The Challenge of Treating Recurrent Prostate Cancer
Michael J. Dattoli M.D.
Virtually all patients who have been treated for prostate cancer live with the possibility that their cancer will reappear at some point in the future. There is some risk of relapse or recurrence over time regardless of the type of treatment or the stage of the cancer when the disease was ﬁrst diagnosed. Of course, the best outcome as far as relapse is not to have one, because a patient’s initial primary treatment offers the best chance for a cure. A properly staged patient who takes advantage of the most advanced diagnostic modalities and chooses the most appropriate treatment for his case stands the best chance of avoiding recurrence.
Since there is no perfect treatment, there will always be cases of recurrence, but the good news is that all treatments for prostate cancer, including salvage therapy for recurrence, have greatly improved in recent years.
While the likelihood of the disease reappearing diminishes with each passing year after initial treatment, as part of a prostate cancer battle plan, it is important for patients to be aware of their options down the line if recurrence should occur. With that knowledge, patients can be empowered to cope with any contingency more effectively. Some men may prefer to ignore the situation until a problem arises, but in the case of recurrence, they will face the task of doing their research and evaluating their treatment options under the emotional duress of the disease as it progresses. Playing ostrich is no way to ﬁght prostate cancer at any stage.
Fortunately, for most patients who must face the disease again, there are still effective courses of treatment available regardless of which treatment they underwent in the past.
Depending on a man’s age and the stage of his disease, recurrence of prostate cancer for some patients may not be life-threatening and may not even require further treatment. Keep in mind that it is never patients who fail, but rather treatments that sometimes fail to completely eradicate the disease. Treatment failure means that a particular form of therapy has not been successful in fully eliminating the cancer or controlling the progression of the disease.
If you are a patient now facing recurrence, above all else, don’t beat yourself up for the treatment choice that you made originally. There is no reason whatsoever to fault yourself for the decision you made. That was then; this is now.
When evaluating treatment failure, it is necessary to determine whether the failure is “local,” “regional,” or “distant.” A local failure indicates the cancer has recurred in the area of the prostate (or in the prostate bed, if the gland was removed by surgery). A regional failure indicates the spread of disease is still conﬁned to the prostate and pelvic region (for example, the pelvic lymph nodes). Distant failure indicates there are metastases at sites in the body distant from the prostate, such as the abdominal lymph nodes or bones. In some cases, advanced imaging may nit reveal anything at all, and there may only be evidence of biochemical recurrence (a rising PSA).
Determining whether treatment failure is local or distant is crucial in deciding what options each patient has for future therapy, and whether or not some form of additional therapy is appropriate. Keep in mind that in some cases a distant failure may actually represent persistent disease that was not detected during the initial workup and staging. In such cases, the cancer was probably there before the primary treatment but not detected by the various diagnostic scans and lab tests.
It is important to understand at this point that treating a recurrence is more challenging than initially treating most prostate cancers, whether the relapse is local, regional, or distant. There will be a new set of critical circumstances and challenges to consider. In the case of patients who have undergone primary surgery (either by open radical prostatectomy or robotic surgical procedures) there will b a void in the pelvic area that rapidly becomes occupied by the bladder and/or rectum. These post-surgical changes make salvage radiotherapy a tricky option to pursue because of the risk of permanently damaging these healthy organs in the process of killing the recurrent or remaining cancer cells.
The surgical process will also have left the prostate bed badly devascularized (decreased blood ﬂow); and therefore, the “target area” will be lacking appropriate oxygenation to activate the most effective cancer-killing response when postoperative Radiation Therapy (RT) is delivered. Higher doses of radiation, like that achieved by the extremely precise Dynamic Adaptive Radiotherapy (DART), often accompanied by hormonal therapy, are the prefered salvage treatment options with these post-surgical cases, which are indeed becoming epidemic. Recurrences after Radical Prostatectomy (RP) is by far the most common scenario for men. Unfortunately, any patients choose surgery mistakenly thinking this option with the most complications will provide the best chance of a cure.
Like failed surgery, failed primary radiotherapy also poses a challenge regarding salvage therapy options. After primary radiation fails, a second treatment with radiation is often not advised by many since the first course of radiation did not cure the cancer and the risk of complications is concerning. However, there is growing interest in treating failed external radiation patients with brachytherapy and/or DART, since seed implant radiation and DART can still be highly focused on the prostate and other targets in the pelvis, with less risk of damage to the rectum and surrounding tissue.
To ensure safety, these men will need the higher doses of radiation available only through the sophistication of treatment delivery programs encompassing all the available tools, especially those available with DART. To maximize the potential of radiation for treating recurrent patients, we often prescribe hormonal therapy—which creates a positive synergy with radiation resulting in mathematically boosting the effects (1+1 = 3 or 4 or 5, for instance).
We have learned that prostate cancer cells are amazingly adaptable—in fact, they can quickly become resistant to external radiation, making it less effective. That fact underscores our choice of combined radiation therapy whenever possible. We have found that by delivering approximately half the “tumor-cidal” (killing) dose of radiation through an external process and implanting the other half through brachytherapy (radioactive seed implantation) intensifies the response, giving higher cure rates with lower side effects. Cancers don’t like change! By combining different forms of radiation along with a short course of hormonal therapy, we increase the odds for success.
In fact, cross specialty studies looking at breast cancer, colorectal cancer, head and neck cancers, etc. all demonstrate an increasing survival rate when a combination of therapies is used.
We don’t subscribe to the philosophy that if a patient has had previous radiation therapy, he is no longer a candidate for further radiation, since most of these failures are due to the failure of the physician in not delivering a proper dose while possibly missing the affected tissues altogether. So, we are often able to re-treat with radiation after reviewing the dosimetry of the previous failed treatment.
