy (ie, curative vs. palliative). The importance of maintaining dose intensity has been demonstrated in early-stage breast cancer patients using adjuvant cyclophosphamide, methotrexate, and 5-fluorouracil, as well as cyclophosphamide and doxorubicin. In gynecologic cancers, the importance of dose intensity has been observed in older patients with ovarian cancer who may have worse outcomes compared to younger patients because of reduced dose intensity and less aggressive dosing of chemotherapy in older patients.¹²

Several mechanisms to deliver chemotherapy in a dose-intense fashion are available to clinicians. First, doses of drugs can simply be escalated. Second, the same doses of drugs can be given in a reduced interval of time (ie, “dose-dense administration”). For example, adjuvant cyclophosphamide and doxorubicin followed by paclitaxel in early breast cancer administered every 2 weeks rather than every 3 weeks demonstrated improvements in the dose-dense regimen.¹³ The prophylactic use of myeloid growth factors has enabled chemotherapy to be delivered at higher doses safely without excess neutropenic events and has enabled chemotherapy to be delivered in a dose-dense manner.

Single Versus Combination Therapy

Decisions regarding choice of single versus combination therapy should be based on the objectives of therapy (curative vs. palliative treatment), published regimens for specific indications and dosing of agents, and predicted toxicities. Specific doses chosen should be based on published studies, but dose alterations can occur based on objectives of treatment; renal, hepatic, or bone marrow function; toxicities experienced by the patient during previous cycles; current performance status and comorbidities of the patient; direct measurement of drug levels in the individual patient when possible; and potential interactions with other concomitant medications. Although combination chemotherapy typically yields higher response rates overall compared to single agents, toxicities are usually higher; outcomes such as overall survival and progression-free survival may better with combinations.¹⁴ Scheduling of drugs is such that the most myelosuppressive agents are given on day 1 and scheduled every 2 to 4 weeks depending on the timing of the myelosuppression nadir. This allows for recovery of bone marrow, gastrointestinal, dermatologic, and other organ toxicities without allowing significant tumor growth to occur. Mechanisms of action of the drugs and duration of infusion may also influence drug sequencing and toxicities.

PHARMACOLOGY

Chemotherapy agents are divided into classes based on their mechanism of actions.

Alkylating Agents

Alkylating agents work by interfering with the mechanisms of DNA and DNA repair, and their actions result in the covalent binding of an electrophilic alkyl group or a substituted alkyl group to different nucleophilic groups such as proteins, RNA, and DNA bases, leading to their cytotoxicity. Bifunctional alkylating agents that have 2 chloroethyl side chains undergo cyclization forming a covalent bond with an adjacent nucleophilic group, leading to DNA–DNA or DNA–protein cross-linking. The 7 nitrogen or 6 oxygen atoms of the base guanine appear to be susceptible to targeting with alkylating agents and may be targets that lead to the cytotoxicity and mutagenicity of treatment using these agents. Alkylating agents are typically highly reactive and overall have short half-lives. Alkylating agents are mostly metabolized via spontaneous hydrolysis, and several also are metabolized via enzymatic conversions. The toxicities of alkylating agents include bone marrow suppression and gastrointestinal toxicities. Contraindications to these agents include patients with significantly depressed bone marrow function as well as allergic reactions, although safe administration can be feasible in certain situations using desensitization protocols (see later section, Allergic or Infusion Reactions).

Hexamethylmelamine

Hexamethylmelamine (altretamine) is an alkylating agent that has an uncertain mechanism of action, and altretamine (Hexalen) capsules are indicated for use as a single agent for the palliative treatment of patients with persistent or recurrent ovarian cancer following firstline therapy with a cisplatin- and/or alkylating agent–based combination.

Following oral administration, hexamethylmelamine is well absorbed and undergoes rapid and extensive hepatic demethylation, resulting in variation of hexamethylmelamine levels. The main metabolites are pentamethylmelamine and tetramethylmelamine, and following administration of doses of 120 to 300 mg/m² in ovarian cancer patients, free fractions of hexamethylmelamine, pentamethylmelamine, and tetramethylmelamine were 6%, 25%, and 50%, respectively, all showing binding to plasma proteins. Peak plasma levels are reached between 0.5 and 3 hours and vary between 0.2 and 20.8 mg/L. There have been no formal studies of use of hexamethylmelamine in patients with hepatic and/or renal compromise. Hexamethylmelamine is administered in 4 divided doses, although there are no formal pharmacokinetic data for this schedule or information on the effect of food on absorption. Hexamethylmelamine has been used in ovarian cancer in varying schedules (either 14 or 21 days out of a 28-day cycle). Coadministration of hexamethylmelamine and monoamine oxidase inhibitors may result in orthostatic hypotension, especially in patients over the age of 60 years, and should be used with caution. Other toxicities of hexamethylmelamine include peripheral neuropathy, other central nervous system toxicities (ataxia, dizziness, and mood disorders), nausea, vomiting, fatigue, and importantly, myelosuppression. Blood count nadirs typically occur by 3 to 4 weeks when the schedule of 21 days out of 28 is used, and continuous dosing results in median nadirs of 6 to 8 weeks. However, because of variable oral absorption and difficulties assessing bone marrow tolerability of this drug, exact prediction of the extent and duration of the nadir is sometimes difficult. Thus, caution should be used in heavily pretreated patients, and counts should be monitored frequently, even weekly, in patients in whom it is uncertain when the exact nadir will occur. Toxicities necessitating changes in dose and perhaps schedule include gastrointestinal intolerance, other grade 3 or 4 toxicities, progressive neurotoxicity, and myelosuppression.

Melphalan

Melphalan is a bifunctional alkylating agent that is a phenylalanine derivative of nitrogen mustard and is also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-sarcolysin. Melphalan’s cytotoxicity results from cross-linking of DNA, likely by binding at the N⁷ position of guanine. Melphalan has been used in gynecologic malignancies, specifically ovarian cancer. Because of melphalan’s toxicities and the institution of more effective and less toxic drugs, melphalan’s use has diminished over time and is very limited. Toxicities include secondary malignancies, specifically acute nonlymphocytic leukemias and myelodysplastic syndrome. The cumulative dose impacts the risk of secondary hematologic malignancies. For cumulative doses above 730 mg and up to 9652 mg, the 10-year cumulative risk was 19.5%, and for doses below 600 mg, the cumulative risk of a secondary hematologic malignancy was less than 2%. Other toxicities include myelosuppression, fatigue, gastrointestinal toxicities, and mutagenesis. Because of melphalan’s toxicities and the difficulty predicting them and the development of less toxic agents, melphalan is rarely used.

Platinum Drugs

Platinum drugs that have been tested in gynecologic cancers include cisplatin, carboplatin, and oxaliplatin. Cisplatin and carboplatin are 2 of the most important agents in treating gynecologic malignancies. All platinum drugs have a fixed, planar platinum core and are surrounded by both carrier ligands and leaving groups; all of the components exist in a 2-dimensional plane. Unlike alkylating agents, which use carbon as the main atom and have reactive arms that move around carbon, platinum compounds have fixed reactive groups relative to platinum, and thus the DNA that binds covalently to the platinum compound bends to conform to the platinum core and ends up being fixed. All of the platinum compounds result in similar DNA lesions: N7-d(GpG)-intrastrand adducts (representing approximately 60% of total DNA binding), N7-d(ApG)-intrastrand adducts (representing about 30% of total DNA binding), N7-d(GpXpG)-intrastrand adducts (representing about 10% of total DNA binding), and N7-d(X)-d(X)G-intrastrand cross-links (representing about < 2% of total DNA binding). The different platinum drugs have different leaving groups and carrier ligands, and how these groups determine the individual behavior and toxicities of the platinum agents has not been determined. The leaving groups for cisplatin are the chloride atoms, which are positioned in the cis configuration of the molecule and dissociate from the molecule under physiologic pH conditions; the carrier ligands are ammonia atoms. The leaving group for carboplatin is the dicarboxylatocyclobutane entity, which does not dissociate as easily as the chloride atoms do in cisplatin and may require active cleavage by an esterase. The leaving group for oxaliplatin is the oxalate moiety, resulting in the parent platinum molecule with 2 reactive cis bonds (similar to cisplatin and carboplatin), and the carrier ligand of oxaliplatin is a diaminocyclohexane moiety and influences DNA repair in addition to inhibition of the platinum-DNA adduct’s replication bypass. Platinum drugs are able to access the intracellular compartment by 2 mechanisms: passive diffusion through the lipid bilayer and carrier-mediated uptake. Described platinum influx transporters include copper transporter proteins, organic cation transporters that belong to the SLC22 family, and a cis configuration–specific platinum influx transporter; the exact roles that these transporters have in actual drug levels intracellularly in addition to platinum resistance and sensitivity mechanisms are unknown.

