Two Studies Focus on Treatment Strategies for Preserving the Larynx While Increasing Survival


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Two recent studies in the Journal of Clinical Oncology focused on treatment strategies to preserve the larynx while increasing survival of patients with cancer of larynx.

RTOG 91-11

Ten-year results from the Radiation Therapy Oncology Group (RTOG) 91-11 trial found that both chemotherapy regimens tested—induction chemotherapy with PF (cisplatin/fluorouracil) followed by radiotherapy and concomitant cisplatin/radiotherapy—were more effective than radiotherapy alone in achieving the composite endpoint of laryngectomy-free survival among patients with stage III or IV glottic or supraglottic squamous cell cancer. The researchers reported that locoregional control and larynx preservation were significantly improved with concomitant cisplatin/radiotherapy compared with both the induction arm and radiotherapy alone.

Among the 520 analyzable patients, 172 were assigned to radiotherapy alone and 174 were assigned to each of the two chemotherapy arms. Of the 148 patients who underwent laryngectomy, 32 patients were in the concomitant arm (81.7% larynx preservation), 55 in the induction arm (67.5% larynx preservation), and 61 in the radiotherapy-alone arm (63.8%)

“Concomitant cisplatin/[radiotherapy] resulted in a 54% relative reduction in risk of laryngectomy compared with [radiotherapy] alone (hazard ratio [HR] = 0.46; 95% confidence interval [CI] = 0.30–0.71; P < .001) and a 42% reduction compared with the induction arm (HR = 0.58; 95% CI = 0.37–0.89; P=.005),” the investigators noted.

“Overall survival did not differ significantly, although there was a possibility of worse outcome with concomitant relative to induction chemotherapy (HR = 1.25; 95% CI = 0.98–1.61; P = .08),” the investigators reported.

A total of 374 patients have died. The radiotherapy group had the highest percentage of deaths attributed to larynx cancer (48.4%) and the concomitant group had the lowest (29.2%). Deaths not attributed to larynx cancer or treatment were higher with concomitant chemotherapy (30.8%) than with induction chemotherapy (20.8%) or radiotherapy alone (16.9%).

“No differences in late toxicity or speech or swallowing function were demonstrated, but there was an unexplained increase in deaths unrelated to cancer in patients who received concomitant cisplatin/[radiotherapy]. This may be responsible for the absence of a survival advantage for the concomitant treatment group,” the researchers concluded.

TREMPLIN Trial

Conducted by researchers in France and Belgium, the phase II TREMPLIN trial compared induction chemotherapy with TPF (docetaxel, cisplatin, and fluorouracil) followed by either chemoradiotherapy or bioradiotherapy for larynx preservation in previously untreated patients with stage III/IV larynx/hypopharynx squamous cell carcinoma. The authors concluded that no evidence supported the superiority of one treatment over another or over outcomes reported with induction chemotherapy followed by radiotherapy alone, as in the French Groupe Oncologie Radiothérapie Tête et Cou (GORTEC) 2000-01 trial.

Induction chemotherapy consisted of three cycles of docetaxel and cisplatin at 75 mg/m2 each on day 1 and fluorouracil at 750 mg/m2 per day on days 1 through 5. The dropout rate after induction chemotherapy was substantial (24%), so only 116 of the 153 enrolled in the study were included in the randomization.

Those with < 50% response underwent salvage surgery, while those with ≥ 50% response were randomly assigned to conventional radiotherapy (70 Gy) with concurrent cisplatin at 100 mg/m2 per day on days 1, 22, and 43 of radiotherapy (arm A, 60 patients) or concurrent cetuximab (Erbitux) at a 400-mg/m2 loading dose and 250 mg/m2 per week during radiotherapy (arm B, 56 patients).

Overall toxicity of both chemoradiotherapy and bioradiotherapy was substantial following induction chemotherapy. However, treatment compliance was higher in the bioradiotherapy arm, the researchers reported. An intent-to-treat analysis found no significant difference in larynx preservation (defined as the absence of any residual disease that would justify salvage total laryngectomy) at 3 months between arm A (95%) and arm B (93%) or in larynx function preservation (defined as a disease-free larynx in place, without tracheotomy or feeding tube), at 87% in arm A and 82% in arm B. Overall survival at 18 months was 92% in arm A and 89% in arm B.

“There were fewer local treatment failures in arm A than in arm B; salvage surgery was feasible in arm B only,” the authors noted.

“Endpoints were evaluated on the randomly assigned population only, which represented 76% of the patients included in the trial; thus, they are inflated. They were considered in an exploratory attempt to possibly selecting one arm for a phase III trial. Of course, no formal test can be made from these data,” the authors stated. They added that comparison to published data from other larynx preservation trials would be inappropriate due to selection bias.

Commentary

In an editorial accompanying the two studies, Everett E. Vokes, MD, of the University of Chicago Medical Center, noted, “Both trials reaffirmed current standards of concurrent chemoradiotherapy (frequently preferred in the United States) and induction chemotherapy (frequently preferred in Europe). RTOG 91-11 provides us with hard data on [laryngectomy-free survival], larynx preservation, and disease-free survival that give an advantage to a concomitant approach over PF induction. The trial also has soft data on late survival that remain unexplained but are concerning and appear to favor induction. Although induction chemotherapy in the short term results in lower larynx preservation and local control, its favorable long-term outcome suggested by RTOG 91-11 should not be ignored.”

Dr. Vokes stated that the conclusion of the TREMPLIN investigators not to move to phase III setting “appears appropriate, especially in view of the toxicities associated with the administration of intensified therapy.” He added that the TREMPLIN trial “confirms that practitioners should continue to choose either induction or concomitant therapy but not both, and it failed to identify a role for cetuximab-based therapy in laryngeal cancer. These results are compatible with similar data from recent larger randomized trials that found no benefit from the addition of induction chemotherapy to concomitant chemoradiotherapy or of a sequential TPF carboplatin/radiation approach compared with concomitant cisplatin radiation alone.”

In addition to the articles summarized above, the Journal of Clinical Oncology also recently published an Oncology Grand Rounds article titled, “Larynx Preservation for Patients With Locally Advanced Laryngeal Cancer.” Along with a case presentation and suggested management approaches, the article includes a review of the relevant literature. ■

Forastiere AA, et al: J Clin Oncol 31:845-852, 2013.
Lefebvre JL, et al: J Clin Oncol 31:853-859, 2013.
Vokes EE: J Clin Oncol 31:833-835, 2013.
Corry J, et al: J Clin Oncol 31:840-844, 2013.



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