Dose-escalated intensity-modulated radiation therapy (IMRT) with use of a moderate hypofractionation regimen can safely treat patients with localized prostate cancer, resulting in limited grade 2 or 3 late toxicity, according to a new study (Int J Radiat Oncol Biol Phys 2014;88:1074-1084).
Based on the data, decreasing the length of radiation for prostate cancer from eight and a half to six weeks may be a possibility, said Karen E. Hoffman, MD, MHSc, MPH, the study's first author, who is Assistant Professor in the Department of Radiation Oncology at the University of Texas MD Anderson Cancer Center.
“We found that the length of radiation treatment can be safely decreased by delivering larger daily doses of radiation therapy, as long as the dose to the normal tissue around the prostate, such as the rectum and bladder, was limited,” she said.
Although the overall risk of a late urinary or rectal toxicity after moderate hyperfractionation was low, “we did find that the amount of moderate- and high-dose radiation delivered to the rectum predicted whether an individual developed late rectal toxicity.”
Asked for his opinion for this article, Chandan Guha, MD, MBBS, PhD, Vice Chair of the Department of Radiation Oncology at Montefiore Medical Center in the Bronx, NY, said that overall, based on this study, “there is no concern about hypofractionation if done properly and if oncologists are cautious of the rectal dose.”
Also commenting, Robert Den, MD, Assistant Professor of Radiation Oncology at Thomas Jefferson University in Philadelphia, said, “Hypofractionation is very intriguing at this point, but it should be studied in the context of a clinical trial and is not ready for primetime.”
The study randomized 203 men (median age of 68) at MD Anderson with organ-confined prostate cancer from January 2001 to January 2010 to receive either conventional IMRT (101 patients) with 75.6 Gy in 1.8 Gy fractions over 8.5 weeks, or dose-escalated hypofractionated IMRT (102 patients) with 72 Gy in 2.4 Gy fractions over six weeks.
Dose-volume histograms (DVH) were used to evaluate the portion of the bladder and rectum receiving radiation, and the researchers prospectively assessed gastrointestinal or genitourinary toxicity at 90 days or later. Median follow-up was six years.
The researchers reported a numeric increase in the absolute frequency of late GI toxicity for men treated with escalated hypofractionated IMRT, but the difference compared with conventional radiation was not statistically significant. In the conventional fractionation and hypofractionation arms, the rates of five-year actuarial grade 2 or 3 late GI toxicity were 5.1 and 10 percent, respectively.
The increase in late GI toxicity for men receiving hypofractionated IMRT was due to moderate and high radiation dose to a larger proportion of the rectum, the researchers said.
Additionally, no statistically significant difference was observed in the absolute frequency of late GU toxicity in men treated in either arm. The five-year actuarial grade 2 or 3 late GU toxicity was 16.5 percent for patients treated with conventional IMRT and 15.8 percent for patients treated with hypofractionation.
In the hypofractionated arm, the five-year actuarial rectal toxicity of grade 2 or higher was 27.3 percent in men who received 64.6 Gy in more than 20 percent of the rectal volume, while the rectal toxicity rate was six percent in those who received 64.6 Gy in less than 20 percent of the rectal volume.
Hoffman said that although an initial look at data in men with larger prostates revealed that they experienced more rectal toxicity, closer inspection showed that larger prostate size was associated with greater radiation dose to the rectum. “We can still treat men with a larger prostate as long as rectal volume constraints are met,” she said.
Treated Rectal Volume
“The fear with hypofractionation is that a larger fraction size will cause normal tissue damage,” Guha said. “The rectum is right next to the prostate, and if the anterior wall of the rectum gets a large dose of radiation, there is always a fear that down the road there will be rectal bleeding from potential ulcers.”
Patients in the hypofractionated arm who received a higher dose to the rectum experienced more side effects, noted Matthew C. Abramowitz, MD, Assistant Professor of Radiation Oncology at the University of Miami Sylvester Comprehensive Cancer Center. “But does this have to do with hypofractionation in and of itself?”
Another explanation is that more of the rectum received a greater bioeffective dose, since a larger percentage of patients in the hypofractionated arm had rectal DVHs that were above protocol constraints.
The planning target volume expansion margins used in this study, which were 1 to 1.5 cm, were larger than what are used in his center, he noted. “This is going to result in a lot more rectal volume being treated. Here we use margins half to a third of that.”
