Treatment- and Disease-Related Complications of Prostate Cancer

16th International Prostate Cancer Update

RIUS0005(Watson)_04-24.qxd 24/4/06 12:37 Page S56 16TH INTERNATIONAL PROSTATE CANCER UPDATE Treatment- and Disease-Related Complications of Prostate Cancer Anne R. Simoneau, MD Department of Urology, University of California, Irvine, Orange, CA One of the highlights of the 16th International Prostate Cancer Update was a session on treatment- and disease-related complications of prostate disease. It began with presentation of a challenging case of rising prostate-specific antigen levels after radical prostatectomy, followed by an overview of the use of zoledronic acid in prostate cancer, a review of side effects of complementary medicines, an overview of complications of cryotherapy, an assessment of complications of brachytherapy and external beam radiation therapy, and a comparison of laparoscopy versus open prostatectomy. [Rev Urol. 2006;8(suppl 2):S56-S67] © 2006 MedReviews, LLC Key words: Prostate cancer • Bisphosphonates • Complementary medicine • Cryotherapy he 16th International Prostate Cancer Update, chaired by E. David Crawford, MD, and held in January 2006 at Beaver Creek, CO, presented many practical updates on prostate care in comprehensive 15-minute talks. Session 7 focused on treatment- and disease-related complications of prostate disease. Chaired by Paul Lange, MD, the session began with a challenging case of rising prostate-specific antigen (PSA) levels after radical prostatectomy, presented by Gerald Chodak, MD. It continued with an overview of zoledronic acid in prostate T S56 VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY RIUS0005(Watson)_04-24.qxd 24/4/06 12:37 Page S57 Treatment and Complications cancer by Bob Djavan, MD, PhD, a review of side effects of complementary medicine by Anne Simoneau, MD, an accounting of complications of cryotherapy for prostate cancer by James Lugg, MD, an assessment of complications of brachytherapy and external beam radiation by Mack Roach III, MD, and a comparison of laparoscopic versus open prostatectomy complications by James Eastham, MD. The panel then participated in discussion generated by the audience’s questions. Rising PSA Levels After Radical Prostatectomy Dr. Chodak began by presenting the case of a 56-year-old man who underwent a radical prostatectomy for T1c prostate cancer. Final pathology demonstrated Gleason score 4
3 with seminal vesicle involvement. PSA was undetectable postoperatively. The audience was then asked what therapeutic option it would choose at this point, and answers were split among adjuvant radiation, hormonal therapy, and observation. Discussion noted that, to date, postoperative adjuvant radiation therapy has been linked to improved local control, but no survival advantage has been documented.1 An abstract presented at the American Society for Therapeutic Radiology and Oncology meeting in October 2005 updated the Southwest Oncology Group (SWOG) trial 8794, in which 473 men with pT3 disease were randomized after surgery to receive radiation or no immediate therapy. At a median follow-up of 9.7 years, there was a statistically significant 25% decrease in disease recurrence and nonsignificant improvement in metastatic disease and overall survival for the group receiving radiation.2 In the case presented, the patient chose observation and his PSA subsequently rose to 0.4 ng/mL at 9 months. The audience was asked what PSA value should trigger a bone scan. Choices included baseline, 1 to 2, 5 to 10, and greater than 10 ng/mL, and no clear preference emerged. Dr. Eastham noted that at Memorial SloanKettering oncologists order a bone scan when there is a change in status— and going from an undetectable PSA to a detectable PSA is a change in status. Dr. Simoneau added that it is not her practice to obtain a bone scan when PSA first becomes detectable, but she would use PSA velocity and symptoms as a guide to ordering a bone scan. Dr. Chodak referenced studies outlining the improbability of a bone scan being positive when PSA values are low; for example, Kane and colleagues reported a 4.5% probability of a bone scan being positive with a PSA level less than 10 ng/mL after radical retropubic prostatectomy (RRP). Elevated PSA and PSA velocity greater than 0.5 ng/mL/mo were associated with a positive bone scan in the same study.3 Cher and