CHAPTER 27: Principles of Chemotherapy

In principle, chemotherapeutic drugs are able to treat cancer and spare normal cells by exploiting inherent differences in their individual growth patterns. Each tumor type has its own characteristics, which explain why the same chemotherapy regimen is not equally effective for the whole spectrum of gynecologic cancers. Selecting appropriate drugs and limiting toxicity demands an understanding of cellular kinetics and biochemistry.

The Cell Cycle

All dividing cells follow the same basic sequence for replication. The cell generation time is the time required to complete the five phases of the cell cycle (Fig. 27-1). The G₁ phase (G = gap) involves various cellular activities, such as protein synthesis, RNA synthesis, and DNA repair. When prolonged, the cell is considered to be in the G₀ phase, that is, the resting phase. G₁ cells may either terminally differentiate into the G₀ phase or reenter the cell cycle after a period of quiescence. During the S phase, new DNA is synthesized. The G₂ (premitotic) phase is characterized by cells having twice the DNA content as they prepare for division. Finally, actual mitosis and chromosomal division takes place during the M phase.

Tumors do not typically have faster generation times. They instead have many more cells in the active phases of replication and have dysfunctional apoptosis (programmed cell death), hence proliferation. In contrast, normal tissues have a much larger number of cells in the G₀ phase. As a result, cancer cells proceeding through the cell cycle may be more sensitive to chemotherapeutic agents, whereas normal cells in G₀ are protected. This growth pattern disparity underlies the effectiveness of chemotherapeutic agents.

Cancer Cell Growth

Tumors are characterized by a gompertzian growth pattern (Fig. 27-2). Fundamentally, a tumor mass requires progressively longer times to double in size as it enlarges. When a cancer is microscopic and nonpalpable, growth is exponential. However, as a tumor enlarges, the number of its cells undergoing replication decreases due to limitations in blood supply and increasing interstitial pressure.

When tumors are in the exponential phase of gompertzian growth, they should be more sensitive to chemotherapy because a larger percentage of cells are in the active phase of the cell cycle. For this reason, metastases should be more sensitive to chemotherapy than the primary tumor. To capitalize on this potential benefit, advanced ovarian cancer is usually first treated with surgery to remove the primary tumor, debulk large masses, and leave only microscopic residual disease for the adjuvant chemotherapy to act on. In addition, when a tumor mass shrinks in response to treatment, the presumption is that a greater number of cells will enter the active phase of the cell cycle to accelerate growth. This larger percentage of replicating cells should also increase the sensitivity of a tumor to chemotherapy.

Doubling Time

The time needed for a tumor to double in size is commonly referred to as its doubling time. Whereas the cell cycle generally refers to the activity of individual tumor cells, doubling time refers to the growth of an entire heterogeneous tumor mass. In humans, the doubling times of specific tumors vary greatly. The speed with which tumors grow and double in size is largely regulated by the number of cells that are actively dividing—known as the growth fraction. Typically, only a small percentage of the tumor will have cells that are rapidly proliferating. The remaining cells are in the G₀ resting phase. In general, tumors that are cured by chemotherapy are those with a high growth fraction, such as gestational trophoblastic neoplasia. When tumor volume is reduced by surgery or chemotherapy, the remaining tumor cells are theoretically propelled from the G₀ phase into the more vulnerable phases of the cell cycle, rendering them susceptible to chemotherapy.

Cell Kinetics

Chemotherapeutic agents typically work by first-order kinetics to kill a constant fraction of cells rather than a constant number. For example, one dose of a cytotoxic drug may result in a few logs (10² to 10⁴) of cell kill. This, however, is not curative since tumor burden may be 10¹² cells or more. Thus, the magnitude of cell kill necessary to eradicate a tumor typically requires intermittent courses of chemotherapy. In general, a cancer’s curability is inversely proportional to the number of viable tumor cells at the beginning of chemotherapy.

Some drugs achieve cell kill at several phases of the cell cycle. These cell cycle-nonspecific agents act in all phases of replication from G₀ to the M phase. Cell cycle-specific agents act only on cells that are in a specific phase. By combining drugs that act in different phases of the cell cycle, the overall cell kill should be enhanced.

Clinical Setting

Chemotherapy may be used in at least five different ways. The term induction chemotherapy is defined as primary treatment for patients with an advanced malignancy when no feasible alternative treatment exists. Adjuvant chemotherapy is given to destroy remaining microscopic cells that may be present after the primary tumor is removed by surgery. Neoadjuvant chemotherapy refers to drug treatment directed at an advanced cancer to decrease preoperatively the extent or morbidity of a subsequent surgical resection. Consolidation (or maintenance) chemotherapy is given after cancer has disappeared following the initial therapy to prolong the duration of clinical remission or to prevent ultimate relapse. Therapy applied to recurrent disease or to a tumor that is refractory to initial treatment is termed salvage (or palliative) chemotherapy. In these incurable patients, the intent is to achieve tumor shrinkage or stability but maintain quality of life.

In general, chemotherapy is used with either curative or palliative intent. When implementing chemotherapy with curative intent, the number of courses is typically predefined. Emphasis is placed on maintaining curative dosages and adhering closely to the treatment schedule. This may lead to significant toxicity and require growth-factor support. However, for the possibility of achieving cure, these side effects are typically deemed acceptable.

Chemotherapy is often not used with curative intent, and the treating clinician must balance several factors to provide effective, compassionate palliation. Thus, in this setting, greater importance is attached to avoiding excessive toxicity. In many ways, the use of chemotherapy for palliation exemplifies the “art” of medicine. Instead of a defined number of treatment courses, a clinician must frequently revisit the treatment effectiveness and alter the dosage and timing of chemotherapy administration accordingly.

Drug Regimens

With few exceptions, single drugs administered at clinically tolerable doses do not cure cancer. However, using two or more drugs simultaneously may greatly exacerbate toxicity. Thus, in principle, the goal of combination chemotherapy is to provide maximum cell kill with minimal or tolerable adverse patient side effects. Drugs are selected based on their proven efficacy as single agents, different mechanisms of action, and toxicities that overlap minimally or not at all.

Combination chemotherapy is more effective in attacking heterogeneous populations of cells. Moreover, the use of multiple drugs with differing mechanisms of action tends to minimize the emergence of drug resistance. Typically, drugs used in combination should have clinical data indicating that their effects will be synergistic or at least additive. Drugs in combination are used at their optimal doses and schedules. Dose reductions initiated solely to allow the addition of other agents are counterproductive because most drugs must be used near their maximum tolerated dose to ensure efficacy.

Frequently, chemotherapy is combined with radiation therapy or sequenced with surgery. With chemoradiation, the goal is to achieve local control by chemically rendering the tumor more sensitive to radiation. For example, care of locally advanced cervical cancer was transformed by adding weekly cisplatin to standard radiotherapy. In addition, concurrent chemotherapy is intended to treat micrometastases outside the radiation field.

However, treatment-related toxicity is also increased. Patients previously treated with radiation therapy may have bone marrow, skin, or other body systems that are more susceptible to chemotherapy toxicity. As a result, dose reductions or delays are commonplace. Furthermore, chemotherapy is generally less effective in tumors that lie within a previously irradiated field due to increased fibrosis and capillary destruction.

Combining chemotherapy with surgery has many different applications. A woman with endometrial cancer may have nodal metastases detected during surgery, and receive pelvic radiation preceded or followed by combination chemotherapy. Alternatively, a woman with recurrent ovarian cancer may be treated by combination chemotherapy with or without preceding secondary cytoreductive surgery. The purpose of sequencing treatment in this way is to reduce tumor bulk and thereby augment chemotherapy effectiveness. In general, adjunctive therapy is begun within a few weeks after surgery.