Mechanisms of resistance of cisplatin have been better studied than carboplatin, but available data suggest that the mechanisms of resistance are quite similar and can either be intrinsic resistance, as seen in cancers that have little initial platinum sensitivity such as prostate and colon cancer, or acquired resistance as is seen in ovarian cancer.^15,16 Examples of resistance mechanisms include increased efflux of drug, reduced influx of drug, decreased blood flow of drug to the tumor, intracellular detoxification by intracellular compounds such as glutathione and metallothioneins, changes in DNA repair such as loss of mismatch repair, enhanced nucleotide excision repair, intrastrand cross-link repair, and defective apoptosis.

Cisplatin

Cisplatin has shown anticancer activity against most gynecologic malignancies. Cisplatin is US Food and Drug Administration (FDA)–approved for metastatic ovarian cancers in established combination therapy with other approved chemotherapeutic agents in patients with advanced ovarian cancers who have already received appropriate surgical therapy and/or radiotherapy. Cisplatin, as a single agent, is indicated as secondary therapy in patients with metastatic ovarian tumors refractory to standard chemotherapy who have not previously received cisplatin therapy. Cisplatin is also indicated for metastatic testicular tumors in established combination therapy with other approved chemotherapeutic agents as well as in advanced bladder cancer as a single agent for patients with transitional cell bladder cancer that is no longer amenable to local treatments, such as surgery and/or radiotherapy.

Once injected intravenously (IV), 90% of the platinum parent drug is bound to plasma proteins including albumin, transferrin, and γ-globulin within 3 hours after a bolus infusion and 2 hours after the end of a 3-hour infusion. Drug concentrations of cisplatin are highest in the liver, kidney, and prostate, and platinum is present in tissues for as long as 180 days after the final administration of the drug. A drug concentration differential exists between the tumor and surrounding tissue; platinum levels are lower in the tumor than in surrounding tissues of the organ where the cancer is located.

Cisplatin can lead to cumulative nephrotoxicity; cisplatin is contraindicated in patients with preexisting renal impairment and should be used with caution in patients who are more prone to renal injury (ie, diabetes mellitus, long-standing hypertension, the elderly). All patients should be prehydrated with 1 to 2 L of normal saline immediately prior to receipt of cisplatin, either IV or intraperitoneal (IP). Failure to hydrate patients in accordance with guidelines and the FDA package insert can and will lead to renal damage and perhaps renal failure. IV fluids should be given after infusion as well because cisplatin remains in tissues. Serum creatinine, blood urea nitrogen, creati-nine clearance, magnesium, sodium, potassium, and chloride must be checked prior to each administration of cisplatin and in between cycles of administration if warranted, making certain that all laboratory tests are adequate to proceed to the next cycle. Other toxici-ties of cisplatin include peripheral neuropathy, loss of motor function, allergic reactions, ototoxicity, development of secondary leukemias, myelosuppression, electrolyte abnormalities, hyperuricemia, hepatotoxicity, other types of neurotoxicity (loss of taste, autonomic neuropathy, dorsal column neuropathy, and seizures), asthenia, cardiac abnormalities, hiccups, rash (may be secondary to an allergic reaction), and alopecia rarely. Neuropathy should be monitored for at each cycle administration, and patients should inform their treating team of the severity of any intracycle neuropathy because the neuropathy may have improved at the time of the start of the next cycle. Symptoms and signs of neuropathy and other central nervous system abnormalities most often occur during treatment, but symptoms of neuropathy can occur following the completion of cisplatin treatment; patients should be warned of this, although it is rare (see later section on neuropathic complications of anticancer agents). Significant and persistent peripheral neuropathy can occur for up to 1 year or more after the completion of IP treatment.¹⁷ Cisplatin should be discontinued following the initiation of significant neuropathy. Peripheral neuropathy may be irreversible in some patients, and patients need to be counseled about this potentially long-term toxicity. Monitoring of auditory acuity may also be necessary, especially if patients have an already existing hearing deficit or if they develop ototoxicity during therapy.

Carboplatin

Carboplatin, much like cisplatin, produces cell cycle nonspecific intrastrand DNA cross-links rather than DNA-protein cross-links. The aquation of carboplatin leads to the active compound, and platinum from carboplatin is irreversibly bound to plasma proteins that are slowly eliminated with a half-life of approximately 5 days.

Carboplatin has an FDA indication for the initial treatment of advanced ovarian carcinoma in combination with other approved chemotherapeutic agents. Carboplatin is also indicated for the palliative treatment of patients with recurrent ovarian carcinoma after prior chemotherapy, including patients who have been previously treated with cisplatin.

The major route of elimination of carboplatin is via renal excretion. Glomerular filtration rate (GFR) determines creatinine clearance (CrCl). Thus, elimination varies based on CrCl; patients with a CrCl of ≥ 60 mL/min will excrete approximately 65% of a carboplatin dose in the urine within 12 hours and 71% of the dose within 24 hours. In patients with lower CrCl (< 60 mL/min) and thus reduced renal clearance of carboplatin, the doses of carboplatin should be reduced. In the elderly population, because their renal function is often decreased, formula dosing of carboplatin based on estimates of GFR should be used to ensure predictable plasma carboplatin area under the curve (AUC) values and thereby minimize toxicity. Obese patients do not appear to have higher toxicities compared to nonobese patients, and in a Gynecologic Oncology Group study that examined carboplatin dosing using the Jelliffe equation to calculate GFR and using a carboplatin dose of AUC 7.5, obese patients appeared to have fewer toxicities compared to nonobese patients.¹⁸ Obese patients with epithelial ovarian cancer appear to have a comparable prognosis to other patients, provided that they receive optimal doses of chemotherapy based on measured GFR and actual body weight.

The dosing of carboplatin has changed over the past 2 decades. Initial studies in ovarian cancer used milligram per meter squared dosing, but recognition that carboplatin elimination is based on GFR led to renal function and age-based dosing, leading to more accurate dosing. Calvert dosing uses AUC dosing in addition to GFR; the dosing is: total dose (mg) = (target AUC) × (GFR + 25). There are currently 2 ways to calculate GFR: the Jelliffe formula and the Cockcroft-Gault formula, and the decision to use one formula or the other should be based on published regimens. In October 2010, the FDA issued an alert on carboplatin dosing safety after discussions with the National Cancer Institute/Cancer Therapy Evaluation Program. By the end of 2010, all clinical laboratories in the United States would be using the new standardized isotope dilution mass spectrometry (IDMS) method for measurement of serum creatinine. The IDMS method appears to underestimate serum creati-nine values compared to older methods when the serum creatinine values are relatively low (eg, ~ 0.7 mg/dL). Thus, measurement of serum creatinine by the IDMS method could result in an overestimation of the GFR in some patients with normal renal function. If a patient’s GFR is estimated based on serum creati-nine measurements by the IDMS method, the FDA recommends that physicians consider capping the dose of carboplatin for desired exposure (AUC) to avoid potential toxicity due to overdosing. The maximum carboplatin dose (mg) = target AUC (mg · min/mL) ×(150 mL/min), which is based on a GFR estimate that is capped at 125 mL/min for patients with normal renal function. No higher estimated GFR values should be used.

