Radiotherapy Gives Long-Term Disease Control in Prostate Cancer

Pam Harrison

October 29, 2018

SAN ANTONIO — Long-term outcomes from a series of separate studies all support the continued efficacy and tolerability of different forms of radiation therapy (RT) in the treatment of localized, mostly low- and intermediate-risk prostate cancer. This is the message of a session here at the American Society for Radiation Oncology (ASTRO) 2018 annual meeting (abstracts 59-63).

"The reason some people don't adopt new types of radiation is the fear that there could be more toxicity beyond 5 years," session co-chair Daniel Spratt, MD, associate professor of radiation oncology, University of Michigan, Ann Arbor, told Medscape Medical News.

"But from trials of stereotactic body radiation therapy (SBRT) to ones on hypofractionation or the use of hormone therapy, there really wasn't any increase in toxicity — they all appear to be safe," he commented. "So I think it will all come down to patient convenience, fewer treatments, and lower cost, as fewer treatments are less costly, so the trials that are still on-going are all trying to shorten sessions down to five treatments in total and we await those trials with interest," he added.

As Amar Kishan, MD, University of California, Los Angeles, discussed in a news briefing, traditional conventional RT for low- and intermediate-risk prostate cancer involved the delivery of small daily doses of radiation over an extended timeframe, typically 8 to 9 weeks.

"The so-called fractionation of radiation is thought to help preferentially kill tumor cells and minimize chronic tissue damage," Kishan explained.

Somewhat uniquely, prostate cancer appears to be more sensitive to higher doses of radiation per treatment session, "suggesting that shorter radiation courses — in other words, higher doses per treatment in fewer total treatments — could be efficacious," he added.

SBRT pushes this hypothesis to the limits by condensing the treatment course to four and five sessions — which explains why SBRT is alternatively known as "extreme hypofractionation" or "stereotactic ablative radiotherapy," Kishan observed.

What radiation oncologists have been waiting for is confirmation that long-term results of SBRT are not, indeed, accompanied by higher late toxicity rates compared with other types of RT.

Now They Have the Answer, and That Answer Is No

As presented by Alan Katz, MD, Flushing Radiology Services, New York, at a median follow-up of 108 months, 515 patients with prostate cancer, most of whom were low- and intermediate-risk, were treated with robotic SBRT at doses ranging from 35 to 36.25 Gy in 5 fractions on consecutive days. Approximately 100 patients received androgen deprivation therapy (ADT) as well as SBRT.

"For the entire cohort, the 10-year biochemical recurrence-free survival (bRFS) was 93%, 81%, and 66% for low-, intermediate-, and high-risk patients, respectively," Katz reported, "while biopsy-proven local failure was found in 2%, 6%, and 10% in the same three risk groups, respectively," he added.

Results were even better for favorable, intermediate-risk patients among whom disease-free survival (DFS) rates at 10 years were highly comparable, at 89%, to rates in low-risk patients, at 93%, Katz noted.

Conversely, intermediate-risk patients with unfavorable features had outcomes that were similar to high-risk patients: DFS rates at 10 years were only 63% in intermediate-risk patients and 66% in high-risk patients.

Grades 2 and 3 late genitourinary (GU) toxicity was higher with the higher fractionation dose, at 14.6%, compared with 8.2% for the lower fractionation dose, but there were no differences in grade 2 gastrointestinal (GI) toxicity between the two schedules.

"For sexual scores, there was a significant drop off of approximately 35% to 40%," Katz observed.

"But this is in a group of men with a median age of 70 years, so there is going to be some significant drop off in sexual function anyway, so it's hard to tell exactly how much comes from the treatment or just from the aging process," he noted.

Interestingly, the use of ADT in higher-risk patients did not appear to improve long-term disease control.

"Prostate SBRT continues to demonstrate excellent local control and excellent quality of life now out to 10 years," Katz concluded.

"And given that most failures were not local, we hypothesize that dose escalation will not translate into improved bRFS," he added.

