Validation of NRG oncology/RTOG‐0129 risk groups for HPV‐positive and HPV‐negative oropharyngeal squamous cell cancer: Implications for risk‐based therapeutic intensity trials

Abstract

Background Radiation Therapy Oncology Group (RTOG)‐0129 recursive partitioning analysis was the basis for risk‐based therapeutic intensification trials for oropharyngeal cancer (OPC). To the authors’ knowledge, the question of whether RTOG‐0129 overall survival (OS) estimates for low‐risk, intermediate‐risk, and high‐risk groups are similar in other data sets or applicable to progression‐free survival (PFS) is unknown. Therefore, the authors evaluated whether survival differences between RTOG‐0129 risk groups persist at 5 years, are reproducible in an independent clinical trial, and are applicable to PFS, and whether toxicities differ across risk groups. Methods Prospective randomized clinical trials were analyzed retrospectively. RTOG‐0129 evaluated standard versus accelerated fractionation radiotherapy concurrent with cisplatin. RTOG‐0522 compared the combination of cisplatin and accelerated fractionation with or without cetuximab. Patients with OPC with available p16 status and tobacco history were eligible. Results There was a total of 260 patients and 287 patients, respectively, from RTOG‐0129 and RTOG‐0522, with median follow‐ups for surviving patients of 7.9 years (range, 1.7‐9.9 years) and 4.7 years (range, 0.1‐7.0 years), respectively. Previous OS differences in RTOG‐0129 persisted at 5 years. In RTOG‐0522, the 5‐year OS rates for the low‐risk, intermediate‐risk, and high‐risk groups were 88.1%, 69.9%, and 45.1%, respectively (P for trend, <.001). The 5‐year PFS rates for the same 3 groups were 72.9%, 56.1%, and 42.2%, respectively. In RTOG‐0522 among a subgroup of patients considered to be at very good risk (p16‐positive disease, smoking history of ≤10 pack‐years, and classified with T1‐T2 disease with ipsilateral lymph nodes measuring ≤6 cm or T3 disease without contralateral or >6 cm lymph nodes), the 5‐year OS and PFS rates were 93.8% and 82.2%, respectively. Overall rates of acute and late toxicities were similar by risk group. Conclusions RTOG‐0129 risk groups persisted at 5 years and were reproducible in RTOG‐0522. However, there was variability in the estimates. These data underscore the importance of long‐term follow‐up and appropriate patient selection in therapeutic deintensification trials.

CD8 infiltration is associated with disease control and tobacco exposure in intermediate-risk oropharyngeal cancer

“…We previously showed that in Veterans with heavy tobacco exposure (a majority) 5,33 , survival for HPV+ and HPV− disease were in line with the rates reported by Ang et al for intermediate-risk and high-risk disease 5,34 . This effect was consistent across racial groups 35 , and matches long term results from both RTOG0129 and RTOG0522 11 . The introduction of immunomodulatory agents for OPSCC represents both an opportunity to improve clinical outcomes and a challenge in terms of stratifying patients to the appropriate treatment regimen and intensity [36][37][38][39][40] .…”

Review of emerging biomarkers in head and neck squamous cell carcinoma in the era of immunotherapy and targeted therapy

“…As excellent outcomes, in general, can be achieved in HPV‐positive HNSCC, the reasonable next step is to de‐intensify therapy, especially radiotherapy, to minimize treatment‐related toxicities and improve quality of life without compromising survival . One thing to be noticed is that the de‐intensification needs to happen carefully and only within the confines of a clinical trial.…”

“…As early as 2000, the use of cisplatin or carboplatin in combination with radiotherapy has become a standard treatment approach for HNSCC . Several tissue biomarkers have shown a potential role in predicting response to platinum‐based therapy.…”

“…58,59 As excellent outcomes, in general, can be achieved in HPV-positive HNSCC, the reasonable next step is to deintensify therapy, especially radiotherapy, to minimize treatment-related toxicities and improve quality of life without compromising survival. 110,111 One thing to be noticed is that the de-intensification needs to happen carefully and only within the confines of a clinical trial. Given the distinctive pathobiology of HPV-positive HNSCC, innovative approaches targeting viral oncogenes and the immune system, integrated with the use of both established and novel biomarkers, are warranted.…”

“…As early as 2000, the use of cisplatin or carboplatin in combination with radiotherapy has become a standard treatment approach for HNSCC. 110,112 Several tissue biomarkers have shown a potential role in predicting response to platinum-based therapy. For example, ERCC1 protein expression may be a valuable marker for platinum chemoresistance, 14,30,32,54 106 radiotherapy toxicity, 52 and response 113 in HNSCC.…”