Potential Benefits of Hypofractionation: Clinical Trial Results
Significant Trials Studying Prostate Hypofractionation
The scope and number of clinical trials investigating prostate hypofractionation have increased substantially in the last decade. It is clear that prostate hypofractionation has varying effects on tumor control, acute toxicity, quality of life, treatment cost, and convenience. Many trial findings show evidence of efficacy in terms of survival or biochemical relapse-free survival. However, the overall number of patients studied is low, and the length of follow-up remains relatively short. The Table summarizes studies investigating hypofractionated radiotherapy for prostate cancer.
Tumor control
Yeoh et al evaluated hypofractionated schedules in patients with low-risk, localized prostate cancer.[9] The randomized trial consisted of 217 men who were enrolled either in a hypofractionated arm (55 Gy in 20 fractions over 4 weeks) or a conventional arm (64 Gy in 32 fractions over 6.5 weeks). The prostate-specific antigen (PSA) relapse-free survival at 90 months was significantly better in the hypofractionated group than in the conventional group. The most recent toxicity data show no difference in late gastrointestinal (GI) and genitourinary (GU) effects between the hypofractionated and the standard fractionated arm at 5 years. Although this report is one of the first studies to show a long-term therapeutic advantage to prostate hypofractionation, the patient base consisted only of men with localized, early-stage prostate carcinoma, and the total dose of radiation on the conventional arm was relatively low.
Most recently, Pollack et al reported on the results of the Fox Chase Cancer Center (FCCC) randomized trial of 307 patients comparing conventionally fractionated intensity-modulated radiation therapy (IMRT) involving 76 Gy of radiation in 38 fractions of 2.0 Gy each to a modestly hypofractionated regimen involving 70.2 Gy of radiation delivered in 2.7-Gy fractions. There was no difference in 5-year biochemical disease-free survival or metastasis-free survival between the two arms.[10]
Kruser et al reported the retrospective results of “salvage hypofractionation” in a specific subgroup of prostate cancer patients who had experienced biochemical recurrence after prostatectomy.[11] This analysis found that modestly hypofractionated radiotherapy was associated with a 4-year biochemical disease-free survival of 67% ± 5%, which compares favorably to standard fractionated series. Additionally, investigators found that a hypofractionated treatment plan reduces the length of treatment by 1.5 to 3 weeks compared with conventionally fractionated schedules. To date, no randomized trial has compared conventional and hypofractionated salvage schedules; however, evidence suggests equivalent GI/GU toxicities and biochemical response between hypofractionated and conventionally fractionated treatments.[12]
A trial conducted by King et al utilized extreme hypofractionation to treat 65 patients with low-risk prostate adenocarcinoma and found a 4-year biochemical control rate of 94% among the entire cohort, with a median follow-up of 2.7 years.[13] Like the study by King et al, other trials that involved treatment of low-risk patients have showed similar, positive results. Boike at al treated 45 low-risk prostate adenocarcinoma patients with extreme hypofractionation (45 Gy, 47.5 Gy, or 50 Gy in 5 fractions) and found no biochemical failure and declining or stable PSA levels at 30 months, 18 months, and 12 months for the 45-Gy, 47.5-Gy, and 50-Gy groups, respectively.[14] McBride et al found no biochemical failures at a median survival of 44.5 months for 45 low-risk patients treated with extreme hypofractionation. Furthermore, progression-free survival at 3 years was 97.7%.[7] It is important to note that although this trial, and the trial by King et al, shows that extreme hypofractionation is effective, the treatments were confined to patients at low risk for treatment failure, and follow-up was short.
Acute and late toxicity
A number of clinical trials report the results of moderate hypofractionation vs standard fractionation with respect to outcomes such as acute and late toxicity (see the Table). Most trials show similar toxicity between moderately hypofractionated therapy and standard fractionated therapy.[6,15] Other trials have shown less long-term toxicity[16,17] and greater short-term toxicity[9,18] for hypofractionated radiotherapy compared to standard fractionated radiation. Nonetheless, since radiation-related complications often take many years to become fully manifest, further long-term follow-up is needed before a definitive judgment can be made with regard to the toxicity of moderately hypofractionated treatment relative to that of standard fractionated treatment.
Quality of life
In addition to assessing medical treatment–related outcomes, a few recent trials have also assessed patient-reported quality of life (QOL) for prostate hypofractionation treatment schedules with androgen deprivation therapy. A prospective phase 1/II study in Canada included patients with high-risk prostate cancer and administered a hypofractionated regimen of 67.5 Gy (2.7 Gy per fraction) in 25 fractions over 5 weeks.[2] The investigators used the Expanded Prostate Cancer Index Composite (EPIC) tool to measure four primary domains (urinary, bowel, sexual, and hormonal) and found modest declines in urinary and bowel QOL at 24 months that caused mild distress to patients. However, severe changes to baseline QOL were not found. These results suggest similar QOL outcomes between hypofractionated treatment and previously published standard fractionated treatment schedules.[19,20]
McBride et al[7] studied extreme hypofractionation in patients with low-risk prostate adenocarcinoma, and as in the Canadian study, they used the EPIC instrument. Overall, they did not observe a statistically significant decrease in sexual function. Furthermore, the reported magnitude of decline in sexual health for potent patients was similar to that reported in patients with low baseline sexual morbidity who received standard fractionation.[7]
Nevertheless, additional follow-up is still needed to examine long-term effects on QOL.
