Not so Fast: De-Intensification Therapy for Locally Advanced Oral Cavity Cancer

In this issue, Lin et al. retrospectively evaluated a large international cohort of 1200 patients with surgically resected SCC of the oral cavity, and the impact of subsequent adjuvant therapy (no evidence of metastatic disease postoperatively) on outcomes examined. A summary of the key results are shown in Table 1. In the subset of patients with intermediate risk factors for adjuvant radiation alone (n=585), the authors compare the current NCCN recommendations with an oral cancer specific system developed by their institution and utilized to guide treatment recommendations since 2008. Their oral cancer specific system adds additional pathologic features to those proposed by NCCN that indicate the need for adjuvant radiation: extrinsic muscle invasion, close margins <2mm, differentiation, and depth of invasion. According to their institutional guideline, adjuvant radiation was not recommended for patients with AJCC v.8 pT3N0, pT4aN0 and low volume pT1–2N1 who did not have the other specified risk factors (n=160). For this small cohort, the study reports excellent 5-year disease free-survival, disease specific survival, and overall survival, suggesting that the NCCN recommendations may be over-treating a subset of patients (28% per this study).

Table 1.

Intermediate risk group pathological factors, treatment recommendations, and outcomes per Lin et al

Intermediate risk factors		Recommendation for Adjuvant Treatment	5yr LRC	5yr DSS	5yr DFS	5yr DM	5yr OS
NCCN	CGMH	NCCN (+) CGMH (+) (n=411)	79%	84%	75%	9%	68%
pT3-4N+ pN+ + level IV/V nodes PNI LVSI
	pT4/EMI Close margins (< 2mm) Poor diff/DOI > 4mm
NCCN	CGMH	NCCN (+) CGMH(−) (n=160)	83%	94%a	83%	2%b	87%c
pT3N0 pT4NN0 Low volume T1-2N1

+ recommendation for adjuvant treatment, − recommendation against adjuvant treatment

^a:p < 0.001

^b:p = 0.003

^c:p < 0.001

EMI – Extrinsic muscle invasion; DOI – Depth of invasion; NCCN – National Comprehensive Cancer Network; CGMH – Chang Gung Memorial Hospital; LRC – local regional control; DSS – disease specific survival; DFS – disease free survival; DM – distant metastases; OS – overall survival

This novel retrospective analysis comparing two multidisciplinary guideline systems suggests de-intensification of therapy may be possible for a specific subpopulation of oral cancer patients and provides a strong rationale for prioritizing the development of prospective multi-institutional randomized trials to precisely quantitate the risks and benefits of such a strategy.

This provocative data is derived from an anatomically homogenous population limited to oral cancer. Historically, OCSCC has been examined collectively in studies that include other head and neck SCC subsites, often due to issues related to statistical power, and we have accepted the anatomical heterogeneity and relied on HPV negative biology to define our current treatment paradigm. Secondly, this study integrates depth of invasion (DOI), a pathological factor that is now included in the AJCC staging system (2), into the analysis. On a more exploratory note, the authors evaluate differentiation status as an indicator of an aggressive phenotype or biology. Each of these biomarkers warrant additional evaluation in prospective and blinded studies (for histopathologic evaluation), as independent or integrative biomarkers, to determine their contribution to prognosis and prediction of outcome relative to treatment strategies.

Importantly, this report is a landmark in the continuing evolution to improve the quality and precision of our multidisciplinary care of SCC. At the present time, evidence continues to accumulate that other factors such as gender (3), age (3,4), and anatomic sub-site warrants consideration and may improve patient selection for adjuvant radiation therapy and inform design of critically needed clinical trials. Studies of targeted intensification and de-intensification are clearly needed as suggested by a study of approximately 8900 oral SCC patients. It was observed that males over the age of 70 with oral tongue cancer who received the standard of care (surgery + adjuvant radiation therapy) had poorer loco-regional recurrence free survival, overall survival and poorer response to adjuvant radiation compared to younger patients (3).

In conclusion, the findings from Lin et al identify a subgroup of locoregionally advanced oral cavity SCC patients that may be optimally treated by surgery alone with good local control and very good disease specific and overall survival. Due to the well-known caveats of retrospective studies, we cannot recommend de-intensification of this cohort as the standard of care at this time. Yet, this work suggests an urgency to test this concept in a large randomized controlled multi-institutional trial. In addition, it would be valuable to assess response to therapy in populations varying in social, economic, and health care access around the globe. Most critically, supporting studies with sufficient resources is critical so that statistical power allows evaluation of the main hypothesis as well as additional patient characteristics such as age, gender, and histopathologic and molecular biomarkers. Ideally, these integrative studies with a strong correlative science program that incorporates genomics, transcriptomics, proteomics and relevant state of the art histopathology will improve the precision of our care.