RADIATION THERAPY FOR PROSTATE CANCER:  How Best to Treat Intermediate- and High-Risk Disease? The ASCENDE trial presents a clear preference.

This article benefitted from the review and suggestions from Dr. Peter Grimm, Radiation Oncologist, Seattle WA.

The ASCENDE trial was conducted by a large group of investigators in British Columbia and was reported as an abstract at both the ASCO Genitourinary Symposium by Morris et al., February 2015, and updated at the ASTRO meeting, November 2015, by Rodda et al.

The ASCENDE trial is a well-conducted randomized study of 398 men with “unfavorable” intermediate- and high-risk prostate cancer (using the NCCN definitions) and compared two therapy regimens. One arm consisted of dose-escalated external beam radiotherapy (DE-EBRT) which delivered 46 Gy to the whole pelvis supplemented with an additional 32 Gy EBRT boost to the prostate. The total dose to the prostate for this arm was 78 Gy (a measure of radiation dosage).

The comparison arm employed the same EBRT dose to the whole pelvis supplemented with a permanent seed brachytherapy boost to the prostate for a minimum of 115 Gy. The combination arm delivered a total does to the prostate of 161 Gy.

The whole pelvis EBRT in both arms included the prostate, seminal vesicles, and the regional node bearing areas. Two hundred men received DE-EBRT as monotherapy; 198 received the combination regimen.  The radiation was preceded in each arm by 8 months of neoadjuvant androgen suppression which was continued throughout the radiation treatment for a total of 12 months.

In essence, the ASCENDE trial compared the effectiveness of external beam radiotherapy boost to an Iodine-125 brachytherapy boost for accentuating treatment to the cancer within the prostate gland.

Some men were excluded from participating in the study because of a PSA > 40 ng/mL or clinical T Stage of >cT2b. Also excluded from the study were men whose prostate gland was > 75 cc, those with prior transurethral resections of the prostate (TURP), and men unfit for general or spinal anesthesia — three features that disqualified men for brachytherapy.

The measure of initial treatment efficacy was the interval from the start of therapy to a rise in the PSA above a threshold level, i.e., a rise in PSA above the lowest post treatment PSA level (the nadir) + 2 ng/mL PSA (the ‘Phoenix” definition).

 

In the ASTRO report the results were further analyzed using the standard surgical definition of PSA recurrence, i.e. a PSA > 0.2 ng/mL. The follow-up to date was 6.5 years.

 

How did the treatments compare?  There was a clear advantage for the brachytherapy boost arm.

PSA values at 7 and 9 years showed a clear difference in biochemical recurrence between the two arms favoring the brachytherapy boost.  Statistical estimates for the percentage of men remaining free from biochemical recurrence for the EBRT boost v. brachytherapy boost were 71% vs 86% and 63% vs 83%, respectively — a greater than 50% improvement.

A subgroup analysis of PSA recurrence-free survival at 9 years favored the brachytherapy boost over the DE-EBRT boost in both intermediate-risk and high-risk groups, 94% vs 70% and 78% vs, 58%, respectively.

“The median PSA at latest follow-up for non-relapsing patients assigned to the brachytherapy arm is 0.02 vs 0.24 ng/mL for EBRT boost group.

The November ASTRO abstract contributed some additional analysis. By using the surgically accepted definition for biochemical recurrence, i.e., PSA > 0.2 ng/mL “the 7-year Kaplan-Meier estimate for PFS [progression-free survival] was 82% for men randomized to LDR-PB [low dose rate brachytherapy] boost compared to only 42% for men assigned to DE-EBRT,” and a benefit was seen in both the intermediate-risk and high-risk groups. For men having the highest risk for recurrence, i.e. those meeting all three of the NCCN elements of high-risk disease, there was no difference in PFS between the two arms.

At this relatively early point of median follow-up it is not surprising that there was no significant difference in metastasis-free survival or overall survival. Future follow-up will be required for those observations.

The explanation for the marked difference in outcome between the two arms is speculative, but likely results from the significantly greater radiation dose to the prostate gland resulting from the Iodine-125 boost, 161 Gy, compared to 78 Gy for the ERBT boost arm.

 

BOTTOM LINE:  The ASCO abstract concludes: “In a randomized trial, an Iodine-125 LDR  boost  was more effective than an EBRT boost in rendering unfavorable-risk prostate cancer patients biochemically disease free.”

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