Targeting treatments for extraprostatic and oligometastatic prostate cancer with curative intent

The moderator of a well-known, prostate cancer-specific Internet forum recently wrote to us, stating,

There has been some assumption on the part of users of internet patient forums that the [newer and] more sensitive scans can be useful to detect major tumors that can be removed laparoscopically or treated with radiation, and that this would be beneficial.

The correspondent was referring to:

  • The use of techniques like [11C]choline PET/CT scans and similar new and developing types of imaging technology (see here) to identify extraprostatic and oligometastatic tumors in men who have progressive disease after receiving definitive treatment for their primary prostate tumor
  • The use of laparoscopic surgery and highly targeted forms of radiation therapy (and some even newer techniques) to treat the tumors so identified in the hope of inducing either further long-term remissions or even cures (or sometimes just to delay the initiation of systemic androgen deprivation therapy)

The value of this combination of sophisticated imaging techniques and therapeutic interventions to remove tumors so identified is, as yet, not well defined at all. What we have at this time are data from case studies. As far as The “New” Prostate Cancer InfoLink is aware, we have no good data from large prospectively collected patient cohorts, let alone data from any type of randomized clinical trial.

The potential value of such approaches to the treatment of progressive and oligometastatic forms of prostate cancer is highly dependent on the individual characteristics of specific patients, and the answers to a number of related questions, as follows:

  • Has the patient’s original, primary tumor been entirely eliminated? Clearly there is limited value to treating positive lymph nodes, let alone micrometastases or actual metastatic sites of prostate cancer with curative intent if the primary tumor is still extant.
  • Is it clear that the imaging technique used to identify secondary extraprostatic and oligometastatic tumors is actually good enough to identify these secondary tumors with a high level of accuracy? In truth, the jury is still out on this question. The newest imaging techniques currently in research (e.g., 177Lu-PSMA-based imaging techniques) may be able to do this. For earlier techniques like [11C]choline PET/CT scans, the level of accuracy may really not be high enough.
  • Can the available targeted therapeutic interventions effectively eliminate the targeted sites of extraprostatic and/or oligometastatic cancer?

For this type of management to be implemented with curative intent (or even just with the intent of getting a patient back into long-term remission), the answer to all three of the questions above must be a definitive “Yes”, and then the clinicians must be able to actually execute against the potential opportunity in any one individual patient.

The “New” Prostate Cancer InfoLink is, in fact, aware of only one specific patient for whom it seriously appears that treatment of an oligometastatic cancer seems to have placed him into long-term remission. This is an unusual patient for all sorts of reasons, but it does appear that a combination of selective imaging technology + targeted external beam radiation therapy of the tumor identified has placed him into long-term remission.

We also recently commented on a meta-analysis of data from 119 patients suggesting that stereotactic body radiation therapy (SBRT), used to treat men with oligometastatic prostate cancer recurrence, was effective in just 15 percent of the patients treated at 5 years of follow-up (i.e., 18/119 patients).

We are aware of several patients who have undergone [11C]choline PET/CT scans and then had subsequent laparoscopic surgeries to remove positive lymph nodes identified by the PET/CT scans. However, all the surgeries we are aware of have been followed by further recurrence of the patients’ cancers within a relatively short time frame, suggesting that not all of the relevant areas of cancer were accurately identified and removed.

The question of whether it is actually possible to place significant numbers of men with targeted sites of extraprostatic and/or oligometastatic cancer into long-term remission (let alone cure them of their cancer) seems to us to be unanswered at the present time. From that perspective, we suggest that any patient who wants to go down this path needs to do so with a very clear understanding that his expectations should be limited. Trying something like this with a high degree of optimism is one thing. Convincing oneself that it is absolutely going to work (based on currently available data) seems to be an unrealistic approach at this time.

Having said that, we are getting better (rapidly, in clinical terms, but not rapidly enough for a lot of today’s patients) at identifying the types of extracapsular cancer and oligometastases that may be amenable to targeted treatment, and we are developing new forms of treatment that may be better at targeting such cancers. Within another decade, we may be much better at treating patients with these types of progressive prostate cancer than we are today … but our suspicion is that really effective management of such patients is not going to arrive much sooner than that.

By contrast, we already have targeted methods of providing palliative care for such patients (e.g., MRI-targeted HIFU for relief of pain from individual spinal metastases and radium-223 in the treatment of disseminated bone mets). However, these types of treatment are primarily palliative. There will probably be very few patients who gain a really meaningful survival benefit from treatment with systemic drugs like radium-223.

