Studies Highlight Complexities of Treating Advanced Head and Neck Cancer
In a large randomized European clinical trial, accelerated radiation therapy for locally advanced, inoperable head and neck cancer—given either with or without chemotherapy—did not prolong the time to disease progression compared with standard radiation therapy plus concurrent chemotherapy (chemoradiotherapy), which has been the standard of care in Europe and the United States. Results from the study were published online January 18 in Lancet Oncology.
Another trial published in 2010, by the U.S. Radiation Therapy Oncology Group (RTOG), showed similar results, but the two research teams have drawn different conclusions, which will affect ongoing clinical trials and, potentially, future research collaborations.
The researchers in the latest study, from the European Groupe d'Oncologie Radiothérapie Tête et Cou (GORTEC), compared two experimental regimens with standard chemoradiotherapy in the trial, called GORTEC 99-02. All participating patients had stage III or stage IV head and neck squamous-cell carcinoma that had not metastasized but that could not be removed surgically.
In one experimental arm, 245 patients received "accelerated chemoradiotherapy," which consisted of two cycles of the same chemotherapy drugs plus radiation therapy accelerated by 1 week. In the second experimental arm, 242 patients received only "very accelerated" radiation therapy, which consisted of a total dose of 64.8 Gy given over 3.5 weeks. (See the tables below.)
Treatment Groups in the GORTEC 99-02 Trial
|Conventional Chemoradiotherapy||70 Gy given over 7 weeks: ||3 cycles of: |
|Accelerated Chemoradiotherapy||70 Gy given over 6 weeks: ||2 cycles of: |
|Very Accelerated Radiotherapy||64.8 Gy given over 3.5 weeks: ||None|
Treatment Groups in the RTOG-0129 Trial
|Conventional Chemoradiotherapy||70 Gy given over 7 weeks: ||3 cycles of: |
|Accelerated Chemoradiotherapy||72 Gy given over 6 weeks: ||2 cycles of: |
On the basis of promising earlier studies of accelerated radiation, the authors hypothesized that the more intense dose of radiation would improve progression-free survival and disease control.
Instead, the trial "showed that there was no such benefit and that acceleration of radiotherapy by 1 week, concomitant to chemotherapy, did not add any benefit when compared with conventional concomitant chemoradiotherapy," wrote the authors. Three years after treatment, 37.6 percent of patients in the conventional chemoradiotherapy arm were alive without progression of their disease, compared with 34.1 percent of those in the accelerated chemoradiotherapy arm.
The very accelerated radiation regimen provided inferior disease control compared with conventional chemoradiotherapy, with 32.2 percent of patients in that group alive and free of disease progression 3 years after treatment. These results were another surprise: "We expected 'very accelerated' radiotherapy to be at least as good as conventional chemoradiotherapy," stated the authors.
Same Results, Divergent Conclusions
The GORTEC trial results are somewhat difficult to interpret because the trial "didn't change just one variable, it changed two—in addition to the radiation regimen, it also changed the chemotherapy," explained Dr. Bhadrasain Vikram, chief of the Clinical Radiation Oncology Branch of the Radiation Research Program in NCI's Division of Cancer Treatment and Diagnosis.
Because patients in the accelerated chemoradiotherapy group received two, rather than three, cycles of chemotherapy (although those two cycles were longer in duration), they received 17 percent less chemotherapy overall than patients in the conventional chemoradiotherapy group.
The RTOG trial that showed similar results (RTOG-0129) also reduced the amount of chemotherapy given, and not just because of fears of toxicity, explained Dr. Maura Gillison, RTOG investigator and professor of medicine at the James Comprehensive Cancer Center at Ohio State University.
—Dr. Maura Gillison
"All of the studies have shown that it's critical to give the chemotherapy with the radiation," she stressed. Chemotherapy given alone does not have as potent an antitumor effect in head and neck cancer, and in the accelerated chemoradiotherapy arms of the two trials, shortening the duration of radiation therapy did not leave enough time for a third cycle of chemotherapy.
Because only about 60 percent of patients with advanced head and neck cancer are healthy enough to complete the third cycle of chemotherapy with conventional chemoradiotherapy, and because the patients in RTOG-0129 who received conventional and accelerated chemoradiotherapy survived for a similar length of time, "we thought that to some extent our results are an advance," Dr. Gillison said. "You can shorten the treatment to 6 weeks instead of 7, and shortening the treatment means you don't have to give that third cycle of chemotherapy, with all its associated toxicities."
While the GORTEC investigators did not see a benefit from accelerated chemoradiotherapy, the RTOG investigators have chosen to use an accelerated chemoradiotherapy regimen as the standard of care in their trials of advanced head and neck cancer.
This decision for trials in the United States was also influenced by changes in modern radiation therapy technology, explained Dr. K. Kian Ang, professor of radiation oncology at the University of Texas M. D. Anderson Cancer Center and former chair of RTOG's Head and Neck Committee. The more widespread availability of intensity modulated radiation therapy (IMRT) has allowed radiation oncologists to reduce the number of visits required for irradiation even further than in the RTOG-0129 trial, which makes it more practical for patients to complete therapy, added Dr. Ang.
HPV Status Makes a Difference
The recent understanding of the importance of human papillomavirus (HPV) as a cause of oropharyngeal cancer also limits the application of the GORTEC results to current practice, added Dr. Vikram. That trial began "before the huge importance of HPV status [in head and neck cancer] was recognized. One would expect about 40 to 50 percent of the tumors in this trial to have been HPV-positive, but the paper unfortunately has no information on that, so we have no idea from this trial if one of the regimens tested might work better for subsets of patients with HPV-positive or HPV-negative tumors," he explained.
Dividing patients into those whose tumors are HPV-positive versus HPV-negative will be increasingly important in future trials for head and neck cancer, as the rate of oral HPV infection continues to rise. In the RTOG-0129 trial, people whose oropharyngeal tumors contain the HPV virus were found to respond much better to treatment than patients with HPV-negative tumors.
"After so many years, we've really started to understand that, although [HPV-positive and HPV-negative tumors] are located in the same small anatomical region, we are dealing with different types of cancers," said Dr. Ang. "Because HPV-positive patients do relatively well on current treatments, one of our main goals now is to reduce toxicity. And for HPV-negative patients, because they do so badly with what we have now, we want to know how we can intensify treatment in order to improve outcomes.
"With these completely different objectives, we don't think we can put [these two groups] in the same protocol—we need to do separate trials," he continued. RTOG recently launched its first trial for HPV-positive patients only (RTOG-1016), to see if using the targeted drug cetuximab instead of cisplatin can reduce the side effects of treatment while controlling tumors.
A big challenge, added Dr. Ang, is that "head and neck cancer is relatively rare, and now we're dividing it into smaller and smaller subsets. International trials will be a necessity to enroll enough patients."
And along with the normal challenges of cross-border funding, quality control, and tumor sample transportation, what should actually be tested will also have to be agreed upon. "Investigators will need to agree on what are the best scientific questions to ask," concluded Dr. Ang.