Directing Care of the Patient

To effectively counsel a gynecologic cancer patient and then guide her chemotherapeutic treatment course requires a comprehensive understanding of the diagnosis, alternatives, and goals of care. Coexisting conditions or tumor-related complications (e.g., deep-vein thrombosis) may need to be addressed. As the intended therapy is finalized, extensive information regarding anticipated side effects is provided to allay concerns and reduce anxiety. A consent form must be reviewed and signed by the patient, in addition to clarification of all potential logistical challenges (e.g., intravenous access).

Prior to drug infusion, a complete medical history and comprehensive physical examination are mandatory. Blood work, including a complete blood count, comprehensive metabolic panel, and tumor markers (e.g., CA125) as indicated, are drawn and reviewed before orders to begin infusion are signed. Drug administration must take place in a setting where staff are immediately available to intervene should the need arise. Afterward, the patient is provided contact numbers in case of questions, problems, or other concerns that can often develop prior to the next visit.

Typically, regular office visits shortly before or on the day of treatment allow assessment of toxicity and general health. Patient examination and review of blood work results, in the context of the tumor response and overall treatment goal, will help determine whether drugs are changed or their dosages revised. Over time, the treatment strategy is continually reassessed as circumstances change.

Dosing and Dose Intensity

Overall, treatment effectiveness depends on drug concentration and duration of exposure to critical tumor sites. Chemotherapeutic agents typically have a narrow therapeutic range or “window.” Thus, doses must be calculated accurately to achieve an optimal effect above a critical threshold while avoiding undue toxicity.

Most commonly, chemotherapy doses are calculated based on the patient’s body surface area (BSA) and are expressed in milligrams per meter squared (mg/m²). BSA is a better indicator of metabolic mass than body weight because it is less affected by abnormal adipose mass. This calculation ensures that each patient receives proportionally similar drug amounts. Although height is a fixed variable, patient weights are obtained prior to every therapy course, as they may fluctuate significantly. Rarely, tissue edema or ascites must be factored, since doses should be based on weight without this coexisting fluid. The BSA is most often calculated by using a nomogram (standard reference graph table). Consistent derivation of the BSA at each visit is important, and various calculators are routinely available via software or online (http://www.globalrph.com/bsa2.htm). “Normal” adult BSA for women approximates 1.7 m².

Alternatively, the dosing of some drugs is more specific. For example, bevacizumab is a monoclonal antibody metabolized and eliminated via the reticuloendothelial system. It is dosed only by patient weight (mg/kg). For renally excreted drugs, such as carboplatin, dosing may be based on an estimate of the glomerular filtration rate (Calvert formula).

The amount of drug administered over time is known as the dose intensity (or density). Its primary importance is in highly responsive tumors, in which cure can be achieved with chemotherapy. However, in other less sensitive tumors, it may not be possible to increase the dose to a level sufficient to produce demonstrable benefit without producing dose-limiting toxicity. On the other hand, reducing dose intensity to decrease toxicity can produce inferior therapeutic results.

Administration Route and Excretion

Chemotherapy may be administered systemically or regionally. Oral, intravenous (IV), subcutaneous (SC), or intramuscular (IM) routes comprise systemic treatment options. Regional chemotherapy is aimed at delivering drugs directly into the cavity in which the tumor is located. Clearance for many agents from a body cavity is slower than from systemic circulation. As a result, cancer cells are exposed longer to higher concentrations of active agents. This technique has been most extensively studied in ovarian cancer, in which tumors are usually confined to the intraperitoneal (IP) space. Clinical studies have uniformly demonstrated a pharmacologic advantage favoring administration into the IP compartment. However, penetration into peritoneal tumor nodules by passive diffusion is often limited by the presence of intraabdominal adhesions, poor fluid circulation, fibrotic tumor encapsulation, and coexisting ascites. Because of these limitations in drug penetration, IP chemotherapy is typically administered to women with minimal residual disease.

During IV administration, several drugs known as vesicants require special care (Table 27-1). Extravasation of these into the subcutaneous tissue can result in severe pain and necrosis. These drugs require slow infusion either through a rapidly flowing peripheral IV catheter or preferably via a central venous catheter. If extravasation is suspected, the infusion is immediately stopped, the affected arm elevated, and ice packs applied. In severe cases, a plastic surgeon should be consulted.

Agent activity and toxicity is influenced dramatically by drug inactivation, elimination, or excretion. For the most part, this takes place primarily via the liver or kidneys. As a result, drug activity may be diminished and toxicity exacerbated when normal hepatic or renal function is impaired. In addition, drug toxicity is often more pronounced in the elderly or malnourished. For example, a low serum creatinine level in cachectic women may not accurately reflect underlying renal function. If a carboplatin dose is calculated using this falsely low value, the amount may be excessive and result in considerable morbidity. Instead, a preset creatinine level may need to be selected (0.8 or 1.0 mg/dL) to aid safer dosing in some patients.

Drug Interactions and Allergic Reaction

Most women who receive chemotherapy are prescribed medication for other noncancerous conditions, such as hypertension. Moreover, women also often receive analgesics, antiemetics, and antibiotics during chemotherapy. Most drug interactions are of little consequence, but some may lead to substantially altered drug toxicity. Drugs that are metabolized in the liver are particularly at risk for such interactions. For example, using methotrexate in a woman taking warfarin (Coumadin) will usually enhance the anticoagulant effect and thus will require a warfarin dose reduction.

An anaphylactic, allergic, or hypersensitivity reaction during or after administration of chemotherapy may develop, despite patient history review and administration of prophylactic medications. Accordingly, a treatment facility must have trained nursing staff and resources to manage these sudden, but common, issues. Prior to drug administration, a woman is instructed to report symptoms that may herald an anaphylactic reaction such as flushing, pruritus, dyspnea, tachycardia, hoarseness, or lightheadedness. Emergency equipment, such as supplemental oxygen, ventilatory face mask and bag, or intubation equipment, must be immediately available. For a localized hypersensitivity response, administration of intravenous diphenhydramine (Benadryl) and/or corticosteroids may be sufficient. However, for a generalized hypersensitivity or anaphylactic response, chemotherapy should be stopped immediately, the emergency team notified, and emergency drugs administered, such as epinephrine (0.1–0.5 mg of a 1:10,000 solution) (Table 27-2).

Drug Resistance

In principle, larger tumor masses have a greater proportion of cells that have already developed resistance. Resistance may be intrinsic or acquired, and it may develop to one drug or to multiple agents. Intrinsic drug resistance is seen if tumors are first exposed to an agent and fail to respond. In contrast, with acquired drug resistance, tumors no longer respond to drugs to which they were initially sensitive. Sometimes, this develops with a specific drug. More often, however, acquired resistance is “pleiotropic,” meaning that a cancer is resistant to multiple chemotherapy agents. This is often mediated by the P-glycoprotein or multidrug resistance pump. Advanced ovarian cancer is a good example. Most patients will initially achieve remission with platinum-based chemotherapy, but 80 percent will ultimately relapse and die from tumors that have become resistant to all cytotoxic therapy.