Overall, carboplatin is better tolerated than cisplatin, and thus, carboplatin should be selected as the drug of choice when both carboplatin and cisplatin show equivalent results. Carboplatin has more minimal nephrotoxicity and a more tolerable nausea/vomiting profile compared to cisplatin. Toxicities of carboplatin include myelosuppression, nausea and vomiting, peripheral neuropathy, ototoxicity, electrolyte abnormalities (including hyponatremia, hypomagnesemia, hypokalemia, and hypocalcemia), allergic reaction, fatigue and malaise, and other more rare side effects such as secondary leukemia, vision loss, central neurotoxicity, alopecia, shortness of breath, cardiovascular toxicities, mucositis, and cancer-associated hemolytic uremic syndrome (FDA package insert). Bone marrow suppression is the dose-limiting toxicity of carboplatin and is more pronounced in patients with reduced CrCl and in those who have received prior chemotherapy or radiation therapy. Bone marrow suppression is cumulative, and blood counts should be monitored in between cycles if indicated; future cycles of carboplatin should only be administered when blood counts have recovered. Nadir toxicity when carboplatin is used as a single agent occurs at about day 21. Dose modifications are listed in the FDA package insert.

When carboplatin is combined with paclitaxel, myelo-suppression, specifically neutropenia, is lessened if paclitaxel is administered first; this has been observed with cisplatin but should be followed with carboplatin as well. In addition, the less toxic sequence of paclitaxel followed by the platinum drug is also more cytotoxic to tumor cells in vitro, so paclitaxel should be administered first, and then the platinum drug thereafter.

Allergic reactions have been reported with carboplatin and tend to occur in patients who have had prior exposure to platinum. Allergic reactions may be mild, such as mild pruritus or flushing, or may include anaphylaxis. Allergic reactions most commonly occur during the infusion and less commonly occur after the infusion has been completed (hives or rash) (see specific toxicities later in this chapter).

Oxaliplatin

Oxaliplatin has not been found to be an active agent in gynecologic cancers. Oxaliplatin undergoes nonenzymatic conversion in physiologic solutions to active forms through displacement of the labile oxalate ligand, resulting in the formation of several transient reactive species including monoaquo- and diaquo-diaminocyclohexane platinum, which then covalently bind with DNA and other proteins. The terminal half-life of the drug is 38 to 47 hours. Current FDA-approved indications for oxaliplatin when used in combination with infusional 5-fluorouracil/leucovorin are: (1) adjuvant treatment of stage III colon cancer in patients who have undergone complete resection of the primary tumor and (2) treatment of advanced colorectal cancer. Toxicities include myelosuppression, diarrhea and mucositis, peripheral neuropathy, hand-foot syndrome, and nausea and vomiting. Oxaliplatin, like the other platinum analogs, can cause anaphylaxis and other unusual toxicities including hemolytic uremic syndrome and anemia and others listed in the package insert. Oxaliplatin can also lead to injection site reactions, which can be severe; signs and symptoms of an injection site reaction include blistering, inflammatory changes, erythema, tenderness, and possibly ulceration and skin breakdown leading to possible skin grafting.

Cyclophosphamide

Cyclophosphamide is one of the most commonly used and successful chemotherapy drugs.¹⁹ Cyclophosphamide was initially thought to selectively target cancer cells via activation of cancer cell phosphamidases, which was later found not to be its mechanism of action. After administration, the prodrug cyclophosphamide is hepatically activated to both active and inactive metabolites. Approximately 70% to 80% of cyclophosphamide are activated by hepatic microsomal P450 mixed function microsomal oxidases to form 4-hydroxycyclophosphamide and is in equilibrium with its tautomer aldophosphamide, and the name 4-hydroxycyclophosphamide applies to them both. Several cytochrome P (CYP) isoenzymes have been implicated in cyclophosphamide activation, including CYP2B6, CYP3A4, CYP3A5, CYP2C9, CYP2C18, and CYP2C19. CYP2B6 has the highest 4-hydroxylase activity. 4-Hydroxycyclophosphamide, which is very unstable, is able to diffuse into cells but is not cytotoxic itself. 4-Hydroxycyclophosphamide decomposes into phosphoramide mustard via β-elimination of acrolein, which are the 2 downstream metabolites of cyclophosphamide. Phosphoramide mustard is a bifunctional DNA alkylating agent that is likely responsible for most of the anticancer effect of cyclophosphamide by cross-linking with DNA in cancer cells. Extracellular phosphoramide mustard is not able to enter cells because it is ionized at physiologic pH. With oral dosing, cyclophosphamide is well absorbed, with a bioavailability greater than 75%, and the unchanged drug has an elimination half-life of 3 to 12 hours. Cyclophosphamide is eliminated primarily in the form of active metabolites, but from 5% to 25% of the dose is excreted in urine as unchanged drug. Following IV administration, metabolites reach a maximum concentration in plasma in 2 to 3 hours. Plasma protein binding of unchanged drug is low, but some metabolites are bound to an extent greater than 60%.

Several toxicities of cyclophosphamide exist, and toxicities are dependent on route of administration and dose. Higher doses of intravenously administered drug can result in myelosuppression, hemorrhagic cystitis, cardiac toxicity (ie, hemorrhagic carditis leading to cardiomyopathy and pericarditis), and anaphylactic reactions. Toxicities that are observed with more standard doses of the drug include myelosuppression; gastrointestinal toxicities such as nausea, vomiting, and mucositis; alopecia; hemorrhagic cystitis; interstitial pneumonia; and carcinogenic and teratogenic toxicities.

Cyclophosphamide’s FDA indications are the following: ovarian cancer, malignant lymphomas, Hodgkin disease, lymphocytic lymphoma, mixed-cell type lymphoma, histiocytic lymphoma, Burkitt lymphoma, multiple myeloma, chronic lymphocytic leukemia, chronic granulocytic leukemia, acute myelogenous and monocytic leukemia, mycosis fungoides, neuroblastoma, retinoblastoma, and breast cancer.

Ifosfamide

Ifosfamide, much like cyclophosphamide, requires metabolic activation by microsomal liver enzymes that lead to biologically active metabolites. Hydroxylation at the ring carbon atom 4 leads to activation and forms 4-hydroxyifosfamide, an unstable metabolite that degrades to a more stable urinary metabolite, 4-ketoifosfamide. When the ring is opened, this forms another stable urinary metabolite, 4-carboxyifosfamide. Ifosfamide’s half-life is 15 hours, and the urinary excretion of metabolites is 15% at 24 hours. Renal clearance of ifosfamide plays a minor role compared to hepatic clearance, but renal insufficiency may increase the risk of neurotoxicity because of more extensive deactivation of ifosfamide, and dose reduction in patients with renal insufficiency should be considered. Like cyclophosphamide, because of acrolein formation, ifosfamide can also lead to hemorrhagic cystitis, and the thiol compound mesna can be given IV or orally and is rapidly auto-oxidized in plasma at pH 7.4 to dimesna, which is inactive. In renal tubular epithelial cells, dimesna is converted back to mesna by glutathione reductase enzymes, and the free sulfhydryl groups of mesna bind to acrolein. The severity and incidence of hemorrhagic cystitis can be lowered with hydration and bladder irrigation if necessary. To protect against hemorrhagic cystitis, mesna should be given continuously before, during, and following ifosfamide administration to any patient receiving high-dose cyclophosphamide and any patient with pre-existing drug-induced cystitis. Other toxicities of ifosfamide include myelosuppression, encephalopathy (which is not observed with cyclophosphamide), nephrotoxicity, alopecia, nausea, vomiting, and rarely cardiotoxicity and interstitial pneumonitis. The encephalopathy observed with ifosfamide is likely due to chloroacetaldehyde, one of its metabolites, and chloroacetaldehyde closely resembles the structure of ethanol. If symptoms of encepha-lopathy do develop, such as confusion, the patient should be treated clinically via electrolyte correction, hydration, and potential hospitalization. Ifosfamide is indicated for relapsed germ cell tumors.

Antimicrotubule Agents

Microtubules are cellular organelles that play a vital role in cell shape, division, signaling, polarity, and the proper transport of other organelles and vesicles and are the conveyor belts of the cell. Structurally, micro-tubules are linear polymers of tubulin, and groups of these are called protofilaments. A protofilament is a linear row of tubulin dimers. Polymerization of tubules proceeds by a nucleation–elongation mechanism. The first stage of formation is called “nucleation,” which requires tubulin, Mg⁺⁺, and guanosine triphosphate. This stage is relatively slow until the microtubule is initially formed. The second phase, called “elongation,” proceeds much more rapidly. The ends of microtubules are distinct; the plus end is more active kinetically, whereas the opposite end is more inert and called the minus end. Microtubules participate in 2 important activities. The first is called treadmilling, resulting in net growth on one end and shortening at the opposite end. The second is called dynamic instability, during which the microtubule ends can switch spontaneously between slow growth and rapid shortening.