colleagues reported a less than 5% probability of a positive bone scan after RRP until PSA increased to 40 to 45 ng/mL; they noted that a bone scan had limited usefulness until PSA was greater than 30 ng/mL.4 A recent nomogram utilizes the pattern of PSA failure in addition to pathologic factors to predict the probability of a positive bone scan, and there are plans to make the software available online at no cost.5 The treatment options for the patient at this point included continued observation, hormonal therapy, or salvage radiation. Among the panelists, Dr. Eastham stated that the chance for cure with salvage radiation in this patient is low, and he referred to a nomogram to calculate the probability of 5-year PSA-free rate with salvage radiation.6 He roughly estimated a 25% response rate in this setting. Dr. Roach stated that a 25% response rate is an acceptable option that should be discussed with the patient. Dr. Simoneau added that in each of these cases the patient’s goals need to be clearly stated. If the man’s goal is for local cure of prostate cancer, salvage radiotherapy is the only option, with the understanding that it may not be effective and the patient may still require additional therapy in the future. If his goal is to minimize treatment and potential complications of treatment, observation until a trigger point for hormonal therapy, if reached, is appropriate. Skeletal Complications Dr. Djavan gave a comprehensive overview of the role of bisphosphonates in urology. He began by elucidating the magnitude of osteoporosis in men, the effects of treatments such as androgen-deprivation therapy (ADT) on osteoporosis, and the degree of metastatic bone disease in prostate cancer. He then reviewed the pharmacology of bisphosphonates, including how they inhibit bone resorption, return bone mass, decrease skeletalrelated events, and may inhibit bone metastasis. Men generally do not consider themselves at risk for osteoporosis. Larger starting bone mass and a later, more gradual decline in bone loss lead to fewer skeletal events in men than women. Longitudinal studies show a 0.5% to 1% loss in cortical bone in men in later life.7,8 Cancellous bone loss occurs more rapidly in older men and causes hip and spine fractures in men older than 75 years.8,9 Certain conditions will place men at risk for osteoporosis, including prolonged steroid use (long-term prednisone therapy with doses  7.5 mg daily), hypogonadism, calcium and vitamin D malabsorption, alcoholism, immobilization, and tobacco use.8 Osteopenia and osteoporosis may be seen in 10% to 25% of men with prostate cancer before initiation of hormonal ther- VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY S57 RIUS0005(Watson)_04-24.qxd 24/4/06 12:37 Page S58 Treatment and Complications continued apy.8,10,11 Studies have shown that once ADT is initiated, average femoral neck bone mineral density (BMD) decreases 7.6% by 1 year. A trial of intermittent ADT begun with 9 months of ADT reported a 2.7% decrease in hip BMD, which stabilized during the off-therapy period.8 For men with advanced prostate cancer, the incidence prostate cancer, but randomized trials did not confirm this benefit.12 Second-generation pamidronate did not significantly reduce pain or skeletal events.14 Second-generation zoledronic acid, given as 4 mg intravenously (IV) every 3 weeks for 15 months, has shown sustained pain reduction, with a lower incidence and a In a 1-year trial in men beginning androgen-deprivation therapy, zoledronic acid was shown to improve bone mineral density at the lumbar spine and hip. of bone metastasis is 65% to 75%, and median survival from diagnosis of bone metastasis is 12 to 53 months.12 Skeletal events during this period include fractures, radiation treatment to bone, and spinal cord compression. In a study with 24 months of follow-up for metastatic prostate disease, the percentage of patients in each successive skeletal category was fractures 25%, radiation treatment to bone 33%, and spinal cord compression 8%.13 Bisphosphonates have become the standard of care for prevention of skeletal complications from metastatic bone disease.12 The class includes firstgeneration drugs etidronate and clodronate and the second-generation nitrogen-containing bisphosphonates, such as zoledronic acid, pamidronate, and ibandronate, which have greater potency.12 Bisphosphonates work by decreasing bone resorption.12 They bind to active areas of bone metabolism, are released during bone resorption, and inhibit osteoclasts’ ability to resorb bone. All osteolytic and blastic lesions have derangement in bone metabolism. Osteoblastic lesions have greater resorption as measured by bone markers than lytic or mixed lesions.12 The first-generation drugs demonstrated transient bone pain palliation in single-arm trials of metastatic S58 VOL. 8 SUPPL. 