Chemotherapy and Radiation Therapy

Chemotherapy and Radiation Therapy
Sonia Dutta
Amanda Nickles Fader
  • Treatment of gynecologic cancer typically requires a multidisciplinary and multitreatment approach involving a combination of surgery, chemotherapy, and radiation therapy. When more than one modality is used, they may be delivered sequentially or at the same time, as with chemoradiation or intraoperative radiation therapy. The sequence of treatment is characterized as “primary,” referring to initial treatment; “adjuvant,” referring to secondary treatment for micrometastatic disease after surgical management; “neoadjuvant,” referring to induction chemotherapy, radiation therapy, or both administered before definitive therapy; and “salvage,” referring to treatment at time of recurrence.
All methods used to treat gynecologic cancer can cause damage to normal tissue. Therefore, the governing principle of both chemotherapy and radiation therapy is to attain maximal therapeutic cytotoxic effects on cancer cells without extreme toxicity to normal tissues. Unfortunately, it is not always possible to obtain a therapeutic effect without temporarily or permanently altering the functions of other healthy cells, tissues, or organs. The term therapeutic index is the ratio of a toxic dose to the curative dose. An optimal treatment goal is to use chemotherapy agents and radiation doses that have a high therapeutic index.
CELL CYCLE
  • Tumor cells grow as a result of deregulation between proliferation and suppression. Our understanding of cancer cell kinetics and the classical cell cycle (Fig. 50-1) has led to the development of several chemotherapy drugs. There are both cell cycle-specific chemotherapeutic agents and cell cycle-nonspecific chemotherapeutic agents.
    • Cell cycle-specific agents depend on the proliferative capacity of the cell and the phase of the cell cycle for their action. They are effective against tumors with relatively long S phases and rapid proliferation rates.
    • Cell cycle-nonspecific drugs kill cells in all phases of the cell cycle and their effectiveness is not dependent on proliferative capacity. Radiation therapy is not cell cycle dependent.
CHEMOTHERAPY
Types of Chemotherapy
  • Chemotherapeutic agents commonly used for the treatment of gynecologic cancer may be grouped into the following categories (Table 50-1):
    • Alkylating agents are cell cycle-nonspecific. They contain an alkyl group that forms a covalent bond with the DNA helix, preventing DNA duplication. They also function by attaching to free guanine bases of DNA thereby prohibiting their action as templates for new DNA formation.
    • Antimetabolites are similar in chemical structure to compounds required by normal and tumor cells for cell division. These antimetabolites may be incorporated into new nuclear material or combined with enzymes to inhibit cell division.
    • Plant alkaloids are derived from various plants and trees, including the periwinkle plant (Vinca rosea), the mayapple (Podophyllum peltatum), and the Pacific yew (Taxus brevifolia). They bind to tubules, blocking microtubule formation, and interfering with spindle formation. This leads to the arrest of metaphase and inhibits mitosis.
    • Antitumor antibiotics have many different modes of action, including increasing cell membrane permeability, inhibiting DNA and RNA syntheses, and blocking DNA replication.
    • Biologics target known mutations to oncogenic signal transduction pathways specific to cancer cells. As cancer biology is further elucidated, increasing numbers of biologics are being discovered and tested.
    • Miscellaneous agents have different modes of action than those previously mentioned.
Figure 50-1. Phases of the cell cycle, relative time intervals, and sites of action of the various classes of antineoplastic agents. (From Trimble EL, Trimble CL, eds. Cancer Obstetrics and Gynecology. Philadelphia, PA: Lippincott Williams & Wilkins, 1999:60, with permission.)
TABLE 50-1 Chemotherapeutic Agents Frequently Used in GynecologicCancer and Their Most Common Toxicities

Chemotherapeutic Agent

Toxicity

Alkylating agents

Cyclophosphamide (Cytoxan)

Myelosuppression (WBCs > platelets), hemorrhagic cystitis, bladder fibrosis, alopecia, hepatitis, amenorrhea

Ifosfamide

Myelosuppression, hemorrhagic cystitis, CNS dysfunction, renal toxicity, emetogenic

Alkylating-like agents

Cis-dichlorodiaminoplatinum (Cisplatin)

Nephrotoxicity, emetogenic, tinnitus and hearing loss, myelosuppression, peripheral neuropathy characterized by paresthesia of the extremities

• Renal insufficiency is the major dose-limiting toxic effect causing elevations in BUN, serum creatinine, and serum uric acid levels within 2 wk of treatment. Irreversible damage can occur. Prevention with IV hydration and diuretics is important during treatment. A 24-hr creatinine clearance is measured to establish baseline renal function before treatment.

• Tinnitus or high-frequency hearing loss may be cumulative and possibly irreversible. Audiograms may be obtained before and during treatment to assess hearing loss.

