Pelvic lymph node treatment area is seldom wide enough

A Mayo Clinic study sought to determine exactly where the recurrences were after failure of radical prostatectomy.

Parker et al. studied recurrences in 41 patients who received a post-prostatectomy [11C]choline PET/CT scan between 2008 and 2015, and at least one recurrence site was identified (median = 2). They were all candidates for whole pelvic field salvage radiation, using at least 45 Gy of external beam radiation. The authors classified the patients’ recurrence sites as:

  1. IF (in-field) if the recurrence site would receive at least 45 Gy
  2. EOF (edge of field) if the recurrence site would receive less than 45 Gy (inadequate dose)
  3. OOF (out of field) if the recurrence site would not receive any radiation

They identified 121 recurrence sites. A sizeable minority (43 percent) of the recurrence sites were within the whole pelvic radiation field; however, when they looked at how many of the patients were adequately treated for all their recurrence sites, a disturbing picture emerges:

  • Only 12 percent had IF recurrences
  • 24 percent had EOF recurrences (median dose = 10 Gy)
  • 88 percent had OOF recurrences.
    • 15 percent had both EOF and OOF recurrences.
    • 10 percent had both IF and OOF recurrences.

It should be mentioned that the patients did not receive the PET/CT scans until their PSA reached a median of 3.1 ng/ml ([11C]choline PET/CT scanning isn’t much good at PSA levels lower than 2 ng/ml.) This occurred a median of 15 months after biochemical failure (PSA ≥ 0.2 ng/ml). And biochemical failure occurred a median of 24 months after prostatectomy. We know that waiting this long is sub-optimal.

A similar study at Memorial Sloan-Kettering Cancer Center looked at the site of failure after first-line radiation therapy to the prostate only (including seminal vesicles in some). They used CT scans (mostly) to detect sites of failure among 60 patients who had their first failure in the pelvic area. Spratt et al. found that, among those patients, only 42 percent would have the first detected lymph node metastasis treated by the standard pelvic lymph node radiation field. They found that expanding the field to include the common iliac lymph nodes would result in treatment of 93 percent of recurrences.

A study at University Hospital Munich used [18F]- or [11C]choline PET/CT scans to determine the site of lymph node involvement in 32 high-risk patients, and in 87 patients who were biochemically recurrent after prostatectomy. Locations of lymph node involvement were similar for both groups, with 39 percent of pelvic lymph nodes missed by the standard treatment field.

The other common method of treating pelvic lymph nodes is via extended pelvic lymph node dissection (ePLND).  In one recent study, almost a quarter of positive lymph nodes would have been missed even if ePLND had been used.

It is possible that as advanced PET scans gain wider use, detection of smaller pelvic lymph node metastases will be possible. Jelle Barentsz at Radboud University Hospital in Nijmegen, Holland claims he can detect lymph nodes metastases as small as 2 mm using USPIO MRI. Even so, we are far from being able to detect all micrometastases in the pelvic area. If the goal is curative therapy, it is necessary to treat what we can’t see as well as what we can see.

Unfortunately, it is not always as simple as expanding the radiation treatment field or increasing the number of pelvic lymph nodes dissected surgically. As the treated area is widened, the risk for side effects increases. Lymphoceles and lymphedema are potentially crippling side effects of surgical excision. Damage to the enteric tissue of the small bowel and vascular damage become risk factors with wider radiation treatment fields. For anatomical reasons, not everyone is a good candidate.

Such risks have to be balanced against the evidence for the potential benefit of such treatment. The success of pelvic radiation in various settings was previously discussed here, and early results from  the STAMPEDE clinical trial among N1 patients are encouraging.

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

13 Responses

  1. Let’s explore the logical implications of your statement: “If the goal is curative therapy, it is necessary to treat what we can’t see as well as what we can see”.

    I think this nicely frames an essential question we face as a community: “Is prostate cancer a disease which we can cure”.

    Simply asking it so boldly raises questions about one’s competence and experience. Yet what have decades of searching for a cure for prostate cancer yielded. Joe Biden is proposing a “moon shot” as if simply providing more resources will provide a positive answer to the question. However, what if prostate cancer is not a “disease” which we can “cure”? Suppose it is like many other conditions affecting us, such as hypertension, a complex manifestation of cascading biopsychosocial influences within our internal and external environments that requires long-term management and a planned staging of treatment strategies?

    I have some skin in this game. My grade 9 (5 + 4) prostate cancer was diagnosed 2.5 years ago and has survived two conventional treatments administered with curative intent — a robot-assisted radical prostatectomy and salvage radiation treatment of the prostate bed. One could argue that my chances for a cure would have been improved had administration of an androgen blocker like Casodex been added to the mix initially, as results published in this week’s New York Times suggest.