2 2006 longer time to onset of skeletal-related events compared with placebo in men with prostate cancer progression despite first-line ADT.13 A 1-year trial in men beginning ADT who received zoledronic acid 4 mg IV every 3 months demonstrated improvement in BMD at the lumbar spine and hip.15 Though generally well tolerated, the standard dose of zoledronic acid was decreased in 1 study from 8 to 4 mg, and the infusion time was increased from 5 to 15 minutes; before infusion serum creatinine monitoring was initiated because of renal safety concerns.16 Dose reductions for renal guidelines for all aspects of bisphosphonate indications or duration. Generally, once started, they are continued unless otherwise contraindicated.16 Table 1 outlines current suggestions from the literature. Complications of Complementary Medicines Dr. Simoneau began by stating five topics she would cover pertaining to complications of complementary medicines: first, the reported adverse events from commonly used supplements with special emphasis on the recent meta-analysis of vitamin E and results of the Heart Outcomes Prevention Evaluation Study Extension (HOPE-TOO); second, commonly used herbal supplements and potential interactions during invasive procedures; third, concerns with complementary medicine while undergoing chemoor radiation therapy; fourth, an overview of heavy metal toxicity, which can occur from contaminants in fish or herbal supplements; and fifth, some of the herbal side effects that urologists and oncologists may encounter in their patients. The daily recommended dose of vitamin E is 15 mg/d, and the recom- In a recently reported meta-analysis of 19 prospective trials that used doses of vitamin E from 16.5 mg to 2000 mg/d and that included many patients with chronic illness or taking combinations of supplements, vitamin E  400 mg/d was associated with increased all-cause mortality. insufficiency are necessary. The most common symptom is an acute-phase reaction with flulike symptoms within 24 hours. To prevent hypocalcemia, calcium 500 to 1000 mg and vitamin D 400 IU should be given.16 Osteonecrosis of the jaw has been reported.17 Recommendations for appropriate preventive dentistry should be considered before bisphosphonate use.16 There is no consensus for REVIEWS IN UROLOGY mended upper limit is 1000 mg/d.18 Vitamin E is a commonly taken supplement19 with several health benefits attributed to it. It has been studied in several cardiovascular and cancer prevention trials, including the ongoing SWOG prostate cancer prevention trial Selenium and Vitamin E (SELECT) using doses of 400 mg.20 Miller and colleagues recently reported a metaanalysis of 19 prospective trials that RIUS0005(Watson)_04-24.qxd 2/5/06 3:27 Page S59 Treatment and Complications Table 1 Possible Role of Bisphosphonates in Men With Prostate Cancer Population Assessment Intervention All men Assess risk factors [see text]; consider baseline study if at risk for osteoporosis Education for healthy bones, vitamin D, calcium, exercise Men beginning ADT Baseline study Education for healthy bones, vitamin D, calcium, exercise Men on ADT without osteopenia/osteoporosis Baseline study and at intervals Education for healthy bones, vitamin D, calcium, exercise Bisphosphonates not yet recommended; long-term studies needed re: safety Men  ADT with osteopenia/ osteoporosis Baseline study and at intervals to monitor therapy Zoledronic acid 4 mg IV every 3 months, vitamin D, calcium, preventive dentistry Caution about heavy lifting Men with bone metastasis Baseline study and at intervals to monitor therapy Zoledronic acid 4 mg IV every 3 weeks, vitamin D, calcium, preventive dentistry Caution about heavy lifting ADT, androgen deprivation therapy; IV, intravenously. used doses of vitamin E from 16.5 mg to 2000 mg/d. Many of the trials were in populations with chronic illness or taking combinations of supplements. Vitamin E doses