A review of neoadjuvant chemotherapy for head and neck cancer: Partially shrunken tumors may be both leaner and meaner

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Chemotherapy can be given in three main sequences in combination with definitive local treatment for solid tumors: before (induction), simultaneously (in the case of radiation therapy), or after (adjuvant or maintenance). The best chemotherapeutic response rates for solid tumors are often achieved before any other treatment. This practice is described fashionably as “neoadjuvant” chemotherapy, and is aimed at the “induction” of a remission. The terms “induction” and “neoadjuvant” are often used interchangeably. The phenomenon of a locally advanced tumor regressing rapidly and even completely can amaze patient and physician alike, especially if a surgeon or radiation oncologist were not initially sanguine about the chances for therapeutic success. It is the patient, though, who experiences the emotional “high” of the drug-induced tumor response and is also intoxicated by it. Toxicity and risk of progression for non-responders are clearly reasonable prices to pay when improved rates of remission are associated with improved rates of survival, for example, as with lymphoma, but the association between response to induction chemotherapy and cure is less well defined for many solid tumors. There has come to be a progressive reliance on the use of neoadjuvant chemotherapy (NACT) for the treatment of solid tumors, perhaps best exemplified in the treatment of locally advanced head and neck cancer. Adjuvant chemotherapy, on the other hand, has more objectively been shown not to be useful for head and neck cancer ( 17,20). The lack of biologic benefit in the adjuvant setting is, perhaps, more easily accepted because there is no measurable cancer, and long-term tumor control must be the end-point. The emphasis with NACT, in contrast, seems to be on initial response-often rapid and impressiveand there has been inexplicably less emphasis on whether or not this translates into improved long-term tumor control and survival. It is the initial emotional reaction to the tumor response that is embraced. The third main sequence for chemotherapy with radiation therapy is concomitant use for which there has been relatively less enthusiasm because of increased acute toxicity and the obfuscation in attributing response. Neoadjuvant chemotherapy has, thus, become a major focus for combined modality head and neck cancer treatment. Neoadjuvant chemotherapy has led to major responses for up to 90% of head and neck cancer patients (19). It has been studied in conjunction with surgery and radiation therapy with two different endpoints: (a) improvement in cure and (b) patient selection for organ preservation without survival decrement. The response to NACT has been purported both to predict and influence the subsequent response to external beam radiation therapy (EBRT) (7, 41). Some even believe that NACT is a sine qua non for organ conservation treatment. There have been many non-randomized trials evaluating the response rates to NACT when given with the goal of improvement in cure rates, but few trials have had controls appropriate specifically to assess the biologic significance of such responses. Randomized trials involving NACT directed at improved survival have had less promising results than might have been assumed based on the impressive initial response rates alone. The biologic and clinical significance of these impressive response rates simply has not yet been established. These trials have actually shown that NACT has either been of no benefit ($28) or that those receiving it have done worse ( 11,40) than controls who had received radiation therapy alone. NACT has also been compared to concomitant chemo-irradiation ( 10) and alternating chemotherapy and radiation therapy (1 I), and in both cases the comparison arm was found to be superior treatment.