Zosia Chustecka

October 19, 2015

SAN ANTONIO ― Since the realization over the last 5 to 10 years that there is a distinct type of oropharyngeal squamous cell carcinoma related to human papilloma virus (HPV) that occurs in much younger patients and is associated with a better prognosis than non-HPV-related disease, there has been speculation and hope that treatment for these patients could be deintensified, with the big bonus of reducing toxicity.

Now there is mounting data showing that deintesification of treatment is feasible and that it does indeed appear to reduce adverse effects without compromising survival, commented Ezra Cohen, MD, from the University of San Diego Moores Cancer Center, in California. He was discussing the issue here at an interactive session at the American Society for Radiation Oncology (ASTRO) 57th Annual Meeting, and said, "We have entered an era of deintesification of treatment."

These HPV-related oropharyngeal cancers are "inherently curable," commented Dr Cohen. Current chemoradiotherapy regimens achieve a cure in 80% to 90% of patients with early-stage cancers, he noted, but these regimens can adversely affect swallowing, sometimes leaving patients with permanent feeding tubes.

Patients presenting with these HPV cancers are much younger, at age 25 to 55 years, than those typically seen with oral cancers. These patients will be living with the adverse effects of treatment for many years, and it has become increasingly important to ensure good quality of life after treatment, Dr Cohen said.

A new phase 2 trial presented at the meeting used a reduced dose of both radiation and chemotherapy and showed comparable efficacy and less toxicity than would be expected with the standard doses. In particular, swallowing did not appear to be affected, noted the lead author, Bhishamjit Chera, MD, associate professor of radiation oncology at the University of North Carolina School of Medicine, in Chapel Hill.

"Our study provides strong preliminary evidence that reduced-intensity chemoradiotherapy may be as effective as standard-dose chemoradiotherapy," Dr Chera concluded.

The new trial was conducted in 43 patients with favorable-risk HPV-associated oropharyngeal squamous cell carcinoma who had a minimal history of smoking.

The current standard of care for such patients is chemoradiation with 70 Gy of radiation delivered over 7 weeks, in conjunction with a high dose (100 mg/m2) of cisplatin for three cycles, Dr Chera explained. Although this standard chemoradiotherapy protocol results in excellent cancer control and survival, it produces substantial adverse side effects, such as chronic, acute difficulties in talking or swallowing, which may necessitate a feeding tube, as well as dry mouth, painful inflammation of the mucous membranes and/or digestive tract, tooth decay, and jawbone osteonecrosis.

In the new trial, radiation was reduced by 16%, with 60 Gy delivered over 6 weeks; the chemotherapy dose was reduced by 40% overall, with low doses (30 mg/m2) of cisplatin given in six weekly doses, Dr Chera said.

After patients completed chemoradiotherapy, biopsies of the tumor sites were performed, and any lymph node regions that were originally cancer positive were removed in order to determine the treatment's efficacy. Dr Chera explained that the decision was made to look at pathologic complete response instead of the usual radiologic complete response, because there are concerns about whether the less intense treatment is as effective as standard treatment with regard to tumor control.

The results show that of the 43 patients studied, 37 (86%) had no residual invasive tumor and no residual lymph node metastasis.

In the remaining six patients, the cancer was microscopic.

The median follow-up was 21 months (range, 4-41 months), and most patients (86%) were followed for at least a year. There has been no evidence of cancer recurrence, and all patients are still alive.

Symptoms and quality of life were evaluated using two patient-reported questionnaires ― the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire.

In addition, patients underwent barium swallow studies.

The pooled results from the patient-reported questionnaires showed that dry mouth was the most troubling symptom, rated as severe in the 6- to 8-weeks period after treatment. That rating was reduced to moderate at 1 year after treatment. Appetite was affected moderately in the 6 to 8 weeks after treatment but returned to baseline levels, and patients reported that swallowing was affected only mildly both at 6 to 8 weeks after treatment and 1 year later. Patients said that their swallowing had almost returned to normal; these results of these reports from the patients were supported by the results of barium swallow tests, Dr Chera commented, which showed that there was very little effect on swallowing.

In this trial with deintensified chemoradiation, only 39% of patients needed a feeding tube. None of the feeding tubes were required permanently.

This is quite a contrast to what has been seen historically with standard chemoradiation, in which the need for feeding tubes has been reported in up to 80% of patients; in around 10% of patients, feeding tubes are needed on a permanent basis.

Dr Chera emphasized that the results are preliminary, but he was enthusiastic about the findings so far. "With further study, this regimen may become the new standard of care for carefully selected patients with HPV-associated squamous cell carcinoma of the oropharynx. The results so far are certainly encouraging, and with longer follow-ups, we hope to confirm less long-term side effects as well," he said in a statement.

Dr Chera cautioned that at present, reduced-intensity treatment should only be given to patients who are enrolled in carefully controlled clinical trials.

This sentiment was reflected by comments from the audience of radiation oncologists at the interactive session. Asked whether they would use a deintestification regimen, only 2% replied yes, 5% said sometimes, and 32% said they would do so only within the context of a clinical trial.

At that session, Dr Cohen reviewed two other phase 2 trials, one of which used a reduced dose of radiation. The other, with which he was involved at the University of Chicago, used a reduced volume of radiation. In both trials, the incidence of adverse events was reduced in comparison with historical controls. "These patients appear to be living better lives," he said.

Other phase 2 trials are in progress. The NRG Oncology group is conducting a randomized study (NRG-HN002) comparing radiotherapy alone (60 Gy adminstered over 5 weeks, with six fractions adminstered a week) with chemoradiation (60 Gy in 6 weeks) with cisplatin weekly for 6 weeks.

Whether there will ever be a definitive trial of deintensified therapy vs standard chemoradiation is unclear, Dr Chera commented. He said it would be very difficult to recruit patients into such a trial, because the patients with HPV-related oropharyngeal cancer whom he is seeing are "very savvy" and are already well informed about how reductions in treatment intensity have reduced toxicity. It may be that collecting data from phase 2 trials with more patients and longer follow-ups will be sufficient, he speculated, although he suggested it may be some years yet before there are enough data to warrant a practice change.

American Society for Radiation Oncology (ASTRO) 57th Annual Meeting: Abstract 3. Presented October 18, 2015.


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