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

It’s now a relatively rare occurrence (about 12 percent of new patients) 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 LNs 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. Multi-parametric MRIs and [11C]choline PET/CT scans 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 (see Lawton et al.), 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.
(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 RTOG 0534.
(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.

In a 2001 study from M. D. 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 percent, but only 46 percent if they only received ADT.

In a 2012 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 percent among those who received definitive RT, but was significantly lower, 50 percent, 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 percent had RT and the rest had no local therapy. The 10-year prostate cancer-specific survival was 67 percent if they received definitive RT, but was 53 percent 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 percent. This compared to only 55 percent among those who were N1 and received only ADT. (The full, recent results of the STAMPEDE study are (discussed in this commentary).

In an analysis of the National Cancer Database, Lin et al. identified 3,682 patients who were clinically diagnosed with positive LNs between 2004 and 2011. A third were treated with ADT only, and half had both RT and ADT. The 5-year overall survival was 86 percent for those who received both RT and ADT, but was 71 percent 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 percent. 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 LNs 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 (see Lawton et al.), Grade 3 lymphopenia, and Grade 3 GI toxicity was a problem for 8 percent and 5 percent, respectively, of 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?

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

8 Responses

  1. As Allen has already mentioned here, the patient newly diagnosed with node-positive prostate cancer is now faced with competing evidence about the value of combining radiation therapy with ADT or chemotherapy with ADT in the first-line treatment of their disease (quite apart from any other issues and possibilities).

    We have no “right” or “wrong” answers to this at the present time. For some patients. the most aggressive possible approach may be the best one (and that may well be radiation + ADT + docetaxel-based chemotherapy too). For others (e.g., those who are older or with a less extended life expectancy for other reasons), optimizing quality of life may be as or more important as optimizing quantity — suggesting a somewhat less aggressive approach.

    From a patient perspective, the important issue is to ensure that all options get discussed with a clinician who is not “pushing” his or her own biases (based on training and experience), but is helping the patient to make the best possible choice for himself and his individual situation.

  2. Good discussion and does leave what may be “most” appropriate still an unknown. I believe Sitemaster summed it up correctly. … We don’t know what is best for one that may not be best for another. For now, good discussion with one’s treating physician pondering the questions and hopefully coming up with reasonable treatment.

  3. As someone who had high-dose adjuvant (post-surgery) radiation to my pelvis and prostate bed about 7 years ago, I am always interested in this kind of information. Thanks for the article, very informative.

    I’d much appreciate your comments on a situation that falls into the scope of this article.

    Gleason 9, two positive lymph nodes according to gallium PSMA scan. Two approaches have been offered:

    1. IMRT to prostate and pelvic lymph nodes with 2 years of ADT.
    2. Radical prostatectomy with probable adjuvant radiation depending on outcome of the surgery.

    What do you think? Are there benefits to surgery, even if adjuvant radiation is probably going to be recommended anyway? Do such benefits outweigh the increased side effects from both? What is the chance that the PSMA scan is wrong and surgery will find the lymph nodes to be actually negative, and would that change anything?

    I personally have on-going, unpleasant side effects from my combined and aggressive treatment, but happily no PSA recurrence after 7 years.


  4. Mycroft,

    I’m confused by your post. You said that you already had whole pelvic salvage radiation after prostatectomy and have had no PSA recurrence since, for which I offer my heartfelt congratulations. So you are asking just out of academic interest?

    I never think it’s a good idea to go into prostatectomy knowing that adjuvant/salvage radiation will follow. The side effects are worse than if either were done alone and there is no advantage. The better choices are between primary whole pelvic radiation and surgery with ePLND. I’d side with the radiation because it treats the pelvic bed, whereas the surgery doesn’t. There are false positives with every kind of scan — we can only make such decisions by taking account of the probabilities.

  5. Allen,
    Yes, the question is not related to my situation. A close friend asked me for advice since I have some experience, and your post seemed to fit the situation. Thanks for the reply. I have personal experience of the side effects of surgery + aggressive radiation and can vouch that they are not pleasant. :)

    Does ePLND remove all the pelvic lymph nodes? And what is the significance of treating the pelvic bed? Is this a possible site of metastasis that would not be addressed by surgery?

  6. Extended pelvic lymph node dissection (ePLND) is an attempt to remove all pelvic lymph nodes; typically, they remove about 20 of them. It’s hard to know if they got them all. Lymph nodes, when not enlarged, can be very small, and are nearly invisible against the background of flesh and blood vessels. Fluorescent dyes can improve their visibility. Also, unlike blood vessels which branch, lymph vessels are in a network and their exact placement can vary.

    The pelvic bed is the first place that prostate cancer invades after leaving the prostate capsule. Surgery cannot cut deeply there without causing very serious morbidity. It is the area usually treated by salvage radiation.

  7. Allen,

    Just to clarify. Did you mean “prostate bed”, if not then what is “pelvic bed”?

  8. I mean all the tissue that surrounds the prostate in the pelvis. When the cancer breaks through the capsule, it grows into it.

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