Induction Chemo in Head and Neck Cancer: Is the Jury Still Out?

Aaron Falchook, MD

Numerous trials have been performed to investigate the role of induction chemotherapy for head and neck cancer patients treated with definitive radiation, but to date there is still no strong evidence that induction chemotherapy improves outcomes for locally advanced head and neck cancer.

We know from prior randomized trials that docetaxel plus cisplatin and 5-fluorouracil (TPF) is superior to cisplatin and 5-fluorouracil (PF), but it is still not clear that induction chemotherapy vs no induction chemotherapy provides a benefit. Therefore, induction chemotherapy remains investigational rather than standard of care. A pair of studies presented at this year’s American Society of Clinical Oncology (ASCO) Annual Meeting further examined the role of induction chemotherapy for head and neck cancer.

The first study, the GORTEC 2007-02 phase III randomized clinical trial, was presented by Dr. Lionnel Geoffrois (abstract 6000). In this trial, the role of induction chemotherapy was directly tested in patients with T2–T4, N2b–N3, M0 disease. The trial randomized 370 patients to radiation therapy concurrent with carboplatin and 5-fluorouracil (control arm, no induction chemotherapy given) vs 3 cycles of TPF chemotherapy followed by radiation therapy concurrent with cetuximab for patients who did not demonstrate progressive disease during induction.

The primary endpoint was progression-free survival, with an 80% power to detect a hazard ratio (HR) of 0.66 in favor of the induction chemotherapy arm, which included 181 patients. Notably, 5.5% of patients experienced progressive disease during induction and therefore did not proceed to receive definitive chemoradiotherapy; 12 patients (7%) died within 30 days of completing induction chemotherapy. In contrast, 3 patients (1.6%) in the non-induction arm died during treatment or within 30 days of completion of chemoradiotherapy. There was no difference in progression-free survival or locoregional control between the two arms. Distant metastasis-free survival was improved in the induction chemotherapy arm (HR, 0.62, P = .03).

Ultimately however, overall survival was not different between the two arms, and there was no patient subgroup (based on performance status, tumor stage, or nodal stage) in the induction chemotherapy arm that had improvement in progression-free or overall survival. Induction TPF modestly delayed development of distant metastases, at the cost of a 7% death rate. Based on these results, concurrent chemoradiotherapy (without induction chemotherapy) should remain the standard treatment for locally advanced head and neck cancer.

In the next study (abstract 6001), Dr. Ricardo Hitt presented results of a trial where 530 patients all received induction TPF chemotherapy followed by randomization to either concurrent cisplatin/radiotherapy (standard of care) or cetuximab/radiotherapy (experimental arm). Of the initial patients enrolled, only 407 were randomized after induction chemotherapy, with the remaining patients having shown disease progression during the induction phase. Results of this trial showed an overall high rate of disease control, with more than 50% of patients controlled at 3 years. Due to the lower than expected number of events, differences in outcomes between the arms has not achieved statistical significance.

In this trial, it appears that induction chemotherapy can be used to select patients who are fit and/or have disease that is more sensitive to treatment and could benefit from chemoradiotherapy. This abstract, however, does not directly address whether induction chemotherapy actually provided a benefit to the patients, vs just identifying patients who are more disposed to respond well to chemoradiotherapy.

In my opinion, the jury is not out. These abstracts are consistent with the overwhelming majority of prior evidence regarding induction chemotherapy-there is still no proven benefit in providing chemotherapy prior to definitive chemoradiotherapy for advanced head and neck cancer. Induction chemotherapy is feasible, however, and further studies are needed to identify potential patient subgroups that may benefit from this treatment intensification.

It is important to recognize that overall outcomes for advanced head and neck cancer patients are not acceptable with current treatments. The low cure rate for advanced disease justifies attempts to intensify therapy to improve outcomes for our patients. Unfortunately, intensification increases toxicity (> 5% treatment-related death seen with induction chemotherapy), adds costs, and delays time to receipt of curative chemoradiotherapy. Due to these factors, definitive chemoradiotherapy (without induction) should remain the standard of care for patients with locally advanced head and neck cancer, and induction chemotherapy should be reserved for use in prospective trials to identify patient subgroups that may benefit from this more aggressive treatment.