Moderately Hypofractionated Therapy

Long-term outcomes evaluating the effect of hypofractionated RT for prostate cancer are also limited, commented Ibrahim Abu-Gheida, MD, Cleveland Clinic Foundation, Ohio. Hence, the 10-year outcomes of a study in which investigators treated 854 patients with a moderately hypofractionated scheme (70 Gy in 28 fractions at 2.5 Gy per fraction) are of particular interest.

Patients again had localized prostate cancer spanning the whole risk spectrum: the study included both favorable intermediate-risk patients and unfavorable intermediate-risk patients as well as low- and high-risk participants.

At 10 years, the bRFS rates were 88% for low-risk patients, 78% for favorable intermediate-risk patients, 71% for unfavorable intermediate-risk patients, and 42% for those with high-risk disease.

Prostate cancer-specific mortality rates were actually low at 10 years ranging from 2% in the low-risk group to a high of 15% in the high-risk group, and 5% in both groups of intermediate-risk patients.

The cumulative incidence of late grade 3 and higher GU toxicity was low, at 2%, as was the incidence of late grade 3 and higher GI toxicity, at 1%.

"This fractionation schedule appears to be acceptable for patients across all risk groups," Abu-Gheida observed.

"High-dose moderately hypofractionated RT for localized prostate cancer continues to show excellent oncological outcomes with a low incidence of toxicity over long-term follow-up," he concluded.

Both ASTRO and its sister organization in Europe have recently endorsed hypofractionation as the standard approach to the treatment of localized prostate cancer, as published data are now strong enough to support this approach, Kishan noted.

Dose Escalation at 20 Years

However, Dario Pasalic, MD, University of Texas MD Anderson Cancer Center, Houston, would tend to disagree with Katz's hypothesis (as above) that dose escalation will not translate into improved bRFS, as he presented a study which found that dose escalation does make a difference.

Conducted between 1993 and 1998, that study involved 301 patients with low- to high-risk prostate cancer randomized to external beam radiation at doses of 70 Gy or 78 Gy with no accompanying neoadjuvant or adjuvant hormone therapy.

At a median follow-up of 14.3 years, freedom from failure rates were 53.8% for those who received 70 Gy, compared with 74.3% for those who received 78 Gy (P = .0018).

The significant difference between the two groups was largely driven by improvements in both biochemical and distant failure, as Pasalic observed.

For example, biochemical failure rates were 24.4% in the lower-dose group compared with 13.5% in the higher-dose group (P = .05), and distant failure rates were 17.4% in the lower-dose group compared with only 5.3% in the higher-dose group (P = .020), he noted.

This group of patients offers unique insight into the impact of increased radiation dose.    Dario Pasalic, MD

The higher-dose fractionation group was also associated with a lower rate of distant metastases, at 5%, compared with 11% for the lower-dose fractionation group.

"Death from prostate cancer was trending toward significance and was nearly halved by dose escalation," Pasalic concluded.

"This group of patients offers unique insight into the impact of increased radiation dose," he added.

Standard Versus Hypofractionated RT

Although shortened, higher-dose hypofractionated RT is gaining the upper hand for the treatment of localized prostate cancer, the standard approach can still hold its own.

This finding comes from a 10-year, head-to-head comparison of conventionally fractionated intensity-modulated radiation (C-IMRT) therapy with hypofractionated IMRT (H-IMRT) for localized prostate cancer.

C-IMRT was delivered at a total dose of 78 Gy in 38 fractions at 2 Gy per fraction and H-IMRT was delivered a total dose of 70.2 Gy in 26 fractions at 2.7 Gy per fraction.

"High-risk patients were scheduled to receive 24 months of ADT, and some intermediate-risk patients were offered up to 4 months of ADT," Vladimir Avkshtol, MD, Fox Chase Cancer Center, Philadelphia, Pennsylvania, told delegates. Equal numbers of men in both groups took ADT.

Approximately 150 men were randomized to each group and close to 30% of the cohort were high-risk.

At a median follow-up of 130 months, biochemical failure rates were similar in both groups at 21.2% in the C-IMRT group versus 25.4% in the H-IMRT group. The incidence of biochemical and/or clinical disease failure was also similar in both groups at 25.9% for patients treated with C-IMRT compared with 30.6% of those treated with H-IMRT.