    Hindsight is always 20/20, but it is reasonable to ask: What actions would have been recommended if long-term management to prevent disease progression and perhaps reduce tumor burden, rather than looking for a cure, had been the guiding principle. After my two failed curative attempts, I tried a very aggressive trial with medical marijuana following the Rick Simpson Oil protocol. A very fine grained analysis of a graphic display of my PSA kinetics across baseline, and the above-mentioned failed treatments, indicates that this is the only intervention that altered the progression of my prostate cancer, although only for a short interval. For one 4-month period I actually had a “negative” PSA doubling time!

    I would have tried this first.

    There is a large body of evidence suggesting that removing the primary tumor stimulates growth of any secondary tumors. I would have delayed my radical prostatectomy until other interventions had been tried.

    Likewise, there is an emerging literature which suggests that detection of the primary tumor is preceded by a long period of dormancy during which time the cancer has likely spread throughout the body (google Leonid Hanin for a slew of references). This suggests that phasing in systemic treatments might be a better approach than saving them for later after curative attempts fail, leaving the patient depleted and demoralized.

    I realize this might sound like a sour grapes account of my treatment history and I hope it is not perceived that way. I am grateful for the help I have received and for the friendships and knowledge I have acquired on my journey thus far. It has occurred to me, however, that searching for a “cure” for prostate cancer might redirect attention and resources away from attempts to find more effective management strategies that benefit individual patients. Large, double-blind, placebo-controlled clinical trials serve a useful purpose, but we have invested little in developing effective biomarkers to supplement or replace PSA kinetics as ways to track tumor progression and cancer cell proliferation in a particular patient.

    If we had such a reliable marker, each patient could serve as the basis for a single subject research design driven by a time-tested continual quality improvement model that works in health care the same way that it has worked in manufacturing for 100 years since it was first formulated by Walter Shewhart. Based on the scientific method, it involves providing re-iterative answers to these three basic questions: (1) What outcome do you want to accomplish? (2) What method will you use to achieve that objective? (3) How will you determine if you are successful?

    This data-based approach to clinical decision making has been described by Don Wheeler and myself in publications that I will be pleased to share with others who might want to consider them for their own use.

    I think you can access two of them by googling “pfadt”, “wheeler” and “statistical process control.”

    Food for thought that hopefully stimulates a discussion.

  2. Great view of past failures. Now, with PSMA PET/CT scanning, we move into a new area of PET/CT guided salvage radiotherapy.

  3. First, here are links to two papers that address Al Pfadt and his colleagues’ hypotheses mentioned in his comments above:

    Using statistical process control to make data-based clinical decisions

    Applied behavior analysis and statistical process control?

    Second, I think it is extremely important to distinguish between the ability to “cure” (meaning completely eliminate) different types of prostate cancer. We have known for decades that some forms of prostate cancer are eminently “curable” (but it is open to question whether they need to be “cured”) and that the forms of prostate cancer that are most in need of highly effective therapy are all too often not “curable” with our currently available skills and techniques.

    Willett Whitmore — an eminent urologic oncologist at Memorial Sloan-Kettering Cancer Center and a very charming and intelligent man, who died of prostate cancer himself in his late 70s — summed this conundrum up succinctly back in the 1980s with his set of rhetorical questions that went as follows: “Is cure possible? Is cure necessary? Is cure only possible when it is not necessary?”

    Trying to cure a form of prostate cancer like Al Pfadt’s is a very different challenge compared to trying to cure a locally confined, Gleason 3 + 4 prostate cancer in a patient with T1c disease and a PSA of 5 ng/ml. Having said that, I am well aware of patients diagnosed with Gleason 5 + 5 = 10 disease who have been treated and apparently cured in that they lived for an additional 20+ years with no apparent sign of recurrence of their cancer.

    Third, I think we need to be clear that an enormous amount of money (and effort) has, in fact, been spent over the past 30 years in trying to find better markers for monitoring the status of patients with prostate cancer (before, during, and after treatment). Have we been as successful as we would like to have been as yet in finding truly meaningful new markers? No, we absolutely haven’t, but it would be inappropriate to think that we haven’t been trying to do this. And arguably, for men initially diagnosed with high-risk forms of prostate cancer, it is only recently that we have started to use all of the tools that are available to determine the precise status of such patients before we initiate treatment. There are some who would argue, for example, that any man diagnosed with Gleason 8 to 10 disease and a PSA of 10 or higher should get an immediate bone marrow biopsy to see whether there is any sign of prostate cancer that has already metastasized to the bones. (But even that is by no means guaranteed to identify such metastatic prostate cancer.)

  4. Thanks, Mike, for posting the links to the articles and for clarifying the quandary we face as a community. If does indeed appear as if the cancers most susceptible to a “cure” are the ones least in need of immediate treatment.

    The phenomenon of ” Dormancy” is getting increased attention. Leonid Hanin addresses this in a recent paper, “Seeing the invisible: how mathematical models uncover tumor dormancy, reconstruct the natural history of cancer and assess the effects of treatment”. If a cancer lurks in our bones at such a low level that it can’t be detected, does it really exist?

    I suspect that many low level cancers that we think we cured left residues somewhere that can’t be detected by our current technologies. Like questions about the number of angels that can dance on the head of a pin, does the answer matter? I suggest it does, but as you note, the ultimate answer lies in the trade-off between anticipated benefits vs likely unintended consequences.

