Hypofractionated radiation therapy for localized prostate cancer: an update

In the past year, we have reviewed several major randomized clinical trials comparing hypofractionated radiation therapy to conventionally fractionated radiation therapy for primary treatment. To recap:

The CHHiP Study (reviewed here and published here) proved that 60 Gy delivered in 20 fractions was not inferior to 74 Gy in 37 fractions in terms of cancer control, patient-reported toxicity, or physician-reported toxicity.

The Fox Chase trial (reviewed here), which focused on men with intermediate and high-risk prostate cancer, proved that 70.2 Gy delivered in 26 fractions was not inferior to 76 Gy in 38 fractions. All functional outcomes (urinary, bowel, and sexual) were similar in the long term.

RTOG 0415 (reviewed here), which focused on men with low-risk prostate cancer, proved that 70 Gy delivered in 28 fractions was not inferior to 73.8 Gy in 41 fractions in terms of cancer control, rectal or urinary toxicity.

Finally, the HYPRO trial, which enrolled predominantly (>70 percent) high-risk patients and some intermediate risk patients,’ previously published its toxicity analysis (reviewed here). They have now released their findings about cancer control (available here). Patients assigned to hypofractionation received 64.6 Gy in 19 fractions; conventional fractionation was 78 Gy in 39 fractions. Radiation was delivered using 3D-CRT rather than IMRT. After 60 months median follow-up, they report:

• ·      Treatment failure occurred in 20 percent of the patients receiving hypofractionated radiation vs. 22 percent of those who received conventional fractionation. No significant difference.
• ·      5-year relapse-free survival was 80.5 percent among the hypofractionated radiation patients vs. 77.1 percent among the conventionally fractionated radiation patients. No significant difference.

They conclude:

“Hypofractionated radiotherapy was not superior to conventional radiotherapy with respect to 5-year relapse-free survival. Our hypofractionated radiotherapy regimen cannot be regarded as the new standard of care for patients with intermediate-risk or high-risk prostate cancer.”

It’s difficult to understand their reticence to adopt hypofractionation as the new standard of care, and W. Robert Lee (in an accompanying editorial) explains the apparent discrepancy. He notes that the HYPRO trial set a goal of raising the relapse-free survival by 10 points, from 70 percent to 80 percent using hypofractionation. While it achieved over 80 percent control, it was not a difference of 10 points. Therefore, they could not prove that the hypofractionated protocol was superior. The other trials only attempted to prove that hypofractionation was not inferior, which they did.

Patients, who are not as concerned with the statistical niceties of the distinction between inferiority studies and superiority studies, have reason to rejoice over these results. Collectively, these studies mean that the treatments can be done as effectively and with about the same toxicity as the typical 9-week IMRT schedule.

It’s worth mentioning that hypofractionation is gaining acceptance for other kinds of cancer as well, such as breast cancer. Extreme hypofractionation, such as SBRT, has been used effectively and with low toxicity in prostate and other cancers, but has not yet been proven in a randomized clinical trial.

There are some appropriate cautions: hypofractionation can be very safe if the radiation oncologist is using the latest fast and accurate linear accelerators that are designed to deliver the higher doses. State-of-the-art image guidance, using such tools as fiducials, radio transmitters, and cone-beam CT imaging, is equally important. And nothing is more important than an experienced radiation oncologist who takes meticulous care to optimize the treatment plan with respect to dose constraints for organs at  risk.

This is a hard sell to many radiation oncologists in private practice because it hits them in the pocketbook. On the other hand, if they don't get on board, they will be left in the dust. Some patients may nevertheless opt for the more conventional treatment, but there is no reason that the hypofractionation option should not be discussed.

For very high-risk patients, EBRT + BT is superior to surgery or EBRT only

A retrospective analysis of oncological outcomes among modern-era patients with a Gleason score of 9 or 10 demonstrates a clear advantage to a combination of external beam radiation therapy (EBRT) with a brachytherapy (BT) boost to the prostate and short–term androgen deprivation therapy (ADT).

Kishan et al. reported on 487 patients with biopsy Gleason scores of 9 or 10 who were consecutively treated between 2000 and 2013 at the University of California Los Angeles and Fox Chase Cancer Center. The patient characteristics were as follows:

• 170 were treated with radical prostatectomy (RP).
• 230 were treated with EBRT only.
• 87 were treated with EBRT + BT, and most of the BT was high dose rate.
• All patients were Gleason 9 or 10 on biopsy.
• RP patients were younger (median 62 years of age) compared to all radiation patients (median 70 years of age).
• RP patients had more favorable disease characteristics: lower initial PSA, and lower clinical stage.

The patient characteristics by treatment category are listed below.

