In the Journals

Cetuximab, radiotherapy show promise for laryngeal preservation in head, neck cancers

The addition of cetuximab to radiation therapy may improve larynx preservation and prolong laryngectomy-free survival for patients with hypopharyngeal or laryngeal cancer, according to a secondary analysis of a randomized phase 3 trial.

However, these findings should be interpreted with caution due to the retrospective study design and small sample size, according to the researchers.

“Historically, locoregionally advanced squamous cell cancers of the larynx or hypopharynx have been treated with surgical resection, usually involving laryngectomy with or without postoperative radiotherapy,” James A. Bonner, MD, FASTRO, Merle M. Salter endowed professor and chairman of the department of radiation oncology at University of Alabama at Birmingham School of Medicine, and colleagues wrote. “Although laryngectomy is an effective treatment, investigators have sought therapeutic strategies that result in voice preservation.”

Several randomized phase 3 trials have shown that induction chemotherapy and radiotherapy confer equivalent OS as surgical resection and postoperative radiotherapy.

Bonner and colleagues conducted a subgroup analysis of a randomized clinical trial evaluating the addition of cetuximab (Erbitux, Eli Lilly) to radiotherapy in patients with stage III or stage IV oropharyngeal cancers.

The trial enrolled 424 patients, of whom 168 patients with laryngeal or hypopharyngeal cancers were included in the secondary analysis.

Patients received primary radiotherapy with curative intent alone (n = 78; median age, 61 years; 79.5% men) or with cetuximab (n = 90; median age, 59 years; 80% men). Patients assigned cetuximab received an initial IV dose of 400 mg/m2 one week prior to radiotherapy initiation, followed by seven weekly infusions of 250 mg/m2.

Larynx preservation and laryngectomy-free survival served as the primary endpoints.

Patients assigned cetuximab and radiotherapy achieved a slight improvement in locoregional control (HR = 0.8; 95% CI, 0.56-1.13), which had served as the phase 3 trial’s primary endpoint.

Patients in the cetuximab–radiotherapy arm demonstrated an 87.9% rate of laryngeal preservation at 2 years, which appeared maintained at 3 years. Patients in the radiotherapy-alone arm demonstrated a laryngeal preservation rate of 85.7% at 2 years and 76.8% at 3 years.

The combination tended to improve laryngeal preservation (HR = 0.57; 95% CI, 0.23-1.42) and laryngectomy-free survival (HR = 0.78; 95% CI, 0.54-1.11); however, these improvements did not reach statistical significance.

Median OS was 27 months in the combination arm compared with 21 months for radiotherapy alone (HR = 0.87; 95% CI, 0.6-1.27).

Both treatment regimens exhibited similar safety profiles, although patients assigned the combination had higher rates of chills (P = .002), fever (P = .01) and headache (P = .004).

The two study arms did not exhibit differences with regard to speech, need for a feeding tube or overall quality of life.

The study was not sufficiently powered to observe treatment effects on organ preservation.

“This treatment approach warrants further evaluation in larger populations to fully assess the potential value of cetuximab or other molecular targeting agents to augment laryngeal preservation rates,” Bonner and colleagues wrote.

Further study must be conducted before cetuximab and radiotherapy can be confirmed as a standard of care for laryngeal preservation, Nabil F. Saba, MD, FACP, and Dong Moon Shin, MD, FACP, both of Emory University’s Winship Cancer Institute, wrote in a related editorial.

“A recent phase 2 randomized clinical trial comparing cetuximab to cisplatin after response to docetaxel platinum and fluorouracil revealed an equivalent rate of laryngeal preservation for the two agents, yet an improved adherence to cetuximab,” Saba and Shin wrote. “These preliminary findings, in addition to the current report by Bonner and colleagues, ought to raise the question of the merit of examining cetuximab as an alternative concurrent agent to cisplatin for laryngeal preservation. … In the meantime and until further notice, cisplatin and radiotherapy remain the current standard of care for laryngeal preservation, at least in the United States.” – by Cameron Kelsall

 

Disclosure: Eli Lilly provided funding for this study. Bonner reports consultant roles with Bristol-Myers Squibb, Eli Lilly and Merck Serono. Please see the full study for a list of all other researchers’ relevant financial disclosures. Saba and Shin report no relevant financial disclosures.