of 400 mg or more were associated with an increased allcause mortality.21 Dr. Simoneau highlighted the large confidence intervals (CIs) for the relative risk (RR) of mortality in the individual studies used in the meta-analysis and noted that 3 studies used doses of 400 mg. HOPE enrolled 9541 persons over 55 years old with cardiovascular risk factors and compared vitamin E, ramipril, and placebo for 4.5 years; it showed no change in mortality.22 The Age-related Eye Diseases Study, a 4629-person trial for persons 55 to 80 years old, compared vitamin E, vitamin C, and beta carotene versus placebo for age-related vision loss; the RR of mortality was 1.06 (CI, 0.84-1.33).23 The Polyp Prevention Study was an 864person trial for persons less than 80 years of age with large bowel ade- noma comparing vitamins E and C, beta carotene, and placebo. There were 15 deaths in the vitamin E supplement arm versus 29 in the placebo arm.24 A HOPE follow-up, HOPE TOO, was reported in 2005. With a median follow-up of 7 years, there was no difference in cancer incidence, cancer deaths, prostate cancer (2.6% vs 2.9%), or major cardiovascular events (death, stroke, and myocardial infarction). There was an increase in congestive heart failure and its hospitalization (5.8% vs 4.2%; P
.002) in the vitamin E arm.25 Because SELECT is using vitamin E 400 mg, patients may ask urologists about the risks. All men should look at their individual risk factors when deciding on supplement use. The SELECT data safety and monitoring committee continues to look for trends in the health effects of both supplements. The meta-analysis does suggest caution regarding supplement use; the perceptions that there is no harm with sup- plements and more is better are prevalent and need to be addressed. The Alpha-Tocopherol and BetaCarotene (ATBC) trial assessed 50 mg of vitamin E and 20 mg of betacarotene in 29,133 male Finnish smokers 50 to 69 years old. Its results give rise to several issues of interest to urologists. There was a 34% reduction in prostate cancer in men receiving vitamin E, and this was part of the rationale for using vitamin E in SELECT.26 The 45% increase in hemorrhagic stroke in the vitamin E arm was of concern and again illustrates the bioactivity, both good and bad, of supplements.27 The SELECT eligibility criteria specifically excluded men with uncontrolled hypertension to deter this event.20 Again, men need to look at their overall health when taking supplements. The main caution is that beta-carotene increased the risk of cancer in this group. A follow-up ATBC report noted that it took 4 years for the deleterious effect of beta- VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY S59 RIUS0005(Watson)_04-24.qxd 24/4/06 12:37 Page S60 Treatment and Complications continued carotene to be seen and the same length of time after stopping it for its effect to go away. The protective effect of vitamin E on prostate cancer was seen in 18 months, and its washout effect for prostate cancer protection was within the first 3 years.27 The concern regarding betacarotene use and lung cancer was confirmed with another large study, the Carotene and Retinol Efficacy Trial (CARET).28,29 The lag time for increased lung cancer for beta-carotene in CARET was 18 months.27 Other supplements have potential toxicity. Selenium has an average dietary intake of 80 to 120 g/d with a daily recommended intake of 55 g/d and an upper limit of 400 g/d. Chronic toxicity is expected after long-term consumption of 2400 to 3000 g/d; reversible symptoms include nausea, fatigue, irritability, dermatitis, cough, bronchitis, hair loss, halitosis, dizziness, and nail tenderness.30 Zinc’s recommended dietary allowance is 11 mg/d, which in the United States is easily achieved.31 Because of reports that doses greater than 150 mg/d caused immune dysfunction and impaired antioxidant effect and that higher zinc levels correlated with increased insulin-like growth factor-1 and testosterone levels, Leitzmann and colleagues reviewed zinc consumption in the Health Professionals Follow-up Study, which began in 1986 and consists of 51,529 men who ranged in age from 40 to 75 years.32 They reported that doses  100 mg increased the risk of prostate cancer, that the RR of advanced prostate cancer was 2.29, and that zinc from food sources was not associated with prostate cancer. Zinc consumption was associated with increased calcium intake and less screening PSA, so further study was suggested to better address zinc effects.32 Dagnelie and colleagues reviewed published prospective dietary studies and outlined 12 studies that reported null association with milk and dairy Figure 1. Number of studies demonstrating protective (relative risk [RR]  0.8), null RR (0.8 to 1.2), or adverse (RR  1.2) effects with various food groups from prospective studies using questionnaires. Figure generated from data in meta-analysis of diet and prostate cancer risk by Dagnelie et al.33 12 10 8 6 4 2 0 RR  0.80 Vegetables Eggs S60 0.80–1.20 Fruit Coffee VOL. 8 SUPPL. 