The very earliest randomized, double-blind, placebo-controlled, multi-center Phase II and Phase III clinical trials of any form of salvage therapy in men with a rising PSA after treatment for early stage (localized) disease are:
- Hormone Therapy Plus Chemotherapy in Treating Patients With Prostate Cancer, which is comparing immediate hormone therapy + docetaxel-based chemotherapy to immediate hormone therapy + delayed docetaxel-based chemotherapy in men at high risk for continued progression who have a rising PSA after radical prostatectomy or primary radiotherapy
- The ARTS or “AVODART After Radical Therapy for Prostate Cancer Study”, which has been designed to compare the effect of treatment with dutasteride to treatment with a placebo in men who have a rising PSA after radical prostatectomy or primary radiotherapy
- Pomegranate Extract in Treating Patients with Rising PSA Levels After Surgery or Radiation Therapy for Localized Prostate Cancer, which is comparing pomegranate extract to placebo in men who have a rising PSA after radical prostatectomy or primary radiotherapy
A similar randomized, placebo-controlled trial of pomegranate extract is also being conducted in a single-center setting.
In addition to surgery, external beam radiation, and hormone therapy — the three forms of “mainstream” salvage therapy that are used when a patient has biochemical disease recurrence after first-line treatment for early stage (localized) disease — there are other forms of salvage therapy that can be categorized as “investigational.” The most obvious of these are the following:
- Brachytherapy (following failure of external beam radiation, cryotherapy, or HIFU)
- Cryotherapy (following failure of external beam radiation, brachytherapy, or HIFU)
- HIFU (following failure of external beam radiation, brachytherapy, or cryotherapy)
A quotation from Huang et al. would seem to be an appropriate comment on the current status of these forms of salvage therapy:
Recently, improvements in technique and technology have [led to] an increased interest in the use of minimally invasive therapies such as brachytherapy, cryotherapy, and high-intensity focused ultrasound in the salvage setting. … [and] concerns remain over incomplete and inadequate treatment with locally ablative therapies. Future studies are required to appropriately select candidates for salvage ablative therapies and to determine the long-term oncologic efficacy of these treatments.
Salvage Brachytherapy for Men in Biochemical Relapse After EBRT
Salvage brachytherapy has been used to treat men with biochemical failure after primary EBRT since the mid- to late 1990s. For example, a study by Grado et al. in 1999 reported on 49 patients of median age 73.3 years (range 52.9 to 86.9) with biopsy-proven localized prostate cancer who underwent transperineal brachytherapy with either iodine 125 or palladium 103 after prior radiotherapy failure. They concluded that, “In a population of patients with poor prognosis, this modality was associated with a high rate of local prostate cancer control and a 34% actuarial rate of biochemical disease-free survival at 5 years. … Salvage brachytherapy warrants further investigation.”
Nearly a decade later, reporting on another small study of 25 cases of the use of salvage brachytherapy after radiation, Nguyen et al. wrote that, ” The current results indicated that MRI-guided salvage brachytherapy … can achieve high PSA control rates, although complications requiring surgical intervention may occur in 10% to 15% of patients.” However, Lee et al. seem to have had better results in their series of 21 patients, stating: “Salvage prostate brachytherapy after external beam radiation failure can be safely performed with acceptable biochemical control. This treatment option should be considered for patients who have prolonged life expectancy after localized external beam radiation failure.”
It is clear that there has been limited progress in this field. If salvage brachytherapy is to become a normal, viable option in men who have failed primary EBRT, we will need to see data from larger series than these.
Salvage Cryotherapy for Men in Biochemical Relapse After EBRT
By contrast with the salvage brachytherapy situation, there is at least one large Canadian series of salvage cryotherapy patients. Ng et al. have reported on a total of 187 patients with locally recurrent prostate cancer who underwent salvage cryoablation of the prostate after prior radiotherapy, and were studied for an average follow-up period of 39 months.
According to Ng and his colleagues:
- The serum PSA value at the time of cryoablation was an important predictive factor for biochemical recurrence.
- Patients with pre-cryoablation PSA levels < 4 ng/ml had a 5- and an 8-year biochemical recurrence-free survival of 56 and 37 percent, respectively.
- Patients with pre-cryoablation PSA levels of ≥ 10 ng/ml had a 5- and an 8-year biochemical recurrence-free survival of only 1 and 7 percent, respectively.
- Overall 5- and 8-year survival was 97 and 92 percent, respectively.