The addition of cetuximab to radiation therapy may improve larynx preservation and prolong laryngectomy-free survival for patients with hypopharyngeal or laryngeal cancer, according to a secondary analysis of a randomized phase 3 trial.

However, these findings should be interpreted with caution due to the retrospective study design and small sample size, according to the researchers.

“Historically, locoregionally advanced squamous cell cancers of the larynx or hypopharynx have been treated with surgical resection, usually involving laryngectomy with or without postoperative radiotherapy,” James A. Bonner, MD, FASTRO, Merle M. Salter endowed professor and chairman of the department of radiation oncology at University of Alabama at Birmingham School of Medicine, and colleagues wrote. “Although laryngectomy is an effective treatment, investigators have sought therapeutic strategies that result in voice preservation.”

Several randomized phase 3 trials have shown that induction chemotherapy and radiotherapy confer equivalent OS as surgical resection and postoperative radiotherapy.

Bonner and colleagues conducted a subgroup analysis of a randomized clinical trial evaluating the addition of cetuximab (Erbitux, Eli Lilly) to radiotherapy in patients with stage III or stage IV oropharyngeal cancers.

The trial enrolled 424 patients, of whom 168 patients with laryngeal or hypopharyngeal cancers were included in the secondary analysis.

Patients received primary radiotherapy with curative intent alone (n = 78; median age, 61 years; 79.5% men) or with cetuximab (n = 90; median age, 59 years; 80% men). Patients assigned cetuximab received an initial IV dose of 400 mg/m2 one week prior to radiotherapy initiation, followed by seven weekly infusions of 250 mg/m2.

Larynx preservation and laryngectomy-free survival served as the primary endpoints.

Patients assigned cetuximab and radiotherapy achieved a slight improvement in locoregional control (HR = 0.8; 95% CI, 0.56-1.13), which had served as the phase 3 trial’s primary endpoint.

Patients in the cetuximab–radiotherapy arm demonstrated an 87.9% rate of laryngeal preservation at 2 years, which appeared maintained at 3 years. Patients in the radiotherapy-alone arm demonstrated a laryngeal preservation rate of 85.7% at 2 years and 76.8% at 3 years.

The combination tended to improve laryngeal preservation (HR = 0.57; 95% CI, 0.23-1.42) and laryngectomy-free survival (HR = 0.78; 95% CI, 0.54-1.11); however, these improvements did not reach statistical significance.

Median OS was 27 months in the combination arm compared with 21 months for radiotherapy alone (HR = 0.87; 95% CI, 0.6-1.27).

Both treatment regimens exhibited similar safety profiles, although patients assigned the combination had higher rates of chills (P = .002), fever (P = .01) and headache (P = .004).

The two study arms did not exhibit differences with regard to speech, need for a feeding tube or overall quality of life.

The study was not sufficiently powered to observe treatment effects on organ preservation.

“This treatment approach warrants further evaluation in larger populations to fully assess the potential value of cetuximab or other molecular targeting agents to augment laryngeal preservation rates,” Bonner and colleagues wrote.

Further study must be conducted before cetuximab and radiotherapy can be confirmed as a standard of care for laryngeal preservation, Nabil F. Saba, MD, FACP, and Dong Moon Shin, MD, FACP, both of Emory University’s Winship Cancer Institute, wrote in a related editorial.

“A recent phase 2 randomized clinical trial comparing cetuximab to cisplatin after response to docetaxel platinum and fluorouracil revealed an equivalent rate of laryngeal preservation for the two agents, yet an improved adherence to cetuximab,” Saba and Shin wrote. “These preliminary findings, in addition to the current report by Bonner and colleagues, ought to raise the question of the merit of examining cetuximab as an alternative concurrent agent to cisplatin for laryngeal preservation. … In the meantime and until further notice, cisplatin and radiotherapy remain the current standard of care for laryngeal preservation, at least in the United States.” – by Cameron Kelsall

 

Disclosure: Eli Lilly provided funding for this study. Bonner reports consultant roles with Bristol-Myers Squibb, Eli Lilly and Merck Serono. Please see the full study for a list of all other researchers’ relevant financial disclosures. Saba and Shin report no relevant financial disclosures.