RTOG® Takes on Head and Neck Cancer
Researchers investigate how radiation therapy affects human papillomavirus-related cancer.
The discovery of human papillomavirus (HPV)-associated head and neck cancer has prompted researchers to explore treatment options specific to a patient's HPV status. The Radiation Therapy Oncology Group® (RTOG®) is conducting two trials based on this new etiology and prognostic factor.
RTOG 1016, Phase-III Trial of Radiotherapy Plus Cetuximab Versus Chemoradiotherapy in HPV-Associated Oropharynx Cancer, is the first RTOG study of a biomarker-selected population of patients with head and neck cancer. Activated in June 2011, 700 study participants will be randomized to receive either radiation therapy (RT) and cisplatin chemotherapy (the trial's standard of care arm) or RT plus cetuximab chemotherapy (the experimental arm). The trial's major rationale is that it has been firmly established that a significantly better survival is seen in patients whose head and neck cancer is determined to be HPV-positive. "We believe that toxicity can be lowered with essentially equally high survival using a targeted agent as an alternative to the highly toxic cisplatin standard of care," explains Andy M. Trotti III, M.D., director of radiation oncology clinical research at H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla., and the trial's co-principal investigator. RTOG 1016 is the first RTOG head and neck cancer noninferiority trial as investigators are expecting a study participant survival rate at three years post treatment for the cetuximab arm of 85 percent — roughly equal to that for participants in the cisplatin arm. "Because more young patients have HPV-positive cancer, the focus is now on reducing the toxicity and morbidity of therapy that patients may be dealing with for 20 to 30 years," reflects Maura L. Gillison, M.D., Ph.D., professor at the College of Medicine at Ohio State University in Columbus, Ohio, co-principal investigator with Trotti. The trial also includes patient-completed quality of life (QOL) surveys, which are designed to give patients a direct voice through reporting their experience during treatment and up to two years following treatment. "Head and neck cancer advocacy organizations have reported that physicians don't accurately measure or deal with their toxicity experiences," explains Gillison. "At the same time, research has demonstrated that care providers underestimate the impact of treatment on patient QOL." To discover the effects on the patients' QOL, the surveys will gather data regarding the treatment's effects on swallowing and hearing as well as work status.
Investigators initially anticipated that sites would experience challenges collecting data for this comprehensive study because it involves 16 objectives, 17 investigators, and a multitude of QOL research aims. Fortunately, another innovative aspect of this trial is that patients and data managers enter data on Apple iPad tables, donated by the Oral Cancer Foundation. An iPad software application developed by Gillison's group at OSU has enabled the trial to effectively surmount issues with extensive data collection. "The iPad platform works quickly and keeps data secure over the Web until they are all downloaded simultaneously to RTOG headquarters," explains Trotti. "The age group targeted by the trial, 45-65 years old with a median of 53 years, is familiar with iPad technology."
The importance of this first prospective trial has gained recognition since the trial's development. As Gillison explains, "the literature regarding whether patients with HPV disease do better or worse with cetuximab than with cisplatin is very confusing, with the recently presented preliminary conference data in favor of cisplatin," clarifies Gillison. "The desire of researchers for a definitive answer to this question seems to be fueling the trial's high accrual rate." Within the first six months of trial activation, 10 percent of study participants had been enrolled and according to Trotti, "We are currently enrolling study participants at a rate of 12 to 15 patients per month, which surpasses our expectations." In addition to its success in enrolling patients, RTOG 1016 has incorporated many layers of scientific questions and data, including molecular markers, tissue banking, and epidemiologic hypotheses about tobacco and other risk factors. "We will be gathering data and reporting results about this whole new type of cancer for years to come," summarizes Trotti.
“Unlike thyroid, renal, and hepatocellular cancers, for which the discovery of many small molecules led to the development of effective drugs, no such breakthroughs have transpired in head and neck cancer.” — Stuart J. Wong, M.D.
RTOG Foundation Supports Study for HPV-Negative Disease
In addition to the RTOG 1016 trial, another head and neck research project is taking place — RTOG Foundation Study 3501. The trial design follows a trend away from basing treatment on anatomical factors such as lesion size or the number of lymph nodes and toward identifying individual biologic, prognostic, and risk factors to tailor treatment to the patient's disease.
Carried out at 20 centers across North America, 176 study participants whose head and neck cancer is not associated with HPV disease — which accounts for the majority of diagnosed head and neck cancer — will be randomized to one of two arms: concurrent RT and cisplatin chemotherapy followed by a placebo or to the same regimen following by the investigative drug lapatinib. "In this trial, we focus on improving results for the larger population of head and neck cancer patients without HPV disease who have a much poorer prognosis," says radiation oncology co-principal investigator George Shenouda, M.D., from the Department of Oncology, Division of Radiation Oncology, at the McGill University Health Centre, in Montreal, Canada.
Principal Investigator Stuart J. Wong, M.D., associate professor of medicine and otolaryngology, at the Medical College of Wisconsin, in Milwaukee, expands on the purpose of the trial, "The field of head and neck cancer has not progressed as far as we had hoped since the introduction of cetuximab. Unlike thyroid, renal, and hepatocellular cancers, for which the discovery of many small molecules led to the development of effective drugs, no such breakthroughs have transpired in head and neck cancer."
The study incorporates state-of-the-art RT techniques and equipment, as well as optimum verification and planning systems for the specific patient population, with the supplemental goal of reducing toxicity on normal head and neck tissues, like the salivary gland and maximizing organ preservation. "Maintaining a smaller margin of security around the tumor is possible only using intensity-modulated radiation therapy (IMRT)," explains Shenouda.
Investigators will also assess for any increased toxicities resulting from the potential interaction between the RT/cisplatin and lapatinib. As Wong clarifies, "Although lapatinib is well documented to be safe and well-tolerated in breast cancer, the real question is how it works when added to RT and chemotherapy. Previous findings from a small study assessing this combination showed that patients receiving lapatinib tolerated it well and did not have significantly different side effects from those receiving RT and chemotherapy alone." The current study focuses on QOL from the patient perspective more than on the usual physician- or nurse-observed toxicities.
Progression-free survival (PFS) at two years, the time period in which 80 percent of head and neck cancer recurrence occurs, will be compared in the study's two arms. If this phase-II study results in better PFS in the lapatinib arm, it may justify the increased sample size, longer follow-up, and additional cost associated with a phase-III study of overall survival. Lapatinib might play a major role in shaping the treatment of this disease.
By Nancy Fredericks, M.B.A., and Julie Catagnus, M.P.H., E.L.S.
Julie Catagnus, M.S.W., E.L.S., is a freelance writer.