Evaluating Response to Chemotherapy

The effective use of chemotherapy is a dynamic process whereby a treating clinician is constantly weighing toxicity to the patient against tumor response. Numerous factors influence toxicity and include the patient’s baseline nutrition, overall health, extent of disease, and prior therapy. In counseling women to continue treatment or switch to a different regimen, a clinician must have objective criteria for response (Table 27-3). The most important indicator is the complete response rate. For ovarian cancer, this would include normal CA125 levels (usually <35 U/mL), physical examination findings, and imaging test results. Ultimately, women who have any possibility of cure are those who first achieve a complete response. However, if chemotherapy results in a partial response, many women still view this as advantageous compared with supportive care, even if a survival benefit is unproven.

Antimetabolites

The antimetabolites are analogues of naturally occurring components of the metabolic pathways that lead to the synthesis of purines, pyrimidines, and nucleic acids. In most cases, they are S phase-specific agents that are most effective in rapidly growing tumors associated with short doubling times and large growth fractions (Table 27-4).

Methotrexate

This antimetabolite is U.S. Food and Drug Administration (FDA)-approved to be used solely for treatment of women with gestational trophoblastic neoplasia (GTN). It is also commonly used for the medical management of ectopic pregnancy. Methotrexate (MTX) tightly binds to dihydrofolate reductase, blocking the reduction of dihydrofolate to tetrahydrofolate (the active form of folic acid) (Fig. 27-3). As a result, thymidylate synthetase and various steps in de novo purine synthesis are halted. This leads to arrest of DNA, RNA, and protein synthesis.

Methotrexate may be administered orally, IM, IV, or intrathecally. Most commonly, single-agent treatment of GTN involves MTX given IM as an 8-day regimen of 1 mg/kg on treatment days 1, 3, 5, and 7, or at dosages of 30 to 50 mg/m² once each week. Combination therapy for high-risk disease includes 100 mg/m² MTX given IV over 30 minutes, followed by a 200 mg/m² IV dose over 12 hours. With MTX, patients are counseled to avoid folate-containing supplements unless specifically directed.

MTX causes few side effects at typical doses. However, at high doses, although used infrequently, this agent can lead to fatal bone marrow toxicity. This toxicity can be prevented by “rescue” doses of leucovorin. Leucovorin is folinic acid, has activity that is equivalent to folic acid, and thus is readily converted to tetrahydrofolate. Leucovorin, however, does not require dihydrofolate reductase for its conversion. Therefore, its function is unaffected by inhibition of this enzyme by MTX. Leucovorin administration, therefore, allows for some purine and pyrimidine synthesis. Leucovorin rescue is incorporated into the 8-day alternating MTX schedule, and a 0.1 mg/kg leucovorin dose is provided orally on treatment days 2, 4, 6, and 8.

In addition to myelosuppression, renal toxicity and acute cerebral dysfunction are typically only seen at high MTX doses. Methotrexate is predominantly excreted through the kidneys, and thus women with renal insufficiency have doses reduced. Serum MTX levels are carefully monitored in these patients, as they may require prolonged leucovorin rescue.

Gemcitabine

This antimetabolite is FDA approved to be used with other agents for treatment of recurrent ovarian cancer but is also commonly used for uterine sarcoma. Gemcitabine (Gemzar) is a synthetic nucleoside analogue that undergoes multiple phosphorylations to form the active metabolite. The resulting triphosphate is subsequently incorporated into DNA as a fraudulent base pair. Following the insertion of gemcitabine, one additional deoxynucleotide is added to the end of the DNA chain before replication is terminated, and thereby, DNA synthesis is halted.

The usual administration of gemcitabine is by 30-minute infusion. Longer durations, such as those greater than 60 min, are associated with increased toxicity due to intracellular accumulation of the triphosphate. Depending on whether it is used as a single agent or in combination, gemcitabine is typically given at doses between 600 and 1250 mg/m² once weekly for 2 to 3 weeks, followed by a week off therapy.

Myelosuppression, especially neutropenia, is the main dose-limiting side effect. Gastrointestinal (GI) toxicity, such as nausea, vomiting, diarrhea, or mucositis, is also common. Approximately 20 percent of patients will develop a flulike syndrome, including fever, malaise, headache, and chills. Pulmonary toxicity is infrequent, but reported.

5-Fluorouracil

5-Fluorouracil (5-FU) is not FDA approved for gynecologic cancer but is occasionally paired with cisplatin during chemoradiation for cervical cancer. A topical form (Efudex) can be used for vaginal intraepithelial neoplasia (VAIN) treatment as discussed in Chapter 29. This “false” pyrimidine antimetabolite acts principally as a thymidine synthetase inhibitor to block DNA replication.

Systemic 5-FU (Adrucil) is usually given as a 96-hour continuous IV infusion of 800 to 1000 mg/m²/d. Mucositis and/or diarrhea may be severe and dose-limiting. Hand-foot syndrome (palmar-plantar erythrodysesthesia), described on page 600, is less common but can also be dose-limiting. Myelosuppression, mainly neutropenia and thrombocytopenia, are less frequent. Nausea and vomiting are usually mild.

Alkylating Agents

Cyclophosphamide

The class of alkylating agents is characterized by positively charged alkyl groups that bind to negatively charged DNA to form adducts (Table 27-5). Binding leads to DNA breaks or cross-links and a halt to DNA synthesis. In general, these drugs are cell cycle-nonspecific agents.

Of alkylating agents, cyclophosphamide (Cytoxan) is FDA approved by itself or in combination for epithelial ovarian cancer treatment. Cyclophosphamide is the “C” of the EMA-CO (etoposide, methotrexate, actinomycin D, cyclophosphamide, Oncovin [vincristine]), which is a regimen prescribed for high-risk GTN. It is also used, albeit infrequently, as salvage therapy for recurrent epithelial ovarian cancer (Bower, 1997; Cantu, 2002). Cyclophosphamide is a derivative of nitrogen mustard and is activated through a multistep process by microsomal enzymes in the liver. It promotes DNA cross-linking and DNA synthesis inhibition.

This agent may be administered IV or orally. It is typically given IV at doses of 500 to 750 mg/m² over 30 minutes every 3 weeks. Orally, a metronomic (repetitive low-dose) regimen of 50 mg daily is often used to minimize toxicity and target the tumor endothelium or stroma in combination with a biologic agent, such as bevacizumab (Chura, 2007).

Myelosuppression, mainly neutropenia, is the usual dose-limiting side effect. Cyclophosphamide is exclusively excreted by the kidneys. One of its metabolites, acrolein, can alkylate and inflame the bladder mucosa. As a result, hemorrhagic cystitis is a classic complication that may follow from 24 hours to several weeks after administration. To prevent this effect, adequate hydration is imperative to aid acrolein excretion. In addition, GI toxicity, such as nausea, vomiting, or anorexia, is common. Alopecia is typically severe. Moreover, later secondary malignancy rates are increased, particularly acute myelogenous leukemia and bladder cancer.

Of chemotherapeutic drugs, alkylating agents are believed to be particularly damaging to ovarian function. Preventatively, adjuvant GnRH agonists may lower rates of chemotherapy-induced ovarian failure, although the efficacy of this approach remains controversial (Chen, 2011; Elgindy, 2013). Through its hypoestrogenic effects, a GnRH agonist may decrease ovarian blood flow, and thereby decrease chemotherapeutic exposure of the ovaries (Blumenfeld, 2003). Alternatively, pituitary-gonadal axis inhibition may protect the germinal epithelium by inhibiting oogenesis. Last, as GnRH receptors have been identified in the ovary, GnRH agonist may act directly in the ovary to decrease granulosa cell metabolism (Peng, 1994). Importantly, advances in oocyte and ovarian tissue cryopreservation make it likely that the removal of oocytes prior to treatment will become the preferred approach when feasible.

