Numeric if not statistically significant differences favoring inclusion of cetuximab (Erbitux, Eli Lilly & Co) in combination with radiation therapy (CRT) vs radiotherapy alone are being reported for several outcomes, including laryngectomy-free survival, in patients with laryngeal cancer.
"The higher rate of laryngeal preservation that was achieved with the use of CRT compared with radiotherapy alone was encouraging," lead author James Bonner, MD, University of Alabama at Birmingham, and coauthors write.
The study was published online July 7 in JAMA Otolaryngology-Head & Neck Surgery.
"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," the researchers conclude.
However, in an invited commentary, experts say that while these results are interesting, for the time being, the combination of cisplatin and radiotherapy should remain the current standard of care for laryngeal preservation, at least in the United States.
Secondary Analysis of Data
The secondary subgroup analysis reported by Dr Bonner and colleagues was based on 168 patients with locoregionally advanced laryngeal and hypopharyngeal cancer who were originally recruited for a phase 3 randomized trial comparing CRT to radiotherapy alone.v
Patients involved in the original trial had stage III or IV, nonmetastatic squamous cell carcinoma of the oropharynx, hypopharynx, or larynx.
"The primary radiotherapy was delivered with curative intent," the authors note.
Treatment regimens involved one of three fractionation regimens: once a day, twice a day, or a concomitant boost regimen.
Patients randomly assigned to the CRT group received cetuximab, at a starting dose of 400 mg/m2, given 1 week before CRT was initiated, after which they received cetuximab infusions while undergoing radiotherapy.
Surgery took place 4 to 8 weeks after patients had completed CRT or radiotherapy, among those for whom surgery had been planned.
Primary Endpoint
At 2 years, 36.9% of the CRT subgroup had achieved locoregional control — the primary endpoint of the phase 3 study — compared with 25.7% of the radiotherapy alone subgroup.
At both 2 and 3 years, 87.9% of the CRT group had no need for salvage laryngectomy compared with 85.7% of the radiotherapy-alone group at 2 years and 76.8% for the same group at 3 years.
"The 2.2% and 11.1% absolute improvements in the rates of laryngeal preservation, at 2 and 3 years, respectively, favored CRT compared with radiotherapy alone," the authors write.
However, this improvement did not achieve statistical significance.
Rates of laryngectomy-free survival at 2 and 3 years were, again, slightly higher at 44.5% and 37.4%, respectively, for the CRT group vs 40.5% and 28.5%, respectively, for the radiotherapy group.
Again, although this translated into a 4% and an 8.9% absolute improvement in laryngectomy-free survival rates in favor of the CRT group at 2 and 3 years, respectively, these differences did not reach statistical significance, the authors report.
Median overall survival was 27 months for the CRT group vs 21 months for the radiotherapy-alone group.
"Patients who received CRT had a greater rate of acneiform rash compared with patients who received radiotherapy alone," the authors acknowledge.
Patients treated with the combination strategy were also significantly more likely to experience chills, fever, and headache than those receiving radiotherapy alone.
In contrast, grade 3 and 4 rates of mucositis, stomatitis, and odynophagia did not significantly differ between the 2 treatment groups.
Life Without a Larynx
"The perception of life without a larynx plays an important role in a patient's treatment decision," the authors observe.
For example, a study in France (Eur Ann Otorhinolaryngol Head Neck Dis. 2014;131:93-97). found that fewer than 30% of patients indicated that they would not consider a treatment option that they knew would be less likely to cure them of their cancer rather than choose total laryngectomy.
In another group of participants (N Engl J Med. 1981;305:982-987) who were asked what they would do if they had laryngeal cancer, participants were willing to accept a 15% to 30% reduction in life expectancy if they could be treated with a larynx-sparing procedure vs total laryngectomy.
"These studies demonstrate the importance of reviewing options and potential adverse effects with patients before making a decision regarding the best treatment," the authors advise.
Cisplatin Remains Modality of Choice
At present, platinum-based chemoradiotheray is "the modality of choice for laryngeal preservation, at least in the US," authors of an invited commentary point out.
Nabil F. Saba, MD, and Dong M. Shin, MD, both from the Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, say that this practice is based on the results from the Radiation Therapy Oncology Group (RTOG) 91-11 trial, which found that laryngeal preservation rates were 54% higher when patients were treated with a concurrent platinum-based chemoradiotherapy strategy.
Longer-term follow-up of the RTOG 91-11 trial also confirmed that the laryngeal-free survival rate was better for patients who received the concurrent and sequential approaches compared with radiotherapy alone.
Commenting on the latest data, they say that, although laryngeal preservation was not the primary endpoint of the current study, "these results are reason to pause and reflect again on the appropriate systemic agent to combine with radiotherapy for LP [laryngeal preservation]."
Other evidence supporting the merit of cetuximab comes from the phase 2 TREMPLIN trial (J Clin Oncol. 2013;31:853-859), in which rates of laryngeal preservation were the same whether patients received cetuximab or cisplatin after achieving a response to induction docetaxel, platinum, and fluorouracil.
However, adherence was better with cetuximab, Dr Saba and Dr Shin note in their commentary. It is noteworthy that the authors of the TREMPLIN trial themselves concluded that no evidence showed that one treatment regimen was superior to the other in any way, including overall survival, and that "substantial overall toxicity" was associated with the induction regimen followed by CRT.
These findings from the TREMPLIN study and the latest data now reported by Dr Bonner and colleagues together "ought to raise the question of the merit of examining cetuximab as an alternative concurrent agent to cisplatin for LP," the editorialists suggest.
However, in the absence of more robust phase 3 data documenting which concurrent agent is superior, "cisplatin and radiotherapy remain the current standard of care for LP, at least in the United States," they conclude.
The study was funded by Eli Lilly and Co. Dr Bonner reported working as a consultant for Eli Lilly and Co, Merck Serono, and Bristol-Myers Squibb. Dr Saba and Dr Shin have disclosed no relevant financial relationships.
JAMA Otolaryngol Head Neck Surg. Published online July 7, 2016
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