Treatment of Locally Advanced Head and Neck Cancer: Historical and Critical Review

Muhyi Al-Sarraf, MD, FRCPC, FACP


Cancer Control. 2002;9(5) 

In This Article

Laryngeal Cancer

The conventional treatment of patients with locally advanced laryngeal cancers has consisted of surgery and/or radiation therapy. Many of these patients lose their larynx. In the early 1980s, we observed that patients who respond to cisplatin-based combination chemotherapy respond further with subsequent radiation therapy and,conversely, those who do not respond to initial chemotherapy, even after six courses, will not respond to radiation therapy.[2] This led us to offer chemotherapy first to patients with locally advanced laryngeal cancers. If a complete or partial response was achieved, they would then be given radiation therapy. The nonresponders would undergo surgery followed by radiation therapy.

At least two prospective, randomized phase III trials have been conducted, one in patients with cancers of the larynx[15] and the second in patients with cancers of the hypopharynx,[25] in which most of the patients previously had a laryngectomy. Both tested induction chemotherapy with cisplatin-5FU and selected the responding patients to receive either radiation therapy or the standard treatment of surgery followed by radiation therapy. The overall survival was the same between the two groups, and 50% to 60% of the surviving patients preserved their larynx on the investigational arm. These two studies demonstrated that laryngectomy (surgery) was equal to three courses of cisplatin-5FU chemotherapy, and surgery plus radiation therapy was equal to chemotherapy plus radiation therapy.

Following these results, the Intergroup Trial R91-11 conducted a study in patients with stage III-IV potentially resectable cancer of the larynx.[26] Patients were randomized to three arms: (1) chemotherapy followed by radiation therapy, (2) concurrent chemotherapyradiation therapy, and (3) standard once-daily radiation therapy alone. The trial selected only concomitant chemotherapy-radiation therapy as the experimental arm., and once-daily radiation therapy was used in the third arm rather than twice-daily (hyperfractionated) irradiation, which may produce higher local control rates (organ preservation) than once-daily fraction radiation therapy. Patients with T4 cancers were not included in the trial. Patients with N2 or N3 neck disease underwent neck dissection at the end of their treatment, regardless of their response to the initial treatment. No differences were reported in overall survival among the three groups, but patients who underwent concurrent chemotherapy-radiation therapy had significantly higher organ preservation rates. The laryngectomy-free survival improved with concurrent treatment vs radiation therapy alone (P=.02). Also, time to laryngectomy for concurrent treatment vs induction (P=.0094) and for concurrent treatment vs radiation therapy alone (P=.00035) was superior.

Some investigators gave one course of chemotherapy to select patients for larynx preservation. Since the response rate to one course of chemotherapy is less than 50%, this led to a higher percentage of patients on that arm losing their larynx, thereby defeating the primary goal of such a study. The usual response rate to three courses of chemotherapy is approximately 90%, leaving only 10% of these patients (the nonresponders) requiring surgery. Thus, the patients who were given just one course of chemotherapy and then concurrent chemotherapy-radiation therapy had an excellent survival, but more patients than expected lost their larynx.

Induction chemotherapy followed by concomitant chemotherapy-radiation therapy is the best nonsurgical treatment for laryngeal cancer we have used to date, and this approach has been confirmed by other investigators.[2,4,11] This total approach of chemotherapy-radiation therapy needs to be confirmed by prospective phase III trials vs concurrent chemotherapy plus radiation therapy.


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