Optimal Radiation Delivery Methods and Dosing Strategies Under Study

Howard M. Sandler, MD, MS

The quest to deliver optimal radiation therapy for patients with prostate cancer has led to a variety of advances in technologies and techniques, yet key questions remain unanswered. Clinical trials now under way are expected to help clarify unsettled issues in several areas, particularly in proton beam therapy and hypofractionation, according to Howard M. Sandler, MD, MS.

Sandler, who is chair of Cancer Therapeutics and chair of Radiation Oncology at Cedars-Sinai Medical Center in Los Angeles, provided an overview of treatment options for radiation therapy in prostate cancer during the 6th Annual Interdisciplinary Prostate Cancer Congress™.

Figure 1. Primary Treatment

of Localized Prostate Cancer¹

Data from 11,892 men in the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry are analyzed.

CAPRA indicates Cancer of the Prostate Risk Assessment scores.

Proton Beam Therapy Growing

Although therapy trends have varied during the past two decades, radiation therapy remains an important modality. The percentage of patients treated with external-beam radiation therapy or brachytherapy ranged from 20.9% to 23.5% depending on risk level, according to the most recent Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) database analysis, which Sandler cited (Figure 1).¹ When it comes to delivering radiation therapy to a patient, Sandler said that determining the best dose of a particular form of radiation therapy is at the heart of the specialty. It also is important to keep that dose of radiation concentrated on the tumor and spare the surrounding tissue as much as possible, he stressed.To achieve those goals, proton beam therapy theoretically would be more beneficial than several other methods of external radiation therapy because the technology allows for greater doses to be delivered to the tumor while reducing the incidence of treatment-related tissue damage, Sandler said.

Indeed, he noted that cancer centers throughout the country are increasingly investing in proton technology, which can cost as much as $150 million or $200 million for large systems. At least 10 centers have established proton sites, and approximately a dozen additional centers are planning to do so.

However, Sandler said there is scant evidence that proton beam therapy delivers superior outcomes, citing a review of 36 studies in various tumor types.² In a 2007 paper, Brada et al found no studies demonstrating that proton beam therapy was superior to best available photon therapies such as intensity-modulated radiation therapy (IMRT) and three-dimensional conformal radiotherapy (3-D CRT).

In April, Gray et al³ reported that results of seven trials indicate patients treated with proton therapy experienced a low rate of acute and late grade 3 gastrointestinal and genitourinary toxicity, and that the method appears to keep disease under control. The paper also noted that smaller systems costing $15 million to $25 million are now hitting the market, which would make the technology more cost-effective.

Currently, the American Society for Radiation Oncology (ASTRO) believes that the role of proton therapy in prostate cancer is unclear and that more research is needed, including data comparing its efficacy to such other modalities as IMRT and brachytherapy.⁴ Indeed, the first head-to-head clinical trial is under way. A phase III trial being conducted at Massachusetts General Hospital and the University of Pennsylvania is currently enrolling 461 patients with low- or low-intermediate risk prostate cancer and randomizing them either to proton beam therapy or IMRT (Figure 2). The results of the study are expected in 2016, at which point Sandler hopes the role of proton beam therapy in prostate cancer will be decided.

“If proton therapy doesn’t reduce toxicity for prostate cancer, then there’s no reason to be doing it,” Sandler said.

Figure 2. Proton Beam Versus IMRT in Low- or Low-Intermediate Risk Prostate Cancer

EPIC, indicates Expanded Prostate Cancer Index Composite; IMRT, intensity-modulated radiation therapy; QoL, quality of life.

Source: www.ClinicalTrials.gov, NCT01617161

Comparing IMRT and 3-D CRT

While proton beam therapy’s benefits have not yet been proven in prostate cancer, other methods of external radiation therapy have been shown to be effective in managing the disease. The National Comprehensive Cancer Network includes both 3-D CRT and IMRT in its practice guidelines for the treatment of localized prostate cancer, but notes that IMRT is the preferred technique because it “appears to decrease rates of salvage therapy without increasing side effects, especially when applied to patients with high-risk disease.”

Sandler compared the amount of radiation delivered by 3-D CRT with the amount delivered by IMRT. By modulating the radiation delivered, IMRT is able to minimize the dose in surrounding tissue, whereas the radiation delivered by 3-D CRT cannot be modified without minimizing the dose delivered to the tumor.

