The recognition that a subset of oropharynx cancers arise because of transforming human papillomavirus (HPV) infection was followed by evidence that not only did these cancers have a different epidemiology from the historically more prevalent tobacco-associated head and neck cancers, but they also had strikingly different biology, natural history, treatment responsiveness, and prognosis.
Treatment paradigms in head and neck cancer have intensified substantially over previous decades, with increased use of multimodality therapy, longer durations of therapy, multidrug regimens, and accelerated radiation fractionation schemes, with an attendant cost in acute and long-term toxicity.
The long-term follow-up of the Intergroup Radiation Therapy Oncology Group study that focused on larynx preservation , INT91-11, suggested the possibility that late toxicity could result in increased late non-cancer mortality for patients receiving concurrent chemoradiation.1
Thus, the growing population of patients with treatment responsive, HPV-associated oropharynx may be unnecessarily exposed to increased morbidity and mortality from treatment approaches that evolved to treat a different cancer.
The Eastern Cooperative Oncology Group (ECOG) conducted a trial to investigate whether treatment deintensification was feasible and achieved high rates of disease control in patients with HPV-associated cancer.2
We hypothesized that response to induction chemotherapy would act as a dynamic biomarker of treatment responsiveness, and predict patients who would achieve cure with reduced dose radiation.
Barbara Burtness, MD
Given our prediction of increased radiation responsiveness, as well as the fact that the response to induction chemotherapy would leave patients with a tumor burden closer to that in the adjuvant setting than in the historical definitive population, radiation for patients with clinical complete response after induction chemotherapy was reduced to 54 Gy.
Additionally, concurrent therapy was cetuximab rather than cisplatin in a further effort to minimize long-term complications. Eligible patients had resectable stage 3/4a,b oropharynx cancer with evidence of HPV-association on p16 staining or HPV in situ hybridization. Q 3 week induction was paclitaxel 90 mg/m2 days 1, 8, 15; cisplatin 75 mg/m2 day 1; and standard cetuximab.
Ninety patients were enrolled and 80 were able to be analyzed. After 2 year median follow-up for the patients with reduced radiation dose, progression-free survival was 84%, primary site local control was 94%, and overall survival was 95%.
These outcomes were superior to those in the full dose radiation dose arm of the trial. Of interest, among non-smokers who did not have T4 cancer and received reduced dose radiation therapy resulted in progression-free survival and overall survival rate of 96% at 2 years.
We concluded that future trials of treatment-deintensification should focus on patients with low lifetime tobacco exposure and those with T-T3 disease.
Prior to embarking on a phase 3 trial to determine whether this approach is equivalent or superior to the current standard of care with radiation and cisplatin, our group plans to study whether the radiation field to the neck can be reduced in volume and whether an alternate, shorter induction regimen is equally effective at selecting patients who are good candidates for 54 Gy radiation.
- Forastiere AA, Zhang Q, Weber RS, et al. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013;31(7):845-852.
- Cmelak A, Li S, Marur S, et al. E1308: Reduced-dose IMRT in human papilloma virus (HPV)-associated resectable oropharyngeal squamous carcinomas (OPSCC) after clinical complete response (cCR) to induction chemotherapy (IC). J Clin Oncol. 2014;32(5s): abstract LBA6006.