ADT and radiation for first-line treatment of node-positive (N1) prostate cancer

It’s now a rare occurrence (12%) to be newly diagnosed with pelvic lymph node positive (N1) prostate cancer. Traditionally, this had been treated with ADT only because radiation therapy (RT) was thought to be of no benefit in extending survival. A new study seems to show that adding RT to ADT can extend survival.

There are a couple of reasons why this kind of diagnosis is rare. First, since PSA-screening became widespread in the US, patients are usually diagnosed before the cancer has spread to the lymph nodes (LNs). Secondly, while detection tools have improved, detection of positive nodes remains challenging. CT scans can only detect lymph nodes that have been seriously enlarged by cancer invasion, and enlargement doesn’t necessarily mean it’s cancerous. For that, a confirming biopsy is necessary yet very difficult because of huge anatomic variation and the near-invisibility of LNs. Multiparametric MRIs and C11-Choline PET/CT may improve diagnostic accuracy over CT alone, but they lack the sensitivity we would ideally want. There is hope that the new generation of PSMA antibody-linked PET-indicators, especially when tied to the new PET/MRI machines, may improve diagnostic accuracy. USPIO MRIs have been used to find cancerous LNs, but not in the first-line therapy setting. Cost of screening may be prohibitive for any of these to be used routinely.

Let’s distinguish between several settings in which radiation might be used on lymph nodes. All of these settings assume there are no distant metastases (M0):

a. First-line RT to the whole pelvis when cancerous nodes have been identified. I will be addressing setting “a” in this article.

b. First-line RT to the whole pelvis when cancerous nodes are suspected but not identified. This was the subject of the clinical trial RTOG 94-13, and the ongoing clinical trial RTOG 0924.

c. Adjuvant or salvage RT to the pelvic LNs when cancerous nodes have been identified. This was the subject of two retrospective studies published last year by Abdollah et al.  and by Rusthoven et al. that showed a benefit to salvage RT, and one by Kaplan et al. that showed no benefit. Update (10/2017) analyses by Zareba et al. of the National Cancer Database and by Touijer et al. of retrospective data from MSK, Mayo and San Raffaele Hospital (Milan) also suggest a benefit to salvage RT.

d. Adjuvant or salvage RT to the pelvic LNs when cancerous nodes are suspected but not identified. This is the subject of the ongoing clinical trial RTOG0534.

e. Spot radiation to one or several LNs upon recurrence after radical prostate treatment. This was the subject of some small studies by Picchio et al., Bonomo et al., and Jereczek-Fossa et al.

(Update 4/2019) Sargos et al. reported the results of a multi-institutional randomized trial comparing whole pelvic radiation+ADT to ADT alone in 263 men with locally advanced prostate cancer.

• all men received 3 years of Lupron
• half the men also received 66-74Gy to the prostate and 46 Gy to the whole pelvis
• 8-year progression-free survival was 48% for RT+ADT vs 7% for ADT alone
• 8-year prostate cancer mortality was reduced by 48% by adding RT
• 8-year overall survival was 65% for RT+ADT vs 57% for ADT alone (similar at 8 years)
• 8-year metastasis-free survival was similar at 8 years, but loco-regional progression was lower in the RT+ADT arm

In a 2001 study from MD Anderson, Zagars et al. retrospectively looked at patients who had a prostatectomy between 1984 and 1998, but where the surgery was not completed after positive LNs were detected. Traditionally, if frozen sections of pelvic nodes revealed cancer, the prostatectomy was discontinued and ADT only was immediately begun. Such patients fared much better in terms of disease progression if they were treated with both ADT and RT than if they were treated with ADT alone. After 10 years, the overall survival among those who received RT and ADT was 67%, but only 46% if they only received ADT.

In a 2013 retrospective analysis of the SEER database, Tward et al. found 1,100 patients who were diagnosed with node-positive prostate cancer between 1988 and 2006. The 10-year prostate cancer specific survival was 63% among those who received definitive RT, but was significantly lower, 50%, among those who did not.

In a similar analysis of the SEER database last year, Rusthoven et al. found 796 patients who were clinically diagnosed with positive lymph nodes between 1995 and 2005. 43% had RT and the rest had no local therapy. The 10-year prostate cancer specific survival was 67% if they received definitive RT, but was 53% if they did not.

In an early subgroup analysis of the STAMPEDE trial, those who were N1 and received ADT and RT (at least RT was planned) had a 2-year failure-free survival of 85%. This compared to only 55% among those who were N1 and received only ADT.

In an analysis of the National Cancer Database, Lin et al. identified 3,682 patients who were clinically diagnosed with positive lymph nodes between from 2004 to 2011. A third were treated with ADT only, and a half had both RT and ADT. The 5-year overall survival was 86% for those who received both RT and ADT, but was 71% if they received ADT only. They found 331 matched pairs of patients who had similar risk factors, and found that adding RT to ADT decreased 5-year mortality by 58%. The authors conclude:

"These data, if appropriately validated, suggest that a significant proportion of such patients at high risk for prostate cancer death may indeed be undertreated warranting a re-evaluation of current practice guidelines.”

Further evidence that whole-pelvic RT may be beneficial for all node-positive patients comes from retrospective analyses of its use in the salvage setting. As mentioned in setting “c” above, several previous studies have looked at adjuvant or salvage RT after positive lymph nodes have been detected during prostatectomy using  pelvic lymph node dissection (PLND). Extended PLND (ePLND) is gaining in popularity, especially in Europe, in which 30 or more pelvic lymph nodes are extracted in hope of a providing a cure without adding RT. Alternatively, the surgeon may remove the prostate, and refer the patient for adjuvant RT. While the two most recent retrospective studies have shown a survival benefit to adjuvant/salvage radiation, one did not, and we do not yet have a randomized clinical trial to provide definitive answers.

While most of these recent studies suggest a benefit to whole pelvic RT treatment of node positive newly diagnosed prostate cancer, we cannot be sure of that until randomized clinical trials are conducted. To my knowledge, there are none so far.

The other side of the equation is the effect of pelvic radiation on quality of life. The data are equivocal. In RTOG 94-13, Grade 3 lymphopenia, and Grade 3 GI toxicity was a problem for 8% and 5%, respectively,  among those receiving neoadjuvant ADT and whole pelvic RT.  DeVille et al. noted a higher rate of acute GI toxicity, but not late GI toxicity. At escalated doses, Johnson et al. noted that late term GI toxicity was much higher in men who received whole pelvic RT, while Patel et al. noted no significant difference in toxicity.

There are many outstanding questions, with few clear answers, for the doctor and patient to discuss with respect to RT for N1 prostate cancer:

• What is the most appropriate radiation dose?
• Is there a limit to the number of infected nodes beyond which it is fruitless to use RT? 
• Should simultaneous integrated boost RT be used on infected nodes? 
• Can SBRT equal or improve the risk/benefit profile over IMRT? 
• What is the best timing for neoadjuvant/concurrent/adjuvant ADT? 
• Can outcomes be improved with docetaxel? 
• Can outcomes be improved with immunotherapy? 
• Is whole pelvic RT or ePLND more effective? 
• Can staging be improved with new imaging techniques? 
• Can RT toxicity be reduced with improved image guidance or advanced delivery devices? 
• Should rectal spacers be used to reduce GI toxicity? 
• What are the patient risk factors that affect oncological control and toxicity? 
• How much of the improved survival is a delay due to cytoreduction, and how much is actual cure?