Options for Treatment of Local Recurrence After Radiation Failure
Radiation therapy in the form of external beam or brachy therapy is a standard treatment for men with localized prostate cancer. A large number of men undergo radiation therapy in the US because men want to avoid radical surgery secondary to risk of impotence and incontinence. Many men are also not eligible for surgery because of older age, and co-morbid conditions such as heart disease, lung disease and risk of anesthesia. However the recurrence rate after radiation is quite high and may range as high as 63%. In 20-30% of cases, these are local recurrences, which means men could still benefit from local "salvage" therapy. However only a small proportion of these patients 0.9-2% are actually getting surgery. Over 90% of men with recurrence are being managed with castration therapy regardless of whether they have local recurrence or metastases. While hormonal therapy can reduce PSA, hormone therapy does not give any chance for cure. (1,2,3)
The newly approved treatment of HIFU is a paradigm shift for the treatment of radiation failure. The results of HIFU in clinical trials are similar or better than that of surgery, but with a 10-fold lower incidence of rectal injury and a 50% lower incidence of incontinence. All men who have recurrence after radiation treatment for prostate cancer should seek a consultation with a physician who has experience in performing HIFU to see if HIFU is indicated for his recurrence.
Treatment options for Local recurrence after radiation failure include HIFU Therapy, Salvage Surgery with Radical Prostatectomy, Cryosurgery, Androgen Deprivation Therapy, either intermittent or continuous, Salvage Radiation Therapy, Observation with surveillance, which is not recommended unless the patient has a poor life expectancy, and Enrollment in investigational clinical trials.
Not all patients with recurrence have the same prognosis and the first requirement is to differentiate patients who have local recurrence from systemic recurrence for discussion on which patients have local recurrence click here.
For patients who have metastatic disease, a strong predictor is PSA doubling time. If PSA doubling time is less than 3 months, it is likely the patient has systemic disease. If the PSA doubling time is greater than 6 months, local recurrence is more likely. (4,5)
Definition of biochemical recurrence following radiation therapy vary widely. An American Urology Panel found that there were 53 different ways of defining recurrence after radiation in the literature. (6) The two commonly used definitions of biochemical recurrence are the ASTRO definition and the Pheonix Definition. The ASTRO definition is defined as the midpoint between the lowest level of PSA after radiation and the first of 3 consecutive rises in PSA. The ASTRO definition requires backdating to find the time to biochemical recurrence and this is a major weakness. The Phoenix definition defines recurrence as the lowest level of PSA reached plus "+2ng/ml". The weakness of this is that the Phoenix definition lowers the estimate of recurrence after 5 years and increases the recurrence after 10 years. (7).
For a discussion on HIFU Therapy for Radiation Failure, go to section Results of HIFU Therapy
Salvage Surgery with Radical Prostatectomy
Salvage surgery with radical prostatectomy is a potentially curative procedure. Most men do not like the option of salvage radical prosectomy because it has significant complications. The procedure is technically challenging because of radiation-induced fibrosis and obliteration of tissue planes. The biochemical disease-free rates have ranged between 47-82% at 5 years. Complications are common with a history of 0-43% blood transfusions, erectile dysfunction at 80-100%, incontinence at 21-90%, anastomotic stricture in 7-41%, and rectal injury in 0-28% (8,9).
In more recent series Stephenson AJ, Scardino P, et al reported on a series of 100 patients undergoing open salvage RP. There was a significant stricture rate, rectal injury and rectal incontinence compared to standard radical prostatectomy. However, they stated that since 1993, the complication rate had reduced with 68% continence and a 28% potency rate (10).
Matei et al. has recently reviewed the results of Salvage Radical Prostatectomy for patients with recurrence after radiation (11).
In a review of 27 single-center or multi-center studies, several conclusions were made. The strongest prognostic factor is pre-salvage PSA, which often predicts long-term and overall survival. The PSA after salvage surgery is variable, but ranges from 0.1 to 0.4 and survival is between 28 and 93%. The side-effects after surgery have not improved in the last twenty years except in terms of wound infections related to laparoscopic procedures. Rectal injury which prior to 1995 varied between 0 to 19% and in the last ten years varied between 0 to 17%. Anastomotic stenosis in the past varied between 9 to 28% and in the last ten years is between 9 to 50%. Incontinence in the older series varied between 25 to 67% and in the new series between 20 to 72%. The addition of robotic surgeries did not change the incidence of incontinence with three of them reporting 46, 67, and 20% incontinence (11).