2 2006 Cereal Black tea Meat Green tea REVIEWS IN UROLOGY RR  1.20 Fish Alcohol Milk, dairy and 6 studies that showed an increase in risk for prostate cancer with these products. Figure 1 tabulates the variability of effect of diet on prostate cancer risk. Although most diet components have studies demonstrating adverse or protective effects, no studies demonstrate a protective effect with dairy. Why is not fully known.33 Giovannucci and colleagues reported an increase in prostate cancer risk with calcium use greater than 2000 mg/d.34 They hypothesized that higher levels of calcium suppressed the body’s synthesis of vitamin D, which may be important in prostate health. Chan and colleagues reported that calcium doses greater than 600 mg decreased circulating levels of vitamin D3.35 A slight increase in risk of prostate cancer with calcium intake was shown in another study, but the investigators cautioned that, owing to calcium’s health benefits in colon disease and osteoporosis, further study is needed.36 Recently Gao and colleagues reported a meta-analysis of dairy and calcium intake with prostate cancer and found slight increases in prostate cancer trends associated with greater calcium and dairy intake and stronger association with advanced prostate cancers.37 Baron and colleagues reported on the secondary endpoint of prostate cancer in a trial for colon polyps using 1200 mg of calcium for 4 years. There was no increase in prostate cancer, and there may have been a protective effect.38 Supplements have the potential to interact with standard medical procedures. Ang-Lee and colleagues reported in 2001 on the 8 most commonly used supplements and their potential to interact in the perioperative period (Table 2).39 In the absence of specific knowledge regarding all potential interactions, it is prudent to limit supplements during the perioperative period. Supplement use during chemo- or radiation therapy is RIUS0005(Watson)_04-24.qxd 24/4/06 12:37 Page S61 Treatment and Complications Table 2 Summary of Commonly Used Supplements and Their Potential Interactions During the Operative and Perioperative Period Name of Agent Action Interactions Echinacea, purple cornflower Cell immunity Allergic reactions, immunosuppression alterations Ephedra, ma huang Sympathomimetic: increased heart rate and blood pressure MI, ventricular arrhythmias with halothane, endogenous catecholamine depletion, MAOI interactions Garlic, ajo Inhibit platelet aggregation, possibly irreversible Bleeding, stop 7 days before invasive procedure Ginkgo, duck foot tree, maidenhair tree, silver apricot Inhibit platelet-activating factor Bleeding, stop 36 hours before invasive procedure Ginseng Lowers blood glucose, inhibits platelet aggregation, increases PT-PTT Hypoglycemia, bleeding, blunt effect of warfarin, stop 7 days before invasive procedure St. John’s wort, amber, goat weed, hardhay, hypericum, klamathe weed Inhibition of neurotransmitter reuptake, MAOI is unlikely Induction of cytochrome P450, affecting cyclosporin, warfarin, steroids, protease inhibitors; decreased digoxin levels Kava, awa, intoxicating pepper, kawa Sedation, anxiolysis Potential to increase sedative effects of anesthetics Valerian, all heal, garden heliotrope, vandal root Sedation Potential to increase sedative effects of anesthetics, withdrawal MI, myocardial infarction; MAOI, monoamine oxidase inhibitor; PT-PTT, prothrombin time-partial thromboplastin time. Data from Ang-Lee et al.39 controversial, but unless specifically studied responses are known, the use of supplements is discouraged. The American Institute for Cancer Research concludes that supplements over the dietary reference intake cannot be recommended as safe or effective. To encourage