Because of their broad anticancer activity, the taxanes are one of the most important classes of anticancer drugs. Paclitaxel was originally identified from the extract of the bark from the Pacific yew tree, Taxus brevifolia, in 1963. Early development of this drug was slowed by limited supply, but eventually large-scale production became available, making widespread use of paclitaxel possible. Paclitaxel is an antimicrotubule drug that promotes assembly of microtubules from tubulin dimers and is obtained via a semi-synthetic process; its chemical name is 5β,20-epoxy-1,2α,4,7β,10β,13α, hexahydroxytax-11-en-9-one 4, 10-diacetate 2-benzoate 13-ester with (2R, 3S)-N-benzoyl-3-phenylisoserine. Paclitaxel stabilizes microtubules by preventing and blocking depolymerization, resulting in inhibition of normal reorganization of the microtubule network. This microtubule reorganization is necessary for interphase and cellular mitotic functions, and paclitaxel exposure also leads to abnormal arrays or bundles of microtubules in the cell cycle and during mitosis. The microtubules formed when paclitaxel is present are dysfunctional yet stable, and cell death arises from disruption of the normal microtubule interactions and dynamics required for cell division. Resistance mechanisms include presence of altered α- and β-tubulin in tumor cells that have an impaired ability to polymerize into microtubules and slowed microtubule assembly and presence of drug efflux pumps.^20,21 Other mechanisms of resistance to taxanes include mutations in tubulin isotype genes and gene amplification.

Docetaxel is synthesized by the addition of a side chain to 10-deacetylbaccatin III, which is an inactive taxane precursor found in the needles of other yew tree species. Commonalities exist in the structures of both paclitaxel and docetaxel. The taxane rings of paclitaxel and docetaxel are linked to an ester side chain, which is located on the C13 position of the taxane ring, and this is essential for the antimicrotubule and thus anticancer activity of both agents. These agents do have different substitutions at position C10 of the taxane ring and position C13 on the ester side chain. Paclitaxel binds to the interior surface of the lumen of the micro-tubule at binding sites that are distinct from those of the vinca alkaloids. Although docetaxel is more water soluble than paclitaxel, it has the same binding site on the microtubule as paclitaxel does. Both paclitaxel and docetaxel alter the tubulin dissociation rate constants at both microtubule ends, resulting in inhibition of both treadmilling and dynamic instability. Vinca alkaloids alter tubulin polymerization, whereas the taxanes do not.

Paclitaxel has been FDA approved for the following indications: (1) treatment of patients with sub-optimally cytoreduced stage III or IV ovarian cancer when combined with a platinum compound as primary induction therapy; (2) recurrent ovarian cancer after failure of first-line or subsequent chemotherapy; (3) advanced breast cancer after failure of combination chemotherapy or at relapse within 6 months of adjuvant chemotherapy; (4) adjuvant combination chemotherapy of lymph node–positive breast cancer sequentially after standard doxorubicin-based chemotherapy; (5) second-line treatment of Kaposi sarcoma associated with acquired immunodeficiency syndrome; and (6) primary treatment of non–small-cell lung cancer in combination with cisplatin. Docetaxel has been approved for the following (1) metastatic breast cancer that has progressed or relapsed after anthracycline-based chemotherapy as well as a second-line indication; (2) adjuvant chemotherapy of lymph node–positive breast cancer in combination with doxorubicin-based chemotherapy; (3) first-line chemotherapy for locally advanced or metastatic breast cancer; (4) nonresectable, locally advanced or metastatic non–small-cell lung cancer after failure of cisplatin-based chemotherapy; (5) first-line treatment of nonresectable, locally advanced or metastatic non–small-cell lung cancer in combination with cisplatin; (6) androgen-independent, hormone refractory metastatic prostate cancer in combination with prednisone; (7) first-line treatment of gastric adenocarcinoma including gastro-esophageal junction adenocarcinoma in combination with cisplatin and 5-fluorouracil; and (8) inoperable locally advanced squamous cell cancer of the head and neck in combination with cisplatin and 5-fluorouracil.

After administration of longer infusions of paclitaxel, plasma levels decline in a biphasic manner; the initial rapid decline is secondary to distribution in the peripheral compartment (≈20-minute half-life), and the second phase represents slower efflux of paclitaxel from this peripheral compartment (6-hour half-life). When shorter infusions are given that are 3 hours or less, the pharmacokinetics of paclitaxel are nonlinear, resulting in small increases in drug dose and a disproportionate increase in drug levels and toxici-ties and dose reductions, leading to a disproportionate decrease in drug exposure and possible lack of anticancer activity. Most of paclitaxel is excreted via stool through enterohepatic circulation 5 days following administration, and renal clearance is minimal. Paclitaxel is metabolized to 6α-hydroxypaclitaxel and 3′p-hydroxypaclitaxel via the isoenzymes CYP2C8 and CYP3A4.

Docetaxel pharmacokinetics on a 1-hour administration schedule are triexponential and linear when given at doses ≤ 115 mg/m², and terminal half-lives between 11 and 18.5 hours have been demonstrated. CYP3A4 and CYP3A5 are important in biotransformation and metabolism of docetaxel.

The sequencing of paclitaxel and other anticancer agents has important implications on toxicity and anticancer activity as discussed in the alkylating section. Sequencing cisplatin prior to paclitaxel in vitro results in enhanced neutropenia in addition to diminished anticancer activity when paclitaxel is administered over a 24-hour infusion; therefore, in clinical practice, taxane administration should precede the platinum infusion when combination taxanes and platinum agents are used.

Neutropenia is a common side effect that in noncumulative, and the duration of plasma levels of paclitaxel that are above biologically active levels (0.05-0.10 μmol) is an important determinant in prolonged neutropenia. Other side effects include an approximately 3% risk of hypersensitivity reactions, which typically occur within the first 10 minutes of the first treatment, although infusion reactions can occur at any time regardless of how many prior paclitaxel treatments the patient has received; the patient should be reminded of the signs and symptoms of paclitaxel reactions periodically. These reactions are thought to be secondary to Cremophor, which allows solubilization of paclitaxel. A standard premedication regimen for paclitaxel includes oral dexamethasone 20 mg 12 and 6 hours before infusion, an H₁-receptor antagonist such as diphenhydramine (Benadryl) 50 mg IV 30 minutes prior to infusion, and an H₂-receptor antagonist (ie, famotidine 20 mg, ranitidine 150 mg, or cimetidine 300 mg, all IV) given 30 minutes before infusion; this regimen was implemented originally when severe reactions were being observed during early clinical testing of this drug, some of which were fatal. Another single dose of a corticosteroid may be administered 30 minutes prior to paclitaxel infusion as well. Despite use of this premedication regimen, hypersensitivity reactions still can occur, and patients and treating staff must be aware of these reactions, which can be life threatening.

Paclitaxel also causes neuropathy that manifests in a stocking and glove distribution. Cardiac arrhythmias can also occur; the most common is asymptomatic bradycardia, but other abnormal rhythms can occur such as sinus tachycardia, atrial fibrillation, and other more malignant atrial and ventricular rhythms. Other toxicities include mild nausea, vomiting and diarrhea, hepatotoxicity, pulmonary toxicity with pneumonitis present on lung imaging, alopecia, nail changes, and rarely optic nerve disturbances. Docetaxel toxicities include neutropenia; hypersensitivity reactions; edema and fluid retention; palmar-plantar erythrodysesthesia; fatigue; mild gastrointestinal toxicities such as nausea, vomiting, and diarrhea; peripheral neurotoxicity; nail changes; and rarely stomatitis. Fluid retention is from increased capillary permeability and leaking and is cumulative with docetaxel, leading to peripheral edema and third-space fluid accumulation such as ascites or pleural effusions that are not malignant but related to docetaxel. Early treatment with diuretics and prophylactic use of corticosteroids are recommended, and the signs and symptoms of the fluid retention syndrome resolve after discontinuation of docetaxel.