Ifosfamide

This alkylating agent is not FDA approved for gynecologic cancers but is sometimes administered for salvage treatment of recurrent epithelial ovarian cancer, cervical cancer, and uterine sarcoma. Ifosfamide (Ifex) is a structural analogue of cyclophosphamide, differing only slightly. However, its metabolic activation occurs more slowly and leads to a greater production of chloracetaldehyde, a possible neurotoxin.

Ifosfamide is administered IV, usually as a short infusion. Common doses of 1.2 to 1.6 g/m² are given on days 1 through 3 of a 3-week cycle. As with cyclophosphamide, adequate hydration is recommended to reduce the incidence of drug-induced hemorrhagic cystitis. In addition, concurrent mesna (Mesnex) is used to prevent severe hematuria. A mesna metabolite chemically binds with acrolein, an ifosfamide metabolite, and detoxifies acrolein in the bladder (Fig. 27-4). Other side effects are similar to those of cyclophosphamide. However, neurotoxicity, manifested as lethargy, confusion, seizure, ataxia, hallucinations, and occasionally coma, is more likely. These symptoms are caused by the chloracetaldehyde metabolite and are reversible with removal of the drug and supportive care. The incidence of neurotoxicity is higher in the rare patient receiving high-dose therapy and also in those with impaired renal function, where a preventive dose reduction is typically necessary.

Antitumor Antibiotics

Dactinomycin

The antitumor antibiotics are generally derived from microorganisms. Most antitumor antibiotics exert their cytotoxic effects by DNA intercalation during multiple phases of the cell cycle. They are considered cell-cycle specific.

In this group, dactinomycin is FDA approved to treat GTN as a single agent or as part of combination chemotherapy (Table 27-6). Dactinomycin (Cosmegen), also known as actinomycin D, is the “A” of the EMA-CO chemotherapy combination. Dactinomycin is a product of a Streptomyces species and becomes anchored into purine-pyrimidine DNA base pairs, resulting in DNA synthesis inhibition. It also produces toxic oxygen free radicals that cause DNA breaks. Dactinomycin is mainly excreted through the biliary system.

The usual “pulse” dosage of dactinomycin is 1.25 mg IV push every other week, but is sometimes administered as a 0.5 mg dose on days 1 through 5 every 2 to 3 weeks. Myelosuppression is the main dose-limiting side effect and may be severe. Moreover, GI toxicity, including nausea, vomiting, mucositis, and diarrhea, is often significant. Alopecia is common. As with others in the antibiotic group, dactinomycin is a potent vesicant (see Table 27-1).

Bleomycin

This antitumor antibiotic is FDA approved for malignant pleural effusion treatment or for palliative therapy of recurrent squamous cervical or vulvar cancer. An off-label use includes bleomycin as the “B” in BEP (bleomycin, etoposide, cisplatin) regimens, which are used as adjuvant treatment of malignant ovarian germ cell or sex cord-stromal tumors (Park, 2011; Weinberg, 2011). Additionally, it is used in GTN salvage treatment (Alazzam, 2012). Bleomycin (Blenoxane), when complexed with iron, creates activated oxygen free radicals, which cause DNA-strand breaks and cell death. It is maximally effective during the G₂ phase.

The usual dosage of bleomycin is 20 units/m² IV (maximum dose of 30 units), given every 3 weeks. Bleomycin can also be administered IM, SC, or intrapleurally. The dose is quantified by international units of “cytotoxic activity.”

Pulmonary toxicity is the main dose-limiting side effect, developing in 10 percent of patients and causing death in 1 percent. Accordingly, for women prescribed bleomycin, chest radiographs and pulmonary function tests (PFTs) are performed at baseline and obtained regularly before every one or two treatment cycles. The most important PFT measurement is the diffusing capacity of the lung for carbon monoxide (DLCO). The DLCO measures the ability to transfer oxygen from the lungs to the blood stream. If the DLCO declines by 15 to 30 percent, it indicates development of restrictive lung disease. In patients receiving bleomycin, therapy may then be stopped before the onset of symptomatic pulmonary fibrosis. Fibrosis often presents clinically as pneumonitis with cough, dyspnea, dry inspiratory crackles, and infiltrates on chest radiograph. This complication is more common in patients older than 70 and with cumulative doses of greater than 400 units. Bleomycin is not myelosuppressive. However, skin reactions are common and include hyperpigmentation or erythema.

Doxorubicin

This antitumor antibiotic is FDA approved to treat epithelial ovarian cancer. Doxorubicin (Adriamycin) is also used on occasion for uterine sarcoma (Hyman, 2014; Mancari, 2014). This agent intercalates into DNA to inhibit DNA synthesis, inhibits topoisomerase II, and forms cytotoxic oxygen free radicals. The drug is metabolized extensively in the liver and eliminated through biliary excretion.

The usual dose of doxorubicin is 45 to 60 mg/m² IV, repeated every 3 weeks. Myelosuppression, particularly neutropenia, is the main dose-limiting side effect. However, cardiotoxicity is a classic complication. Patients are monitored with a multiple-gated acquisition (MUGA) radionuclide scan at baseline and periodically during therapy. The risk of cardiotoxicity is higher in women older than 70 and those with cumulative doses exceeding 550 mg/m². Ultimately, women may develop an irreversible dilated cardiomyopathy associated with congestive heart failure. Gastrointestinal toxicities are generally mild, but alopecia is universal.

Doxorubicin Hydrochloride Liposome

This antitumor antibiotic is FDA approved for the salvage treatment of recurrent epithelial ovarian cancer (Gordon, 2004). The liposomal encapsulation of doxorubicin (Doxil) dramatically alters the pharmacokinetic and toxicity profiles of the drug. Researchers developed liposomal doxorubicin to reduce cardiotoxicity and to selectively target tumor tissues.

Liposomal doxorubicin may be administered as an IV infusion over 30 to 60 minutes and is dosed at 40 to 50 mg/m² every 4 weeks. In contrast to doxorubicin, administration of the encapsulated liposome is associated with minimal nausea, vomiting, alopecia, and cardiotoxicity. Infusion-related reactions develop in less than 10 percent of patients and are most common during the first treatment course. However, an increased rate of stomatitis and palmar-plantar erythrodysesthesia (PPE) is noted.

PPE is characterized by a cutaneous reaction of varying intensity. Patients may initially complain of tingling sensations on their soles and palms that generally progresses to swelling and tenderness to touch. Erythematous plaques typically develop that can become extremely painful and often lead to desquamation and skin cracking. Symptoms result from the prolonged blood levels of this time-released cytotoxic agent and may last several weeks.

Plant-derived Agents

Taxanes

The cytotoxic activity of all the plant-derived agents stems from the disturbance of normal assembly, disassembly, and stabilization of intracellular microtubules to halt cell division during mitosis (Fig. 27-5). The group includes the taxanes, vinca alkaloids, and topoisomerase inhibitors.

Of the taxanes, paclitaxel and docetaxel are both cell cycle-specific agents that have maximal activity during the M phase (Table 27-7). Derived from yew tree species, they act to “poison” the mitotic spindle by preventing depolymerization of the microtubules and inhibiting cellular replication.

Paclitaxel

The best-selling cancer drug ever manufactured, paclitaxel (Taxol) is FDA approved for the treatment of primary or recurrent epithelial ovarian cancer. It is also extensively used for endometrial cancers, cervical cancers, and GTN.

