Therapeutic Chemotherapy

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COMBINED-MODALITY THERAPY

Radiotherapy has proved effective in head and neck cancer. Its mechanism of cell killing is postulated to be mediated by the direct interaction of superoxide radicals with cellular enzymes and DNA, indicating that adequate oxygen content of the tumor is necessary for efficacy of this treatment.35 In addition, radiotherapy has been found to be most effective during the G2 and M stages of the cell cycle. Adding chemotherapy to radiation has several theoretical benefits. Chemotherapy can prevent the repair of sublethal damage inflicted by ionizing radiation. Certain drugs act as sensitizers (e.g., 5-FU) and improve the effect of radiation on tumors. Some drugs are particularly toxic to hypoxic cells (mitomycin C) and thus can target a population that is radioresistant. Both cause apoptosis, probably by different mechanisms, so each potentiates the other.12 Chemotherapy often causes growth arrest of cells at a certain part of the cell cycle, allowing them to be more sensitive to radiation.35

One of the difficulties of combining the two treatment modalities has been in determining the appropriate timing of each. The schedule for adding chemotherapy to radiation has traditionally been divided into three groups: induction or neoadjuvant, concomitant (including alternating), and adjuvant (posttreatment) administration.

NEOADJUVANT CHEMOTHERAPY

Giving chemotherapy before radiation has theoretical benefits and risks. By reducing the size of the tumor without interrupting the blood supply, the oxygen content of the mass should be higher, leading to greater sensitivity to radiation. In addition, responders to chemotherapy may be treated effectively with a single modality treatment, usually radiation, and thus spared surgery (at least as a primary modality). On the downside, Toohill et al.36 reported a worse survival rate with the neoadjuvant arm than with the standard (radiotherapy) arm. This raises the possibility that delaying definitive therapy may allow the tumor to become further disseminated and reduce survival.

A large number of trials have been designed to evaluate the benefit of neoadjuvant chemotherapy.1,13-17,36-41 Many show high response rates, up to 98% in operable laryngeal cancer.17 But survival data show no statistically significant change in overall or (where available) disease-specific survival (Table 8-2). Many of these studies have been criticized with respect to low patient numbers, inadequate drug dosages, and variable "standard" treatment arms, but several well-controlled studies have been completed.

Is there a role for induction chemotherapy? Several trials have looked at this specific question, especially in light of the organ-preservation protocols. According to this concept, an increase in survival might not be a realistic goal, but improved quality of life by retaining organs such as the larynx might be obtainable. To this end, the Veteran's Affairs Laryngeal Cancer Cooperative Study (VALCS) was designed.16 It included 332 patients who were randomized to receive either surgery and postoperative radiotherapy or neoadjuvant chemotherapy (cisplatin and 5-FU) and definitive locoregional therapy. In the chemotherapy arm, the patient was evaluated after two cycles. If the tumor response was greater than 50%, a third dose of chemotherapy was administered, followed by definitive radiotherapy. For those patients who failed to respond, surgery was perfomed (usually total laryngectomy), followed by postoperative radiation. Of those patients who received chemotherapy, 85% showed a major response (31% CR) and 64% retained their larynx. The 2-year survival data showed no difference compared with the control arm. In a follow-up study, the 4-year evaluation showed that 31% of the 166 patients randomized to the chemotherapy arm were alive and retained their larynx.17 Their overall survival rate was 46% for the chemotherapy group and 43% for the control group.

A similar study was performed by the European Organization for Research and Treatment of Cancer (EORTC), except that eligible patients had T2-4, N0-2b squamous cell carcinoma of the aryepiglottic fold or piriform sinus.37 Another difference was that only those patients showing a complete response to chemotherapy were allowed to progress to radiotherapy. In this study, 43% of patients required a laryngectomy for lack of

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