For the RP patients:

• 11% had pre-surgery ADT or chemotherapy.
• 55% had adjuvant or salvage radiation therapy (68 Gy).
  • 39% of them had adjuvant ADT with radiation for a median of 22 months if adjuvant radiation, 12 months if salvage radiation.
• 85% with biochemical recurrence and no detected distant metastases had salvage radiation.
• 21% had a lower Gleason score (7 or 8) on final pathology, but 91 percent had any Gleason pattern 5 on final pathology.
• 78% were stage T3 or T4 on final pathology (vs. 12 percent clinically).
• 41% had positive surgical margins.
• 16% had positive lymph nodes
  • Among those, 64% received no immediate treatment because of patient preference.

For the EBRT patients:

• Median dose of radiation was 76.4 Gy.
• 94% had ADT starting before EBRT.
  • The median duration of ADT was 24 months.
• 76% had pelvic lymph nodes treated.
• 2 patients received salvage cryotherapy.

For the EBRT + BT patients:

• The median equivalent dose of radiation was 88.7 Gy
• 86% had ADT starting before radiation.
  • The median duration of ADT was 8 months.
• 78% had pelvic lymph nodes treated.
• 1 patient received salvage cryotherapy.

After a median follow-up of 4.6 years, the oncological outcomes were as follows:

• The 10-year biochemical recurrence rates (BCRs) were
  • 84% for RP
  • 40% for EBRT
  • 30% for EBRT + BT
  • Differences between RP and EBRT and between RP and EBRT + BT were statistically significant.
• Percentages of patients who began lifelong ADT after therapy failure were
  • 31% for RP
  • 21% for EBRT
  • 16% for EBRT + BT
  • Differences between RP and EBRT and between RP and EBRT + BT were statistically significant.
• The 10-year rates of distant metastases were
  • 39% for RP
  • 33% for EBRT
  • 10% for EBRT + BT
  • Differences between EBRT + BT and the two others were statistically significant, while the differences between RP and EBRT were not.
• The 10-year rates of prostate cancer-specific mortality were
  • 22% for RP
  • 20% for EBRT
  • 12% for EBRT + BT
  • None of the differences were statistically significant.
• The 10-year rates of overall survival were
  • 75% for RP (they were younger and healthier)
  • 65% for EBRT
  • 59% for EBRT + BT
  • None of the differences were statistically significant.

The authors conclude:

These data suggest that extremely dose-escalated radiotherapy with ADT might be the optimal upfront treatment for patients with biopsy GS 9–10 prostate cancer.

It will come as no surprise to readers that EBRT + BT boost has better outcomes than EBRT alone (see this link and this one). Dose escalation has been found to improve outcomes, and the use of ADT to radiosensitize the cancer, and to systemically clear up micrometastasis, seems to improve outcomes still further. However, ADT for as long as 2 years could not compensate for the lower radiation dose of EBRT used by itself. Longer duration of ADT was not associated with improved outcomes after accounting for the dose effect.

Those who were treated with EBRT + BT were at a considerable disadvantage in this study: they were older, had worse disease characteristics, and were given less local salvage, yet they performed much better. When controlling for those disparities, the total radiation dose emerged as the single most important variable, affecting biochemical recurrence, metastases-free survival, and prostate cancer-specific survival. No other variable – neither duration of ADT nor adjuvant/salvage radiation – was statistically significant.

Prostate cancer-specific mortality rates were cut in half by combining EBRT with a BT boost. While the combination therapy did not make a statistically significant difference in prostate cancer-specific survival, the study was probably under-powered to detect that with statistical significance. The survival curves between EBRT + BT and the other two therapies did consistently diverge throughout the follow-up period, so the difference might well be statistically significant on a larger sample size or longer follow-up.

Not everyone in this study received optimal therapy. The EBRT-only dose was sometimes low by today’s standards, salvage radiation was under-utilized, use of concurrent ADT with adjuvant/salvage radiation was low (see this link) and of too-short duration.  However, most were treated according to the standards of care. The authors looked at the subset of patients who were treated optimally and found no difference in conclusions. The conclusions were robust even excluding those who were lymph-node positive.

What is new here is the comparison of the three potentially curative treatments for very high-risk prostate cancer in the 21st Century. There have been several long-term database analyses that compared surgery to radiation therapy as offered in the 1990s, when radiation doses were often inadequate to achieve cures. We recently saw a comparative benefit to radiation over surgery in the modern era among high-risk patients at the University of Alabama Birmingham (see this link). Ideally, we would like to see a randomized comparative trial between surgery and radiation, but that is unlikely to occur. Meanwhile, this kind of analysis is about the best we have to inform our treatment decisions.

We understand that a future, expanded analysis will include data from other institutions, including Harvard, the Cleveland Clinic, and Memorial Sloan-Kettering Cancer Center. That analysis will also include toxicity data. We will certainly report on that when it is published.

note: Thanks to Drs. King and Kishan for allowing me to see the full text of this analysis, and responding to questions.