Postoperative risk stratification in oral squamous cell carcinoma

Available online at www.sciencedirect.com

ScienceDirect British Journal of Oral and Maxillofacial Surgery 58 (2020) 462–468

Postoperative risk stratification in oral squamous cell carcinoma J.D. McMahon a,∗ , R. Pitts b , J. Isbister c , B. Aslam-Pervez d , A. James e , D. McLellan a , S. Wright a , C.J. Wales a , J. McCaul a , E. Thomson f , M.J. Ansell a , W.S. Hislop g , C. MacIver h , J.C. Devine h , E. Carson a a

Queen Elizabeth University Hospital, NHS Greater Glasgow and Clyde Health Board Medical and Life Sciences Schools, University of Dundee c University of Glasgow Medical School d QueenElizabeth University Hospital, Glasgow e Beatson Oncology Centre, NHS Greater Glasgow and Clyde Health Board f NHS Forth Valley Health Board g NHS Ayrshire and Arran Crosshouse Hospital h Maxillofacial / Head and Neck Unit, Mafraq Hospital b

Accepted 24 February 2020 Available online 25 March 2020

Abstract Postoperative prognostic stratification using the Union for International Cancer Control (UICC) TNM 8th edition staging rules (UICC 8) may identify additional groups of patients who could benefit from adjuvant radiotherapy. Currently, selection for such treatment is not based on all known prognostic factors, and their relative importance may vary depending on the overall risk category. The objective of this study therefore was to evaluate these possibilities. We retrospectively studied 644 patients who had surgery with curative intent for oral squamous cell carcinoma (OSCC) between March 2006 and February 2017. The outcomes of interest were disease-specific survival (DSS) and locoregional recurrence (LRR). Patients were re-staged according to the UICC 8 staging rules. Putative clinical and pathological prognostic variables were evaluated and hazard ratios estimated. Regression analysis was done to identify independent prognostic factors, and iterative analyses identified clinically-relevant risk categories with a minimum of residual prognostic variables. The significance of recognised pathological prognostic factors differed according to the overall risk category. An intermediate risk group comprising patients with pN1 disease as well those with pT3 disease solely on the basis of a depth of invasion (DOI) of more than 10 mm, was identified. A trial to evaluate the benefit or otherwise of adjuvant radiotherapy in this group is now required. Individual prognostic risk factors should be considered within the context of the overall risk category in patients with OSCC. © 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Keywords: Mouth neoplasms; squamous cell carcinoma; prognosis; surgery; adjuvant radiotherapy; perineurial invasion

∗

Corresponding author. E-mail addresses: [email protected] (J.D. McMahon), [email protected] (R. Pitts), [email protected] (J. Isbister), [email protected] (B. Aslam-Pervez), [email protected] (A. James), [email protected] (D. McLellan), [email protected] (S. Wright), [email protected] (C.J. Wales), [email protected] (J. McCaul), [email protected] (E. Thomson), [email protected] (M.J. Ansell), [email protected] (W.S. Hislop), [email protected] (C. MacIver), [email protected] (J.C. Devine), [email protected] (E. Carson). https://doi.org/10.1016/j.bjoms.2020.02.026 0266-4356/© 2020 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

J.D. McMahon et al. / British Journal of Oral and Maxillofacial Surgery 58 (2020) 462–468

Introduction Changes to the staging rules for oral squamous cell carcinoma (OSCC) in the 8th edition of the Union for International Cancer Control (UICC) TNM staging rules (UICC 8),1 which were made in response to a clearer understanding of clinical and pathological prognostic characteristics, had the intention of improving risk stratification, balance in distribution, and hazard consistency.2,3 These changes comprise the introduction of depth of invasion as a criterion for allocation to T stages 1 - 3, the dropping of invasion of the extrinsic muscles of the tongue as a criterion for T4 status, and the incorporation into the pN staging rules of extranodal tumour extension. Improved prognostic stratification could potentially reveal previously unrecognised subgroups with a relatively adverse prognosis that may benefit from adjuvant treatment. Furthermore, the relative importance of known clinical and pathological prognostic variables may vary depending on the overall stratification of risk. The objective of this study was to investigate these possibilities.

