Current options for treatment of radiorecurrent, localized prostate cancer

For men who choose to have radiotherapy (external photon beam, external proton beam, or brachytherapy of some type) as first-line therapy for localized prostate cancer, a major issue is, “What if the cancer recurs after treatment?”

In light of the recent decision by an FDA advisory committee not to recommend approval of high-intensity focused ultrasound (HIFU) using the Sonablate 450 technology for treatment of radiorecurrent prostate cancer here in the USA, it is worth reviewing the current options (with a little help from a new review by Soulié et al.).

The proportion of men who have radiorecurrent prostate cancer after first-line radiation therapy seems to be somewhere between about 25 and 30 percent of all patients so treated. This is relatively high, and it is still unclear to what extent the use of radiation therapy as a first-line option has been expanding in recent years to include younger and healthier men who are at really serious, long-term risk of death from prostate cancer or whether it is still largely confined to older men and other men who, for one reason or another, are poor candidates for (or simply refuse to have) any form of surgical treatment.

The options for salvage therapy among men with radiorecurrent prostate cancer are relatively few today, here in the USA:

  • Salvage radical prostatectomy
  • Salvage cryotherapy
  • The possibility of HIFU in a clinical trial

It is therefore worth looking carefully at what Soulié et al. have to say about each of these options.

As has been known for years, salvage radical prostatectomy can quite certainly be used to eliminate radiorecurrent prostate cancer. However (and it is a big “however”), this is a much more difficult operation that a first-line radical prostatectomy. Few surgeons have carried out this procedure enough times to be able to claim that they are really “skilled and experienced” at it. The risk for post-surgical impotence is near to 100 percent, and the risk for long-term, post-surgical incontinence is also very high. In other words, this is a procedure that one would only want to go though to save your life, because the quality of that life is going to be reduced — significantly. To quote Soulié et al., salvage radical prostatecomy should only be carried out “subject to strict technical conditions” (on everything from patient eligibility to the skill set of the surgical team and the way the procedure is carried out).

Salvage cryotherapy is another very difficult procedure, and while it is less invasive than radical prostatectomy, the real question with salvage cryotherapy is whether one is able to identify with accuracy the site of the radiorecurrent disease so that that tissue can be appropriately treated. And let’s not forget that cryotherapy has long been associated with significant risk for side effects and complications and that the number of cryotherapists with significant experience of salvage cryotherapy is probably tiny. Data on the actual efficacy and safety of salvage cryotherapy in treatment of radiorecurrent prostate cancer are very limited.

The role of HIFU as a potential salvage treatment for radiorecurrent prostate cancer is best described as investigational at this time. Ahmed et al. reported data from 84 patients back in 2011 and described the procedure as “high risk” — with slightly less than half the patients remaining progression-free after 2 years. The data provided by SonaCare recently from their US trial indicated that, at best, 50/78 patients who met the study protocol requirements (64 percent) obtained local control of their prostate cancer after just 1 year of follow-up; that 7 rectal fistulas were observed in 5 patients; and that 44/100 patients experienced urinary incontinence post-HIFU. Clearly this is not a “benign” procedure either.

Soulié et al. note that HIFU and cryotherapy do have value as salvage therapies but only when patients conform to “specific indications.” Those specific indications are presumably described in the full text of their paper … but alas that is in French (even if we had seen it).

Of course the only other treatment option is some form of androgen deprivation therapy (ADT), and that is not a curative treatment. It is long-term palliative care (whether carried out using continuous or intermittent ADT). In addition, it comes with all of the well-known side effects of ADT — from impotence and loss of libido to hot flashes and effects on mental function.

The bottom line here is that we have no really good form of salvage treatment for patients with radiorecurrent prostate cancer after first-line radiation therapy. Soulié et al. identify a series of important factors in discussing the decision-making process about the management of such patients:

  • Every individual case should be carefully discussed by a multidisciplinary team.
  • The oncologic and functional status of the patient at the time of radio recurrence needs to be carefully assessed.
  • The risk/benefit ratio of each potential treatment for the specific case under consideration is key.
  • The patient’s wishes and the probability of  short- and long-term survival must absolutely be considered and discussed.

The “New” Prostate Cancer InfoLink would concur with those four important factors.

There appears to be little question at present that HIFU is “no worse” as a salvage form of treatment for radiorecurrent prostate cancer than surgery or cryotherapy. However, it would be a big plus if the developers could clearly show that it was better for the patients who most need it, i.e., the men for whom palliative care really is not a good option because they have a reasonable life expectancy of > 10 years if their cancer can be controlled.