    A current meme in the medical community is: It is more important to determine what person the disease has that to determine what disease the person has. Genomic medicine is an example of that approach, as are holistic strategies that consider all aspects of a person’s life space (diet, lifestyle preferences, one’s partner’s needs, etc.) in creating a comprehensive biopsychosocial treatment plan.

  5. This reminds me of an orthopedic discussion about acetabular (hip socket ) fractures. The fractures that can be fixed, don’t need it. The fractures that need to be fixed, can’t be fixed.

  6. Al:

    As of now, I am cured.


    Even the most accurate PET scan won’t detect micrometastases. That’s why we have to treat what we can’t see. We are still learning how to do that. The pelvic lymph nodes are a special case where cure may still be possible, but it will never be cured by treating only what we can see.

  7. Thanks for the info.

  8. Allen:

    I think it is Dr. “Snuffy” Smith who is credited with the phrase “a durable remission”. Disconcerting when you were hoping for a “cure” but more realistic and action oriented.

    If you are “cured”, then the battle is over. You won and cancer lost.

    A “durable state of remission” reminds us that we must still be vigilant and actively involved in sustaining the gains we have made so far.

  9. Dear Al:

    I don’t know who “Snuffy” Smith is. You may be referring to Dr. “Snuffy” Myers. But even though I know “Snuffy” Myers refers to “durable remissions” on a regular basis, the term itself has been around for decades. At this point in time I think it would be hard to determine with whom (or even where) it originated.

  10. pfadtag:

    Doctors can use whatever term they want to, perhaps to legally protect themselves. As a patient, I prefer the term “cure.” I have no evidence of disease, so as of the present moment, I consider myself cured. It is no different than considering myself cured, rather than in a “durable remission,” when I get over a cold. I continue to have my PSA checked annually, just as I check my cholesterol and blood sugar levels — it’s now part of health maintenance. I believe it is important for patients to stay in the present moment. This attitude toward my previous disease, and towards my life in general, helps me psychologically. I highly recommend it.

  11. Caught me in a senior moment. Snuff Smith was, I think, a character in the Al Capp Li’l Abner cartoon series.

    Thanks for providing a context for the phrase “durable remission”.

    We could also speak of a “return to dormancy”.

    If you regard cancer not as a “thing” but as a “biobehavioral process”, then you can characterize its current state in terms that are observable, in so far as PSA measurements can be considered to provide meaningful surrogate measurements of its activity.

    It can be considered to be “under control”, if all of the values in the time series fall within the upper and lower process behavior limits for the most current PSA test results, displayed on a process behavior chart using procedures described in the articles I mentioned earlier.
    It can be considered to be “actively growing” if it can be shown that sequential PSA values do not represent random variation about a set point or central value, represented by the mean of the time series, but rather that one or more values in the time series are “outliers” above the threshold value identified by the upper process behavior limit of a process behavior chart. You can also make this determination by looking at the slope of the regression line connecting consecutive values displayed on a semi-log {celeration} chart. Likewise, it can be considered to be “actively decreasing”, if the slope of the line connecting consecutive points is negative or if one or more values in the time series lie below the lower behavior process limit.

    Finally, the operational definition of “in remission” is the failure to detect a PSA value above a threshold value specified by the laboratory that analyzes the test results.

    This is where the question of “being able to treat what you cannot see” comes into play. It is not true that you can’t “treat” cancer that is undetectable by ultrasensitive PSA tests. You just cannot use those test results to determine if your treatment of a presumed cancer was successful or not.

    Like the proverbial tree falling in a forest when no one is around to hear it, an event takes place whether or not it is observed. A cancer does not cease to exist just because we cannot measure any traces of its activity. The absence of detectable PSA test results after a radical prostatectomy does not mean that all cancer was eradicated and that the patient was cured. Only that there is no evidence to prove its existence. However, lack of such evidence does not prove its absence.

  12. Dear Al:

    I think we may be becoming a tad overly psycho-philosophical about all this. As Allen points out, what one wants to “call” the state of long-term remission which may or may not be a “cure” is a rather personal matter, because it rather depends on how one thinks about one’s life in its entirety and one’s willingness to “move on” from one difficult event to the next stage in life.

    I had a heart attack a decade ago. I don’t think about it in terms of cured or not cured at all. It is simply something that happened. If I am asked about it, my answer is always the same: “There are two sorts of heart attack: the ones that kill you and ones that don’t. The latter is the prefered event for most people.” And apart from the fact that I now take some drugs I didn’t take previously, and I check in with my cardiologist once a year, I have just “moved on”. Most of the time I don’t think about it at all.

  13. Thanks for the advice. Truly, the same glass is either ” half full” or “half empty”.

    As a research scientist I acquired a mindset that may not be in my best interests as a patient!

    I am reading Full Catastrophe Living by Jon Kabat Zinn and his approach to coping with chronic disease using mindfulness-based stress reduction certainly supports your position.

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