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Recursive partitioning analysis forms new stages for HPV-related oropharyngeal cancer
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Recursive partitioning analysis-based TNM stage groupings were associated with significantly improved survival prediction for patients with HPV-related non-metastatic oropharyngeal carcinomas, according to study results.
Brian O’Sullivan, MD, of Princess Margaret Hospital in Toronto, and colleagues evaluated data from patients with HPV-related (n = 573) and HPV-unrelated (n = 237) non-metastatic oropharyngeal cancer. Patients underwent radiation therapy with or without chemotherapy between 2000 and 2010.
Median follow-up was 5.1 years.
Researchers compared patient survival data with their American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) seventh edition TNM stage.
Survival was significantly associated with TNM stage for patients with HPV-unrelated disease. Five-year OS rates were 70% for patients with stage I disease, 58% for those with stage II disease, 50% for those with stage III disease and 30% for those with stage IV disease (P = .004).
However, 5-year OS did not significantly differ according to TNM stage among patients with HPV-related oropharyngeal cancer (stage I, 88%; stage II, 78%; stage III, 71%; stage IV, 74%).
Using a recursive partitioning analysis, researchers refined AJCC/UICC staging for patients with HPV-related disease into RPA-I (T1-3N0-2b), RPA-II (T1-3N2c) and RPA-III (T4 or N3) stages. RPA-IV would include patients with M1 or metastatic disease.
Patients with RPA-1 disease demonstrated the highest rate of 5-year OS (82%), followed by patients with RPA-II disease (76%) and RPA-III disease (54%; P ˂ .001).
Researchers also developed new staging criteria using adjusted HRs. Although these stages were significantly associated with 5-year OS (P ˂ .01), the survival prediction was greater with the RPA stages.
An RPA that also included RPA stage, patient age and smoking pack-years further improved survival prediction. These stages include group 1 for patients with 20 or fewer pack-years (T1-3N0-N2c), group II for patients with more than 20 pack-years (T1-3N0-N2c), group III for patients aged 70 years or younger (T4 or N3), and group IVA for patients aged older than 70 years (T4 or N3). Five-year OS was significantly associated with these staging groups (group I, 89%; group II, 64%; group III, 57%; group IV, 40%; P ˂ .001).
“This large cohort study suggests that the seventh edition AJCC/UICC TNM staging system is unsuited for HPV-related oropharyngeal cancer but acceptable for HPV-unrelated disease,” O’Sullivan and colleagues concluded. “An RPA-based TNM stage schema is proposed for HPV-related oropharyngeal cancer … Prognostic risk groupings incorporating non-anatomic factors provide additional enhancement.”
These findings may lead to the formal revision of head and neck squamous carcinoma staging criteria, David M. Brizel, MD, of Duke Cancer Institute, wrote in an invited commentary.
“Clearly, the findings of Huang [and colleagues] need to be confirmed and refined both by other institutions and through analysis of larger multicenter and national databases such as SEER,” Brizel wrote. “That said, the AJCC is currently reviewing and revising its head and neck squamous carcinoma staging criteria. The revisions proposed by Huang [and colleagues] offer a first step in the way forward with the potential to identify patients with HPV-positive disease and an unfavorable prognosis via the integration of disease- and patient-specific factors. This process would allow us to more effectively choose treatment for our patients, both in the context of routine care and clinical trials.” – by Alexandra Todak
Disclosure: The researchers report consulting/advisory roles with, research funding from and travel expenses from Elekta. Brizel reports a consulting/advisory role with Pfizer and honoraria from UpToDate Oncology.
Perspective
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David J. Adelstein, MD
Tumor staging is one of the most important tools available to the oncologist. It serves to define and standardize treatment, inform prognosis, evaluate outcomes and facilitate communication. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging system is an anatomic one, meant to describe tumor extent. T, N and M descriptors for each disease have been defined and stage groupings constructed. The prognostic importance of this anatomic staging is clear, just as it is clear that there are other, perhaps even more important prognosticators. These include patient demographics like age and race, tumor characteristics such as hormone receptors and molecular markers, and patient lifestyle choices like smoking.
TNM staging for non-nasopharyngeal squamous cell head and neck cancers has changed little over time and, until recently, has performed well. The recent recognition of the etiologic and prognostic importance of HPV in oropharynx cancer, however, has led to new questions about the value of staging. Patients with HPV-related oropharynx cancer have very different demographic profiles, are often non-smokers, and have a well-demonstrated improved prognosis. Several researchers have suggested that in HPV-related disease, the current AJCC TNM-based anatomic stage grouping is no longer able to provide any prognostically or therapeutically useful discrimination.
Huang and colleagues have reviewed their 10-year experience with oropharynx cancer at Princess Margaret Hospital in Toronto. Although AJCC staging performed well in those patients with HPV-unrelated disease, there was little difference in OS by stage in the patients with HPV-related cancers. Using recursive partitioning analysis (RPA), the authors then define new TNM stage groupings for the HPV-related tumors. These RPA-defined stage groupings differ considerably from the AJCC groupings, and appear to be far more successful in identifying stage-based outcome differences. The authors suggest that the HPV-related and unrelated oropharynx cancers will require different staging, with two distinct sets of TNM-based stage groupings, and that the current seventh edition of the AJCC staging system needs revision. Recent clinical trials have already made this transition, by separately approaching the study of these two diseases, and by defining patient eligibility using different TNM stage groupings than the AJCC. The authors further suggest combining the prognostically important non-anatomic factors of age, and smoking history, with this revised RPA TNM stage grouping to produce even more clinically useful “prognostic groups” for patients with HPV-related oropharynx cancers.
This work adds further support to the current consensus that HPV-related and HPV-unrelated oropharynx cancers are not the same disease, and that they should be staged, investigated and possibly treated differently. These authors, the RTOG and others have successfully merged anatomic and non-anatomic factors in developing useful prognostic models for HPV-related oropharynx cancer. Anatomic stage will remain an important component of the prognostic groups we define and, as the authors demonstrate, it can and should have independent validity.
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