HPV OROPHARYNGEAL CANCER 

Deintensification of chemotherapy might not be the best option for all patients with oropharyngeal cancer whose disease is associated with human papillomavirus (HPV).

However, such an approach might be reasonable for patients with a low risk for distant recurrence; namely, those with less advanced disease and limited exposure to smoking, according to a large retrospective institutional study conducted by Brian O'Sullivan, MD, from the Princess Margaret Hospital in Toronto, Ontario, Canada, and colleagues.

The study was published in the February 10 issue of theJournal of Clinical Oncology.

The findings "provocatively suggest there is a limit to the favorable biology of HPV-associated OPSCC [oropharyngeal squamous cell carcinoma]," write Harry Quon, MD, and Arlene Forastiere, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, Maryland, in an accompanying editorial.

"It could be that today's treatment paradigms result in the overtreatment of many patients (and the consequent late effects on swallowing function) and undertreatment of a smaller subset," they add.

There is growing concern among OPSCC experts about patients' risks for radiation-related morbidity, particularly severe late swallowing complications, Dr. Forastiere told Medscape Medical News.

"The potential for this damage is increased when chemotherapy is added to the radiation," she explained. "One simple strategy is to drop the chemotherapy from the treatment of those with a low risk for recurrence of tumor in the oropharynx or the regional lymph nodes in the neck."

However, she pointed out that Dr. O'Sullivan and colleagues "have refined this 'risk definition' by focusing not just on local failure, but also on predictors of distant failure.... As we consider strategies to deintensify treatment, we do not want to alter chemotherapy in those at increased risk for metastatic disease."

The researchers examined 505 patients with OPSCC (382 HPV-positive and 123 HPV-negative) who were treated from 2001 to 2009 with either radiotherapy (RT) alone or chemoradiotherapy (CRT). Median follow-up was 3.9 years.

In the 2 HPV groups, they compared overall survival; recurrence-free survival; local, regional, and distant control; and late toxicity.

HPV status, age, sex, tumor and node categories, smoking and alcohol consumption, and treatment modality were used in the univariate and multivariate analyses to identify predictors of outcomes.

More Favorable Outcomes, But Only for Some

As expected, HPV-positive patients had more favorable 3-year outcomes than HPV-negative patients. This included better overall survival (83% vs 49%), better recurrence-free survival (84% vs 64%), and significantly higher rates of local control (94% vs 80%; P < .01) and regional control (95% vs 82%; P < .01).

Distant control rates were similar in the HPV-positive and HPV-negative groups (90% vs 86%; P = .53), but the temporal pattern of distant relapse was different. "The HPV-positive curve continued to decline for up to 5 years, in contrast to the relatively stable HPV-negative curve beyond 2 years," the researchers report.

Because distant metastasis "remains the predominant pattern of failure," deintensification "might best be deployed in subgroups least likely to develop [distant metastasis]," they note.

Using recursive partitioning analysis to identify such subgroups, the researchers found that advanced-stage disease significantly increased the risk for distant metastasis in all patients.

In HPV-positive patients, those with stages T1–3 and N0–2c disease were classified as low risk (a 3-year distant control rate of 93%), and those with stages T4 and N3 disease were classified as high risk (a 3-year distant control rate of 76%).

However, even in the low-risk HPV-positive group, there was a subgroup of patients for whom deintensified treatment (RT alone) produced worse outcomes than chemoradiotherapy (CRT).

Two subgroups of patients had worse distant control when treated with RT alone (n = 150) than when treated with CRT (n = 136): those with stage N2b disease (89% vs 98%; P = .03); and those with N2c disease (73% vs 92%; P = .02).

In the RT-treated N2b subgroup, the risk increased with heavy smoking (at least 10 pack-years); distant control rate was 84%.

"It seems prudent to exclude N2c disease from deintensification strategies that do not include conventional chemotherapy," the researchers suggest. They add that reducing the intensity of or omitting chemotherapy might also be unsuitable for N2b heavy smokers.

However, HPV-positive patients with T1–3 and N0–2a disease and patients with N2b disease who are heavy smokers have minimal risk for distant metastasis, irrespective of treatment approaches. In such subgroups, deintensification might be optimal, they conclude.

"Overall survival can be misleading because it includes deaths from causes unrelated to the cancer," Dr. Forastiere told Medscape Medical News. "Individuals with non-HPV-associated cancers have comorbid conditions as a result of tobacco and alcohol use," she said. On that basis alone, we would expect them to have worse survival. Using disease-specific survival allows for a comparison of "apples to apples," she explained.

The editorialists emphasize that, given current knowledge, treatment of HPV-associated locoregionally advanced cancers with anything less than the standard full doses of radiotherapy and concurrent cisplatin should only occur in the context of a clinical trial."

The study authors and the editorialists have disclosed no relevant financial relationships.

J Clin Oncol. 2013;31:543-550, 520-522. Abstract, Editorial