Postoperative Concurrent Chemoradiotherapy Versus Postoperative Radiotherapy in High-Risk Cutaneous Squamous Cell Carcinoma of the Head and Neck: The Randomized Phase III TROG 05.01 Trial

Abstract

Purpose To report the results of the Trans Tasman Radiation Oncology Group randomized phase III trial designed to determine whether the addition of concurrent chemotherapy to postoperative radiotherapy (CRT) improved locoregional control in patients with high-risk cutaneous squamous cell carcinoma of the head and neck. Patients and Methods The primary objective was to determine whether there was a difference in freedom from locoregional relapse (FFLRR) between 60 or 66 Gy (6 to 6.5 weeks) with or without weekly carboplatin (area under the curve 2) after resection of gross disease. Secondary efficacy objectives were to compare disease-free survival and overall survival. Results Three hundred twenty-one patients were randomly assigned, with 310 patients commencing allocated treatment (radiotherapy [RT] alone, n = 157; CRT, n = 153). Two hundred thirty-eight patients (77%) had high-risk nodal disease, 59 (19%) had high-risk primary or in-transit disease, and 13 (4%) had both. Median follow-up was 60 months. Median RT dose was 60 Gy, with 84% of patients randomly assigned to CRT completing six cycles of carboplatin. The 2- and 5-year FFLRR rates were 88% (95% CI, 83% to 93%) and 83% (95% CI, 77% to 90%), respectively, for RT and 89% (95% CI, 84% to 94%) and 87% (95% CI, 81% to 93%; hazard ratio, 0.84; 95% CI, 0.46 to 1.55; P = .58), respectively, for CRT. There were no significant differences in disease-free or overall survival. Locoregional failure was the most common site of first treatment failure, with isolated distant metastases as the first site of failure seen in 7% of both arms. Treatment was well tolerated in both arms, with no observed enhancement of RT toxicity with carboplatin. Grade 3 or 4 late toxicities were infrequent. Conclusion Although surgery and postoperative RT provided excellent FFLRR, there was no observed benefit with the addition of weekly carboplatin.

Positive survival trend in metastatic head and neck cutaneous squamous cell carcinoma over four‐decades: Multicenter study

“…Without effective systemic therapy, further improvements are unlikely to be achieved as has been shown in stage IV colorectal cancer with the introduction of chemotherapy around 2000 . In this context, the recent negative results of the randomized multicenter postoperative chemoradiation study in regionally metastatic HNcSCC were disappointing . However, recent studies evaluating immunotherapy demonstrate that cSCC has a high response rate to PD‐1/PD‐L1 blockade, and this treatment option may also be better suited to an aging population than platinum‐based chemotherapy .…”

“…31 In this context, the recent negative results of the randomized multicenter postoperative chemoradiation study in regionally metastatic HNcSCC were disappointing. 32 However, recent studies evaluating immunotherapy demonstrate that cSCC has a high response rate to PD-1/PD-L1 blockade, and this treatment option may also be better suited to an aging population than platinum-based chemotherapy. 33 It is very likely that the next generation of adjuvant trials in HNcSCC will incorporate PD-1/PD-L1 immunotherapy in conjunction with adjuvant RT.…”

Ultraviolet light‐related DNA damage mutation signature distinguishes cutaneous from mucosal or other origin for head and neck squamous cell carcinoma of unknown primary site

“…Second, radiation‐based treatments to the bilateral neck and potential primary sites in the upper aerodigestive mucosa are often recommended for locoregionally advanced mucosal SCC without distant metastases, whereas for advanced cSCC, surgery and postoperative radiotherapy including the ipsilateral neck are the dominant recommended treatments. Third, after surgery, radiation is often delivered with concurrent systemic therapy for high‐risk mucosal SCC, whereas in high‐risk cSCC, a major phase III study found no locoregional control or survival benefits from the addition of concurrent platinum‐based chemotherapy to postoperative radiotherapy …”

“…Third, after surgery, radiation is often delivered with concurrent systemic therapy for high-risk mucosal SCC, whereas in high-risk cSCC, a major phase III study found no locoregional control or survival benefits from the addition of concurrent platinum-based chemotherapy to postoperative radiotherapy. 15 For metastatic cSCC, immunotherapy is a promising first-line treatment option. A recent study of PD-1 blockade with cemiplimab in advanced cSCC reported a response in 47% of the patients.…”

Number of nodal metastases and prognosis in metastatic cutaneous squamous cell carcinoma of the head and neck

“…The potential management implications of our findings require further study, particularly given the majority of patients with metastatic cSCCHN are offered adjuvant radiotherapy and the lack of data to support the use of chemotherapy. 12 However, a recent phase 2 study of the PD-1 inhibitor cemiplimab demonstrated disease response in 47% of patients with regional or distant metastatic disease from cutaneous SCC. 13 If immunotherapy is proven to be a viable treatment option in the adjuvant setting, identifying high-risk patients based on the number of nodal metastases may be useful.…”