Convenience
Compared to standard fractionated schedules, hypofractionation has also been associated with improved convenience because patients on this abbreviated regimen undergo fewer treatments. Several studies have reported increased convenience associated with hypofractionation at other disease sites. For example, a Greek trial compared a hypofractionated schedule to a standard fractionated schedule in the treatment of 92 patients with locally advanced non–small-cell lung cancer (NSCLC). Not only did the investigators find increased efficacy with the hypofractionated schedule, they also reported that the hypofractionated schedule offered more convenience to their patients coming from remote areas where there is a lack of radiation therapy facilities.[21]
There is geographic variation in access to radiation services in the United States, with limited availability of radiation oncologists particularly in rural areas.[22] A hypofractionated radiation therapy schedule offers one possible solution to potential geographic disparities in radiation therapy service—by allowing a more convenient treatment, with fewer commutes to the treatment facility for the patient.
Cost-effectiveness
With approximately 180,000 new diagnoses per year, prostate cancer treatment remains a significant cost burden to the US health care system.[23] In radiation therapy, standard fractionated IMRT has been adopted as the current standard of external beam radiotherapy. When treatment preoperative evaluation, imaging, laboratory tests, and treatment complications are all accounted for, radiation therapy to treat prostate cancer with IMRT is estimated to cost between $31,574 and $37,125.[23] Moreover, new technologies such as proton therapy are associated with even further increases in the cost of treating prostate cancer compared to external beam radiotherapy.[24] Given the push for financially conservative health care models, the high cost of treating prostate cancer with IMRT and proton therapy has led to investigation of the comparative effectiveness of the various prostate cancer treatment modalities, and of ways to reduce the overall cost of treatment.
Because the cost of radiation therapy is largely driven by total treatment time, calculated as the daily treatment time multiplied by the number of fractions, hypofractionation serves as a potentially more cost-effective method that can curtail rising prostate cancer treatment costs.[25] Although there is little research specifically evaluating the cost-effectiveness of prostate cancer hypofractionation compared to standard fractionated schedules, there is evidence suggesting that hypofractionation reduces treatment costs in other disease sites.
In a breast cancer treatment study at the Leuven Radiotherapy Department in Belgium, there was a 60% decrease in total treatment cost with hypofractionated treatment compared to standard treatment schedules in the Belgian health care system. The decrease was a direct consequence of the reduction in daily irradiation cost. An Australian study reported a 24% reduction in treatment costs in the Australian health care system for breast cancer patients on a hypofractionated schedule.[26] Variations in cost reductions are dependent on the number by which the hypofractionated schedule reduces the total number of fractions, as well as on the payment structure of the particular health care system involved. Along with demonstrating a reduction in total treatment costs, all cost analyses for standard breast, chest wall, or loco-regional lymph node irradiation with hypofractionated schedules have shown the costs of these regimens to be well below the currently accepted willingness-to-pay thresholds of various countries.[25] However, it is important to note that the cost of treatment preparation becomes proportionally more important when hypofractionated schedules are used.
There are also reports of lower costs with hypofractionation in the palliative treatment of lung cancer with radiotherapy. Van den Hout et al performed an extensive cost-utility analysis of short- vs long-course schedules and compared quality-adjusted life-years, an overall measure of the patients’ quantity and quality of life, to the total cost of disease treatment, including the costs of radiation as well as the various other costs incurred by patients during their remaining lifetime. Hypofractionated treatment schedules for these poor-prognosis patients reduced costs by approximately 52%.[27] However, in contrast, in the Greek study that looked at locally advanced NSCLC, hypofractionated treatment schedules were also associated with a 39% decrease in life expectancy, suggesting that they may not be as clinically efficacious for the palliative treatment of lung cancer and that the benefit from hypofractionated treatment may not be uniform across disparate groups of patients.[28]
Van den Hout et al also conducted a cost-analysis of single- vs multiple-fraction radiation treatment in patients with painful bone metastases.[29] Single-fraction radiotherapy was associated with a 27% reduction in cost and was associated with equivalent palliation and quality of life. Because single- and multiple-fraction radiotherapy were shown to provide equal palliation, the authors strongly suggested the adoption of single-fraction treatment because of its lower societal and medical costs. Although provocative, the results of these studies are difficult to apply to prostate radiotherapy, since patients with localized prostate cancer on average live much longer than patients with bone metastases. Therefore, each incremental difference in quality of life must be multiplied by many years of survival.
