Efficacy and safety in the curative treatment of progressive, lymph node-positive prostate cancer

The salvage treatment of men found to have positive lymph nodes after prior (surgical) treatment and the identification of such positive lymph nodes using techniques such as [11C]choline PET/CT scans is still not well established, but it does offer opportunity for some men.

The ability to identify cancerous lymph nodes has been enhanced by the availability of [11C]choline PET/CT scans (and other evolving techniques) in men with a PSA level of about 2 ng/ml or higher. This ability clearly then raises the question of whether such men can be treated with curative intent by surgical removal of the positive lymph nodes or by other forms of treatment.

In 2105 we reported on data published by Karnes et al. from the Mayo Clinic group (still the only place in America where [11C]choline PET/CT scans are available.. These data were from an initial series of 52 patients with a rising PSA after first-line surgery who had all undergone salvage lymph node dissections between 2009 and 2013 after identification of nodal recurrence of their cancer by [11C]choline PET/CT scans.

We now have data reported by Rischke et al. from a cohort of 25 German patients. All these patients had previously received first-line treatment with or without salvage radiation therapy to the prostate bed. Positive lymph nodes in these patients were suspected after a rising PSA and confirmed by [11C]choline PET/CT scanning and by MRI scans. The authors report the following data after treating these patient not with surgical excision of the lymph nodes but by targeted, extended salvage radiation therapy:

  • 10/25 patients (40 percent) had previously received salvage radiation therapy to the prostate bed after a primary radical prostatectomy.
  • 21/25 patients (84 percent) required only radiation of pelvic lymph nodes.
  • 2/25 patients (12 percent) required only radiation of retroperitoneal lymph nodes.
  • 1/25 patients (4 percent) required radiation of pelvic and retroperitoneal lymph nodes.
  • Average (median) patient follow-up post-treatment was 2.9 years or 59 months.
  • Average (median) times to PSA progression were
    • 16.6 months for the entire cohort.
    • 34.9 months for the 15 patients with just one or two PET-positive lymph nodes.
    • 12.7 months for the 10 patients with three or more PET-positive lymph nodes.
  • Acute and late toxicities were said to be mild to moderate, and there were no grade 3 adverse events observed.

The longest available data on follow-up of patients receiving salvage treatment to the lymph nodes after documentation of lymph node positive disease using [11C]choline PET/CT scans appears to have been reported by Suardi et al. on a cohort of 59 Italian patients. These patients were initially treated between 2002 and 2008 and so are among the earliest whose positive lymph nodes would have been identified by [11C]choline PET/CT scanning.

  • Average (median) follow-up after salvage lymph node dissection in these patients was 81.1 months.
  • 35/59 patients (59.3 percent) achieved a biochemical response (with their PSA falling back to < 0.2 ng/ml).
  • The actuarial 8-year response rates in the 35 patients with complete biochemical responses were
    • A biochemical progression-free response rate of 23 percent
    • An overall clinical recurrence rate of 38 percent
    • A prostate cancer-specific survival rate of 81 percent, respectively
  • PSA level at the time of salvage lymph node dissection was the only predictor of clinical recurrence prior to salvage surgery (p = 0.03).
  • Biochemical response and the presence of retroperitoneal lymph node metastases were associated with the likelihood of clinical recurrence after salvage surgery was completed (p ≤ 0.04).

It appears to be clear from these three studies that it is possible to identify and successfully treat at least some men with positive lymph nodes through the use of [11C]choline PET/CT scans and multiparametric MRIs. It is also clear that lower numbers of positive lymph nodes increase the likelihood of treatment success. However, this type of treatment still seems to be as much an art as a science in that there is a great deal of skill involved in determining precisely which patients will be good candidates for treatment (by surgery or by targeted radiation therapy).

4 Responses

  1. I’m afraid I disagree with the title and some of the conclusions you drew here, which is why I didn’t comment on this small radiation study. It is not at all clear to me, at least from the abstract, that the goal here was “curative,” as you assert in the title. If it was, it certainly was not proved by this study. Often the goal of such salvage radiation is to delay progression, rather than cure. It is not at all clear to me that either goal was accomplished here.

    In fact, there can be no clear conclusions about cancer control or delay without a randomized trial with an untreated control group. Recently, we looked at a meta-analysis (https://prostatecancerinfolink.net/2015/09/26/sbrt-for-oligometastatic-recurrence/) of salvage radiation for oligometastases ( 60% of which were for nodal metastases). In that pooled analysis, the authors found that only 15% were free of distant progression by 5 years from salvage treatment, with the trend going downward.

