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).
TABLE 27-4Chemotherapy Antimetabolites Used for Gynecologic Cancer ||Download (.pdf) TABLE 27-4 Chemotherapy Antimetabolites Used for Gynecologic Cancer
|Generic Name ||Brand Name ||Indications ||Routes ||Common Dosages ||Common Toxicity |
|Methotrexate ||Trexall, Rheumatrex ||GTN ||PO, IM, IV, intrathecal ||IM: 1 mg/kg on days 1, 3, 5, 7 of 8-day cycle or 30–50 mg/m 2/wk |
IV: 100 mg/m 2 during 30 min, then 200 mg/m 2 during 12 hr
|BMD, mucositis, renal toxicity, CNS dysfunction |
|Gemcitabine ||Gemzar ||Recurrent ovarian CA, uterine sarcoma ||IV ||600–1250 mg/m 2/wk over 30 min × 2–3 wk ||BMD, N/V/D, malaise and fever |
|5-Fluorouracil ||Adrucil |
|Cervical CA, vulvar CA |
|800–1000 mg/m 2/d during 96 hr |
3 mL QOD × 1 wk, then weekly up to 10 wk
|Mucositis, PPE |
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’s primary target is the enzyme dihydrofolate reductase (DHFR). Inhibition of DHFR leads to partial depletion of 5,10 methylene tetrahydrofolic acid and N-10 formyl tetrahydrofolic acid, which are cofactors required for the respective synthesis of thymidylate and purines. As a result, methotrexate leads to arrested DNA, RNA, and protein synthesis. dTMP = deoxythymidine monophosphate; dUMP = deoxyuridine monophosphate.
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.
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-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.
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.
TABLE 27-5Chemotherapy Alkylating Agents Used for Gynecologic Cancer ||Download (.pdf) TABLE 27-5 Chemotherapy Alkylating Agents Used for Gynecologic Cancer
|Generic Name ||Brand Name ||Indication ||Routes ||Dosages ||Toxicity |
|Cyclophosphamide ||Cytoxan ||GTN, recurrent ovarian CA ||PO, IV ||IV: 500–750 mg/m 2 over 30 min, every 3 wk |
PO: 50 mg/d
|BMD, cystitis, N/V, alopecia |
|Ifosfamide ||Ifex ||Recurrent ovarian CA, cervical CA, uterine sarcoma ||IV ||1.2–1.6 g/m 2/d, days 1–3 of 3-wk cycle ||BMD, cystitis, N/V, alopecia, CNS and renal toxicity |
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.
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.
Ifosfamide is a prodrug, which is ultimately metabolized into active and inactive metabolites. Isophosphoramide mustard is the main active alkylating metabolite. The inactive metabolite, acrolein, is concentrated in the bladder and is bladder toxic. The drug mesna and acrolein join in the bladder to create an inactive compound, which is then excreted by the bladder. This conversion of acrolein to an inactive compound minimizes ifosfamide’s bladder toxicity.
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.
TABLE 27-6Chemotherapeutic Antibiotics Used for Gynecologic Cancer ||Download (.pdf) TABLE 27-6 Chemotherapeutic Antibiotics Used for Gynecologic Cancer
|Generic Name ||Brand Name ||Indication ||Route ||Dosage ||Toxicity |
|Actinomycin D (dactinomycin) ||Cosmegen ||GTN ||IV ||1.25 mg IV push every other wk or 0.5 mg on days 1–5, every 2–3 wk ||BMD, N/V/D, alopecia, vesicant |
|Bleomycin ||Blenoxane ||Germ cell or SCST ovarian CA, GTN ||IV, IM, SC, intrapleural ||IV: 20 U/m 2 (maximum dose of 30 U), every 3 wk ||Pulmonary toxicity, fever, skin reaction |
|Doxorubicin ||Adriamycin ||Uterine sarcoma, recurrent epithelial ovarian CA ||IV ||45–60 mg/m 2 every 3 wk ||BMD, cardiac toxicity, alopecia, vesicant |
|Liposomal doxorubicin ||Doxil ||Recurrent epithelial ovarian CA ||IV ||40–50 mg/m 2 over 30 min, every 4 wk ||PPE, stomatitis, infusion reaction |
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).
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.
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.
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.
Diagram of taxane’s and vinca alkaloid’s mechanism of action. Parts B and C show magnified microtubule structure. A. During cellular mitosis, microtubules are essential for chromosome alignment and separation. B. Vincristine, one of the vinca alkaloids, attaches consistently to one end of the microtubule to inhibit microtubule assembly. C. Paclitaxel, one of the taxanes, binds to the inner ring of the microtubule and prohibits microtubule disassembly. In both B and C, microtubule function is impaired.
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.
TABLE 27-7Chemotherapeutic Plant Alkaloids Used for Gynecologic Cancer ||Download (.pdf) TABLE 27-7 Chemotherapeutic Plant Alkaloids Used for Gynecologic Cancer
|Generic Name ||Brand Name ||Indications ||Routes ||Dosages ||Toxicity |
|Paclitaxel ||Taxol ||Recurrent epithelial ovarian CA, endometrial CA, cervical CA, GTN ||IV, IP ||IV: 135–175 mg/m 2 every 3 wk, or |
80 mg/m 2/wk for 3 weeks
IP: 60 mg/m 2 on day 8 following a day-1 IV dose
|HSR, peripheral neurotoxicity, BMD, alopecia, bradycardia and arrhythmia |
|Docetaxel ||Taxotere ||Recurrent epithelial ovarian CA, uterine sarcoma ||IV ||75–100 mg/m 2 every 3 weeks, or |
35 mg/m 2/week for 3 weeks
|BMD, peripheral edema, HSR, alopecia |
|Vincristine ||Oncovin ||GTN ||IV ||0.8–1.0 mg/m 2 every other week ||Neurotoxicity, abdominal pain, alopecia |
|Etoposide ||VP-16 ||Germ cell or SCST ovarian CA; recurrent epithelial ovarian CA ||IV, PO ||IV: 100 mg/m 2 days 1 & 2, every 2 wk, or |
75–100 mg/m 2, days 1–5, every 3 wk
PO: 50 mg/m 2/day for 3 wk
|BMD, alopecia, secondary cancers |
|Topotecan ||Hycamtin ||Recurrent epithelial ovarian CA, cervical CA ||IV ||1.5 mg/m 2/d, days 1–5, every 3 wk, or |
4 mg/m 2/wk for 3 wk, or
0.75 mg/m 2/d, days 1–3, every 3 wk
|BMD, N/V, alopecia, fever, malaise |
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.
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.
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 (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.
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.
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.
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.
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.
TABLE 27-8Dose and Schedule of Antiemetics to Prevent Emesis Induced by Antineoplastic Therapy of High Emetic Risk ||Download (.pdf) TABLE 27-8 Dose and Schedule of Antiemetics to Prevent Emesis Induced by Antineoplastic Therapy of High Emetic Risk
|Antiemetics ||Brand Name ||Single Dose Administered before Chemotherapy ||Single Dose Administered Daily |
|5-HT3 serotonin-receptor antagonists |
| Granisetron ||Kytril ||Oral: 2 mg |
IV: 1 mg or 0.01 mg/kg
| Ondansetron ||Zofran ||Oral: 24 mg |
IV: 8 mg or 0.15 mg/kg
| Palonosetron ||Aloxi ||IV: 0.25 mg |
|Dexamethasone ||Decadron ||Oral: 12 mg ||Oral: 8 mg, days 2–4 |
| Aprepitant ||Emend ||Oral: 125 mg ||Oral: 80 mg, days 2 and 3 |
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.
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.