However, even with the modulated dose of radiation, IMRT might not be superior to 3-D CRT, Sandler noted. In the phase III Radiation Therapy Oncology Group (RTOG) 0126 study,⁵ 706 patients with localized prostate cancer were randomized to receive high-dose (79.2 Gy) treatment, with 473 patients receiving 3DCRT with 55.8 Gy delivered to the prostate and proximal seminal vesicles followed by 23.4 Gy to the prostate only, and 233 receiving IMRT with 79.2 Gy to the prostate and proximal seminal vesicles, with a median follow-up of 4.6 years and 3.5 years, respectively.

The study found that the five-year Kaplan-Meier incidence of grade 2 or higher gastrointestinal toxicity was slightly higher for 3-D CRT (25%) compared with IMRT (21%; P = .06), but the difference was not statistically significant. A preliminary analysis had shown a statistically significant difference favoring IMRT. While Sandler said that IMRT is probably better, that difference is marginal at best.

“Whether it’s cost-effective, I think, remains to be seen,” said Sandler, noting that IMRT is more expensive. “There is a benefit, but the benefit is probably not as big as radiation oncologists believe that it is.”

Exploring Hypofractionation

Sandler said that newer IMRT technology might prove more effective than the existing systems. A device that delivers IMRT via volume-modulated arc therapy (VMAT) moves and delivers the radiation in an arc. Sandler said this offers a few advantages, such as a short treatment time as well as a dose that is spread more widely around the patient, which, while different, is not worse than existing methods, in his opinion.Another outstanding issue in radiation therapy is whether administering larger fractions less frequently would be more beneficial than the current standard. Sandler said this hypothesis is being evaluated in a series of clinical trials, such as RTOG 04156 (Figure 3). “This accrued very quickly, and we hope within a year or so to have an endpoint,” he said.

The rationale for investigating hypofractionation (less frequent, larger fractions) emanates from models that calculate a low alpha-beta ratio of dose-response for prostate cancer, leading researchers to believe that patients might be able to handle more-intense dosing, according to the protocol for RTOG 0415.⁶ When the trial was conceived about four years ago, the optimal schedule for curative treatment was unknown, and some clinicians were attempting to increase radiation doses by lengthening therapy to 9-10 consecutive weeks from the standard 7-8 week regimens, the researchers noted.

Figure 3. RTOG 0415: Radiation Therapy Dosing Evaluation^1-3

3D-CRT indicates three-dimensional conformal radiotherapy; Fx, fractions; GS, Gleason score; Gy, gray; IMRT, intensity-modulated radiation therapy; PSA, prostate-specific antigen; RTOG, Radiation Therapy Oncology Group.

Sources:

1. Sandler HM. Comparing current options in radiation therapy. Presented at: 6th Annual Interdisciplinary Prostate Cancer Congress; March 16, 2013; New York, NY.

2. www.ClinicalTrials.gov, NCT00331773. Updated August 3, 2012.

Accessed May 8, 2013.

3. RTOG 0415 protocol information, Radiation Therapy Oncology Group website www.rtog.org. Updated March 8, 2011. Accessed May 8, 2013.

Sandler said ASTRO’s position is that short treatment regimens are investigational at this point. “I think that that’s an accurate assessment in this state of the art,” he said. “In my hospital, the only way I would treat a patient with a five-fraction approach is a clinical trial.”

References

1. Cooperberg MR, Broering JM, Carroll PR. Time trends and local variation in primary treatment of localized prostate cancer. J Clin Oncol. 2010;28(7):1117-1123.
2. Brada M, Pijls-Johannesma M, De Ruysscher D. Proton therapy in clinical practice: current clinical evidence. J Clin Oncol. 2007;25(8):965-970.
3. Gray PJ, Efstathiou JA. Proton beam radiation therapy for prostate cancer⎯is the hype (and the cost) justified? Curr Urol Rep. Published online April 2, 2013. doi: 10.1007/s11934-013-0320-2.
4. ASTRO Board of Directors approves statement on use of proton beam therapy for prostate cancer [press release]. Fairfax, VA: American Society for Radiation Oncology; March 13, 2013.
5. Michalski JM, Yan Y, Tucker S, et al. Dose volume analysis of grade 2+ late GI toxicity on RTOG 0126 after high-dose 3DCRT or IMRT. Int J Radiat Oncol Biol Phys. 2012;84(3 suppl):S14-S15; abstr 32.
6. RTOG 0415 protocol information, Radiation Therapy Oncology Group website www.rtog.org. Updated March 8, 2011. Accessed May 8, 2013.