Searching for less toxic larynx preservation: a need for common definitions and metrics.

JNCI | Editorials 129 In this issue of the Journal, Lefebvre et al. ( 1 ) report the results of a randomized controlled trial addressing preservation of the larynx in patients with cancers of the hypopharynx and the larynx. This is the second controlled trial from the European Organization for Research and Treatment of Cancer (EORTC) to focus on the strategy of induction chemotherapy (ie, administering several cycles of cisplatin plus 5-fluorouracil), followed by radiotherapy in the patients who respond to treatment (responders). The first trial, which was published in 1996 ( 2 ), was limited to patients with cancer of the hypopharynx and compared up to three cycles of cisplatin plus 5-fluorouracil, followed by radiotherapy with laryngopharyngectomy alone . In that study, they found that the larynx could be preserved in 42% of patients at 3 years but that survival did not differ statistically significantly between the two treatment groups. These results and those of another trial that was limited to patients with larynx cancer ( 3 ) solidified organ preservation as a treatment option for patients with cancers of either the larynx or the hypopharynx. The current trial attempts to take another step forward by comparing four cycles of induction chemotherapy with cisplatin plus 5-fl uorouracil, followed by radiotherapy in the responders (control group) with a regimen of alternating cisplatin plus 5-fl uorouracil chemotherapy and radiotherapy. The results show some trends for improved outcomes with the alternating approach but overall no statistically signifi cant difference for larynx preservation, pattern of treatment failure, or survival outcomes. The alternating regimen was chosen as the experimental treatment because it was previously shown ( 4 ) to confer a survival advantage compared with radiotherapy alone and because of the notion that the associated toxicity would be less than a concomitant regimen . Investigators in the United States ( 5 ), by contrast, compared concomitant cisplatin and radiotherapy with induction cisplatin plus 5-fl uorouracil in patients with locally advanced larynx cancer and reported statistically signifi cantly better larynx preservation and local control with concomitant cisplatin but no difference in survival outcomes. How should we view the results of the EORTC trial on the current management of larynx and hypopharynx cancers ? First, the primary site terminology warrants clarifi cation. The Europeans use the term epilarynx for the anatomical site that is the medial wall of the pyriform sinus, which is a subsite of the hypopharynx in the American Joint Commission on Cancer staging system ( 6 ). With that in mind, only 95 (21%) of the 450 patients enrolled had cancers arising in the larynx, and so the study was not powered for effi cacy analysis for this small cohort . The primary site is important because cancers arising in the hypopharynx (including pyriform sinus) are biologically distinct from those arising in the larynx, with a worse overall prognosis and a high rate of distant dissemination ( 7 ). Additionally, the radiotherapy ports differ, so that patients with hypopharynx cancer are at greater risk for pharyngeal strictures and gastrostomy tube dependence because of a larger target volume and higher radiotherapy dose to the pharyngeal constrictors. We can conclude that fi ndings from the EORTC trial 24954 are similar to those reported in 1996 ( 2 ) that support induction therapy with cisplatin plus 5-fl uorouracil as an alternative to laryngopharyngectomy for stage T2 – T4, N0 – N2 cancers arising in the hypopharynx. These results lead to several questions, including what is the defi nition of response to induction therapy with cisplatin plus 5-fl uorouracil, how many cycles of induction therapy with cisplatin plus 5-fl uorouracil should be given, what is the role of combination therapy with taxane and cisplatin plus 5-fl uorouracil, and what is the defi nition of the larynx preservation endpoint . The most commonly used defi nition of response for induction organ preservation trials that allows patients to proceed with radiotherapy is a partial response ( ≥ 50% regression) of the primary tumor . However, this defi nition varies from complete response, which was used in the fi rst EORTC hypopharynx trial ( 2 ), to the requirement for “substantial” reduction in tumor and partial recovery of larynx mobility as specifi ed in the trial conducted by Lefebvre et al. ( 1 ) . The reduction of tumor in response to cisplatin-based therapy is a crude surrogate biomarker for sensitivity to subsequent radiotherapy that is based on the similarity of mechanism of DNA strand breakage caused by alkylating agents and radiotherapy. However, there has not been a systematic study of the degree of response and success of subsequent radiotherapy to control the disease, and some believe that it is the rapidity of tumor shrinkage that predicts outcome ( 8 ). Additionally, it has been repeatedly shown that induction cisplatin plus 5-fl uorouracil does not affect local – regional control but can suppress distant metastases. By contrast, concomitant administration of cisplatin and radiotherapy can theoretically kill cells that are resistant to one or the other modality, and statistically signifi cant improvement in local – regional control and survival is well documented ( 9 ). With the emergence of combination regimens with taxane and cisplatin plus 5-fl uorouracil, which have been found to be superior to cisplatin plus 5-fl uorouracil ( 10 – 12 ), agreed-upon defi nitions of response, the number of cycles of cisplatin plus 5-fl uorouracil, and goal of induction (as a surrogate biomarker to