Cryosurgery is freezing of the prostate using transperineal needles and gasses such as liquid nitrogen and argon. The procedure is done as an outpatient. Pisters LL, et al. compared the treatment outcomes of Salvage Surgery and Salvage Cryotherapy for patients with locally recurrent prostate cancer after initial Radiation Therapy. (12) Compared to salvage cryotherapy, Salvage Surgery resulted in superior biochemical survival. The progression-free survival rates after Salvage Cryotherapy at 5 years ranged from 40% to 59%. The morbidity of cryosurgery is significant with 73% urinary incontinence, 67% obstructive symptoms, 72% ED, and 8% of men reported perineal pain. Perotte P, et al. reported a poor quality of life in men undergoing salvage cryotherapy.
In more recent series, cryotherapy has had less side effects, improved results, but with short follow-up. (13) Ismail M, et al reported on 100 patients who had salvage cryotherapy for prostate after radiation recurrence. They had a 5 year biochemical disease free survival of 73% for low risk, 45% for intermediate risk and 11% for low risk. Complications included incontinence 14%, erectile dysfunction 86%, perineal pain 4%, urinary tract symptoms 16%, rectal injury 1%. (14)
Salvage radiation therapy is still new and few studies are reported. Toxicity of salvage radiation include urinary frequency and urge incontinence due to bladder irritation, bleeding from hemorrhagic cystitis, radation proctitis, impotence and the long-term risk of secondary malignancies. A proportion of men after radiation already have some of these side effects. Repeat radiation is not feasible in many of these men.
Salvage Brachy therapy has been tried for local failure after radiation for prostate cancer. The biochemical disease free rate was 34 and 48% at 4 and 5 years. (15) The complications are high with incontinence at 36%, recto-urethral fistula 3.4% and rectal grade 3–4 toxicity 5.6%. (16)
Gomez-Veiga et al. reported the results of 10 trials of salvage brachytherapy for EBRT failure: the 5-year biochemical disease-free survival rates ranged from 20% to 87%. One study reported a 10-year biochemical disease free rate of 54%. The incidence of gastrointestinal complications ranged from 5.4% to 65% and 2.7% to 20% for grade 1–2 and grade 3–4 complications, respectively. (16)
Androgen Deprivation Therapy
The commonly administered Androgen Deprivation Therapy (ADT) for treatment of Recurrent Prostate Cancer include Gonadotrophin-releasing hormone (GnRH) agonists, such as leuprolide (Lupron) and similar agents. Another way to cause chemical castration is the use of GnRH Antagonist which may cause more rapid reduction of testosterone.
ADT is given when patients have metastatic disease, to prevent progression, improve pain, prevent fractures and spinal cord compression. However, ADT may not improve overall survival because of increases in deaths from other causes (17,18).
Continuous or Intermittent ADT
Intermittent ADT is a process in which treatment is given until there is PSA response and once there is maximal PSA response the ADT is stopped until the PSA rises. The advantages of intermittent treatment is to cause less side effects on sexual function and loss of bone mass. Intermittent ADT also lowers costs. Studies have shown that this approach has the same results on cancer control as continuous ADT. (19,20). This topic is discussed more under the section on Systemic Therapy for Recurrence.
Sipuleucel-T (Provenge) is still has been FDA approved for treatment of patients with castrate-resistant prostate cancer and does prolong life expectancy in patients with metastatic disease. Bevascizumab (Avastin) is an antiangiogenesis monoclonal antibody approved in the USA for multiple tumor types but not prostate cancer. It inhibits vascular endothelial growth factor and in laboratory studies seems to cause prostate cancer cell depth. Clinical trials of this agent are on going.
Several other agents that have been tested for Prostate Cancer include celecoxib (Celebrex), rosiglitazone (Avandia), imatinib (Gleevec), lenalidomide (Revlimid) and others. None of these agents have been shown to have major benefit although some trials are still on going.
Herbal products have also been tried including pomegranate juice and extract, grape skin extract, Chinese grass seed oil, and others. The rationale supporting these studies focuses on inhibition of certain nuclear factors that prevent cell division.
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