乌鸦传媒

SAN DIEGO -- A bold 50% reduction in radiation dose for human papillomavirus (HPV)-positive oropharyngeal cancer led to a dramatic reduction in toxicity with no early drop off in efficacy, according to a preliminary clinical study reported here.

The 80 patients treated with a radiation dose of 30 or 36 Gy had a 2-year locoregional disease control rate of 96.3% and a progression-free survival (PFS) of 91.3%. Both outcomes compared favorably with historical results from patients treated with radiation doses of 60 to 66 Gy.

The reduced-intensity chemoradiation regimen led to a 2-year cumulative incidence of grade ≥2 toxicity of 10%, as compared with historical rates exceeding 50% with standard-dose radiotherapy protocols, a presentation at the meeting indicated.

"No patients required a feeding tube during treatment; swallowing function improved significantly between pre-irradiation and 12-month follow-up, and quality of life remained essentially unchanged between pre- and post-treatment," said Daniel Ma, MD, of the Mayo Clinic in Rochester, Minn.

Research into HPV-related oropharyngeal cancer revealed a genetically and molecularly distinct tumor type as compared with HPV-negative disease, leading many researchers and clinicians to reconsider standard approaches to treatment, said Paul Harari, MD, of the University of Wisconsin in Madison.

"I don't think any of us would have been surprised that this approach would lower the side-effect profile," said Harari, who moderated a press briefing on the study. "When you give 30 to 36 Gray to a head-and-neck cancer patient versus 70 Gray, you are going to see markedly, profoundly diminished side-effect profiles.

"The more intense question ... is can you maintain safely the cure rate. The early look they have provided is quite encouraging. Nevertheless, it is a phase II study that requires validation in a larger phase III cohort in a randomized fashion, which they are pursuing."

Over the past 10 to 12 years, the incidence and prevalence of HPV-related oropharyngeal increased dramatically, outstripping growth rates for most other types of cancer. In the United States, HPV accounts for about 70% of all new cases of oropharyngeal cancer. If current epidemiologic trends continue, HPV infection will account for half of all forms of head and neck cancer by 2030, said Ma.

As compared with HPV-negative oropharyngeal cancer, HPV-positive disease has a favorable prognosis with standard treatment, consisting of 7 weeks of chemoradiation or surgery followed by 6 weeks of adjuvant radiation and/or chemotherapy. Though effective for disease control, standard therapy can cause serious, potentially life-altering adverse events, Ma continued.

The generally favorable prognosis of HPV-related oropharyngeal cancer provided the impetus for exploration of reduced-dose radiation therapy regimens, or therapeutic de-escalation. The challenge of de-escalation is to reduce the toxic effects of standard-dose radiation therapy or chemoradiation without sacrificing disease control.

Rather than evaluate incremental reductions in radiation therapy dose, Ma and colleagues investigated a de-escalation strategy that cut the dose in half, as compared with standard therapy. The bold approach had a precedent in the treatment of HPV-related anal cancer, albeit in combination with potent chemotherapy.

Ma also offered a philosophical argument in favor of the 50% reduction. Reducing the radiation dose to 30 or 36 Gy "paradoxically might be safer than an incremental approach to de-escalation," he said.

The argument rests on the view that a modest incremental reduction in radiation dose -- from 60 Gy to 55 or 50 Gy, for example -- might still cause substantial tissue damage, thereby limiting options for salvage therapy if the lower dose fails to achieve disease control. A more dramatic upfront dose reduction helps preserve higher-dose therapy as a salvage option.

To evaluate the strategy, investigators enrolled 80 patients with HPV-positive oropharyngeal cancer and <10 pack-year history of smoking. All patients underwent margin-clearing surgery and were assigned to two treatment groups.

Patients with stage ≥T3, ≥N2, lymphovascular invasion, or perineural invasion (N=37) received a 30-Gy total dose of radiation therapy plus docetaxel chemotherapy. Patients with extension (N=43) received a 36-Gy radiation dose plus docetaxel.

The trial had a primary endpoint of locoregional disease control 2 years after treatment, and 2-year DFS was a key secondary endpoint. The primary analysis occurred after a median follow-up of 24 months.

Two of the 80 patients had local recurrences, and one had recurrence in lymph nodes, resulting in a 2-year freedom from recurrence of 96.3%. Four additional patients had distant recurrences.

The seven recurrences translated into a 2-year PFS of 91.3%. That compared with a 2-year PFS of 86.4% in a of standard-dose postoperative chemoradiation for high-risk oropharyngeal cancer. Additionally, the standard-dose regimen was associated with a 55% incidence of cumulative grade ≥2 toxicity at 2 years.

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