Still Awaiting Outcomes Data
Hoffman said that overall, the study results, in addition to available data from Fox Chase Cancer Center (JCO 2013;31:3860-3868) and Cleveland Clinic (Int J Radiat Oncol Biol Phys 2005;63:1463-1468), indicate that moderate hypofractionated radiation is associated with limited urinary and bowel toxicity. Her group, though, she said, has not yet reported the cancer control outcomes.
Prostate cancer is more sensitive to radiation delivered in higher doses, she continued. Moreover, shorter courses of radiation therapy delivered in larger doses each day are believed to be more biologically effective—“consequently, researchers hypothesize that a dose-escalated hypofractionated regimen would improve control.”
Asked for his perspective, Eric M. Horwitz, MD, Chairman of Radiation Oncology at Fox Chase Cancer Center, said that the study results are fairly consistent with what he and his colleagues saw in their large randomized study.
“The original concern of researchers was that hypofractionated radiation would cause patients to experience more side effects, especially with older delivery techniques,” he said, ‘However, we now have multiple studies showing that it's safe if you use modern IMRT with quality daily imaging.”
The Fox Chase study reported outcomes that were equivalent between the conventional and hypofractionated arms. “We had thought that the hypofractionation would be better, but we didn't see that,” Horwitz said. Although more outcomes data are needed, if the treatment turns out to be equivalent to conventional radiation, patients benefit because their treatment is shortened by a couple of weeks.
Provides Useful Cut Points
Abramowitz said that one especially useful piece of information from the study is that it gives high-quality data for predicted rectal toxicity DVH cut points for use with hypofractionation, and that based on the results from the study, radiation oncologists can consider what the goals of treatment should be while avoiding rectal toxicity.
The study cut point of 64.6 Gy in less than 20 percent of the rectal volume is useful for other providers who want to assess their radiation planning, Horwitz noted. “We've always used this cut point, but the publication of data allows everyone to assess the quality of their radiation plan.”
With this information, “you have a guideline,” Guha said. “If you're doing this type of treatment you have to be careful about how much dose the rectal wall is getting.”
Benefits for Patients
One reason hypofractionation is of interest to researchers is because fewer weeks of treatment will make radiation more convenient for patients, said Hoffman.
Hypofractionated therapy creates better accessibility, said Abramowitz. “It's difficult for people to come in for seven to nine weeks of treatment, especially for 30 minutes to an hour for five days a week,” he said. Employers may be a little more flexible with people taking off five or six weeks for radiation. “This benefit is even greater when we look at five fraction courses of treatment,” he said.
If the regimen is found to decrease long-term toxicity, patients will have less need for secondary procedures, Den noted.
Hypofractionated treatment also has the potential to reduce costs because in the United States, reimbursement is per treatment at a facility. So, the shorter the course, the lower the cost, Abramowitz said.
While this study adds to the body of literature on hypofractionation, “we need to wait for larger cooperative group randomized trials,” said Justin Bekelman, MD, Assistant Professor of Radiation Oncology at the Hospital of the University of Pennsylvania.
For example, he noted, the Radiation Therapy Oncology Group has the ongoing Protocol 0415 trial comparing standard fractionation with mild hypofractionation, which has completed accrual of 1,115 individuals with prostate cancer across a broad subsection of community care.
Follow-up time in these clinical trials is important because radiation oncologists are concerned about late toxicity, and standard fractionation regimens have been shown to be safe and effective in the long-term, he added.
Further research in the academic and community settings also needs to determine whether standard versus mild hypofractionated therapy is better in certain subsets of patients, he said.
Den said that overall, longer follow-up is needed to detect differences in biochemical failure or changes in metastatic rate after hypofractionated radiation in comparison with standard fractionation regimens.
Guha explained that in the time since this study was first initiated, radiation technology has improved and an increasing number of oncologists are giving patients larger fraction sizes through methods such as stereotactic body radiation therapy. However, these patients should only be treated in a clinical trial so oncologists know what the long-term toxicity profile is, he said.
At Sylvester, Abramowitz said, they will be conducting the Miami HEAT trial, comparing the use of 70.2 Gy in 2.7-Gy fractions, or the Fox Chase regimen, with stereotactic therapy of 36.35 Gy in five fractions. Extreme hypofractionation generally uses only five fractions and margins as tight as 3 mm, he said. “A body of literature to this approach is also growing.”