Methods Patients undergoing surgery with curative intent between March 2006 and February 2017 were identified from the multidisciplinary team database (2010 onwards), operating theatre log (whole period), and pathology department database (2006-2010). Between 2006 and June 2008, clinical, pathological, and treatment details, together with outcome data, were obtained from the paper clinical case records, and thereafter from the electronic healthcare records. Survivors had a minimum follow up of 24 months. The outcomes of interest were locoregional recurrence (LRR) and disease-specific survival (DSS). Time to recurrence or death was recorded from the date of operation. In the case of a second primary cancer of the head and neck, imaging was assessed to ensure no overlap between two sites. Where there was doubt, events were attributed to the primary index tumour. In the case of non-small cell lung cancer, reports of multidisciplinary meetings and imaging were evaluated. Unless an unequivocal allocation as a second primary lung tumour could be made, the occurrence was recorded as distant metastasis and therefore a disease-related event. Patients were restaged according to the UICC 8 pathological staging rules based on the clinical, radiological, and pathological findings. Surgery to the primary site was planned using clinical assessment and multiplanar, contrast-enhanced, crosssectional imaging, and aimed to achieve a 1 cm macroscopic clearance in all planes. When imaging suggested proximity to what might be a functionally vital structure, but oncological clearance of more than 3-4 mm was judged feasible, this was accepted. Examples include the contralateral lingual artery in tongue cancer, the hyoid bone, and the internal carotid artery. Staining with Lugol’s iodine was done selectively throughout

463

the study period in an effort to remove associated severe dysplasia. Surgical staging of the neck was done in all but 113 patients (17%). Over the study period 85 patients had sentinel lymph node biopsies. Nodal metastases were identified in 18 (21%) of them. A further patient staged as pN0 on sentinel lymph node biopsy had a regional relapse with the primary controlled (false negative). The remaining 447 patients had selective lymphadenectomy for staging. Two or more lymph node metastases were considered an indication to recommend adjuvant radiotherapy. Adjuvant platinum-based concurrent chemoradiotherapy was recommended for patients under 71 years of age who had involved margins (defined as tumour less than 1 mm from a surgical margin), or extranodal extension of tumour with a performance status of 0 or 1. A primary tumour stage of T3 based on a diameter of more than 4 cm, and T4 status were regarded as indications for adjuvant radiotherapy. An exception was made for pT4 N0 status, solely on the basis of bony invasion when a tumour had arisen on alveolar mucosa of the mandible or maxilla. Similarly, allocation of pT4 (under the 7th edition UICC staging rules) solely on the basis of invasion of the extrinsic muscles of the tongue was not considered an indication for adjuvant therapy. Statistical analysis was done with the help of IBM SPSS Statistics for Windows version 20.0 (IBM Corp). The Kaplan-Meier method was used to evaluate survival, and the categorical factors were compared with the log-rank test. The Cox proportional hazard method was used to estimate hazard ratios. Prognostic variables significant at the 0.10 level were entered into multivariate modelling using Cox regression to identify independent prognostic variables. Hazard ratios and independent prognostic factors were used to allocate patients to risk categories, and these were analysed to determine variables of residual risk stratification. Iterations of categories were assessed until the optimal hazard stratification and the minimum of residual risk groups remained in each category.

Results A total of 644 patients underwent primary surgery with curative intent for OSCC over the study period. The mean age was 62.5 years (range 22-94, SD 11.26). The categorical characteristics of the study population are shown in Table 1. The presence of dysplasia at margins, the presence of lichenoid inflammation in association with the primary tumour, and age at the time of operation were not found to be prognostic for LRR or DSS. Variables independently predictive for LRR and DSS are shown in Table 2. A “very high risk” category of 113 patients was identified comprising those with pN3b disease and involved surgical margins. In this group perineural invasion adversely influenced DSS (p=0.021; HR 1.88; 95% CI 1.20 to 3.20) (Fig. 1). For LRR the finding of dysplasia in adjacent mucosa pre-

464

J.D. McMahon et al. / British Journal of Oral and Maxillofacial Surgery 58 (2020) 462–468

Table 1 Patient, tumour, treatment, recurrence, and disease-specific survival characteristics. Variable

Subcategory

No. (%)

Sig LRRt (p value)

Sig DSSa (p value)

Hazard ratio DSS (95% CI)x

Sex

Male Female Tongue Floor of mouth Mandibular gum Maxillary gum/palate Buccal Retromolar trigone Unspecified pT1 pT2 pT3 pT4 pNx pN0 pN1 pN2a pN2b pN2c pN3b 0.1-5mm 5.1-10mm >10mm Unknown Clear >/=5mm Close 1-4.9mm Involved <1mm Yes No Cohesive Non-cohesive Not recorded Well Moderate Poor Unreported No Yes No Yes Absent Present N0 or Nx Not reported Reported present 0 1 2 Unknown Surgery only Postoperative RT Postoperative CT-RT Neoadjuvant CT Local Regional Distant Second primary head and neck cancer