14 Responses

  1. More than 5 years ago I attended a friend’s appointment with a prominent genitourinary medical oncologist when he was first discovered to have oligometastasis to the bone. While encouraging spot radiation, the doctor indicated that the likelihood of cure was maybe 10% — somewhat consistent with the meta-analysis Sitemaster references.

    Albeit anecdotal, I have “worked” with many men who have undergone spot radiation for oligometastaic disease; I have yet to see it stem the disease. On the other hand, I have seen success (to date) with men who have had adjuvant radiation + ADT for local advancement. It makes me question whether we should lump extraprostatic with oligometastatic?

  2. Dear Rick:

    I very carefully used the term “extraprostatic” as opposed to “locally advanced” disease.

    We know that cancer that is in the process of local advancement into the seminal vesicles and the lymph nodes can be treated successfully with a combination or radiation therapy + ADT. However, a man with true micrometastasis to (say) the pelvic bone structure which is not strictly oligometastatic (because it is too small to be seen on a bone scan) has what I am referring to as “extraprostatic” cancer. Such cancers can often not be treated with standard forms of radiation therapy + ADT because of their position, and it is unclear whether they can be treated effectively with other forms of targeted therapy either (with or without adjuvant ADT).

  3. Do you have any information on the possibility of removing an encapsulated, non-metastatic prostate tumor by laparoscopic procedures, if that is even feasible?

  4. All I can say to this is, what is one to do when RP, and SRT have failed and MRI found two suspicious iliac nodes after PSA had climbed from < 0.1 to 1.22 in 8 months? My main tumor was removed when my prostate was removed — as were the seminal vesicles and 10 nodes. Scans found no prostate cancer in the prostate bed, which I take to mean that the RP and SRT were successful, but I had micrometasases in some pelvic nodes. No prostate cancer was found in bones or other nodes or organs.

    The fact that no large studies have been done doesn't mean that IMRT, particularly using Dattoli's DART process, which is more accurate than plain vanilla IMRT, can't be more successful at extending life than lifelong ADT.

  5. I think one important question that this approach raises is, with a fully informed patient, understanding all of the pitfalls, lack of evidence, and questions that this approach presents; and understanding that this approach will not likely result in a cure, but possibly could represent a year or more of remission where the patient goes off systemic therapy; should that patient always be strongly dissuaded from considering this approach by his physician, because of the unknowns, because there are not good studies providing evidence of long term benefit, or because the doctor has never heard of the concept.

  6. Dear Fred:

    The use of laparoscopic surgical techniques to remove the entire prostate and/or to remove lymph nodes believed to be cancerous as a consequence of local advancement of prostate cancer became widespread in the early years of this century after a small number of clinicians had pioneered the relevant techniques in the late 1990s.

    The vast majority of surgical removals of the prostate are now carried out using laparoscopic techniques (with the assistance of the da Vinci robot or otherwise). However, if what you are referring to is the removal of only a part of the prostate (focal therapy), we are not aware that this has been seriously attempted using surgical techniques. Focal therapy can be conducted laparoscopically using techniques like focal laser ablation.

  7. Dear Robert:

    Individual situations like yours are, obviously, extremely challenging. No one is saying that it may not be possible to improve on the current situation.

    Unfortunately, as yet, however, we have no really good long-term follow-up data from patients who have undergone Dr. Dattoli’s DART technique or from the few centers that have been pioneering laparoscopic lymph node removal following specific imaging techniques.

    Given the lack of such data, individual patients like you need to make decisions about their care that they are comfortable with. Our goal is only to help them make those decisions with access to actual data as opposed to just the opinions of clinicians who have — or at least may have — a financial or other personal interest in the innovative techniques that they may be promoting.

  8. Dear Gene:

    The point you make is important. More conservative clinicians will often tell patients that they have either real doubts or at least suspicions about the effectiveness and safety of new techniques as they go through the early stages of development. Some clinicians will tell their patients that certain techniques are simply not effective or safe — even when there are data to contradict such opinions. (See the current and ongoing pro/con debate about the efficacy and safety of focal therapy as an example.)

