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Postoperative chemotherapy offers no benefit in high-risk squamous cell head and neck carcinoma
Weekly carboplatin did not confer any additional benefit when paired with postoperative radiotherapy for high-risk cutaneous squamous cell carcinoma of the head and neck, according to findings from a randomized phase 3 study conducted in Australia and New Zealand.
“Concurrent, platinum-based, postoperative chemoradiotherapy has demonstrated improvement in locoregional control, PFS and OS compared with radiotherapy alone [among] patients with high-risk mucosal squamous cell carcinoma of the head and neck,” Sandro Virgilio Porceddu, MD, radiation oncologist at Princess Alexandra Hospital in Australia, and colleagues wrote. “Although many have extrapolated the use of postoperative chemoradiotherapy from these studies to cutaneous squamous cell carcinoma of the head and neck, there is no high-level evidence to support its use in this setting.”
The effect of 60 Gy or 66 Gy of radiotherapy with or without weekly carboplatin on freedom from locoregional relapse following surgery served as the primary objective. Secondary outcomes included DFS and OS.
Researchers randomly assigned 321 patients, 310 of whom received treatment with radiotherapy alone (n = 157) or chemoradiotherapy (n = 153). Seventy-seven percent (n = 238) of patients had high-risk nodal disease, 19% (n = 59) had high-risk primary or in-transit disease, and 4% (n = 13) had both.
The median dose for radiotherapy was 60 Gy. Most patients (84%) assigned to chemoradiotherapy underwent six cycles of carboplatin.
Median follow-up was 60 months.
Two-year freedom from locoregional relapse rates were 88% (95% CI, 83-93) in the radiotherapy group and 89% (95% CI, 84-94) in the chemoradiotherapy group. At 5 years, rates were 83% (95% CI, 77-90) in the radiotherapy group and 87% (95% CI, 81-93) for the chemoradiotherapy group. The difference did not show a significant benefit with chemoradiotherapy (HR = 0.84; 95% CI, 0.46-1.55).
The two groups also showed no significant differences in DFS or OS.
Locoregional failure was the most common site of first treatment failure. In both arms, 7% of patients experienced isolated distant metastases as the first site of failure.
Patients in both arms tolerated treatment equally well, and carboplatin did not appear to cause any toxicity. Few grade 3 or grade 4 late toxicities occurred in either arm.
After 2011, accrual for the study slowed because of the increasing use of intensity-modulated radiation as standard treatment, whereas the study did not allow for this therapy, Aarti K. Bhatia, MD, MPH, assistant professor of medicine at Yale Cancer Center, and colleagues wrote in a related editorial. Recruitment ended after the researchers had randomly assigned 321 patients.
“Aspects of the clinical design including the statistical assumptions, the failure to complete accrual, patient selection and the regimen under study all contributed to reducing the power of this study to detect a meaningful benefit from the addition of chemotherapy to postoperative radiotherapy in cutaneous squamous cell carcinoma, if one exists,” Bhatia and colleagues wrote. “Closer examination of these aspects of this report may help establish the direction for future trials in this setting.” – by Andy Polhamus
Disclosures: Porceddu reports consultant/advisory roles with Merck Serono, Merck Sharpe & Dohme, Oral Oncology and UpToDate, as well as travel, accommodations and expenses from Merck Serono and Merck Sharpe & Dohme. Please see the full study for all other authors’ relevant financial disclosures. Bhatia reports a consultant/advisory role with Bristol-Myers Squibb and research funding from Boehringer Ingelheim. Please see the full editorial for all other authors’ relevant financial disclosures.
Perspective
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Porceddu and colleagues from the Trans Tasman Radiation Oncology Group (TROG) have reported results from the first phase 3 trial of adjuvant therapy in cutaneous squamous cell carcinoma (CSCC) of the head and neck. Extrapolating from the positive results of two adjuvant trials — EORTC 22931 and RTOG 9501 — of chemoradiotherapy among patients with mucosal squamous cell head and neck cancer (SCHNC), the authors postulated that there might be a similar benefit from adding concurrent weekly carboplatin to standard postoperative radiation for patients with high-risk skin cancer. This trial, however, was negative. The investigators identified no improvements in any endpoint.
It is important to recognize the limitations of this result. In the mucosal head and neck cancer population, appropriately identifying the truly high-risk patient population is critical. A subsequent pooled analysis of these two SCHNC trials suggested that the benefit from adding concurrent chemotherapy to radiation was most apparent for those patients at highest risk for recurrence — patients with positive surgical margins or with extracapsular nodal involvement. Although CSCC is a different disease, eligibility criteria for this TROG study included patients with a number of other “high-risk” features, a study design choice that likely diluted any potential benefit from the chemotherapy. That the observed primary endpoint — 2-year freedom from locoregional recurrence — was 88% for the control arm, when the original sample size projections were built around an estimate of 70%, is evidence to that effect. Such an excellent outcome in the control population might argue against the importance of any attempt to improve adjuvant therapy. A stronger argument can be made for attempting to better define a higher-risk population.
The choice of single-agent weekly carboplatin in this TROG study also proved unfortunate, particularly because high-dose cisplatin is the only treatment regimen supported by phase 3 evidence in the mucosal squamous cell cancer population. These investigators chose carboplatin because of concern about cisplatin tolerance given the advanced age and potential comorbidities of the CSCC patients. The carboplatin was indeed very well tolerated. However, limited data, generated after initiation of this trial, did not suggest benefit from carboplatin in the mucosal squamous cell cancer. It is not surprising that a benefit would also be difficult to identify among the patients with CSCC.
Although this trial was clearly negative and does not support the use of concurrent carboplatin and radiation in the postoperative adjuvant setting, it should not be overinterpreted. Efforts to intensify adjuvant treatment in CSCC remain reasonable if we can better define the high-risk population likely to benefit, and if we can employ more effective interventions. Based on recent preliminary evidence suggesting significant activity from the checkpoint inhibitors in this disease, follow-up adjuvant studies using these agents are in development. The demonstration by TROG that such studies are feasible and of clinical interest to the oncologic community is perhaps the most important message from this report.
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