391 (61) 253 (39) 271 (42) 160 (25) 69 (11) 31 (5) 29 (4) 70 (11) 14 (2) 205 (32) 173 (27) 127 (19) 139 (13) 113 (17) 297 (46) 56 (9) 23 (4) 41 (6) 11 (2) 103 (16) 259 (40) 184 (29) 196 (30.4) 45 (0.6) 394 (61) 216 (34) 34 (5) 73 (11) 571 (89) 187 (29) 407 (63) 50 (8) 54 (8) 468 (73) 93 (14.5) 29 (4.5) 501 (88) 143 (22) 447 (69) 197 (31) 109 (47) 125 (53) 410 478 (74) 166 (26) 365 (72) 80 (16) 64 (12) 215 387 (60) 151 (23.5) 104 (16.2) 2 (0.3) 61 (9.5) 68 (10.5) 49 (7.6) 52 (8.1)

0.113

0.007

0.033

0.046

<0.001

<0.001

<0.001

<0.001

<0.001

<0.001

1.63 (1.15 to 2.33) Reference Reference 0.60 (0.38 to 0.96) 0.60 (0.31 to 1.17) 1.41 (0.75 to 2.67) 1.48 (0.76 to 2.88) 1.16 (0.57 to 1.16) 0.52 (0.13 to 2.10) Reference 2.674 (1.443 to 4.954) 6.346 (3.547 to 11.355) 6.882 (3.886 to 12.252) 1.622 (0.87 to 3.01) Reference 5.046 (2.850 to 8.932) 4.501 (2.044 to 9.912) 4.266 (2.211 to 8.309 6.138 (2.363 to 15.94) 8.752 (5.51 to 13.91) Reference 3.33 (1.97 to 5.61) 6.71 (4.14 to 10.87)

<0.001

<0.001

0.002

<0.001

0.006

<0.001

0.003

0.001

Reference 2.26 (0.99 to 5.14) 3.97 (1.67 to 9.46)

<0.001

<0.001

3.058 (2.190 to 4.269)

<0.001

<0.001

<0.001

<0.001

Reference 3.13 (2.26 to 4.35) Reference 4.57 (3.28 to 6.39)

0.045

NS

<0.001

<0.001

Reference 1.57 (0.90 to 2.74) 3.00 (1.82 to 4.93)

–

–

–

–

–

–

Subsite

pT stage

pN stage

DOI categorical

Margin status

Dysplasia associated Invasive front

Differentiation

Lymphovascular invasion Perineural invasion Extranodal extension

Tumour infiltrating lymphocytes (TILS) *Modified Glasgow prognostic score

Adjuvant treatment

Recurrence

Reference 1.21 (0.85 to 1.72) 5.56 (3.15 to 9.84) Reference 2.049 (1.475to 2.330) Reference 2.18 (1.42 to 3.33)

∗ Modified Glasgow prognostic score (mGPS) is derived from preoperative estimations of serum C-reactive protein and albumin using the following rules: CRP < or =10: mGPS =0; CRP>10 and sAlb> or =35: mGPS=1; CRP >10 and sAlb<35: mGPS =2. ␶ – locoregional recurrence; a –disease-specific survival; x 95% CI on hazard ratio.

J.D. McMahon et al. / British Journal of Oral and Maxillofacial Surgery 58 (2020) 462–468

465

Table 2 Independent prognostic variables (Cox regression) – all patients. Variable

Sig LRR

Hazard ratio LRR (95% CI)*

Sig DSS

Hazard ratio DSS (95% CI)

pN Nx N1 N2a N2b N2c N3b Depth category 5.1-10 mm >10 mm Surgical margin Close Involved Perineural invasion

–

–

<0.001

0.008

0.1-5 mm reference 3.26 (1.26 to 8.42) 5.27 (2.12 to 13.09) Clear reference 0.82 (0.42 to 1.61) 3.52 (1.42 to 8.73) –

–

pN0 reference 3.19 (1.51 to 6.72) 3.76 (2.00 to 7.09) 4.39 (1.79 to 10.79) 3.26 (1.50 to 7.09) 4.85 (1.82 to 12.91) 5.31 (3.16 to 8.93) –

0.012

–

0.005

0.018

Clear reference 1.32 (0.88 to 2.00) 2.93 (1.51 to 5.67) 1.32 (1.08 to 2.36)

LRR: locoregional recurrence; DSS: disease-specific survival; CI: Confidence Interval. *95% Confidence Interval.

