Strategies to Preserve Larynx Function in Patients with Head and Neck Cancer
Abstract & commentary
By William B. Ershler, MD
Synopsis: In a randomized, phase 3 trial of two different schedules of chemotherapy and radiotherapy for patients with advanced larynx or hypopharynx cancer, no difference was observed in progression-free survival, overall survival, or the maintenance of laryngeal function. Future studies are called for to define the optimal management of patients with locally advanced head and neck cancer.
Source: Levebvre JL, et al. Phase 3 randomized trial of larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst. 2009; 101: 142-152.
The european organization for research and Treatment of Cancer (EORTC) published results from its first trial addressing the issue of preservation of laryngeal function in patients with cancer of the hypopharynx, employing induction chemotherapy followed by radiation therapy in 1996.1 That trial, comparing three cycles of cisplatin plus 5-flurouracil, followed by radiotherapy with laryngopharyngectomy alone, found that the larynx could be preserved in 42% of patients at three years, but survival between the two groups was not different. Although that trial did not include patients with laryngeal carcinoma, an earlier trial conducted by the Department of Veterans Affairs demonstrated similar findings.2 These studies established this particular treatment strategy in an effort to preserve laryngeal function for patients with locally advanced head and neck cancer of either hypopharynx or laryngeal origin. Subsequent trials indicated that concurrent administration of chemotherapy and radiation resulted in a statistically significant improvement in larynx preservation but was associated with more serious acute toxicity and possibly long-term side effects.3
The currently published trial (EORTC 249540) addresses the question of whether the standard sequential (ie, chemotherapy followed by radiotherapy) could be improved upon by a slightly more complicated alternating schedule. Patients (n = 450) with resectable advanced squamous cell carcinoma of the larynx (tumor stage T3-T4) or hypopharynx (T2-T4), with regional lymph nodes in the neck staged as N0-N2, and with no metastasis, were randomly assigned to treatment in the sequential (or control) or the alternating (or experimental) arms.
In the sequential arm, patients with a 50% or more reduction in primary tumor size after two cycles of cisplatin and 5-fluorouracil received another two cycles, followed by radiotherapy (70 Gy total). In the alternating arm, a total of four cycles of cisplatin and 5-fluorouracil (in weeks 1, 4, 7, and 10) were alternated with radiotherapy with 20 Gy during the three two-week intervals between chemotherapy cycles (60 Gy total). All non-responders underwent salvage surgery and postoperative radiotherapy.
The 450 patients were randomly assigned to treatment (224 to the sequential arm and 226 to the alternating arm). Median follow-up was 6.5 years. Survival with a functional larynx was similar in sequential and alternating arms (hazard ratio of death and/or event = 0.85, 95% confidence interval = 0.68-1.06), as were median overall survival (4.4 and 5.1 years, respectively) and median progression-free interval (3.0 and 3.1 years, respectively). Grade 3 or 4 mucositis occurred in 64 (32%) of the 200 patients in the sequential arm who received radiotherapy and in 47 (21%) of the 220 patients in the alternating arm. Late severe edema and/or fibrosis was observed in 32 (16%) patients in the sequential arm and in 25 (11%) in the alternating arm.
Commentary
Thus, with a median follow-up of 6.5 years, there was no significant difference in clinical outcomes between the two treatment groups. Larynx preservation, overall survival, and progression-free survival were similar for patients treated with sequential and alternating chemotherapy and radiation. As described in an accompanying editorial,4 several points regarding the interpretation of this trial warrant mention. First, there remains some discrepancy in anatomic terminology of relevance. In Europe, tumors that occur on the medial wall of the pyriform sinus are considered "epilarynx," whereas the American Joint Commission on Cancer Staging would consider these hypopharyngeal. Accordingly, such distinction would leave only 21% of the current series as laryngeal, a number that might provide insufficient power to detect treatment-related difference to a degree of statistical significance between the two treatment groups. This is particularly relevant because tumors that arise in this region (pyriform sinus) are particularly aggressive and have a propensity for distant metastases.5
In the interval since this study was launched, additional trials have indicated that fewer than four cycles of chemotherapy would be as likely to produce the maximal pre-radiotherapy response3 and that the addition of a taxane would improve chemotherapy responses.6
Thus, there remain a number of unanswered questions regarding the optimal approach to both preserve laryngeal function and improve survival for patients with larynx and hypopharynx cancer. The EORTC 24954 trial revealed no advantage for alternating chemotherapy and radiation when compared to the standard sequence of initial chemotherapy followed by radiotherapy. Nonetheless, the trial does reinforce the feasibility of sparing of laryngeal function for a large subset of patients with these locally advanced head and neck malignancies, and highlights the need for standardization of terminology and classification.
References
1. Lefebvre JL, et al. Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group. J Natl Cancer Inst. 1996;88: 890-899.
2. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group. N Engl J Med. 1991; 324: 1685-1690.
3. Forastiere AA, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003;349: 2091-2908.
4. Forastiere AA, Trotti AM. Searching for less toxic larynx preservation: a need for common definitions and metrics. J Natl Cancer Inst. 2009;101: 129-131.
5. Kotwall C, et al. Metastatic patterns in squamous cell cancer of the head and neck. Am J Surg. 1987;154: 439-442.
6. Schrijvers D, et al. Docetaxel, cisplatin and 5-fluorouracil in patients with locally advanced unresectable head and neck cancer: a phase I-II feasibility study. Ann Oncol. 2004;15: 638-645.