    In the Ritschke et al. study, men with fewer metastases had longer times before progression. But wouldn’t that be true whether they received salvage treatment or not? Other risk factors – PSA, PSA kinetics, time before PSA progression, previous salvage and use of ADT, original Gleason score – are strongly correlated with the number of detected metastases. It is not at all clear whether the differences are due to treatment or due to detection of two distinct cancer phenotypes that have different natural histories.

    Toxicity is very much at issue. While SBRT of 1 to 3 detected LNs is usually very safe, safety concerns go up as the radiation field is expanded. And it probably ought to be expanded to the full pelvic LN area if cure or significant delay is the goal. In the Suardi et al. study of salvage extended PLND, 13% suffered grade 3 lymphoceles (requiring surgical intervention).

    It’s not yet clear to me that any patients are cured, or that the time to death from prostate cancer has been prolonged. I think patients should have very realistic expectations for this kind of secondary salvage, especially with surgery, and I look forward to randomized clinical trials that will help us make more informed decisions.

  2. Dear Allen:

    I never suggested that any of these men were cured … and neither did the authors, but that doesn’t mean that the goal of treatment wasn’t, ideally, to cure them. The term “curative intent” is applicable even if only 1 in 1,000 patients actually can be cured. And since none of the studies have followed patients for long enough to establish the causes of their deaths, naturally we don’t know whether time of death from prostate cancer was prolonged (although since there was no comparator group in any of the studies we can’t tell that anyway).

    My only point is the very simple one that lymph node excision or targeted lymph node radiation appear to be therapeutic options, with the very big if about whether the patients are really good candidates (based on low numbers of positive lymph nodes and the skills of the treating clinicians and — you are correct — other unknown factors like genetic subtypes that may be more or less aggressive). The whole point of the radiation study was that they were not doing wide-field radiation, which was presumably why toxicity was less of an issue … and for all I can tell, from this abstract, maybe they were using SBRT anyway! It doesn’t tell us the form of radiotherapy being used.

    Of course we need the randomized clinical trials to actually prove whether any of this is possible … but what is a patient with one or two small node-positive lesions to do in the meantime? The only other option is wide-field radiation + 2 or 3 years of ADT, which is a pretty poor option if targeted therapy can produce comparable or better outcomes.

  3. “IF targeted therapy can produce comparable or better outcomes” is a very big IF, and this study doesn’t really give us a clue about that. Just as extended pelvic lymph node dissection (ePLND) seems to provide better outcomes than PLND (but with the risk of greater toxicity), the same may hold true for whole pelvic lymph node treatment rather than treatment of isolated nodes.

    In the Schick et al. study, all 32 patients with lymph node relapse received salvage EBRT radiation to the full pelvic lymph node area, and all were treated with ADT. They reported 65% 3-year biochemical relapse-free survival in those patients; none relapsed in the pelvic nodes, and none experienced any acute or late toxicity > grade 2.

    By contrast, in the Decaestecker et al. study, only isolated nodes were treated with SBRT in 24 patients, none with adjuvant ADT. 15 of the 24 patients (63%) relapsed within 2 years and 10 of those 15 (67%) relapsed in untreated pelvic nodes. Only 1 patient had toxicity as high as grade 2. It may be a wasted effort to treat isolated pelvic lymph nodes.

    Lymph node metastases are often micrometastatic and are undetectable by any kind of imaging at our disposal. As more lymph nodes are infected, the probability that the cancer has disseminated broadly throughout the lymphatic system goes up geometrically. Because lymph nodes are connected in networks, rather than serially, I think it will seldom be curative to treat just one or two. Radiation oncologists may choose to treat an area of several inches around pelvic LNs identified by the PET scan, or they may choose to treat the entire area, recognizing the potential for bowel toxicity in doing so.

  4. Dear Allen:

    I don’t think that anyone would disagree with the fact that if we are ever to be able to effectively and safely treat most patients with lymph node-positive recurrence with curative intent, there are two critical and as yet unavailable requirements:

    — The ability to identify the presence of very small amounts of cancer in the lymphatic system with very high accuracy
    — The ability to direct effective therapy to the same very small amounts of cancer with very high accuracy

    I would point out that 20 years ago few would have dreamt that we could use things like[11C]choline PET/CT scans and other developing scans to identify positive lymph nodes with the accuracy that we can today; nor would they have envisaged the therapeutic accuracy already available using techniques like SBRT. The question is going to be to what extent we can build on those advances (or use other techniques entirely) to make progress over the next 20 years.

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