Paclitaxel is typically administered IV as a 3-hour infusion, but may also be given as an intraperitoneal (IP) dose. The usual IV dosage is 135 to 175 mg/m² every 3 weeks. Weekly paclitaxel is also effective in a regimen of 80 mg/m² IV for 3 consecutive weeks on a 21-day schedule (“dose-dense” regimen) for primary disease or on a 28-day schedule for recurrent disease (Katsumata, 2009; Markman, 2006). For initial therapy of optimally debulked ovarian cancer following a day-1 IV dose, paclitaxel is usually given IP on day 8 at a dose of 60 mg/m² (Armstrong, 2006).

Myelosuppression is the usual dose-limiting side effect. Additionally, a hypersensitivity reaction occurs in approximately one third of patients due to its formulation in Cremophor-EL, an emulsifying agent. Typically, the reaction develops within minutes of starting an initial infusion. Fortunately, the incidence can be decreased 10-fold by premedication with corticosteroids, usually dexamethasone, 20 mg orally 12 and 6 hours before paclitaxel infusion. Neurotoxicity is the principal nonhematologic dose-limiting side effect. Common symptoms include numbness, tingling, and/or burning pain in a stocking-glove distribution. Peripheral neuropathy progresses with increased paclitaxel exposure and may become debilitating. Alopecia affects almost all patients and results in total body hair loss.

Docetaxel

This taxane is not FDA approved for gynecologic cancers but is often used to treat recurrent epithelial ovarian cancer and uterine sarcoma (Gockley, 2014; Herzog, 2014b). In addition, patients with worsening peripheral neuropathy with paclitaxel are often switched to docetaxel. Clinical efficacy is similar, but docetaxel is associated with less neurotoxicity.

The usual dosage of docetaxel (Taxotere) is 75 to 100 mg/m² IV, repeated every 3 weeks. For recurrent ovarian cancer, weekly docetaxel is also effective at a dosage of 35 mg/m² IV for 3 consecutive weeks on a 28-day schedule (Tinker, 2007).

Unlike paclitaxel, myelosuppression is the main dose-limiting side effect. Fluid retention syndrome develops in approximately half of patients and manifests as weight gain, peripheral edema, pleural effusion, and ascites. Corticosteroid prophylaxis prevents most of this toxicity, as well as dermatologic side effects and hypersensitivity reactions.

Vinca Alkaloids

Vincristine, vinblastine, and vinorelbine are cell cycle-specific drugs derived from the periwinkle plant with maximal activity in the M phase. These compounds inhibit normal microtubular polymerization by binding to the tubulin subunit at a site distinct from the taxane-binding site (see Fig. 27-5). These drugs are infrequently used in gynecologic oncology. That said, vincristine is the “O” of EMA-CO combination chemotherapy for GTN treatment. The usual dosage of vincristine (Oncovin) is 0.8 to 1.0 mg/m² given IV every other week. The total individual dose is capped at 2 mg to prevent or delay neurotoxicity. This is the most common dose-limiting toxicity and may include peripheral neuropathy, autonomic nervous system dysfunction, cranial nerve palsies, ataxia, or seizures. Moreover, concurrent administration with other neurotoxic agents such as cisplatin and paclitaxel may increase severity. GI toxicity is also common, including constipation, abdominal pain, and paralytic ileus. However, myelosuppression is typically mild.

Topoisomerase Inhibitors

Topoisomerase (TOPO) enzymes unwind and rewind DNA to aid DNA replication. Topoisomerase inhibitors interfere with this function and halt DNA synthesis. This group is further divided into categories based on the specific topoisomerase enzyme they inhibit. The camptothecins inhibit TOPO I and include topotecan. The podophyllotoxins inhibit TOPO II and include etoposide.

Topotecan

This TOPO I inhibitor is a semisynthetic analogue of the alkaloid extract camptothecin. It binds to and stabilizes a transient TOPO I-DNA complex, resulting in double-strand breakage and lethal DNA damage. Topotecan (Hycamtin) is FDA approved as salvage therapy of recurrent epithelial ovarian cancer and recurrent cervical cancer (Long, 2005).

Topotecan is usually administered IV in two different schedules. Standard dosage for recurrent ovarian cancer is 1.5 mg/m² for days 1 through 5, given every 3 weeks (Gordon, 2004). However, this schedule is associated with a greater than 80-percent incidence of severe neutropenia. A less toxic regimen is 4 mg/m² weekly for 3 weeks during a 28-day schedule (Spannuth, 2007). The usual dosage when combined with cisplatin for recurrent cervical cancer is 0.75 mg/m² on days 1 through 3, given every 3 weeks (Long, 2005).

Myelosuppression, most commonly neutropenia, is the main dose-limiting side effect. GI toxicity is also frequent and includes nausea, vomiting, diarrhea, and abdominal pain. Systemic symptoms such as headache, fever, malaise, arthralgias, and myalgias are typical. Alopecia is often as complete as that seen with paclitaxel therapy.

Etoposide

This cell-cycle specific agent has maximal activity in the late S and G₂ phase. Etoposide “poisons” the TOPO II enzyme by stabilizing an otherwise transient form of the TOPO II-DNA complex. As a result, DNA cannot unwind, and double-strand DNA breaks form. This agent is not FDA approved for gynecologic cancers. However, it is often used IV as part of combination chemotherapy. Etoposide (VP-16) represents the “E” of the EMA-CO regimen, which is used for GTN. In addition, it is a component of the BEP regimen, used for ovarian germ cell or sex cord-stromal tumors. Oral etoposide may be efficacious as a single agent for salvage treatment of recurrent epithelial ovarian cancer.

The dosage of etoposide varies. In the EMA-CO regimen, 100 mg/m² is administered IV on days 1 and 2, every 2 weeks. In the BEP regimen, it is usually prescribed in dosages of 75 to 100 mg/m² IV on days 1 through 5, given every 3 weeks. The oral dosage is 50 mg/m²/d for 3 weeks, followed by a week off during a 28-day schedule.

Up to 95 percent of etoposide is protein-bound, mainly to albumin. Thus, decreased albumin levels result in a higher fraction of free drug and potentially a higher incidence of toxicity. Myelosuppression, most commonly neutropenia, is the main dose-limiting side effect. GI symptoms of nausea, vomiting, and anorexia are usually minor, except with oral administration. Most patients will develop alopecia. With etoposide, particularly if the total dose exceeds 2000 mg/m², there is a small but significant risk (approximately 1 in 1000) of later secondary malignancies. Of these, acute myelogenous leukemia is the most common.

Miscellaneous

Carboplatin

Several antineoplastic compounds do not clearly fit into any of the preceding categories but have similarities with alkylating agents. Among these cell-cycle nonspecific drugs are carboplatin and cisplatin.

Carboplatin (Paraplatin) produces DNA adducts that inhibit DNA synthesis. This agent is one of the most widely used, particularly in adjuvant or salvage treatment of epithelial ovarian cancer, and is FDA approved for this indication. It is also frequently used off-label for endometrial cancer.

The usual IV dose of carboplatin is calculated to a target “area under the curve” (AUC) of 6, based on the glomerular filtration rate (GFR). The Calvert equation is the most often used (carboplatin total dose [mg] = AUC × [GFR + 25]) for dose calculation. In clinical practice, the estimated creatinine clearance (CrCl) is usually substituted for the GFR and may be calculated by the Cockcroft-Gault equation (CrCl = [140 – age] × weight [kg]/0.72 × serum creatinine level [mg/100 mL]). The infusion takes 30 to 60 minutes, and dosing is repeated every 3 to 4 weeks.