It should be noted, however, that 32 percent of the patients in this study were started on hormonal therapy for disease progression at a mean of 31 months postoperatively.
Reviewing the potential of salvage cryotherapy, Chin and Touma stated that: “The five-year biochemical disease-free rate is approximately 40%. The complication rate is acceptable. Salvage cryoablation definitely has a role in the management of localized prostate cancer treatment failure following radiotherapy, especially in older patients and those with some comorbidities.”
Salvage cryoablation is currently in multi-center clinical trials in an attempt to further define the value of this type of salvage treatment. The “New” Prostate Cancer InfoLink would encourage patients considering salvage cryotherapy to enroll in such trials. Data published by Pisters et al. in 2008 report that the Cryo On-Line Data (COLD) Registry contained a total of 267 salvage cryotherapy patients at the time of submission of their paper. Unfortunately there is no breakdown of the first-line treatments given for these 267 patients. We would assume that the vast majority had received first-line EBRT.
Salvage HIFU for Men in Biochemical Relapse After EBRT
Reviewing the potential of HIFU as a salvage treatment for men in biochemical relapse after first-line radiation therapy, Chalasani et al. wrote that, “There are no randomized or prospective studies in this area. Efficacy results of 17-57% have been reported from retrospective case series, with reported toxicity including rectal fistula in 0-16%, and incontinence in 10-50%. The ideal patient, while yet to be clearly defined, should have preradiotherapy low or intermediate risk disease. Salvage HIFU appears most appropriate for those patients with histologically proven local recurrence only, with a life expectancy of at least 5 years and with some medical comorbidities rendering them not ideal for salvage prostatectomy.”
Data from the largest available series of salvage HIFU patients to date was published by Murat et al. in late 2008. It includes all patients so-treated by this French group between 1997 and 2006. The results of this paper can be briefly summarized:
- 194 HIFU sessions were competed in a total of 167 patients.
- Negative biopsy results were obtained in 122/167 patients (73 percent).
- The median PSA nadir was 0.19 ng/ml.
- The mean follow-up period was 18.1 months (range 3 to 121 months).
- 74/167 patients (44 percent) required no hormone therapy.
- The actuarial 5-year overall survival rate was 84 percent.
- With respect to adverse reactions, no rectal complications were observed and urinary incontinence accounted for about half the urinary sphincter implantations required in 11 percent of patients.
The authors conclude that salvage HIFU is a curative treatment option for local relapse after EBRT with acceptable morbidity. They also define prognostic factors that are important to optimization of good patient outcomes.
Repetitive Treatment (Using HIFU, Cryotherapy, or Brachytherapy)
It may be splitting hairs to decide whether (for example) a repeated HIFU exposure 3 months after an initial round of HIFU treatment is salvage HIFU or simply a “further course of therapy.” The point we would make is a simple one. If the physician repeats a prior treatment of theis type, (s)he presumably does so because either there is real evidence that the first round of treatment didn’t work well enough or there is sufficient clinical evidence to suggest strongly that it isn’t going to.
Repeated HIFU therapy is easy and relatively common. As can be seen from data in the paper by Murat et al. mentioned above, at least some of their patients had two rounds of salvage HIFU therapy, and one or two may have had three rounds. According to Barquawi and Crawford, “Up to 22% of patients undergoing primary HIFU treatment for localized prostate cancer may require a second or even a third HIFU session to complete the treatment. … Studies of both the Ablatherm and Sonablate HIFU devices have reported a similar incidence of repeat treatment sessions: retreatment rates of 1.4 and 1.2 sessions per patient for Ablatherm and Sonablate, respectively.”
Repeated cryotherapy is less common but far from unknown, and selective re-radiation of some area or areas of the prostate using brachytherapy has certainly been reported, although this seems to be much more unusual.
As with the more traditional use of salvage external beam radiation therapy, it is first of all worth remembering that cryotherapy, brachytherapy, and HIFU can all be used as salvage therapies with and without adjuvant hormone therapy. The “New” Prostate Cancer InfoLink suspects that as the equipment and the skills of the operators continue to evolve, there will be gradually increasing use of cryotherapy and HIFU in the salvage setting. Brachytherapy may be a more challenging form of therapy in the salvage setting, however.
From a patient viewpoint, such treatments are currently for the brave or the naive. There are limited data and only a small and select group of physicians who really have sufficient experience to qualify themselves as “skilled” in conducting such procedures. Lending one’s prostate to this type of research is something to be done in a state of complete ignorance or with steely determination!