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Chemotherapy/radiation combination shows efficacy in larynx cancer
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Combination therapy with chemotherapy and radiation was associated with improvements in laryngectomy-free survival in patients with glottic or supraglottic squamous cell cancer, according to study results.
Arlene A. Forastiere, MD, professor of oncology and professor of otolaryngology — head and neck surgery at Johns Hopkins Medicine, and colleagues conducted the RTOG 91-11 study to investigate the role of chemotherapy when added to radiation therapy for the preservation of the larynx in patients with stage III or IV glottic or supraglottic squamous cell cancer.
The analysis included 520 patients. Researchers assigned patients to one of three treatment arms: cisplatin/fluorouracil followed by radiation, concomitant cisplatin/radiation or radiation alone. The primary endpoint was a composite of laryngectomy-free survival.
The median follow-up duration for survivors was 10.8 years.
Both chemotherapy regimens were linked to improvements in the survival outcome compared with radiation alone. When compared with radiation, induction chemotherapy yielded an HR of 0.75 (95% CI, 0.59-0.95), and concomitant therapy and radiation yielded an HR of 0.78 (95% CI, 0.78-0.98).
Researchers observed no significant difference regarding OS. However, a worse outcome may have been present with concomitant chemotherapy compared with induction therapy (HR=1.25; 95% CI, 0.98-1.61).
The concomitant regimen preserved the larynx when compared with induction therapy plus radiation (HR=0.58; 95% CI, 0.37-0.89) and when compared with radiation alone (P<.001).
Induction plus radiation failed to improve larynx preservation when compared with radiation alone (HR=1.26; 95% CI, 0.88-1.82).
The researchers did not observe a difference in late effects. The mortality rate not attributed to larynx cancer or treatment was 30.8% in the concomitant group vs. 20.8% in the induction group and 16.9% in the radiation-alone group.
“For intermediate-stage larynx cancer, new strategies focusing on improved locoregional control should be undertaken, and better assessment of late events should be performed,” Forastiere and colleagues concluded.
In an accompanying editorial, Everett E. Vokes, MD, the John E. Ultmann professor of medicine and radiation oncology and chair of the department of medicine at the University of Chicago, said the decreased long-term survival in the concomitant arm could have been a random occurrence or may have been due to risk factor–associated comorbidities that were not specific to the treatment delivered.
“Alternatively, these deaths could have been due to a latent increase of delayed functional decline that led to chronic toxicities, including aspiration pneumonia and associated cardiopulmonary compromise,” Vokes wrote. “It is clearly recognized that, in this 20-year-old trial, older radiation techniques were used, and current radiation techniques such as intensity-modulated radiation therapy might lead to a lower incidence of late toxicities.”
The trial helps reaffirm current standards of concurrent chemoradiotherapy — often preferred in the United States — and induction chemotherapy, often preferred in Europe, Vokes said.
“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 [cisplatin and fluorouracil] induction,” he wrote. “The trial also has soft data on late survival that remain unexplained but 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,” Vokes wrote. “At a minimum, induction chemotherapy emerges as a stronger alternative to standard concurrent chemoradiotherapy from these updated study results.”
Perspective
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Barbara Burtness, MD
RTOG 91-11 was a landmark study in the history of combined modality therapy for head and neck cancer, demonstrating an improvement in laryngectomy-free survival for patients who received concurrent chemoradiation or induction chemotherapy followed by radiation, rather than radiation alone, for locally advanced larynx cancer. The benefit was greatest when concurrent cisplatin was used. Overall survival had not previously been shown to differ among the arms, conventionally explained by the efficacy of salvage laryngectomy in those with persistent or recurrent disease in the larynx. The authors now update the results from this trial with over 10 years of follow-up, in a highly interesting report.
The long term results again demonstrate the greatest advantage in laryngectomy-free survival for concurrent cisplatin and radiation, but with an uncomfortable twist. This is, that the authors now describe a non-significant worsening in overall survival for the patients who received concurrent chemoradiation relative to those who received induction followed by radiation, to 28% alive at 10 years from 39% alive at 10 years. We cannot not know whether this difference would have been confirmed had the trial been powered for overall survival, but the difference is large enough to engender real concern. The excess late deaths in the concurrent arm of the trial appear to be predominantly from non-cancer causes, and are not well-explained.
Certainly, we are increasingly aware of the chronic toxicity from chemoradiation, and the possibility of late vascular and renal disease contributing to increased mortality is a genuine threat to these patients. We are also increasingly aware that not all patients benefit equally from cisplatin therapy, given differences in DNA repair enzymes such as ERCC1 and RRM1. Future trials which spare cisplatin exposure in patients with intrinsic resistance may be one approach to modifying the risk of late mortality; introduction of novel agents, improved radiation techniques and better management of cardiovascular risk in survivors also merit study.
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