Carboplatin

Less neuropathy, ototoxicity, and nephrotoxicity but more myelosuppression (platelets > WBC) than cisplatin

Antitumor antibiotics

Actinomycin D (Dactinomycin)

Nausea and vomiting, skin necrosis, mucosal ulceration, myelosuppression, alopecia

Bleomycin sulfate

Pulmonary toxicity, fever, anaphylactic reactions, dermatologic reactions, mucositis, alopecia

• May cause significant pulmonary fibrosis. Generally, both dose- and age-related but can be idiopathic. Pulmonary function tests are performed to assess baseline pulmonary capacity before the first dose is administered.

• Can cause anaphylaxis, skin reactions, fever, and chills. Because of the high incidence of allergic reactions, patients are given a test dose of 2-4 U intramuscularly before the first dose of drug.

Doxorubicin hydrochloride (Adriamycin)

Myelosuppression, cardiac toxicity, alopecia, mucosal ulcerations, emetogenic, cholestasis, hyperpigmentation

Irreversible cardiomyopathies that involve progressive congestive heart failure, pleural effusions, heart dilation, and venous congestion. These are generally cumulative; therefore, dosages are kept under the maximum. Multiple-gated acquisition (MUGA) scans are commonly obtained before treatment to obtain a baseline ejection fraction and may be repeated as necessary.

Liposomal doxorubicin (Doxil)

Myelosuppression, skin and mucosal toxicity, hand-foot syndrome

Antimetabolites

5-Fluorouracil (5-FU)

Myelosuppression, emetogenic, anorexia, alopecia, hyperpigmentation, mucosal ulceration, cardiotoxic (MI, angina, arrhythmia)

Methotrexate sodium (MTX)

Myelosuppression, mucosal ulceration (stomatitis and mucositis), hepatotoxicity, acute pulmonary infiltrates that respond to steroid therapy, emetogenic, alopecia, peripheral neuropathy

Gemcitabine hydrochloride (Gemzar)

Mild myelosuppression, flu-like syndrome, emetogenic

Plant alkaloids

Vincristine sulfate (Oncovin)

Neurotoxicity (peripheral, central, and visceral neuropathies that are cumulative), alopecia, myelosuppression, cranial nerve palsies

Epipodophyllotoxin (etoposide, VP-16)

Myelosuppression, alopecia, hypotension, allergic reaction, emetogenic

Paclitaxel (Taxol)

Myelosuppression (WBC > platelets), alopecia, allergic reactions, cardiac arrhythmias, peripheral neuropathies, emetogenic

• Asymptomatic and transient bradycardia (40-60 beats/min), ventricular tachycardia, and atypical chest pain during infusion. These symptoms resolve with slowing of infusion.

• Hypersensitivity reactions with characteristic bradycardia, diaphoresis, hypotension, cutaneous flushing, and abdominal pain. Premedications of diphenhydramine hydrochloride, dexamethasone, and ranitidine are given prophylactically.

Docetaxel (Taxotere)

Myelosuppression (neutropenia), hypersensitivity; cutaneous reactions, alopecia, mucosal ulcerations, paresthesias

Biologics

Bevacizumab (Avastin)— monoclonal antibody, anti-VEGF

Hypertension, proteinuria, small risk of bowel perforations

Erlotinib, gefitinib— anti-EGFR

Skin rash, diarrhea

Rapamycin—anti-mTOR

Unknown side effects, still in clinical trials

Miscellaneous

Topotecan hydrochloride (Hycamtin; topoisomerase 1 inhibitor)

Myelosuppression (WBC > platelets), mucosal ulcerations, emetogenic, paresthesias

WBC, white blood cell; CNS, central nervous system; BUN, blood urea nitrogen; IV, intravenous; MI, myocardial infarction; VEGF, vascular endothelial growth factor; EGFR, epidermal growth factor receptor; mTOR, mammalian target of rapamycin.

Common Side Effects of Chemotherapy
  • Hematologic toxicity and myelosuppression is a dangerous effect of chemotherapy that varies in severity depending on the drug administered. A nadir in white cell, red cell, or platelet count is usually observed 7 to 14 days after drug administration. Most agents are readministered every 3 to 4 weeks if the patient has recovered from pancytopenia.
  • Neutropenia is defined as an absolute neutrophil count (ANC) less than 500/mL. Recombinant human granulocyte colony-stimulating factor (G-CSF) (filgrastim, Neupogen) or pegylated filgrastim (Neulasta) is administered to at-risk patients or the cycle after neutropenia is diagnosed as prophylaxis against this reaction in subsequent cycles. Use of G-CSF is contraindicated during the actual administration of chemotherapy or during a neutropenic fever.
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Oct 7, 2016 | Posted by in GYNECOLOGY | Comments Off on Chemotherapy and Radiation Therapy

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