Patients experiencing recurrence following single modality radiation are often eligible for additional treatment using a different form of radiation. For instance, the man who had External Beam Radiation Therapy (EBRT) alone may benefit from a small dose of DART followed immediately by seed implantation (depending on the location of the active cancer cells).
Patients who have had seed implantation without initial success may have the option of being re-seeded. This approach appears to be promising, and typically involves using a different isotope the second time around. If the patient was first implanted with iodine (I-125), then palladium (Pd-103) or cesium (Cs-131) might be used as a salvage therapy in the hope that the cancer will be more sensitive to the second isotope. If the first implant was technically mishandled, then a second implant affords the opportunity of correcting misplacements that may have caused underdosing.
We use hormonal therapy judiciously during and after radiation therapy. We also limit the dose of the implant for salvage brachytherapy, which turns out to be effective thanks to its radiosensitivity with hormonal therapy. We use palladium whenever possible because of its steep dose radial fall off. That means at any distance from the seed, the dose is lower than with any other isotope. That’s important with patients who have been previously treated. We don’t want to give the patient the same implant that failed previously. We also use urethral sparing techniques to avoid implanting the distal or external sphincter to avoid the risk of incontinence.
If a man’s PSA after external radiation (or brachytherapy) rises only very slowly over a period of one to three years, then the cancer may still be confined within the prostate. These patients have the most options among those patients whose treatments fail with radiation, including Active Surveillance depending on the age and life expectancy of the patient. Various studies have shown that there are patients with biopsy-detected, Gleason 6 local recurrence who have survived 10 years or more without experiencing any progression of the disease. However, recurrences are typically more aggressive tumors with Gleason scores of 7 to 10 and may secrete little PSA if any; and in those cases even a slow PSA rise may be significant with respect to tumor growth and cancer spread.
Meticulous re-staging workup research is mandatory. We have to know how extensive the disease is. It may be that the PSA value is high, but the disease is still confined to the prostate. Lower pre-salvage PSAs have more favorable outcomes. We want to see patients sooner rather than later – before their PSA values rise significantly.
It should be noted that before deciding on any second course of treatment, you should fully investigate the likelihood of eradicating the cancer and the risk of side effects that may alter your quality of life. These are the most important considerations in deciding on salvage therapy. Given your age and overall health, you will want to ﬁnd a balance between effectiveness and side effects—a balance with which you are comfortable, that you can live with both before and after treatment. Knowing what to expect each step of the way is one of the essential keys to ﬁghting this disease at every stage.
The Dattoli Team has recently reported original research on failed radiotherapy patients treated with a salvage combination of external radiation of brachytherapy. This Dattoli Team presentation is featured in the January 2024 Genitourinary Cancers Symposium of the American Society of Clinical Oncology. While most recent studies of prostate cancer recurrence report only actuarial data for a few years, thus slanting their results favorably, we report longer-term results at 5-years (91% success) and 14-years (72% success). These long-term results are far more telling and relevant given the current life expectancy of many patients experiencing recurrence.
The Dattoli Team recurrence publication reads as follows:
Long-term outcomes for patients with radiorecurrent prostate cancer treated with salvage combination IMRT and brachytherapy.
Michael J. Dattoli, Arvind B. Soni, Lauren Yanthis, Jone Fay, Gregory Lawrence; Dattoli Cancer Center & Brachytherapy Research Institute, Sarasota, FL; Dattoli Cancer Foundation, Sarasota, FL
Background: Effective salvage of locally recurrent prostate cancer after definitive radiation is typically disappointing and may be associated with significant complications.
Methods: 133 consecutive prostate cancer patients (ages 46-78) with biopsy proven local failures were treated between 2001 and 2021 and followed, prospectively with respect to clinical and/or biochemical failure and toxicity. Pre-recurrence treatment had consisted of external beam radiation (Photons: 102 patients, Protons: 16 patients) or iodine 125 brachytherapy (15 patients). Prior to salvage treatment, an extensive workup ruled out gross extracapsular extension or distant disease spread.
Salvage treatment consisted of an attenuated dose of IMRT to the prostate (1200 cGy/8 fxs) followed by an attenuated Pd-103 brachytherapy boost (median 9000 cGy) within 24-72 hours. The Pd-103 isotope was used given its steep radial dose fall off, thereby reducing dosage to previously irradiated surrounding tissues. All patients were treated with a median 6 months of androgen deprivation. Mean pretreatment PSA was 5.9 ng/mL (range 1.9 – 22.3, median 3.9) with 64 patients having a Gleason score of greater than or equal to 8, 61 patients having a Gleason score of 7, and 8 patients having a Gleason score of 6. Follow-up from date of implant ranged from 3 years to 20 years (median 14 years). Biochemical failure was defined using PSA greater than or equal to 0.2 and nadir +2 at last follow up. All biochemically failing patients underwent transperineal prostate biopsies (median 18 cores).
Results: Overall, 72% (96/133 patients) have maintained a PSA less than or equal to 0.2 ng/mL at median 14 years. Biochemical freedom at 5 years was 91%. PSA prior to re-treatment was highly predictive of distant progression with no patient having a PSA greater than 15 being successfully salvaged. Prostate biopsies of failing patients revealed only 3 local failures. 4 patients required post-implant TURP and 2 TURP patients developed low volume stress incontinence, 2 patients developed urethral strictures which were successfully treated to resolution. No patient has developed rectal ulceration, prostatic-vesicorectal fistula, or chronic cystoproctitis.
Conclusions: This study helps strengthen the rationale for the use of Brachytherapy-based regimens in the treatment of radiorecurrent prostate cancer. In view of its even steeper radial dose falloff, we are currently exploring the advantages of Cs-131 in these patients.