Albumin-bound paclitaxel (ABI-007) is a formulation of paclitaxel that is solvent free, is a colloidal suspension with nanoparticle albumin, and has limited study in gynecologic cancers. Advantages of its use are that hypersensitivity reactions are markedly reduced because it is solvent free and no premedication with steroids is required, which is an advantage when treating patients with diabetes mellitus. Toxicities appear to be similar to equivalent doses of paclitaxel, but this drug has not been adequately studied in gynecologic cancers, and safety of its use has not been studied in patients with prior hypersensitivity reactions to either paclitaxel or docetaxel.

Vinca Plant Alkaloids

This class of agents includes vincristine, vinorelbine, and vinblastine. Vinca alkaloids were originally isolated from the leaves of the periwinkle plant, Catharanthus roseus G. Don, and were discovered in the late 1950s. The mechanism of action of the vinca alkaloids at clinically relevant concentrations is to block mitosis by binding to the β subunit of tubulin dimers at the vinca-binding domain. Vinca alkaloid binding of tubulin leads to a conformational change and altering treadmilling or growth/shortening of the microtubules which ultimately blocks mitosis. Vinca alkaloids enter cancer cells by simple diffusion, which is temperature independent and nonsaturable. Lipophilicity also plays a role in how the drug is able to enter cells. Vinca alkaloids are administered intravenously, and the drugs within this class have in common large volumes of distribution and long terminal half-lives. Metabolism and elimination of these drugs are predominantly via the hepatobiliary system and predominantly via the hepatic cytochrome CYP3A. Because of the importance of CYP3A metabolism, concomitant administration of vinca alkaloids with inhibitors and inducers of CYP3A may alter vinca alkaloid metabolism, and the treating clinician should know about these potential interactions. In addition, vinca alkaloids are potent vesicants, and extravasation could lead to significant tissue damage. If extravasation occurs, the drug infusion should be stopped immediately, and aspiration of any remaining drug in the soft tissues should be performed.

The vinca alkaloids differ with respect to toxici-ties. Neurotoxicity is more common with vincristine than the other vinca alkaloids, although neurotoxicity can occur with any of the agents. Neurotoxicity is most common with vincristine, can occur quickly, and is cumulative, and any patients with pre-existing neuropathic disorders or altered hepatic metabolism will predispose that patient to enhanced neurotoxicity. Vinorelbine and vinblastine also can cause neuropathy, and mild to moderate neuropathy can occur in up to 30% of patients. Gastrointestinal autonomic dysfunction can be observed with any of the vinca alkaloids, and these symptoms are manifested by constipation, bloating, abdominal pain, and an ileus. Patient education at the start of therapy is important, and patients should be encouraged to avoid narcotics that slow peristalsis, if possible, and take laxatives, if necessary. Neutropenia is the main toxicity of vinorelbine and vincristine, and myelosuppression is not cumulative. Other rare side effects include alopecia, hand-foot syndrome, acute cardiac ischemia, hepatic and pulmonary toxicity, and syndrome of inappropriate antidiuretic hormone (SIADH).

Antimetabolites

Methotrexate

Methotrexate (MTX) is the most widely used antifolate in cancer treatment; it binds and inhibits dihydro-folate reductase (DHFR), which is a critical enzyme in folate metabolism. DHFR maintains the intracellular folate pool in the reduced form as tetrahydrofolates, which serve as precursors for de novo production of thymidylate and purine nucleotides. The purported mechanism of MTX is the irreversible binding of DHFR, resulting in stoppage of thymidylate and purine nucleotide synthesis as well as other amino acid synthesis through the lack of reduced folates. Through polyglutamation, the cytotoxic effects of MTX are prolonged because MTX polyglutamated forms have a longer half-life with a higher propensity to have effects in malignant rather than normal cells. MTX polyglutamates themselves are direct inhibitors of several folate-dependent enzymes such as DHFR and thymidylate synthase (TS).

MTX is metabolized and cleared renally, and the majority of the dose is excreted unchanged (80%-90%) in the urine. Therefore, patients with reduced renal clearance (CrCl < 60 mL/min) should not receive high-dose MTX; MTX is not significantly hepatically metabolized, so hepatic impairment will not alter MTX dosing. Renal excretion of MTX is inhibited by several drugs, including aspirin, penicillins, cephalosporins, probenecid, and nonsteroidal anti-inflammatory medications. MTX is third-spaced, and the presence of large-volume ascites or pleural effusions can alter the pharmacokinetics of MTX by slowing elimination. Clinicians should consider draining large third-space volumes prior to MTX administration.

MTX metabolism, when administered IV, results in a 3-phase elimination pattern, and absorption is optimal when given IV, with oral doses above 25 mg/m² more inconsistent. The initial phase of IV infusion lasts a few minutes; the second phase lasts 12 to 24 hours, during which the drug has a half-life of 2 to 3 hours; and during the third phase, MTX clearance is prolonged with a half-life of 8 to 10 hours. The second and third phases of clearance are affected and lengthened in patients with renal impairment. High-dose MTX is considered to be any dose of MTX that is 500 mg/m² or higher and is given over 6 to 42 hours. These doses are considered lethal and should not be administered to patients with impaired renal function. When administering high-dose MTX, care must be given to adequate IV hydration of the patient, alkalinization of urine, careful monitoring of MTX levels, and adequate administration of leucovorin. Following high-dose MTX administration, MTX levels should be monitored every 24 hours. Leucovorin should be given until the MTX level is 50 nM or less; excessive leucovorin can negatively affect the levels of MTX. Leucovorin can be administered orally or IV; higher doses are more effectively administered IV because oral absorption is impaired at doses of ≥ 40 mg.

Toxicities of MTX are predominantly myelosuppression and gastrointestinal, and these toxicities are dose and schedule dependent; even small doses of MTX can result in significant renal toxicity in patients with impaired renal function. Mucositis precedes myelo-suppression, and these toxicities resolve usually within 14 days unless MTX clearance is impeded. High-dose MTX administration can lead to elevated hepatic enzymes, and bilirubin can be observed, which typically resolves within 10 days. Other side effects include pneumonitis, which is manifested by fevers, pulmonary infiltrates, and a cough. In addition, high-dose MTX can give rise to cerebral dysfunction with behavioral changes, paresis, seizures, and aphasia. Chronic MTX administration can lead to chronic neurotoxicity after 2 to 3 months of therapy, and symptoms include encephalopathy, motor paresis, and dementia; the etiology of MTX-induced neurotoxicity is unknown.

Pemetrexed

Pemetrexed is a multitargeted antifolate drug that inhibits several enzymes important for folate production such as DHFR, TS, ribonucleotide formyltransferase, and aminoimidazole carboxamide formyltransferase.²² Pemetrexed enters cells mainly via the reduced folate carrier system and via the folate receptor transporter as a more minor component of entry. Intracellularly, pemetrexed undergoes polyglutamation, making its potency 60-fold higher than the nonpolyglutamated parent compound. Pemetrexed is cleared renally, has a half-life of 3.1 hours, and must be used with caution with impaired renal function. Dose reduction in patients with renal dysfunction should be considered. Toxicities include myelosuppression, skin rash, and mucositis, with the latter 2 toxicities being significant in patients who are not pretreated with folic acid and vitamin B₁₂. Other toxicities include fatigue, anorexia, and reversible transaminitis. Patients pretreated with folic acid (350 µg/d) and vitamin B₁₂ (1000 μg intramuscularly given at least 1 week prior to starting drug) exhibit decreased rates of toxicities, specifically rash and mucositis.