    In my opinion, there is a very significant onus on the developers and the “early adopters” of all new forms of therapy to publish as much data as they can make available about the use and the effectiveness of these new types of treatment as soon as they can. By doing this they make such information publicly available to their peers as well as to their potential patients. Without such peer-reviewed information, the only thing one has to go on is the word of the developer or early adopter … and that’s demonstrably not always the most reliable source of unbiased information.

  9. How did using Feraheme to detect lymph node cancer that Dr Dattoli was using work out?

  10. Dear David:

    The Feraheme scans were actually being carried out by Sand Lake Imaging, and it is my understanding that Dr. Dattoli would refer relevant patients to Sand Lake for their scans.

    As indicated in this earlier commentary, Sand Lake Imaging is no longer using Feraheme. They have apparently stated that this was because of cost issues.

    This article from 2014 gives information about the investigational uses of Feraheme in conjunction with MRI scanning as an imaging agent. Alas it provides no information whatsoever on the accuracy of this type of scanning in identification of specific body parts and cancer types.

    The only actual publicly available data we have ever seen on the efficacy and safety of Feraheme as a prostate cancer imaging agent is this abstract of a presentation by Choyke et al. (from the National Cancer Institute) at a meeting of the Prostate Cancer Foundation. The data presented are best described as “equivocal.”

  11. David:

    Here is a link to another abstract (from 2014) by Dattoli and the Sand Lake Imaging personnel which I just found on Dr. Dattoli’s web site. I have not been able to find any information about the proposed 2015 update. This abstract seems to show that one can use Feraheme-based imaging to find positive lymph nodes but since everyone got Feraheme one has no idea what percentage of these patients had false negative scan results. There are no data on the effectiveness of treatment of these patients.

  12. Mike

    Just to throw in my two cents. … I completely agree with statement that each individual needs to understand the risk and make a decision that is right for the individual. That was certainly true in my case. I did go against the advice of the MSKCC oncologists, but at the time it was worth it for me to take the risk. The treatment was not successful but at least now, when I find myself in a fairly difficult place, I do take some comfort in knowing I did everything I could think of before I got to this place. [Editorial note: Bill had a laparoscopic lymphadenectomy after a positive [11C]choline PET/CT scan at the Mayo Clinic.]

    I think many of us find a fairly large disconnect between what we read on the Internet and what we find available to us in clinical practice.

    Currently I see a lot of talk about gene profiling and PARP inhibitors. I am scheduling a new biopsy on my liver lesions for genetic profiling but I know there is a low probability that I will have an actionable anomaly. Even if I do that, any drugs available are unlikely to have a significant effect on my outcome. However, it is important to me to keep trying.


  13. Bill:

    Keep the faith!

    While lung cancer and not prostate cancer, a close friend recently got a gene profile indicating Herceptin may be effective; in three weeks his tumors have shrunk significantly. Let’s see how Dom and Bill fare with olaparib.

    At the same time I absolutely agree that men seeking to profile their tumor should understand the likelihood of identifying an actionable gene is low. Larry Fong at UCSF suggests 10%, albeit Foundation One not surprisingly suggests a much higher number.

  14. As the Sitemaster pointed it, it is difficult to ascertain the sensitivity of any of the detection techniques. Extended pelvic lymph node dissection (ePLND) has been used as the “gold standard,” but ePLND can only cover a limited area in the surgical field, and even with the fluorescent technique that Mayo and others use, it’s hard to know if they were all extracted.

    While Feraheme (ferumoxytol) did not work out, Radboud University in Nijmegen has gone back to using Combidex (ferumoxtran-10), which is now available again. Combidex brings the detection limit down to about 2 mm, compared to 6 mm for an [11C]choline PET/CT scan. It only detects lymph node metastases, but not metastases in bone or viscera. But even at 2 mm, there may be many smaller cells or groups of cells floating around the network of pelvic and abdominal lymph nodes. The new generation of PET radiotracers that detect specific targets on the cancer cell surface may be able to take that limit lower, but even when detected with a PET/MRI, there will not be sufficient uptake and spatial resolution to find it all.

    For that reason, it may make more sense to radiate the entire pelvic LN area if LN invasion is detected or suspected. This decision cannot be made lightly, however, because of the danger of long-term bowel toxicity. Individual anatomical differences may have a big impact. I know Dattoli is using “hyperfractionation” in the hopes of mitigating bowel toxicity, while others are using conventional fractionation, or extreme hypofractionation in the same hope. There is an ongoing clinical trial in Dresden, Germany, investigating whether normal fractionation or SBRT is better for that purpose.

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