Induction chemotherapy is given before definitive local therapy in an attempt to downstage local disease and make it more amenable to local therapy, to improve both local recurrence rates, and to treat microscopic systemic disease. This approach is attractive in that the drug is delivered to the tumor bed before it has been interfered with by surgery or radiotherapy and is delivered before the cells have had the chance to develop resistance to therapy. Preliminary studies from single institutions using this approach reported response rates as high as 90% with cisplatin-based regimens, with 40% complete response (CR) rates. Two-thirds of these had a pathologic CR. When followed with definitive radiotherapy, it was found that the response to induction chemotherapy was predictive of the subsequent response to radiation, and ultimately with survival.
Several randomized controlled trials of chemotherapy given before surgery14-18 and before radiation19'20 have been reported. The first of these large multi-institutional studies reported was the Head and Neck Contracts Program. The three arms of this study compared standard surgery and postoperative radiotherapy, induction chemotherapy with a single course of cisplatin and bleomycin before standard treatment, and induction chemotherapy plus standard treatment plus maintenance cisplatin.14 The overall response rate to the chemotherapy was only 37%, and no survival benefit was demonstrated; however, lower rates of distant metastasis were obtained with chemotherapy, and the disease-free interval was prolonged in those who received maintenance therapy.
The Southwest Oncology Group investigated three preoperative cycles of cisplatin, bleomycin, methotrexate, and vincristine. No significant difference in survival rate was demonstrated with survival favoring the standard arm, but the rate of distant metastases was lower in those receiving chemotherapy.16
Perhaps the most successful trial of neoadjuvant therapy was reported by the Veterans' Affairs (VA) Laryngeal Cancer Study Group.19 This trial compared intravenous cisplatin and 5-FU given before definitive radiotherapy with total laryngectomy. Patients were assessed after two courses of chemotherapy. If a significant response was not seen, the patient underwent total laryngectomy. If a good response was seen, the patient received a third cycle of chemotherapy and then underwent definitive radiotherapy. No difference in survival was seen between the two groups. Significantly, the survival was not compromised in the group receiving chemotherapy, yet two-thirds of patients surviving in this group retained a functioning larynx. Again, there was a reduction in the rate of systemic metastases in the chemotherapy group. It remains debatable as to whether this effect is durable, with some believing that the differences in the rates of distant metastases in the two groups become more similar with more prolonged follow-up.21,22 The VA study did establish induction chemotherapy followed by definitive radiotherapy as a standard treatment option in advanced carcinoma of the larynx.
Positive findings in these studies were that high response rates to induction chemotherapy could be achieved, a significant proportion of which were complete, and that survival times were increased in those that did respond. Chemotherapy response predicted response to subsequent radiotherapy, and rates of distant metastases were significantly lowered in the groups receiving chemotherapy. The induction chemotherapy did not increase complications from subsequent surgery or radiotherapy. Perhaps most importantly, laryngeal preservation could be achieved without compromising survival. Despite this good evidence of the drugs' activity, the trials were disappointing because the responses were translated neither into an increase in locoregional control, nor an increase in overall survival. A subset analysis of the Head and Neck Contracts Program study did, however, demonstrate an improvement in survival in oral cavity carcinomas and in those with limited neck disease.23 Concerns have been raised about the adverse effects of delaying definitive therapy in those who do not respond.24,25 A meta-analysis of early trials showed a nonsignificant trend to the harmful effects of the addition of chemotherapy.26
The success of the VA Laryngeal Cancer Study has established induction chemotherapy and definitive radiotherapy as a standard treatment option in laryngeal cancer, allowing preservation of laryngeal speech in most patients. This approach has been applied to advanced primary tumors of the oropharynx and hypopharynx in which total laryngectomy would be required as part of standard therapy. A large randomized trial by the European Organization for Research and Treatment of Cancer (EORTC) applied the VA protocol to patients with piriform sinus cancer. As with the laryngeal experience, survival was not compromised by a trial of induction chemotherapy, and 42% of patients in the experimental arm had a functioning larynx at 3 years.27 This protocol is now considered the standard therapy arm in ongoing EORTC trials. The addition of chemotherapy to other forms of definitive therapy comes at the cost of significant morbidity. Despite the success of organ preservation studies, chemotherapy is used as part of initial definitive therapy of head and neck cancer in only about 6% of cases in the United States, although its use appears to be increasing in the treatment of advanced cancer.28 The actual contribution made by chemotherapy in these trials is controversial. Large studies employing radiation alone have yielded disease specific survival rates similar to those achieved in induction chemotherapy tri-als29, 30 and improved survival of induction chemotherapy over radiation alone has yet to be established in a randomized trial.
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