5-Fluorouracil

5-Fluorouracil (5-FU) was originally synthesized in 1957 and remains one of the most widely used anticancer drugs. 5-FU enters the intracellular compartment via facilitated uracil transport and is metabolized. 5-FU is mainly metabolized by dihydropyrimidine dehydrogenase (DPD). 5-FU is cytotoxic through several mechanisms, including inhibition of TS and incorporation into both RNA and DNA, leading to changes in mRNA translation, RNA processing, and inhibition of DNA function and synthesis. 5-FU may also exert cytotoxicity through Fas signaling pathways. The main mechanisms of resistance are through alterations in the target enzyme TS and its level of expression and degree of enzymatic activity, which can be altered by mutations. The toxicities of 5-FU are schedule and dose dependent, with the main toxicities being gastrointestinal toxicity and myelosuppression. When 5-FU is given daily for 5 days every 4 weeks, the main toxicities are diarrhea and mucositis. When given weekly, toxicities include myelosuppression and diarrhea, and when given as a continuous infusion, the toxicities are diarrhea and hand-foot syndrome. Other toxicities include rash, mild nausea and vomiting, and a rare acute neurologic syndrome, which includes ataxia, somnolence, and upper motor neuron signs. 5-FU can also rarely lead to chest pain, electrocardiogram changes, and elevations in cardiac enzymes. DPD is the main and rate-limiting enzyme in the catabolism of 5-FU, and deficiencies of this enzyme can lead to significant and, at times, life-threatening toxicities such as diarrhea and neurotoxicity. If a patient is known to have a DPD deficiency or if the toxicities with 5-FU are more significant than expected and DPD levels are found to be decreased, appropriate dose reductions should be done or the drug should not be given.

Capecitabine

Capecitabine is an oral fluoropyrimidine carbamate that was originally approved for metastatic breast cancer by the FDA in 1998 that is resistant to both taxanes and anthracyclines. Capecitabine has 80% oral bio-availability, is inactive in its parent compound, and must undergo 3 enzymatic steps before activation. First, it is hydrolyzed intrahepatically by carboxylesterase to the intermediate 5′-deoxy-5-fluorocytidine, which is then converted by cytidine deaminase to 5′-deoxy-5-fluorourodine. The third activation is performed by the enzyme thymidine phosphorylase (TP), which is located at higher concentrations in the cervix, breast, colon, head and neck, and stomach; TP converts 5′-deoxy-5-fluorourodine to 5-FU. Capecitabine and its metabolites are predominantly renally cleared, so clinicians should use caution when dosing this drug in patients with renal impairment, and it is contraindicated in patients with a CrCl < 30 mL/min.

Toxicities of capecitabine include hand-foot syndrome and diarrhea. Other toxicities associated with 5-FU such as myelosuppression, alopecia, nausea, and vomiting are much lower in incidence with capecitabine. Alternate dosing with capecitabine has been explored given the high toxicities associated with the FDA-approved dosing of this drug,²³ and clinicians should carefully choose a starting dose of this drug and educate patients about the specific toxicities of this drug. Patients should be instructed to call their physician if diarrhea starts and be told to hold the drug if diarrhea becomes severe. Interestingly, patients in the United State are less able to tolerate starting doses of capecitabine compared to European patients, and this may be related to vitamin supplementation in US diets.

Gemcitabine

Gemcitabine (2′,2′-difluorodeoxycytidine [dFdC]) has shown activity in many gynecologic tumors and is a radiation sensitizer. Gemcitabine is administered IV and undergoes deamination to a catabolic metabolite, difluorodeoxyuridine. Gemcitabine in its parent form is inactive and requires intracellular metabolism and activation intracellularly to become cytotoxic. Cytarabine and gemcitabine have similar enzymatic activation patterns; the enzyme deoxycytidine kinase converts dFdC into gemcitabine monophosphate, and this molecule is phosphorylated by nucleoside monophosphate and diphosphate kinases to di- (dFdCDP) and triphosphate (dFdCTP) metabolites. Ultimately, dFdCTP is incorporated into DNA, resulting in the inhibition of DNA synthesis and normal functioning as well as interference with DNA repair and chain elongation. Resistance to gemcitabine includes the presence of nucleoside transport-deficient cells or cells that have decreased quantities of these transporters, deficiency of enzymes that are involved in the intra-cellular metabolism of gemcitabine, and increased amount or activity of certain catabolic enzymes.

Greater than 90% of the drug following IV administration is found in the urine. Gemcitabine clearance is lowered in the elderly, and increased hepatic toxicity is observed when gemcitabine is given when total bilirubin levels are > 1.6 mg/dL; gemcitabine doses should be lowered in this setting. Toxicities of gemcitabine are dose dependent, and longer infusions lead to more myelosuppression. Toxicity includes myelo-suppression, and both neutropenia and thrombocytopenia are observed. Other side effects include fevers, transient elevation of transaminases, myalgias, and asthenia. Rarer complications that require discontinuation of gemcitabine include dyspnea and hemolytic uremic syndrome. Both of these toxicities should be recognized early and treated, and gemcitabine should be stopped.

Topoisomerase Inhibitors

Topoisomerases are enzymes that alter the topology of DNA. During replication, transcription, and recombination, the double helix DNA is separated, resulting in torsional stress, and DNA topoisomerases reduce and resolve torsional stress. Type I and type II topoisomerases exist, and they differ based on the number of DNA strand breaks they can make. Type I topoisomerases cleave a single DNA strand and alter DNA linking number by 1 per activity cycle. Type II topoisomerases cleave both DNA strands and change DNA linking number by 2. Mammalian cells contain 1 type IB topoisomerase, topoisomerase I (Top1); 2 type IA topoisomerases, topoisomerase IIIα. (Top3α) and topoisomerase IIIβ) (Top3β); and 2 type II topoisomerases, topoisomerase IIβ (Top2β) and topoisomerase IIα (Top2α). These different topoisomerases perform different functions; Top1, Top2α, and Top2β, are essential for cell viability. Top1 is also important in replication fork movement during DNA replication as well as relaxing supercoiled DNA that is formed during transcription. Top2α also allows DNA relaxation during transcription as well as unlinking daughter duplexes during DNA replication and helps remodel chromatin structure.

Camptothecin

Camptothecin was identified in the 1960s and is a naturally occurring alkaloid derived from the Camptotheca acuminata tree. Initial studies of camptothecin were complicated by severe toxicities of myelosuppression and hemorrhagic cystitis and showed only minimal anticancer activity. Active lactone forms that are water-soluble derivatives of camptothecin, irinotecan and topotecan, are currently FDA approved for cancer treatment. Camptothecins work by stabilizing the typically transient reaction in which the enzyme is covalently linked to DNA. Resistance to camptothecins is likely multifactorial and result from inadequate intracellular drug levels, impaired metabolism of the prodrug such as occurs with irinotecan, changes in the cell’s response to the drug–Top1 interaction, and alterations in the normal topoisomerases themselves.

Irinotecan

Irinotecan is a prodrug that possesses a large dipiperidino side chain at C10 that must be cleaved intrahepatically as well as in other tissues by a carboxylesterase-converting enzyme in order to form the active metabolite, SN-38. Renal excretion accounts for 25% of irinotecan, and excretion is through hepatic metabolism and biliary excretion. Thus, dose reductions should be performed for patients with hepatic impairment. In addition, SN-38 is metabolized via glucuronidation intrahepatically by the enzyme UGT1A1, and patients who are homozygous for the UGT1A1 allele should undergo dose reductions of irinotecan. An FDA-approved test for the detection of UGT1A1 allele exists. The most common toxicities of irinotecan are diarrhea and myelosuppression. Irinotecan-induced diarrhea is predominantly caused by 2 mechanisms, which are also temporally different. Acute cholinergic effects caused by the prodrug’s inhibition of acetylcholinesterase can lead to diarrhea and abdominal cramping within 24 hours, which can be treated with atropine. Direct mucosal cytotoxicity can also lead to diarrhea, which is usually observed greater than 24 hours after drug administration and is treated with loperamide. Patients with deficiencies of UGT1A1 may experience more side effects of diarrhea and myelosuppression.

