Follow-up on the largest randomized study of fractionation techniques for radiation treatment has shown that hyperfractionated radiotherapy improves local-regional control and overall survival at five years for patients with locally advanced squamous cell cancer compared with standard fractionation and other accelerated fractionation techniques.
Moreover, hyperfractionation did not increase long-term toxicity compared with standard fractionation.
The findings are from the final results of the Radiation Therapy Oncology Group (RTOG) 9003 phase 3 trial, which looked at three altered fractionation techniques and their ability to improve local-regional control in those with locally advanced squamous cell cancer of the head and neck. Hyperfractionation boosts the total dose administered by breaking up treatments into smaller fractions given twice a day.
“Instead of giving a conventional dose--which is 1.8 to 2 Gy per day--instead of doing that once a day, what if we gave 1.2 Gy, a lot less, but did it twice a day? The aim is to increase total dose while minimizing side effects, which is basically what happened,” explained Jonathan J. Beitler, MD, MBA, FASTRO, lead author of the study and professor of radiation oncology, otolaryngology and hematology/medical oncology at the Winship Cancer Institute of Emory University School of Medicine in Atlanta, in an interview with Health Imaging.
Beitler and colleagues published the findings in the International Journal of Radiation Oncology • Biology • Physics, the official scientific journal of the American Society for Radiation Oncology, in May.
From Sept. 30, 1991, to Aug. 1, 1997, more than 1,000 patients with stage III or IV squamous cell cancer were randomized to four treatment arms:
- Standard fractionation – 70 Gy given in 35 daily fractions over seven weeks
- Hyperfractionation – 81.6 Gy given in 68 twice-daily fractions over seven weeks
- Continuous accelerated fractionation – 72 Gy given in 42 fractions over six weeks
- Accelerated fractionation with split – 67.2 Gy given in 42 fractions over six weeks, but with a two week rest after 38.4 Gy
Local-regional failure was analyzed at two years, five years and at last follow-up, with the median follow-up at 14.1 years as of Oct. 1, 2012. Beitler noted that follow-up of this length is like an eternity in the study of head and neck cancers. Older patients have many comorbidities and may die within a few years even if the cancer is successfully treated. However, that scenario has been changing in recent years with HPV-related oropharyngeal cancers leading to younger patients who are otherwise healthier.
At five years post-treatment, study results showed the hyperfractionation arm had the highest overall survival rates at 37.1 percent, compared with 29.3 percent for the standard fractionation arm.
Both hyperfractionation and continuous accelerated fractionation decreased five-year local-regional failure by 19 percent compared with the standard, though hyperfractionation, unlike the other experimental arms, did not increase late toxicities. An ad hoc analysis showed that the treatments delivered over seven weeks may increase toxicity at five years compared with treatment delivered over seven weeks.
One finding that took the researchers by surprise was the decrease in second malignancies at 5.5 years. For all study arms, the incidence of a second primary cancer was 1 percent per year or less after this time. Beitler suggested this may be due to the fact that cancer survivors are going to drink and smoke less, and at 5+ years are farther from the event that caused the disease. “Whatever the mutagenesis is, you're at less risk for it at year six than at year three, for example."
More studies on hyperfractionation could open the door to changing who receives concurrent chemotherapy and who doesn’t. Chemotherapy can act as a radiation sensitizer to boost treatment effectiveness, however chemo drugs, like the commonly used cisplatin, can cause renal toxicity, high frequency hearing loss and peripheral nephropathy, creating a quality of life issue for patients. Based on the long-term efficacy and toxicity rates of hyperfractionated radiation therapy, it may be a better option than standard fractionation and concurrent cisplatin therapy. The evidence is not yet there, but the researchers noted that improvements in radiation techniques and growing knowledge of disease biomarkers could trigger a reconsideration of therapeutic strategies.
Beitler noted that RTOG 9003 was conducted prior to the advent of intensity modulated radiotherapy (IMRT), and that the lessons learned about hyperfractionation from the trial could be combined with IMRT and improved imaging to deliver very high doses to gross disease, while using lower doses per fraction to areas of subclinical disease where normal tissues are irradiated.
"We may be able to identify a group of patients who have a low risk for distant metastases and treat them with one modality," said Beitler.