Myelosuppression, most commonly thrombocytopenia, is the main dose-limiting side effect. GI toxicity and peripheral neuropathy are notably less severe than with cisplatin. Hypersensitivity reactions will eventually develop in up to 25 percent of women receiving more than six cycles.

Cisplatin

Similar to carboplatin, this agent produces DNA adducts that inhibit DNA synthesis. Cisplatin is one of the oldest and most widely used agents and is FDA approved for ovarian, cervical, and germ cell cancer. It may be given concomitantly with radiation as a radiosensitizing agent for primary treatment of cervical cancer or either as a single agent or in combination for recurrent cervical cancer. Alternatively, cisplatin is part of combination chemotherapy as the “P” of BEP, given for ovarian germ cell or sex cord-stromal tumors. However, for use in epithelial ovarian cancer, cisplatin has largely been replaced by carboplatin, except for IP therapy, due to possibly superior tissue penetration and potentially better outcomes.

The dosage of cisplatin varies depending on the indication. In cervical cancer, dosages of 40 mg/m² IV weekly or 75 mg/m² are given every 3 weeks during radiation therapy, or 50 mg/m² IV is provided every 3 weeks for patients with recurrent disease (Long, 2005). As part of the BEP protocol, cisplatin is administered 20 mg/m² IV on days 1 through 5 every 3 weeks. Alternatively, for ovarian cancer IP chemotherapy, cisplatin is given on day 1 or 2 of a 21-day cycle at a dose of 75 to 100 mg/m² (Armstrong, 2006; Dizon, 2011).

Cisplatin has several significant toxicities. Of these, nephrotoxicity is the main dose-limiting side effect. Accordingly, patients must be aggressively hydrated before, during, and after drug administration. Mannitol (10 g) or furosemide (20 to 40 mg) may be necessary to maintain a urine output of at least 100 to 150 mL/hour. With cisplatin, electrolyte abnormalities, such as hypomagnesemia and hypokalemia, are common. In addition, severe, prolonged nausea and vomiting can be dramatic without adequate premedication (Table 27-8). Patients often describe a metallic taste and loss of appetite following treatment. Neurotoxicity, usually in the form of peripheral neuropathy, can also be dose limiting and irreversible. Ototoxicity typically manifests as high-frequency hearing loss and tinnitus. Similar to carboplatin, hypersensitivity reactions may develop with prolonged use. Overall, cisplatin is significantly more toxic than carboplatin, except for its reduced hematologic toxicity.

Hormonal Agents

Tamoxifen

Due to their minimal toxicity and reasonable activity, hormonal agents are often used for palliative treatment of endometrial and ovarian cancers despite lacking formal FDA approval for these indications. Of these, tamoxifen is a selective estrogen-receptor modulator. It is a nonsteroidal prodrug and is metabolized into a high-affinity estrogen-receptor antagonist in breast tissue. It does not activate the estrogen receptor and thereby blocks breast cancer cell growth. The complex is then transported into the tumor cell nucleus, where it binds to DNA and halts cellular growth and proliferation in the G₀ or G₁ phase. Antiangiogenic effects have also been suggested. In addition to breast cancer, tamoxifen (Nolvadex) is occasionally used to treat endometrial and ovarian cancer (Fiorica, 2004; Hurteau, 2010).

Tamoxifen is orally administered, usually prescribed in doses of 20 to 40 mg for continuous daily use. Toxicity associated with tamoxifen is minimal, mainly consisting of menopausal symptoms such as hot flushes, nausea, and vaginal dryness or discharge. Moreover, some degree of fluid retention and peripheral edema develops in one third of patients. Reduced cognition and libido may also be noted during therapy.

In the endometrium, tamoxifen acts as a partial estrogen-receptor agonist. Sustained use increases the risk for endometrial polyp formation, and endometrial cancer risks triple. Moreover, thromboembolic event rates are raised, especially during and immediately after major surgery or periods of immobility. In contrast, tamoxifen prevents osteoporosis due to its partial agonist properties in bone and has beneficial effects on the serum lipid profile.

Megestrol Acetate

This agent is a synthetic derivative of progesterone that has activity on tumors through its antiestrogenic effects. As such, megestrol acetate (Megace) is most often used to treat endometrial hyperplasia, nonoperable endometrial cancer, and recurrent endometrial cancer, especially in those patients with grade 1 disease (Chap. 33).

The usual oral dosage is 80 mg twice daily. Megestrol acetate has minimal toxicity, but patients often gain weight from a combination of fluid retention and increased appetite. Thromboembolic events are rare. Patients with diabetes mellitus are carefully monitored because of the possibility of exacerbating hyperglycemia due to its concurrent glucocorticoid activity.

Differing molecular pathways within normal and malignant cells have led to targeted agents that exploit these differences. Targeted therapies offer the potential for improved long-term disease control with less toxicity. Many of these novel agents are currently being evaluated in clinical trials. Thus, an overview of noncytotoxic drug development is critical for understanding future medical treatment of gynecologic cancer.

Antiangiogenesis Agents

Angiogenesis is a normal physiologic process that forms new blood vessels and remodels vasculature for oxygen and nutrient transport to tissues. This process is usually transient and tightly regulated by various pro- and antiangiogenic factors. However, the homeostatic balance is dysregulated in malignancy. In cancers, sustained angiogenesis leads to tumor growth and metastasis and provides access to systemic lymphatic and circulatory systems. Thus, targeted inhibition of angiogenesis is an appealing therapeutic approach.

The binding of vascular endothelial growth factor (VEGF) to the VEGF receptor is a vital first step in stimulating normal angiogenesis. Many malignancies, such as ovarian cancer, are characterized by increased levels of VEGF or other proangiogenic factors. Several novel agents interfere with this process to halt tumor growth.

Bevacizumab

This agent is a monoclonal antibody that binds to VEGF to prevent VEGF interaction with its receptor (Fig. 27-6A). Currently, bevacizumab (Avastin) is FDA-approved for persistent, recurrent, or metastatic cervical cancer, as well as relapsed platinum-resistant epithelial ovarian cancer (Pujade-Lauraine, 2014; Tewari, 2014). Its usual dosage is 15 mg/kg given IV every 3 weeks with or without cytotoxic chemotherapy. In most cases, toxicity with bevacizumab is minimal. However, GI perforation may occur in up to 10 percent of patients (Cannistra, 2007). This complication is more likely in women with preexisting inflammatory bowel disease or in those with bowel resection at their primary surgery for advanced ovarian cancer (Burger, 2014). Elevated blood pressure is common and may lead to hypertensive crisis. Other possible toxicities include incomplete wound healing, weakness, pain, nosebleed, and proteinuria.

VEGF Trap

VEGF-A is the main isoform of VEGF. It can be bound by bevacizumab, as just described, or by a recombinant “fusion protein” named VEGF Trap (aflibercept). VEGF Trap is constructed by fusing two specific portions of the VEGF receptor and the “Fc” constant region of the IgG molecule. The receptor portions provide high-affinity binding of VEGF (Fig. 27-6B). Clinical experience in gynecologic cancers is preliminary. Early reports suggest a risk of GI perforation similar to that for bevacizumab (Coleman, 2012; Gotlieb, 2012; Mackay, 2012; Tew, 2014).