On the other hand, we do need to become better at not immediately treating every man with a rising PSA after first-line treatment. Some of those men have long PSA doubling times (of the order of years) and may never actually have clinically significant recurrence in their lifetime. Adding to the complications and side effects of treatment for such men through immediate salvage therapy is just as bad an idea as early and long-term palliative care.


6 Responses

  1. First, the numbers. Men can do quite a bit better by seeking treatment from expert practitioners with the best equipment. Alicikus et al. at MSKCC has reported the longest running series of dose-escalated EBRT. They report 10-year biochemical relapse-free survival (bRFS) of 81% for the low-risk group, 78% for the intermediate-risk group, and 62% for the high-risk group. 12-year bRFS for brachytherapy (with combo therapy for higher risk) has been reported by Taira et al. to be 98.6%, 96.5%, and 90.5% for low-, medium-, and high-risk patients, respectively. In the longest reported series for SBRT, Katz reports 7-year freedom from biochemical failure was 95.6 and 89.6% for low- and intermediate-risk groups, and separately he reported 6-year biochemical disease-free survival (bDFS) for high-risk men was 69%. The most recent figures of the new generation proton machine at the University of Florida at Jacksonville are reporting 5-year biochemical and clinical freedom from disease progression were 99%, 99%, and 76% in low-, intermediate-, and high-risk patients, respectively.

    But these superior numbers from the best practitioners begs the question: How many of the failures were local and, therefore, appropriate for salvage therapy at all? Katz reports that among the 31% of high-risk failures, 22% (i.e., 7% of all high-risk patients) were confirmed to be local failures. Only 0.9% and 2.6% of low- and intermediate-risk patients were confirmed as local failures.

    My point in going through these numbers is that, at least among the best practitioners, and remembering that incidence of high risk men at diagnosis these days is very low, local failure is very low and there is not a lot of experience with salvage after radiation failure. I agree completely that not every man with a local recurrence needs salvage therapy, especially not whole gland salvage.

    Other than salvage HIFU and cryo, which you mentioned, there are several other options that may be better after local recurrence after failed radiation. One of the first questions, sometimes answered by mpMRI-targeted biopsy, is whether the recurrence is focal or widespread throughout the prostate. If it is a focal recurrence, focal salvage may be all that is necessary, with hopefully, minimal side effects. If it is widespread, the whole gland may have to be ablated, with higher probability of more serious side effects.

    Once that is determined, salvage, either whole gland or focal, can be accomplished with more radiation — LDR or HDR brachy, or SBRT. Ablative options include laser, RF, microwave, photodynamic therapy, and irreversible electroporation. All of these are currently available in clinical trials. However, because the numbers are so low, accrual is difficult, and better data may be a long time in coming.

  2. Isn’t “more radiation” a common treatment for recurrence, after first-line radiation treatment has failed but there is no evidence of systemic disease? I thought that was more common than salvage prostatectomy, or salvage HIFU or cryo.

  3. Barry:

    Second-line radiation therapy for men with radiorecurrent disease is sometimes an option, but the use of such second-line radiation therapy is certainly not commonplace, and it can only be carried out on carefully selected patients. The ability to use second-line radiation like this depends on how the prior radiotherapy was carried out, exactly what dose levels of radiation were originally given to what areas of the prostate (and the pelvis), and whether it is possible to identify the areas of the prostate and the prostate bed (or the pelvis) that may need re-treatment.

  4. I understand that HDR brachytherapy has been used in some trials for salvage therapy at UCSF. The current protocol seems to be a single treatment of 15 Gy. The low dose appears to be compatible in cases of primary radiation since it is much lower than the initial dose up to 81 grays. However, a concern is whether the HDR is effective against the residual prostate cancer and also whether that residual prostate cancer has developed a radiation resistance. I am considering whether the HDR is more effective over conventional cryotherapy as a salvage technique. I have consulted with specialists on both sides and both say theirs is the way to go. Any thoughts?

  5. Dear hpmizue:

    Alas, the available data (which is very limited) really doesn’t provide enough information to say that one technique is either safer or more effective than the other. This is one of those cases in which, almost inevitably, the brachytherapists are going to “believe in” the potential merits of brachytherapy and the cryotherapists are going to believe in the potential merits of cryotherapy, and it is almost impossible for a patient to be able to get meaningful, neutral guidance.

  6. Hello Sitemaster:

    I would have to concur with your views — each practitioner tends to push their technology. Reminds me of the difficulty in selecting a primary treatment — that was much more complex — but the concern about the lack of a neutral position remains. The NCCN guidance is good but not very useful in aggressive salvage therapy — promotes the so-called “gold standard” of ADT or hormone therapy which is simply a holding pattern rife with side effects.

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