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Men with high-risk, locally advanced prostate cancer had significantly lower odds of biochemical recurrence and improved disease-free survival (DFS) with pelvic nodal irradiation versus prostate only, a randomized trial showed.

The 5-year biochemical failure-free survival (BFFS) rate improved from 81.2% with prostate radiotherapy to 95% with irradiation of the pelvic lymph nodes. The DFS rate at 5 years improved from 77.2% to 89.5%. Distant metastasis-free survival (DMFS) also improved with treatment of pelvic nodes, but overall survival (OS) was similar between treatment groups.

Whole-pelvis irradiation was associated with more late grade ≥2 bladder toxicity, reported Vedang Murthy, MD, of Tata Memorial Hospital in Mumbai, India, and co-authors in the .

"Until the long-term outcomes of the ongoing trials are reported, prophylactic pelvic radiotherapy should be routinely considered for these patients," the authors concluded.

"The choice of BFFS as the primary endpoint is not ideal," they acknowledged. "Although OS may be an impractical endpoint in trials of localized prostate cancer, the secondary endpoint of DFS is more acceptable to define practice. In this trial, the large early difference in BFFS is the main contributor to improved DFS."

Controversy and Bias

The results added to the knowledge base for a radiation oncology controversy, but clinicians' interpretation and application of the findings will likely depend on their existing biases, said Zachary Zumsteg, MD, of Cedars-Sinai Medical Center in Los Angeles.

"Those who are skeptical regarding the utility of pelvic nodal irradiation could point out that this is a relatively small trial enrolling just over 200 patients from a single institution that showed no difference in overall survival, but a mild increase in long-term genitourinary toxicity," Zumsteg, a clinical expert for the American Society for Radiation Oncology (ASTRO), told 番茄社区 via email. " and were both larger multi-institutional trials that showed no benefit from pelvic lymph node irradiation in the past. Thus, some may argue the preponderance of the evidence still favors treatment of the prostate alone."

"On the other hand, many practitioners (including myself) already use whole-pelvis radiation therapy as a standard of care for high-risk prostate patients because of the relatively high risk of microscopic nodal spread in this situation, combined with relatively limited increases in toxicity with nodal irradiation when modern radiation techniques are employed. In my opinion, this trial adds further support for this practice, with a significant improvement in biochemical and distant metastasis-free survival in a setting that is more applicable to modern practice than prior trials."

The authors noted that the value of prophylactic pelvic irradiation in the absence of nodal involvement has been debated for decades. The rationale for treatment beyond the prostate is eradication of nodal micrometastases to improve regional control and possibly survival.

Murthy and colleagues continued the evaluation of whole-pelvis irradiation in a randomized trial of 224 patients with node-negative localized prostate cancer at high risk of recurrence. All patients received dose-escalated, hypofractionated radiotherapy but were randomized to a treatment field limited to the prostate or to whole-pelvis coverage.

In addition to radiotherapy, patients received androgen suppression with systemic therapy or by orchiectomy. The primary endpoint was BFFS at 5 years. Failure was defined as serum prostate-specific antigen (PSA) exceeding the nadir by 2 ng/mL.

After a median follow-up of 68 months, the data showed that seven patients randomized to whole-pelvis irradiation had met the primary endpoint as compared with 29 who received radiation to the prostate only, representing a 77% reduction in the hazard ratio (HR; 95% CI 0.10-0.52, P<0.0001). The 12.3% absolute difference in DFS translated into a 60% reduction in the HR (95% CI 0.22-0.73, P=0.002).

The 5-year DMFS rate was 95.0% with whole-pelvis treatment and 87.9% with prostate-only treatment (HR 0.35, 95% CI 0.15-0.82, P=0.01). The OS rate was 92.5% versus 90.8% (HR 0.92, 95% CI 0.41-2.05).

Late grade ≥2 genitourinary toxicity occurred more than twice as often with whole-pelvis treatment (20.0% vs 8.9%, P=0.02), but late grade ≥2 gastrointestinal toxicity did not differ significantly between groups (8.2% vs 4.5%, P=0.28).

Another Controversy Resolved?

The report from India followed final results of a randomized trial that addressed another unresolved issue in high-risk prostate cancer: the value of an external-beam radiotherapy boost to macroscopically visible tumor. As originally reported at the 2020 ASTRO virtual meeting, results of the showed a greater than 50% improvement in biochemical (b)DFS in men who received a radiotherapy boost to improve local tumor control.

With additional follow-up, results continued to favor the radiotherapy boost: the 5-year bDFS rate was 92% vs 85%, representing a 55% reduction in the hazard for biochemical recurrence (95% CI 0.28-0.71, P<0.001). The benefit occurred with no increase in late genitourinary or gastrointestinal toxicity, reported Uulke van der Heide, PhD, of the Netherlands Cancer Institute in Amsterdam, and co-authors in the .

The results have the potential to influence clinical practice in the U.S., according to Anthony Zietman, MD, of the Massachusetts General Hospital Cancer Center in Boston.

"For many years now, folks have been investigating whether giving higher radiation doses would improve the chance of eradicating the cancer," Zietman said in an email. "Many studies have shown that it does, but the problem is how to give high enough doses both safely and conveniently. Others have used brachytherapy (seeds) to 'top off' the radiation dose, but this is an inconvenient extra procedure, and it carries some urinary risks."

"In this trial, the investigators used more conventional radiation to give extra doses to the MR-identified cancer nodule. No extra procedure needed and, it seems, no increase in morbidity. This is likely something that most radiation oncologists would be able to do in their clinics with equipment they already have available."

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