One of the long-term debates in the head and neck cancer community is whether chemotherapy provides greater benefit when administered in the induction setting or concomitantly with radiation therapy. For some time, the discussion fell along party lines, so to speak: Radiation oncologists cited randomized trial data demonstrating that induction chemotherapy was not more effective than chemotherapy given along with radiation treatment and that what benefits there were did not outweigh the toxicities. On the other hand, medical oncologists cited preliminary data comparing one regimen of induction chemotherapy to another and inferring a survival advantage.
JONATHAN J. BEITLER, MD, MBA
At an American Society of Clinical Oncology (ASCO) 2010 education session, Jonathan J. Beitler, MD, MBA, highlighted current thinking on the role of induction therapy in head and neck cancer from the radiation oncology standpoint: Results from numerous clinical trials have reshaped the radiation oncology perspective on the role of chemotherapy in locally advanced squamous cell cancer of the head and neck. Dr. Beitler is a professor of radiation oncology, otolaryngology and hematology and medical oncology at Emory University in Atlanta.
Dr. Beitler's presentation started with an overview of radiation oncology in head and neck cancer patients, including fractionation. One of the seminal studies in head and neck radiation therapy was a Radiation Therapy Oncology Group trial (9003) that tested the efficacy of hyperfractionation and two types of accelerated fractionation against standard fractionation (Int J Radiat Oncol Biol Phys 48:7-16, 2000).
Human papillomavirus status is one of four factors that influence a head and neck cancer patient's survival chances. Investigators at Houston's M.D. Anderson Cancer Center and other institutions performed a retrospective analysis of the association between tumor HPV status and survival among 323 patients with stage III or IV oropharyngeal squamous cell carcinoma enrolled in the RTOG 0129 trial.
The authors found the three-year overall survival rate was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy. The median follow-up period was 4.8 years.
A total of 63.8% of patients with oropharyngeal cancer had HPV-positive tumors and these patients had better three-year overall survival rates (82.4%, vs 57.1% for patients with HPV-negative tumors; P < .001), the authors reported. Pack-years of tobacco smoking, tumor stage, and nodal stage also played a part in the level of risk (N Engl J Med 363:24-35, 2010).
"RTOG 9003 was the best radiobiology ever done. Compared with standard fractionation, hyperfractionation improved local control," he explained.
Another study, out of Yugoslavia, assessed whether the addition of cisplatin-based chemotherapy to hyperfractionation radiation therapy offered an advantage over hyperfractionation radiation alone in locally advanced stage III and IV squamous cell carcinoma of the head and neck. In another study, RTOG 9111, patients with laryngeal cancer benefited from radiotherapy with concurrent administration of cisplatin vs induction chemotherapy followed by radiotherapy or radiotherapy alone (J Clin Oncol 18:1458-1464, 2000; N Engl J Med 349:2091-2098, 2003).
In both studies, local control was improved, but the addition of chemotherapy brought very little change in the rate of distant metastases. "My first conclusion is that distant metastases are relatively unchanged, and that concurrent chemotherapy is working as a radiation sensitizer. That's what is increasing our local control," Dr. Beitler said, adding that his conclusion is backed up by a meta-analysis of RTOG 9111 and other major trials (Radiother Oncol 92:4-14, 2009).
This trend continued in subsequent studies, such as RTOG 9914, which looked at the feasibility of combining a concomitant boost-accelerated radiation regimen with cisplatin. While the combination was 95% successful at local control, there was still a 20% distant metastases rate and a 17% rate of the gastrostomy tube still being in place at four years. The increased toxicity of this treatment approach was confirmed in a meta-analysis of late toxicity (Int J Radiat Oncol Biol Phys 71:1351-1355, 2008; J Clin Oncol 26:3582-3589, 2008).
"So if conclusion number two is that concurrent chemotherapy adds toxicity, is the chemotherapy worth the increased toxicity?" Dr. Beitler asked. The answer is "yes," because the addition of chemotherapy allows for a radiation dose escalation.