Whole-pelvic radiation therapy for high-risk patients

The decision about whether or not to treat the entire pelvic lymph node area along with the prostate (called whole pelvic radiation therapy (WPRT)) or to treat just the prostate with a margin around it (called prostate-only radiation therapy (PORT)) has long been a matter of judgment. Now we have proof of its benefit in most high-risk patients.

Murthy et al. reported the results of "POP-RT," a randomized clinical trial conducted among 224 high-risk and very high-risk patients treated at the Tata Memorial Hospital in Mumbai, India between 2011 to 2017. What sets this trial apart from previous trials that had equivocal results (like RTOG 9413 and GETUG-01) are the rigorous patient selection criteria and the now-proven treatments they received.

80% of patients were screened using PSMA PET/CT to rule out those with already-detectable lymph node or distant metastases. The rest were staged using bone scan/CT. Local staging (T1-4) was done with CT, MRI, and physical examination. Patients had to have a probability of microscopic lymph node metastases of greater than 20% using the Roach formula:

Probability of cancer in pelvic lymph nodes = (⅔ x PSA) + (10 x (Gleason score - 6))

This meant that high-risk patients had to have the following risk characteristics:

• If Gleason Score 8-10: Any PSA, T1- T3a N0 M0 
• If Gleason Score 7: PSA > 15, T1-T3a N0 M0 
• If Gleason Score 6: PSA > 30, T1-T3a N0 M0
• Also, any other "Very High Risk" including T3b-T4 N0 M0, with any Gleason Score, any PSA, if their Roach probability was > 20%
• In this group of patients, the median Roach probability was about 40% and the median PSA was 28 ng/ml.

Treatment consisted of dose-escalated IMRT and 2 years of adjuvant androgen deprivation therapy (ADT):

• Prostate dose= 68 Gy in 25 fractions or treatments (equivalent to about 81 Gy in 40 treatments)
• Pelvic lymph node dose = 50 Gy in 25 treatments (note: this is somewhat higher than the 45 Gy in 25 treatments that is usually given)
• Pelvic lymph nodes up to the aortic bifurcation were treated, which conforms to current RTOG specs.
• ADT was started 2 months before IMRT and continued for a total of 2 years
• Note: this trial began before ASCENDE-RT proved the superiority of brachy boost therapy, but used a higher IMRT dose and longer ADT. This high-dose IMRT/long-term ADT treatment was proven effective by the DART 01/03 GICOR trial.

After median follow-up of 68 months, the oncological results were:

• 5-year biochemical failure-free survival was 95% for the WPRT group vs. 81% for the PORT group.
• 5-year disease-free survival, which means they had no PSA progression and no radiographic progression, was 90% for WPRT (15 recurrences) vs 77% for PORT (36 recurrences).
• 5-year metastasis-free survival, which is a good surrogate endpoint for overall survival, was 95% for WPRT vs 88% for PORT
• Younger patients (< 66) derived more benefit from WPRT
• Among those with recurrences, most (52%) of the recurrences in the PORT arm were in pelvic lymph nodes, whereas few (12.5%) were nodal recurrences in the WPRT arm.

Murthy et al. also reported on toxicity and patient-reported quality of life outcomes comparing the two treatments.

• Acute grade 2 or greater GI toxicity was 33% for WPRT vs 25% for  PORT (not statistically different)
• Acute grade 2 or greater GU toxicity was 33% for WPRT vs 24% for PORT (not statistically different)
• Late-term grade 2 or greater GI toxicity was 8.2% for WPRT vs 4.5% for  PORT (not statistically different)
• Late-term grade 2 or greater GU toxicity was 20.0% for WPRT vs 8.9% for PORT (statistically different)
• Very few patients in either arm suffered serious (grade 3) toxicity. There was no grade 4 toxicity.
• While higher rectal radiation doses were not associated with higher bowel toxicity, higher bladder doses were associated with higher urinary toxicity.
• Patient-reported outcomes were not significantly different for urinary, bowel or sexual adverse effects.
• (update 3/24) no significant changes at 75 months.

It is worth noting that cancer in the Indian population is generally more progressed than in the US population at the time of diagnosis. Those with Stage T3b/T4 (seminal vesicle invasion and invasion into surrounding organs) accounted for 47% of this group, whereas it's a rare finding in the US because of more prevalent earlier PSA testing. Another difference is that 27% of patients had a previous TURP, which is high compared to the US. It is possible that the high TURP rate may have contributed to extra urinary toxicity seen in men getting WPRT.

Given the relatively mild side effect profile with no clinically significant difference to patients, WPRT should be the standard of care for high-risk patients at high risk of pelvic lymph node involvement. In 2027, we will have the results of a much larger, multi-institutional randomized trial (RTOG 0924) of WPRT vs PORT. Also, there was no increase in second malignancies due to the expanded coverage in this study.