Elsevier

The Lancet Oncology

Volume 17, Issue 4, April 2016, Pages 440-451
The Lancet Oncology

Articles
Development and validation of a staging system for HPV-related oropharyngeal cancer by the International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S): a multicentre cohort study

https://doi.org/10.1016/S1470-2045(15)00560-4Get rights and content

Summary

Background

Human papillomavirus-related (HPV+) oropharyngeal cancer is a rapidly emerging disease with generally good prognosis. Many prognostic algorithms for oropharyngeal cancer incorporate HPV status as a stratification factor, rather than recognising the uniqueness of HPV+ disease. The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) aimed to develop a TNM classification specific to HPV+ oropharyngeal cancer.

Methods

The ICON-S study included patients with non-metastatic oropharyngeal cancer from seven cancer centres located across Europe and North America; one centre comprised the training cohort and six formed the validation cohorts. We ascertained patients' HPV status with p16 staining or in-situ hybridisation. We compared overall survival at 5 years between training and validation cohorts according to 7th edition TNM classifications and HPV status. We used recursive partitioning analysis (RPA) and adjusted hazard ratio (AHR) modelling methods to derive new staging classifications for HPV+ oropharyngeal cancer. Recent hypotheses concerning the effect of lower neck lymph nodes and number of lymph nodes were also investigated in an exploratory training cohort to assess relevance within the ICON-S classification.

Findings

Of 1907 patients with HPV+ oropharyngeal cancer, 661 (35%) were recruited at the training centre and 1246 (65%) were enrolled at the validation centres. 5-year overall survival was similar for 7th edition TNM stage I, II, III, and IVA (respectively; 88% [95% CI 74–100]; 82% [71–95]; 84% [79–89]; and 81% [79–83]; global p=0·25) but was lower for stage IVB (60% [53–68]; p<0·0001). 5-year overall survival did not differ among N0 (80% [95% CI 73–87]), N1–N2a (87% [83–90]), and N2b (83% [80–86]) subsets, but was significantly lower for those with N3 disease (59% [51–69]; p<0·0001). Stage classifications derived by RPA and AHR models were ranked according to survival performance, and AHR-New was ranked first, followed by AHR-Orig, RPA, and 7th edition TNM. AHR-New was selected as the proposed ICON-S stage classification. Because 5-year overall survival was similar for patients classed as T4a and T4b, T4 is no longer subdivided in the re-termed ICON-S T categories. Since 5-year overall survival was similar among N1, N2a, and N2b, we re-termed the 7th edition N categories as follows: ICON-S N0, no lymph nodes; ICON-S N1, ipsilateral lymph nodes; ICON-S N2, bilateral or contralateral lymph nodes; and ICON-S N3, lymph nodes larger than 6 cm. This resembles the N classification of nasopharyngeal carcinoma but without a lower neck lymph node variable. The proposed ICON-S classification is stage I (T1–T2N0–N1), stage II (T1–T2N2 or T3N0–N2), and stage III (T4 or N3). Metastatic disease (M1) is classified as ICON-S stage IV. In an exploratory training cohort (n=702), lower lymph node neck involvement had a significant effect on survival in ICON-S stage III but had no effect in ICON-S stage I and II and was not significant as an independent factor. Overall survival was similar for patients with fewer than five lymph nodes and those with five or more lymph nodes, within all ICON-S stages.

Interpretation

Our proposed ICON-S staging system for HPV+ oropharyngeal cancer is suitable for the 8th edition of the Union for International Cancer Control/American Joint Committee on Cancer TNM classification. Future work is needed to ascertain whether T and N categories should be further refined and whether non-anatomical factors might augment the full classification.

Funding

None.

Introduction

Human papillomavirus-related (HPV+) oropharyngeal cancer is a rapidly emerging disease in many countries that differs from tobacco-related and alcohol-related (HPV–) oropharyngeal cancer. Both diseases share similar histological features, arise from the oropharynx, and use the 7th edition Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) TNM staging system, but patients with HPV+ oropharyngeal cancer have remarkably higher overall survival than do those with HPV– disease.1, 2 In fact, most patients with HPV+ oropharyngeal cancer at a numerically advanced stage do not experience the same poor outcome as do those with HPV– disease. For example, fewer than 50% of patients with stage IV HPV– oropharyngeal cancer will be alive at 5 years compared with more than 70% with HPV+ disease.1 This disparity in overall survival affects clinical trial design and outcomes research and interferes with clinical decision making, because prognosis is not reflected by the 7th edition TNM staging system.2, 3