Topotecan

Topotecan is a semisynthetic analog of camptothecin that binds Top1. Topotecan undergoes reversible, pH-dependent hydrolysis of the active lactone moiety, forming an open-ring hydroxyacid, which is inactive. The terminal half-life of topotecan in patients with normal renal function is 2 to 3 hours, and this is increased to 5 hours in patients with renal dysfunction; topotecan clearance is decreased by approximately 25% in patients with moderate renal function impairment (CrCl, 20-39 mL/min). Toxicities are dependent on dose and schedule, and toxicities include myelosuppression, including neutropenia, anemia, and thrombocytopenia; mild nausea; fatigue; alopecia when given on the 5 days in a row schedule; and less commonly transient hepatic transaminitis, rash, and low-grade fevers. Receipt of heavy pretreatment with other cytotoxic drugs and prior radiation therapy can worsen myelosuppression, so clinicians may consider dose reduction in those patients. Because renal clearance is the predominant clearance of topotecan, clinicians should dose reduce topotecan in patients with renal impairment or choose an alternative therapy. Entry of topotecan into the cerebrospinal fluid (CSF) is higher than other camptothecins, but that does not appear to contribute to its toxicities; CSF levels of topotecan are approximately 30% of plasma levels. Topotecan has been approved for the treatment of recurrent ovarian cancer, lung cancer, and stage IVB recurrent or persistent carcinoma of the cervix cancer that is not amenable to curative treatment with surgery and/or radiation therapy.

Anthracyclines and Anthracenediones

Anthracyclines are derived from Streptomyces peucetius var. caesius. These drugs target Top2 through DNA intercalation leading to RNA and DNA synthesis inhibition and DNA–Top2 complex stabilization resulting in DNA double-stranded breaks. In addition, anthracyclines also enhance the catalysis of oxidation–reduction reactions through their quinone structure and promote the generation of oxygen free radicals, thereby leading to additional anticancer effect via DNA and cell membrane damage. Anthracyclines enter cells through passive diffusion and are hydrophobic. They are substrates for P-glycoprotein and Mrp-1. Major mechanisms of resistance include drug efflux, mutations in Top2 enzymes or reduced expression, overexpression of Bcl-2, p53 mutations, and increase in neutralizing molecules such as glutathione or glutathione transferase. The different anthracyclines are doxorubicin, pegylated liposomal doxorubicin, daunorubicin, epirubicin, and idarubicin; anthracyclines are metabolized hepatically and excreted in the bile. Dose reductions are mandatory in patients with decreased hepatic function and elevated total bilirubin levels. Urinary excretion of anthracyclines is minimal and represents about 10% or less of the dose administered.

Doxorubicin

Doxorubicin is available in a standard salt form or as a liposomal formulation. The major toxicity of anthracyclines is cardiac toxicity, and both acute and chronic toxicities can be observed with this class of anticancer agents. Acute doxorubicin toxicity, which is typically reversible and occurs within a few days of the infusion, is clinically manifested by hypotension, dropped left ventricular ejection fraction, tachycardia, and electrocardiogram changes. Chronic toxicity is more common than acute toxicity and is cumulative and usually irreversible. Direct myocardial damage occurs via reactive oxygen species generated during election transfer from the semiquinone to quinone moieties and production of hydrogen peroxide and the peroxidation of myocardial lipids. Chronic cardiac damage is manifested by congestive heart failure from congestive cardiomyopathy, and cardiac biopsies in patients with chronic cardiac damage and congestive heart failure show interstitial fibrosis and occasional vacuolated myocardial cells. Myocytes hypertrophy and degenerate, along with loss of cross-striations. Risk factors for chronic cardiomyopathy include the dose, schedule of drug administration, cumulative dosing, and other risk factors such as previous heart disease history, radiation to the mediastinum, age younger than 4 years old, prior use of other cardiac toxins, concomitant administration of other chemotherapy such as paclitaxel or trastuzumab, and a history of hypertension. When doxorubicin is given as an IV bolus infusion every 3 to 4 weeks, the risk of congestive heart failure is 3% to 5% once the cumulative dose of doxorubicin reaches 400 mg/m², 5% to 8% when the dose reaches 450 mg/m², and 6% to 20% when the dose reaches 500 mg/m². Cardiac function should be monitored during treatment with anthracyclines by echocardiography or radionuclide scans. If arrhythmias are suspected, electrocardiograms should be monitored. Left ventricular ejection fraction (LVEF) should be checked prior to starting an anthracycline. Anthracyclines become contraindicated when either the baseline LVEF in patients is < 50% or the LVEF drops by more than 10% during therapy. Dexrazoxane is a metal chelator that can lessen myocardial toxicity of doxorubicin by chelating iron and copper and thus interferes with redox reactions that can generate free radicals and damage myocardial lipids. Other toxicities of doxorubicin include myelosuppression, alopecia, nausea, vomiting, mucositis, and fatigue, and all of these toxicities are dose and schedule dependent.

Doxorubicin is a vesicant, and care should be taken to avoid extravasations; central venous catheters should be placed if peripheral venous access is poor. Extravasations of doxorubicin can lead to skin and local tissue necrosis that may be treated with ice and dimethyl-sulfoxide to minimize the extravasation and possible surgical debridement and/or skin grafts if the extravasation is extensive enough. Flare reaction consisting of erythema around the injection site is a benign reaction. Other toxicities of doxorubicin include radiation recall, which consists of an inflammatory, erythematous reaction that occurs at sites of previous radiation leading to skin rash, pericarditis, and pleural effusions. Careful attention to ruling out other causes of skin rash besides a recall reaction such as inflammatory breast cancer, skin metastases, or other drug reactions or systemic disorders should occur. Secondary leukemias or myelodysplastic syndrome have been reported in patients treated with doxorubicin, and this risk is increased in patients who are treated concomitantly with other DNA-damaging anticancer agents or radiotherapy or with escalated doses of anthracyclines and when patients have been heavily pretreated with cytotoxic drugs. The risk of acute myeloid leukemia or myelodysplastic syndrome is more sharply elevated with intensified doses of cyclophosphamide in combination with standard doses of doxorubicin.

Pegylated Liposomal Doxorubicin

Pegylated liposomal doxorubicin (PLD) (doxorubicin HCl liposome injection; Doxil or Caelyx) is doxorubicin that has been encapsulated in extended-circulating liposomes. Liposomes are microscopic vesicles, composed of a phospholipid bilayer, that encapsulate active drugs, and PLD consists of a liquid suspension of vesicles with a mean size of 80 to 90 nm. Doxorubicin is encapsulated in the internal compartment of the liposome, and a single lipid bilayer membrane separates the internal compartment from the external one. There are approximately 10,000 to 15,000 doxorubicin molecules per liposome, and polyethylene glycol is located on the liposome surface for liposome stability. Most of the doxorubicin is present as a crystalline-like precipitate without osmotic effects, and this gives stability to the entrapment of doxorubicin. During circulation, at least 90% of PLD remains encapsulated, and the drug has a half-life of approximately 30 to 55 hours depending on the study reported, patient population, and patient age. PLD is eliminated via 2 phases, the distribution phase, where a minor fraction of drug is cleared from the circulation with a half-life of approximately an hour, and the elimination phase, which is significantly longer. Approximately 95% of PLD in the plasma remains encapsulated within liposomes and is not bioavailable. The volume of distribution is approximately the total blood volume, and the AUC is increased approximately 60-fold higher compared to free doxorubicin.

PLD is considered an irritant, and precautions should be taken to avoid extravasation. The most common adverse events associated with PLD are hand-foot syndrome (also known as palmar-plantar erythrodysesthesia) and stomatitis, and these adverse events are schedule and dose dependent. Patients should be carefully monitored for toxicity. Adverse reactions, such as hand-foot syndrome, hematologic toxicities, and stomatitis, may be managed by dose delays and adjustments. Following the first appearance of a grade 2 or higher adverse reaction, the dosing should be adjusted or delayed. Once the dose has been reduced, it should not be increased at a later time. Following administration of PLD, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. Other side effects include some nausea and fatigue; the cardiac effects of PLD are less than doxorubicin. For patients with hepatic impairment, it is recommended that the PLD dosage be reduced if the bilirubin is elevated as follows: serum bilirubin 1.2 to 3.0 mg/dL, give 50% of normal dose; serum bilirubin > 3 mg/dL, give 25% of normal dose (package insert). Dose reductions for skin toxicity are listed in the package insert.