Fig. 1. Locoregional recurrence and postoperative risk stratification.

dicted a lower likelihood of recurrence (p=0.025; HR 0.46; 95% CI 0.24 to 0.91). A “high risk” group comprised 186 patients with T3 or T4 disease (or pN2, UICC 8) and R0 surgical margins. For this category, a depth of invasion (DOI) of more than 10 mm (reference 0.1-5 mm; p=0.05; HR 3.32; 95% CI 1.00 to 11.01), perineural invasion (p<0.000; HR 2.76; 95% CI 1.57 to 4.86), and the presence of tumour infiltrating lymphocytes (p=0.037; HR 0.393; 95% CI 0.16 to 0.94) were independent predictors for DSS. The same variables were independently predictive for LRR but with the addition of poor tumour differentiation (p=0.039; HR 2.21; 95% CI 1.04 to 4.72) and a modified Glasgow prognostic score (mGPS) higher than 0 (p=0.048; HR 1.60; 95% CI 1.00 to 2.54).

Patients with pN1disease had a similar prognosis to those with pN2 disease. Those with pT3 disease had a similar prognosis to those with pT4, and a depth of more than 10 mm was highly prognostic. Neither pT3 status based solely on a DOI of more than 10 mm, nor pN1 (UICC 8) was considered an indication for adjuvant radiotherapy over the study period. Patients who had uninvolved margins, a pT stage of T1 or T2, those staged as pT3 solely on the basis of a DOI of more than 10 mm, and those with N0, Nx, or N1 disease who did not have adjuvant treatment, were analysed separately (n=327) (Table 3). Of them, 98 did not have surgical staging of the neck at the primary procedure (Nx). Ten of them had regional recurrence and of them, eight died of disease. On multivariate analysis only pN1 status was found to be independently

466

J.D. McMahon et al. / British Journal of Oral and Maxillofacial Surgery 58 (2020) 462–468

Table 3 Significant prognostic variables for group with clear surgical margins, pT1, pT2, and pT3 solely on the basis of a depth of invasion (DOI) of more than10 mm, pN0 or pN1, and no adjuvant treatment. Variable

Subcategory

No.

No. LRR

No. DOD

Sig LRR (p value)

Sig DSS (p value)

DSS HR (95% CI)

pT

pT1 pT2 pT3 pN0 pN1 pNx No Yes 0.1-5 mm 5.1-10 mm >10 mm Cohesive Non-cohesive No Yes Absent Present 0 1 2

182 109 39 210 21 98 279 51 213 84 34 120 176 300 30 267 63 206 27 20

14 14 7 14 6 15 26 9 18 10 7 6 26 29 6 25 10 18 2 6

9 14 7 11 8

0.029

0.006

0.00013

<0.001

23 7 13 11 7 5 25 25 5 21 10 17 3 5

0.040

NS

0.015

0.004

0.007

0.006

0.045

NS

0.014

0.058

0.025

0.043

Reference 2.779 (1.202 to 6.425) 4.174 (1.552 to 11.226 Reference 8.31 (3.21 to 21.54) 2.51 (1.11 to 5.68) Reference 1.84 (0.79 to 4.30) Reference 2.15 (0.94 to 4.91) 4.13 (1.65 to 10.37) Reference 3.42 (1.31 to 9.00) Reference 2.15 (0.82 to 5.61) Reference 2.14 (0.98 to 4.68) Reference 1.52 (0.45 to 5.20) 3.33 (1.23 to 9.04)

pN

Dysplasia at margin Depth code

Invasive front Lymphovascular invasion Perineural invasion mGPS

mGPS: modified Glasgow prognostic score; LRR: locoregional recurrence; DSS: disease-specific survival; DOD: died of disease.