Sunitinib

Receptor tyrosine kinases (RTKs) are proteins that span the plasma membrane of cells and act as receptors (Fig. 27-7C). If two side-by-side receptors bind a ligand, then an active dimer is formed. Ligands for RTKs include cytokines, hormones, and growth factors. The activated dimer then phosphorylates tyrosine residues. Phosphorylation first of the tyrosine kinase itself, and then of other proteins, activates them. By this means, RTKs regulate normal cellular processes but also play a critical role in cancer development and progression.

Sunitinib (Sutent) is an oral agent that inhibits several RTKs, including those that bind proangiogenic growth factors, such as VEGF and platelet-derived growth factor. For gynecologic cancers, the clinical efficacy of a 50 mg daily dose is currently under investigation (Baumann, 2012; Hensley, 2009).

Cediranib

Another RTK inhibitor of VEGF, cediranib (Recentin), has demonstrated significant clinical activity in relapsed ovarian cancer. With an oral daily dose of 30 mg, a 17-percent response rate was reported when used as a single agent (Matulonis, 2009). Even more promising results have been recently observed when combined with olaparib, a poly(ADP) ribose polymerase inhibitor (Liu, 2014).

Mammalian Target of Rapamycin Inhibitors

The mammalian target of rapamycin (mTOR) is a protein kinase that regulates membrane trafficking, transcription, translation, and cell cytoskeleton maintenance. mTOR has downstream effects that include increased VEGF production. Thus, efforts to inhibit mTOR signaling also can lead to angiogenesis inhibition. Rapamycin inhibits mTOR, and analogues of this drug, such as temsirolimus (CCI-779) and everolimus (RAD001), are currently being studied for gynecologic cancer treatment (Alvarez, 2013; Fleming, 2014; Slomovitz, 2010).

Poly(ADP) Ribose Polymerase Inhibitors

Another promising group of targeted therapies, poly(ADP) ribose polymerase (PARP) inhibitors, exploit the differences in DNA damage repair between normal and malignant cells. During the cell cycle, DNA is routinely damaged thousands of times. The BRCA protein repairs double-strand breaks, and PARP repairs single-strand breaks. In the functioning cell, if BRCA does not repair the break, PARP will (Fig. 27-7).

Five to 10 percent of ovarian cancer patients have a germline BRCA1 or BRCA2 gene mutation, which predisposes them to loss of homologous DNA repair. Normal cells do not replicate their DNA as often as cancer cells, and without mutated BRCA1 or BRCA2, still have functional homologous repair. This allows them to survive PARP inhibition. Thus, only tumor cells with BRCA defects are almost entirely dependent on PARP repair. If PARP repair is prevented, damaged cancer cell DNA cannot be repaired and cells die. In contrast, normal cells are unaffected. Several PARP inhibitors are currently in development to take advantage of this unique tumor cell vulnerability.

Olaparib (AZD2281)

This PARP inhibitor is now FDA-approved for BRCA1 and BRCA2 mutation carriers with relapsed ovarian cancer that has demonstrated resistance to platinum drugs (Kaufman, 2015). It also has clinical activity in patients without mutations (Ledermann, 2014). As a single agent, the usual oral dose is 400 mg twice daily. The most frequent side effects are fatigue, nausea, and vomiting (Kaufman, 2015). Further encouraging studies are evaluating standard cytotoxic drugs compared against olaparib plus other targeted agents as maintenance therapy (Liu, 2014).

Chemotherapy regimens, especially those including cytotoxic drugs, are universally toxic and display a narrow margin of safety. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a detailed and comprehensive set of guidelines for the description and grading of toxicity. Termed the Common Terminology Criteria for Adverse Events (CTCAE), the most recent revision is version 4.0 and is available at: http://evs.nci.nih.gov/ftp1/CTCAE/About.html.

In general, treatment modifications depend on the degree (grade) and duration of toxicity experienced during the preceding therapy course. Doses are reduced if a woman experiences a severe reaction but then may be subsequently increased if tolerance improves. However, treatment is not resumed until toxicity has resolved to baseline or “Grade 1” levels and may be delayed on a week-to-week basis to permit recovery. Dose modification and supportive care are implemented to prevent delays of greater than 2 weeks, which would otherwise compromise therapeutic efficacy. Serious myelosuppression can be partially corrected with the use of hematopoietic growth factors. Many of the common toxicities can be prevented with proper use of premedications or alleviated with supportive measures.

Bone Marrow Toxicity

Myelosuppression, especially neutropenia, is the most common dose-limiting side effect of cytotoxic drugs. The absolute neutrophil count (ANC) is the critical measure when determining patient infection risk and may reflect mild (1000–1500/mm³), moderate (500–1000/mm³), or severe (<500/mm³) neutropenia. Frequently, patients receiving therapy will have a nadir (lowest measurement) into the neutropenic range that will recover before the next scheduled course of treatment. However, if they are admitted to the hospital for fever or other condition, neutropenic precautions should be observed. Although guidelines vary, precautions include assiduous provider hand washing; provider outer gowns, gloves, and masks; and patient isolation from potential infection carriers.

Moderate degrees of anemia often develop in cancer patients receiving chemotherapy and may contribute to chronic fatigue. Frequent transfusions are not practical or recommended, and many patients will adapt to chronic anemia with minimal symptoms. Synthetic erythropoietin is infrequently indicated.

Thrombocytopenia is less common but may predispose the patient to serious bleeding if the platelet count drops below 10,000/mm³. No predetermined platelet value should prompt routine transfusion, but ongoing bleeding in affected patients is a warranted indication.

Gastrointestinal Toxicity

Most anticancer agents are associated with some degree of nausea, vomiting, and anorexia. Typically, the emetogenic potential of a particular drug or regimen will dictate the antiemetic regimen used (Tables 27-9 and 27-10). Mild nausea and vomiting can often be managed effectively by prochlorperazine (Compazine) with or without dexamethasone (Table 42-7). If drugs with more severe emetogenic effects such as cisplatin are administered, then ondansetron, granisetron, or palonosetron, which are 5-hydroxytryptamine antagonists, can be given IV before chemotherapy. Ondansetron (Zofran) and granisetron (Kytril) can also be provided orally to manage delayed and/or chronic nausea after chemotherapy. However, these drugs can induce significant constipation as a side effect. Chemotherapy-related diarrhea, oral mucositis, esophagitis, and gastroenteritis are treated with supportive care.

Dermatologic Toxicity

Most drugs can cause a toxicity spectrum to the skin or subcutaneous tissues that includes hyperpigmentation, photosensitivity, nail abnormalities, rashes, urticaria, erythema, and alopecia. Many of these are drug specific and self-limited, but occasionally, they may be dose limiting. As discussed earlier, palmar-plantar erythrodysesthesia is a known toxicity of liposomal doxorubicin. In addition, changes in skin pigmentation are seen with bleomycin, whereas nail discoloration and onycholysis have been associated with docetaxel therapy. Mild urticarial reactions are prevented or alleviated by premedication with diphenhydramine hydrochloride, 50 mg IV or orally.

One of the most emotionally distressing side effects of many chemotherapeutic agents is scalp alopecia. Fortunately, this is usually reversible. With some drugs such as paclitaxel, women will also experience loss of eyelashes, eyebrows, and other body hair. In general, techniques to minimize alopecia are unsuccessful. Instead, women are counseled regarding cosmetic options such as false eyelashes and wigs.