Mitoxantrone

Mitoxantrone was originally synthesized in the 1970s. It is a DNA intercalator and stabilizes the Top2–DNA complex, which leads to breaks in double-stranded DNA. Unlike anthracyclines, mitoxantrone undergoes oxidative–reduction reactions and formation of free radicals less frequently, so cardiac toxicity is less. Currently, mitoxantrone is FDA approved for hormone-refractory prostate cancer and acute myeloid leukemia. Toxicities include myelosuppression and, less commonly, nausea, vomiting, alopecia, and mucositis. Cardiac toxicity can be observed at cumulative doses greater than 160 mg/m². Dose reductions should be undertaken for patients with hepatic dysfunction.

Actinomycin

Actinomycin was originally isolated from the culture broth of Streptomyces in the 1940s. Dactinomycin is FDA approved for Ewing sarcoma, gestational trophoblastic disease (GTD), metastatic testicular cancer, rhabdomyosarcoma, and nephroblastoma. Dactinomycin is indicated as a single agent or in combination with other chemotherapeutic agents for treatment of GTD. Dactinomycin consists of a planar phenoxazone ring that is attached to 2 peptide side chains, and its mechanism of action is DNA intercalation between adjacent guanine–cytosine bases. This intercalation results in inhibiting Top2 and leads to double-stranded DNA breaks. Dactinomycin is transported by P-glycoprotein and represents a resistance mechanism. Its half-life is 36 hours. Toxicities include myelosuppression, nausea, vomiting, alopecia, mucositis, hepatotoxicity including veno-occlusive disease, fatigue, and acne. Elimination of dactinomycin is predominantly biliary and in feces and, to a lesser extent, renal; dactinomycin is typically excreted via these routes unchanged.

Epipodophyllotoxins

This class of drugs is comprised of etoposide and teniposide, both of which poison Top2 as their mechanism of anticancer activity. These drugs are glycoside derivatives of podophyllotoxin, which is an antimicrotubule agent originally extracted from the mandrake plant. Etoposide’s chemical formula is 4′-demethylepipodophyllotoxin 9-[4,6-0-(R)-ethylidene-β-D-glucopyranoside]. Etoposide can be administered either orally or IV, and it has FDA approval for use in small-cell lung cancer and refractory testicular cancer. In gynecologic cancers, etoposide has activity in recurrent ovarian cancer, germ cell tumors, GTD, and small-cell tumors of the gynecologic tract.

Teniposide is FDA approved in refractory pediatric acute lymphoid leukemia but is not used in gynecologic cancers. In adults, clearance of etoposide is correlated with CrCl, serum albumin concentration, and nonrenal clearance. Thus, patients with impaired renal function receiving etoposide have exhibited reduced total body clearance, increased AUC, and a lower volume of distribution at steady state. The IV route is typically administered daily for 3 to 5 days every 3 to 4 weeks, and the main toxicities include myelo-suppression, nausea, vomiting, diarrhea, fatigue, and alopecia. Other side effects include transient hypotension following rapid IV administration, which has been reported in 1% to 2% of patients; this has not been associated with cardiac toxicity or electrocardiographic changes. To prevent this rare toxicity, it is recommended that etoposide be administered by slow IV infusion over a 30- to 60-minute period. Another rare side effect is the development of anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, and/or hypotension, which have been reported in 0.7% to 2% of patients receiving IV etoposide and in less than 1% of patients treated with oral capsules. These reactions typically respond to cessation of the infusion and administration of pressor agents, corticosteroids, antihistamines, or volume expanders, as appropriate; however, the reactions can be fatal.

Epipodophyllotoxins are associated with the development of secondary acute myeloid leukemias (French-American-British [FAB] class M4 and M5) due to balanced translocations affecting the breakpoint cluster region of the MLL gene at chromosome 11q23. The cumulative risk of secondary acute myeloid leukemias with this drug is approximately 4% over 6 years. The bioavailability of oral etoposide is very variable, with an average bioavailability of 50%. Etoposide is primarily cleared unchanged in the kidneys, and dose reductions are recommended; as per the package insert, a 25% dose reduction should be done for patients with a CrCl between 15 and 50 mL/min, and a 50% dose reduction should be done for patients with a CrCl < 15 mL/min.

Miscellaneous Chemotherapy Agents

Bleomycin

Bleomycin sulfate is comprised of a mixture of glyco-peptide antineoplastic antibiotics, bleomycin A₂ and bleomycin B₂, which are isolated from the fungus Streptomyces verticillus. Bleomycin’s anticancer mechanism is derived from oxygen-free radical formation that then lead to single-stranded and double-stranded DNA breaks. The presence of a redox-active Fe²⁺ metal ion is necessary to generate the active free moieties. Bleomycin’s effects are cell cycle specific and are specific for G2 and M phases of the cell cycle. Bleomycin is used as part of germ cell tumor regimens and is used intracavitary to treat malignant pleural effusions. Mechanisms of resistance to bleomycin include decreased drug accumulation intracellularly because of altered cell uptake, increased drug inactivation through increased expression of bleomycin hydrolase, and enhanced repair of DNA through the increased expression of DNA repair enzymes. Interestingly, bleomycin hydrolase is widely distributed in normal tissues with the exception of the skin and lungs, both targets of bleomycin toxicity. Bleomycin is given IV or intramuscularly and has an initial half-life of 10 to 20 minutes with a terminal half-life of 3 hours. Excretion is predominantly renal, and most of the drug is eliminated unchanged in the urine. The major toxicities of bleomycin are pulmonary. Pulmonary toxicity can occur in up to 10% of patients, and this toxicity is related to the cumulative dose received. The incidence of this toxicity is higher in patients above the age of 70 and in those who have received a total cumulative dose of 400 units. Additional risk factors include smoking, any underlying previous lung disease, prior chest irradiation, exposure to high concentrations of oxygen, and use of granulocyte colony-stimulating factor (G-CSF). The use of G-CSF and risk of pulmonary toxicity may be related to neutrophil presence and infiltration within areas of lung injury. The use of pulmonary function testing to monitor for pulmonary toxicity is controversial. It is recommended that the diffusing capacity of the lung for carbon monoxide (D_LCO) be monitored monthly if it is to be used to detect pulmonary toxicities, and the drug should be discontinued when the D_LCO falls below 30% to 35% of the pretreatment value. Frequent serial chest imaging via chest x-ray or computed tomography should also be performed. Signs and symptoms include dyspnea and cough, evidence of inspiratory crackles on physical examination, and pulmonary infiltrates or interstitial changes on chest imaging. A hypersensitivity reaction with fevers, chills, and urticaria is observed in up to 25% of patients; in 1% of lymphoma patients, a severe idiosyncratic reaction (similar to anaphylaxis) consisting of hypotension, mental confusion, fever, chills, and wheezing has been reported.

Because of bleomycin’s sensitization of lung tissue, patients who have received bleomycin and who will receive oxygen administered at surgery are at greater risk of developing pulmonary toxicity. Even following bleomycin administration, lung damage can occur at lower concentrations of oxygen that are usually considered safe. Suggested preventive measures include maintaining fractional inspired oxygen (FIO₂) at concentrations approximating that of room air (25%) during surgery and the postoperative period and careful monitoring of fluid replacement. Skin toxicities can occur in up to 50% of treated patients, and this side effect consists of erythema, rash, hyperpigmentation, and tenderness of the skin. Hyperkeratosis, nail changes, alopecia, pruritus, and stomatitis have also been reported. Skin toxicities rarely result in discontinuation of bleomycin (2% of cases). Skin toxicity is a late manifestation and usually develops in the second and third week of treatment after 150 to 200 units of bleomycin have been administered; it appears to be related to the cumulative dose. Fevers can occur with the infusion or following completion of the infusion and can be quite elevated. Other rare toxicities include vascular toxicities such as myocardial infarction, cerebrovascular accidents, thrombotic microangiopathy (hemolytic uremic syndrome), or cerebral arteritis.

Renal insufficiency markedly alters bleomycin elimination. The terminal elimination half-life increases exponentially as the CrCl decreases. Dosing reductions have been proposed by the package insert for patients with CrCl values of < 50 mL/min, with incremental dose reductions for each 10 mL/min drop below 50 mL/min.

PRINCIPLES OF CHEMOTHERAPY MANAGEMENT AND SIDE EFFECTS

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