Fig. 2. Disease-specific survival and postoperative risk stratification.

prognostic for DSS (p<0.005; HR 9.9; 95% CI 3.7 to 26.6) (Fig. 2). For LRR, mGPS (p=0.004; HR 2.1; 95% CI 1.3 to 3.4), lymphovascular invasion (p=0.036; HR 3.0; 95% CI 1.1 to 8.2), invasive front (p=0.018; HR 4.3; 95% CI 1.3 to 14.4), and presence of dysplasia at a surgical margin (p=0.001; HR 5.0; 95% CI 2.0 to 12.3), were independently prognostic. Finally, the patients who were pT1, pT2, and pT3 solely on the basis of a DOI of more than 10 mm, who were pN0 with uninvolved surgical margins, and did not have adju-

vant treatment (n=211), were evaluated to identify any further subgroups with a relatively poor prognosis. On multivariate analysis the DOI category was independently prognostic for both LRR (p=0.024; HR 1.79; 95% CI 1.08 to 2.95) and DSS (p=0.051; HR 1.71; 95% CI 1.00 to 2.95). Based on these findings, 55 patients were categorised into an “intermediate risk” group comprising those with pN1 (UICC 8) disease as well as those with pN0 tumours and a DOI of more than 10 mm, a diameter of less than 4 cm, and

J.D. McMahon et al. / British Journal of Oral and Maxillofacial Surgery 58 (2020) 462–468

467

Table 4 Risk category, event rate, adjuvant treatment, locoregional recurrence (LRR), and disease-specific survival (DSS). Postoperative risk category

No.

No. died of disease

No. second primary HNSCC

Adjuvant treatment No. (%)*

Hazard ratio LRR (95% CI)

Low Intermediate High Very high

290 55 186 113

21 12 56 55

29 1 17 5

12 (4) 16 (29) 121(65) 99 (88)

Reference 3.21 (1.68 to 6.12) 2.39 (1.44 to 3.96) 5.55 (3.36 to 9.14)

∗

Sig LRR

<0.001 0.001 <0.001

Hazard ratio DSS (95% CI) Reference 3.45 (1.70 to 7.93) 4.79 (2.89 to 8.11) 10.69 (6.47 to 17.66)

Sig DSS

0.001 <0.001 <0.001

Adjuvant radiotherapy or concurrent chemoradiotherapy.

uninvolved (R0) surgical margins (Fig. 1). In this group no variable showed residual independent prognostic significance for LRR or DSS. A “low risk” group comprised 290 patients with T1 and T2N0 disease with R0 margins (Fig. 1). In this group only a DOI of 5.1-10 mm was independently prognostic of DSS (11 of 85 patients died of disease) (p=0.012; HR 3.81; 95% CI 1.34 to 10.85). LRR was predicted by a DOI of 5.1-10 mm (p<0.005; HR 8.58; 95% CI 2.75 to 26.75), no neck staging procedure (pNx) at primary operation (p<0.005; HR 1.25; 95% CI 1.10 to 1.41), and a mGPS score of more than 0 (p=0.001; HR 2.65; 95% CI 1.46 to 4.81). The hazard ratios and event rate for the four risk categories are shown in Table 4, and depicted in Figs. 1 and 2 for both LRR and DSS. The relation between the risk categories and overall survival was also significant (supplemental Fig. 2).

Discussion The options for the curative treatment of OSCC remain limited to operation and radiotherapy, although systemic treatment has an adjunctive role in some.4 Surgery remains the primary curative treatment of choice for most patients,5 but the best way to deploy adjuvant therapy remains an area of contention for several combinations of patient and tumour characteristics. Adverse prognostic features are well known, but how to incorporate the relative weighting of numerous, potentially interacting variables is less well understood. Validated nomograms, which provide individual estimates of prognosis with and without adjuvant treatment, can guide decision making,6 but current iterations do not include all the recognised pathological prognostic variables. Doubtless they will be further refined, but as yet they have not been widely adopted into head and neck clinical practice in the UK. Rather than the individualisation of prognosis, this study aimed to categorise risk, to identify groups that might benefit from further trials, and to examine the relative influence of known prognostic factors within those categories. This retrospective study supports trial data on the existence of a “very high risk” category that comprises patients with involved surgical margins (tumour within 1 mm of surgical margin) or pathological extranodal extension. The category was identified in the unplanned subgroup analysis of pooled data from two randomised controlled trials.