Research in context

Evidence before this study

Human papillomavirus-related (HPV+) oropharyngeal cancer is a rapidly emerging disease with generally good prognosis. To date, most prognostic algorithms for oropharyngeal cancer incorporate HPV status as a stratification factor, rather than recognising the uniqueness of HPV+ disease, which affects a disparate population of patients and is anticipated to require different treatments. Opinions have converged on the principle that a novel staging system is needed urgently to properly depict the character and prognosis of HPV+ disease, which contrasts with smoking-related (ie, HPV-unrelated [HPV–]) oropharyngeal cancer, from which the 7th edition of the Union for International Cancer Control/American Joint Committee on Cancer (UICC/AJCC) TNM classification was derived. A challenge in developing a new TNM classification is to obtain an adequate study sample covering the full disease spectrum (including early to advanced stages). Most trials in head and neck cancer have, in general, addressed locally advanced disease only, and trials specific to oropharyngeal cancer are scarce. Trials also lack HPV-specific data, as do administrative and registry data sources.

Added value of this study

The International Collaboration on Oropharyngeal cancer Network for Staging (ICON-S) study represents an international effort to develop a pretreatment TNM clinical staging classification for HPV+ oropharyngeal cancer. The ICON-S study included almost 2000 patients with HPV+ oropharyngeal cancer from seven institutions across Europe and North America. Heterogeneity tests showed that hazard ratios for stage III versus II disease, and for stage II versus I disease, were in the same direction (>1·0 for higher stages) across all institutions, which supports applicability of the ICON-S classification across various patient populations.

Implications of all the available evidence

At the present time, most patients with HPV+ oropharyngeal cancer are told they have stage IV disease, but the reality is that their outlook is similar to that of patients with the most curable malignant diseases. This situation is alarming for many patients when first faced with their diagnosis and might perpetuate the idea that traditional intensified treatments are always needed—a notion that is being challenged. The proposed ICON-S classification for HPV+ oropharyngeal cancer permits a more appropriate depiction of prognosis of HPV+ disease than is available with the 7th edition of the UICC/AJCC TNM classification. Moreover, the ICON-S classification will enhance stratification into more appropriate groups to both facilitate translational research and optimise clinical trial design and outcome reporting.

A novel clinical staging system based on a single-centre dataset has been proposed for HPV+ oropharyngeal cancer.1 Favourable outcomes led to all disease classified as 7th edition TNM stage III and most disease categorised as stage IVA (T1–T3N0–N2c) to be amended to earlier disease stages. Whether this classification is generalisable across different geographic jurisdictions needs validation. Therefore, we aimed to do a multicentre study (International Collaboration on Oropharyngeal cancer Network for Staging [ICON-S]), expanding on data from the initial single centre,1 to construct a validated clinical TNM classification for HPV+ oropharyngeal cancer applicable before any treatment—eg, surgery, radiotherapy, or chemotherapy.

Section snippets

Patients

We did the ICON-S study in an expanded population from the initial single centre (Princess Margaret Cancer Centre, University of Toronto),1 with additional cohorts from four North American cancer centres (M D Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Cleveland Clinic Taussig Cancer Institute, and University of Colorado Cancer Center) and two European centres (Rigshospitalet, Copenhagen University Hospital, and Maastricht University Medical Centre). We chose these centres

Results

Between 1998–2007 and 2011, 3998 consecutive patients with oropharyngeal cancer were identified at the participating centres (recruitment start dates differed by centre and are shown in the appendix p 1). HPV status could be ascertained in 2603 (65%) patients, including 1907 with HPV+ disease and 696 with HPV– disease (appendix p 1). Patients' characteristics are shown in table 1. Primary radiotherapy with or without chemotherapy was used in 2553 (98%) patients, with the remainder receiving

Discussion

The findings of the multicentre ICON-S have created a new, validated clinical staging system for HPV+ oropharyngeal cancer to be proposed for the 8th edition UICC/AJCC TNM classification. The current 7th edition TNM stage system is inadequate for HPV+ oropharyngeal cancer to depict prognosis, although it is acceptable for HPV– disease. Therefore, a new clinical staging system is necessary and feasible for HPV+ oropharyngeal cancer. Our results, showing similar overall survival for N1–N2b and

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