Rates of prostate cancer-specific mortality were also similar at 2.7% for C-IMRT and 4% for H-IMRT. At 10 years, 78.4% of men in the C-IMRT group were still alive compared with 71.1% in the H-IMRT group.

The main difference between the two treatments was rates of metastatic disease, which were lower at 5.3% for those treated with the standard approach compared with 12.7% for those treated with the hypofractionated approach (P = .06).

"Previously published work showed that long-term quality of life changes were similar in both groups," Avkshtol concluded.

"This phase 3 trial supports utilization of moderate hypofractionation in intermediate- and high-risk prostate cancer," he suggested.

Upfront or Delayed RT

Timing of RT has not been widely explored, making noteworthy the results of a phase 3 trial evaluating the optimal sequencing of dose escalated RT given either 4 months after initiating ADT or concurrently on day 1 with ADT. The ADT used in this particular study consisted of goserelin plus bicalutamide.

A total of 438 intermediate- and high-risk prostate cancer patients — but not low-risk patients — were included in the trial, noted Shawn Malone, MD, University of Ottawa, Ontario, Canada.

At a median follow-up in excess of 12 years, there were no significant differences between the two treatment groups in terms of DFS, at 81% for the delayed RT group and 86% for the upfront group.

Local control rates were also very high and similar in both groups, at 96% for the delayed group and 94% for the upfront group, and distant DFS rates were similarly high, at 99% and 96% for the delayed versus upfront RT group, respectively.

Late grade 3 and higher GI toxicity rates were higher in the upfront group, at 4.5%, compared with 2.8% for the delayed sequencing group, as was late grade 3 GU toxicity, at 5.1% versus 1.9%.

Nevertheless, Malone concluded that the sequencing of RT given in combination with ADT did not influence clinical outcomes. In addition, the durable outcomes seen in both groups support the benefit of treating this group of prostate cancer patients with ADT in combination with dose-escalated RT regardless of when RT is given.

ADT With and Without RT

A previous report of the RTOG 9408 study (N Engl J Med. 2011;365:107-118) demonstrated that at 10 years the addition of 4 months of ADT before and during RT improved all relevant endpoints in early localized prostate cancer.

At the ASTRO meeting, Christopher Jones, MD, Sutter Medical Group and Cancer Center, Sacramento, California, gave a long-term update on the results. They show that the addition of short-term ADT to radiotherapy, given at a dose of 66.6 Gy in 1.8 Gy fractions, continued to provide superior disease control at a median follow-up of 18 years, although the earlier overall survival advantage seen at 10 years in favor of additional ADT was no longer apparent.

At a median follow-up of 18 years, rates of biochemical failure were slightly higher than they were at 10 years, occurring in 37% of patients in the RT plus ADT group and 51% of the RT alone group (P < .01), Jones noted.

Similarly, rates of distant metastases at a median of 18 years were again slightly higher than they were at 10 years, occurring in 8% of the RT plus ADT group and 12% of the RT alone group (P = .01), Jones added.

Patients in the RT plus ADT group also were less likely to experience local progression, at 12%, compared with 18% for those receiving RT alone (P < .01).

Late grade 3 GU toxicity rates, at 6.2% in the additional ADT group versus 5.3% in the RT alone group, were similar between the two groups, as were rates of grade 4 GU toxicity, at 1.4% and 0.1% in the two groups, respectively. Rates of late grade 3 and 4 GI toxicity were very low in both groups.  

"Survival differences at 10 years are still important as all survival curves go to zero at some point," Jones said.

"But these results continue to support the conclusion that the addition of short-term ADT benefits men with intermediate-risk, though not low-risk, adenocarcinoma of the prostate," he concluded. 

Malone has reported receiving honoraria from AbbVie, Amgen, Astellas, AstraZeneca, Janssen, and Sanofi, and travel expenses from TerSera. The other presenters have reported no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2018. Abstracts 59-63. Presented October 22.

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