When patient factors permit, concurrent chemoradiotherapy is recommended.7–10 With an event rate of around 50%, this subset is the obvious choice in which to pursue clinical trials of an escalation in treatment. Perineural invasion further stratifies prognosis in this group. We identified a relatively small “intermediate risk” category of patients who may benefit from adjuvant therapy. This comprised those with pN1 disease, and those with pN0 disease, but with a tumour diameter of less than 4 cm and a DOI of more than 10 mm. Previous studies,11 including a matched-pair analysis,12 have indicated that patients with N1 disease are at higher risk and may benefit from adjuvant therapy. A randomised controlled trial to test this hypothesis has been registered and was due to report in December 2018 (the last update was posted in 2012).13 Assuming a 10% improvement in survival after five years with adjuvant radiotherapy, it planned to recruit 560 patients with a 70% power to detect a difference at the 5% level. However, with less than 10% of patients meeting the criteria for eligibility this is a formidable undertaking that is likely to require multicentre and, in Europe, multinational collaboration. In the interim, decisions about adjuvant treatment in this group will continue to be made on a case-by-case basis and will involve discussion of the relative risks and benefits. A “low risk” group could be further stratified by depth category, but for most patients there are insufficient events in the 5.1-10 mm depth category to justify adjuvant therapy. In this group none of the commonly cited adverse features (close margins, perineural invasion, lymphovascular invasion, absence of tumour infiltrating lymphocytes, invasive front, and tumour differentiation) was significantly associated with outcome. This emphasises the importance of an overall risk stratification of patients when considering the relative importance of individual prognostic factors. It is noteworthy that in this category, the event rate of a second primary head and neck cancer equates to that of the index primary, and is a further consideration for initial management (Table 4). This study has important limitations. Its retrospective design means that it relies heavily on contemporaneous reports by a number of histopathologists. The attention given to prognostic factors is likely to have both intra-individual and inter-individual variation over the study period. In particular, the fact that the presence of tumour infiltrating lymphocytes was reported in less than 12% of patients in the first two years of the study, and in 42% in the last two years, means

468

J.D. McMahon et al. / British Journal of Oral and Maxillofacial Surgery 58 (2020) 462–468

that it is highly probable that the significance of this prognostic factor was underestimated. A mGPS was not available in one-third of the patients. Further clarification of risk categories with large pooled datasets would be beneficial. The data presented are insufficient to draw firm conclusions and should be regarded as hypothesis generating.

Conflict of interest We have no conflicts of interest.

Ethics statement/confirmation of patients’ permission The data set is registered on the Greater Glasgow and Clyde Information Asset Registry. The institution’s Research and Development Department categorise this work as audit. No patient identifiable data is included.

Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/ j.bjoms.2020.02.026.

References 1. Brierley JD, Gospodarowicz MK, Wittekind C, editors. TNM classification of malignant tumours. 8th edition John Wiley & Sons; 2017. 2. Lydiatt WM, Patel SG, O’Sullivan B, et al. Head and neck cancers - major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin 2017;67:122–37.

3. Groome PA, Schulze KM, Mackillop WJ, et al. A comparison of published head and neck stage groupings in carcinomas of the tonsillar region. Cancer 2001;92:1484–94. 4. National Comprehensive Cancer Network (NCCN): Clinical practice guidelines in oncology: cancer of the oral cavity; 2016. 5. Spiotto MT, Jefferson G, Wenig B, et al. Differences in survival with surgery and postoperative radiotherapy compared with definitive chemoradiotherapy for oral cavity cancer – a national cancer database analysis. JAMA Otolaryngol Head Neck Surg 2017;143:691–9. 6. Wang SJ, Patel SG, Shah JP, et al. An oral cavity carcinoma nomogram to predict benefit of adjuvant radiotherapy. JAMA Otolaryngol Head Neck Surg 2013;139:554–9. 7. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. N Engl J Med 2004;350:1937–44. 8. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 2004;350:1945–52. 9. Bernier J, Cooper JS, Pajak TF, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (22931) and RTOG (9501). Head Neck 2005;27:843–50. 10. Cooper JS, Zhang Q, Pajak TF, et al. Long-term follow-up of the RTOG 9501/intergroup phase III trial: postoperative concurrent radiation therapy and chemotherapy in high-risk squamous cell carcinoma of the head and neck. Int J Radiat Oncol Biol Phys 2012;84:1198–205. 11. Shrime MG, Gullane PJ, Dawson L, et al. The impact of adjuvant radiotherapy on survival in T1-2N1 squamous cell carcinoma of the oral cavity. Arch Otolaryngol Head Neck Surg 2010;136:225–8. 12. Barry CP, Wong D, Clark JR, et al. Postoperative radiotherapy for patients with oral squamous cell carcinoma with intermediate risk of recurrence: a case match study. Head Neck 2017;39:1399–404. 13. Moergel M, Jahn-Eimermacher A, Krummenauer F, et al. Effectiveness of adjuvant radiotherapy in patients with oropharyngeal and floor of mouth squamous cell carcinoma and concomitant histological verification of singular ipsilateral cervical lymph node metastasis (pN1-state) – a prospective multicenter randomized controlled clinical trial using a comprehensive cohort design. Trials 2009;10:118.