Neurotoxicity

Peripheral neuropathy develops commonly with cisplatin, paclitaxel, and the vinca alkaloids. Cisplatin-induced neurotoxicity usually resolves slowly, due to axonal demyelination and loss. This toxicity is related to cumulative dose and intensity. To counter this toxicity, amifostine (Ethyol) may be administered, but substitution of carboplatin will avoid much of the toxicity. Gabapentin (Neurontin) is the usual treatment for neuropathic pain, starting at a dosage of 300 mg daily. Other options to treat symptomatic peripheral neuropathy that have shown some efficacy include oral glutamine (up to 15 g twice daily) or oral vitamin B₆ (up to 50 mg three times daily).

With chemotherapeutic agents in general, drug dosing may need to be adjusted if peripheral neuropathy becomes problematic—for example, if a patient can no longer hold a cup of coffee. More dramatic instances of acute cerebellar syndromes, cranial nerve palsies or paralysis, and occasionally acute and chronic encephalopathies are managed with supportive care and usually with discontinuation of the offending agent.

Synthetic Erythropoietins

In some clinical situations, incorporation of hematopoietic drug factors to prompt red blood cell (RBC) or granulocyte production may have merit. Of these, epoetin alfa and darbepoetin alfa are synthetic erythropoietins that have the same biologic effects as endogenous erythropoietin to stimulate RBC production. These agents are recommended for patients with chemotherapy-associated anemia who have a hemoglobin concentration that is approaching, or has fallen below, 10 g/dL. However, when used at higher hemoglobin levels, they may actually be associated with tumor progression and shorten survival (Rizzo, 2008). Moreover, several large studies have shown that despite reducing the need for RBC transfusions, erythropoiesis stimulating agents (ESAs) increase the risk for thromboembolic events and death in cancer patients treated with epoetin alfa (Aapro, 2012; Tonia, 2012). As a result, the FDA has issued a “black-box” warning to state that a higher mortality rate and/or shortened time to tumor progression were found when ESAs were dosed with the intent to achieve hemoglobin values ≥12 g/dL compared with placebo or observational controls. Once routinely used, these agents are now infrequently administered to gynecologic cancer patients due to safety concerns.

When used, epoetin alfa (Procrit, Eprex, and Epogen) is usually prescribed as 40,000 units SC, given weekly (Case, 2006). Beyond local pain at the injection site, this agent has minimal side effects. Possible toxicity may include diarrhea, nausea, or hypertension (Bohlius, 2006; Khuri, 2007). For darbepoetin alfa (Aranesp), the usual SC dose is 200 μg every other week or 500 μg given every 3 weeks. Darbepoetin alfa has minimal side effects beyond local pain at the injection site.

Granulocyte Colony-Stimulating Factors

Filgrastim and pegfilgrastim are human granulocyte colony-stimulating factors (G-CSF) produced by recombinant DNA technology. As such, these cytokines bind to hematopoietic cells and activate proliferation, differentiation, and activation of granulocyte progenitor cells. These growth factors are mainly used to prevent episodes of febrile neutropenia (ANC <1500), particularly in patients with a greater than 20-percent risk for such an event. Fortunately, none of the common regimens used in the treatment of gynecologic cancer have a risk that exceeds 20-percent, and thus growth factors are typically not required for initial prophylaxis. Instead, growth factors are usually indicated to permit a patient to maintain her treatment schedule.

Filgrastim (Neupogen) is given SC, and the usual SC dose is 5 μg/kg/d. However, patients typically are given either 300 μg or 480 μg, which is the content of manufactured vials. It should be administered at least 24 hours after chemotherapy completion. Therapy is terminated when the white blood count (WBC) exceeds 10,000/mm³ or when the absolute neutrophil count exceeds 1000/mm³ for 3 consecutive days. Toxicity with filgrastim is limited, and transient bone pain is usually mild to moderate.

Pegfilgrastim (Neulasta) acts similarly to filgrastim to stimulate production of granulocyte progenitor cells within the bone marrow. The “peg” in pegfilgrastim refers to a polyethylene glycol unit that prolongs the time it remains in the body. Pegfilgrastim is given as a single 6-mg SC injection once per chemotherapy cycle. This is usually far more convenient than daily filgrastim doses. It should not be administered during the 14 days before and within 24 hours after administration of cytotoxic chemotherapy. Transient bone pain is usually mild to moderate, but often more pronounced than with filgrastim.

Routinely, the selection of specific chemotherapeutic agents is based on clinical literature describing outcomes for a specific gynecologic cancer. In contrast to this empiric approach, chemotherapy sensitivity and resistance assays are theoretically appealing due to the possibility of tailoring treatment. Using this strategy, viable tumor tissue is collected from the patient during surgery or other intervention (e.g., paracentesis). The sample is shipped to a specialized laboratory. Here, in vitro analysis determines whether tumor growth is inhibited by a drug or panel of drugs.

The potential of selecting effective cancer treatments while sparing unnecessary ones is intriguing, and patients may even request testing. However, no current assay has demonstrated sufficient efficacy to support its use. Thus, these assays are not recommended for individual patients outside of a clinical trial (Burstein, 2011).

The only proven way to improve cancer treatment success rates is to test new agents, higher doses, novel combinations of drugs, or unique ways of administering treatment. Since gynecologic cancers are relatively uncommon, most landmark Phase III studies are conducted within large collaborative groups such as the NRG Oncology Group. Promising drugs are first identified by demonstrating success in cancer cell lines or in animals inoculated with tumor. After preclinical steps are completed, novel agents proceed through four phases of clinical testing.

Phase I trials use a dose-escalating design to determine the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacokinetic parameters of the drug. Groups of three to six patients with varied tumor types are enrolled and receive escalating dose levels. The MTD is determined as the dose below which two patients experience dose-limiting toxicity. In a Phase I trial, detecting a tumor response is not critical, since enrolled patients have typically completed extensive prior therapy. However, observed responses would encourage further disease-specific Phase II trials.

After the recommended dose and treatment schedule have been defined in a Phase I trial, the regimen can proceed to Phase II. The primary goal of this trial type is to define the actual response rate in patients with a specific cancer type. Usually a measure of disease (MOD) is required to allow accurate determination of a complete response, partial response, stable disease, or progression. Typically, patients enrolled in Phase II trials have received only one prior chemotherapy regimen. This allows for a reasonable chance of response compared with subjects in Phase I studies. Secondary end points of Phase II trials include determination of the “progression-free interval,” cumulative incidence of dose-limiting toxicity over multiple cycles, and overall survival rates.

Phase III randomized trials are designed to directly compare the drug with existing standard regimens in a particular stage and type of cancer. Phase III trials generally require a minimum of 150 patients per “arm” to provide adequate statistical precision. Finally, Phase IV clinical trials evaluate drugs that are already FDA approved. The goal of Phase IV trials is to study long-term drug safety and efficacy.

The emergence of biologic and targeted therapies has necessitated a reanalysis of this traditional paradigm of cancer drug development. For example, antiangiogenic agents and PARP inhibitors do not have dose-dependent toxicities to establish a MTD. Additionally, instead of measuring tumor shrinkage as an indicator of response for these cytostatic agents, new end points are being developed and validated (e.g., 6-month progression-free survival). Novel clinical trial designs will be a vital part of future drug development (Herzog, 2014a).

In general, patients are strongly encouraged to participate in appropriate Phase I, II, and III clinical trials. Doing so expands their options for treatment. In addition, the results of such studies are the primary method to improve the outcomes of women diagnosed with gynecologic cancer in the future. However, fewer than 5 percent of cancer patients currently enroll in a clinical trial.