adequate nutrition, the Institute recommends 5 fruits and vegetables a day, if able.40 A recent study illustrates how supplements, instead of supporting healthy cells during the stress of therapy, may actually interfere with therapy to the tumor. Bairati and colleagues randomized patients undergoing head-and-neck radiation to receive either placebo or antioxidants. There was a decrease in acute side effects, although no side effects were limiting, but there was also an increase in local recurrence (hazard ratio, 1.37) in the group receiving antioxidants.41,42 Contaminants are another concern with supplements and other forms of complementary medicines. With the American Heart Association and other diets recommending 2 servings of fish per week for the cardiac benefit of omega 3 fatty acids, mercury toxicity should be considered and a dietary history taken.43 Mercury blood levels are normally less than 5 g/L and, in addition to fish, Chinese herbal balls, Indian herbal treatments,44 and Mexican beauty creams have been shown to be contaminated. Toxicity can be subtle and can include paresthesia of the extremities (early sign  200 g/L blood), visual changes, constriction of visual fields, behavior changes, memory loss, agitation, insomnia, headache, ataxia, and hearing loss. Lead is another contaminant. Levels for children should be less than 10 g/dL, and for adults less than 30 or 50 g/dL. Recently, 20% of Ayurveda Indian herbal medicines sold in Boston were reported to have toxic levels of heavy metals.44 Other sources of toxicity are environmental pollutants, paint, litharge/litargirio, powder herbal deodorant, and Mexican candy. Toxicity symptoms include abdominal and back pain, nausea, vomiting, fatigue, loss of libido, neuropathy, microcytic anemia with basophilic stippling, and nephropathy. Toxicities that are relevant to urologists and oncologists include Chinese herb nephropathy from aristolochic acid. This was first reported in Belgium when substitution at the wholesale level of Aristolochia fangchi for Stephania tetranda in a “diet pill” led to progressive renal deterioration and end-stage renal disease in young women.45 As transitional cell carcinoma was also seen in these cases, the VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY S61 RIUS0005(Watson)_04-24.qxd 2/5/06 3:27 Page S62 Treatment and Complications continued investigators performed bilateral nephrectomies in patients on dialysis or after renal transplant. Of the 39 patients, 46% had transitional cell carcinoma in the renal pelvis or ureter.46 Other reports from Hong Kong and Taiwan have been published.47,48 In addition, bone marrow necrosis has been reported with St. John’s wort49 and Cantharanthus roseus (vinca).50 Dr. Simoneau concluded her presentation with these thoughts: • Careful review of supplements for side effects, including effects on cancer rates is ongoing. • Commonly used herbal supplements have potential for interactions during invasive procedures. • Complementary medicine while undergoing chemo- or radiation therapy is not recommended. • Heavy metal toxicity should be considered in differential diagnoses and a dietary/product-usage history taken. • Although rare, serious complications can occur with supplements. Side Effects of Cryotherapy Dr. Lugg gave a comprehensive overview of the history of cryotherapy, its evolution in delivery design and safety, and a review of the current literature for efficacy and side effects in the treatment of prostate cancer. Prostate cryotherapy was first attempted by Gondar in 1966.51 High complication and incomplete cure rates limited its use.52 In 1988, intraoperative ultrasound was used to monitor the ice ball applied to the prostate. Further improvements were insulated 3.2-mm probes for liquid nitrogen and thermosensors.52 Early reports of urethral sloughing and fistulas again limited enthusiasm. The slowness of the liquid nitrogen to respond to input from the surgeon on the size of the ice ball was also a weakness.52 In 2000 argon gas-driven 17-gauge probes were used with a brachytherapy template for freezing and helium gas was used for warming.53 Temperature can change from 86°C to 40°C in 30 seconds.53,54 The size and sharpness of the needles allow placement through a brachytherapy template and negates the need to use dilators and insertion kits.55 To minimize the amount of necrotic tissue postoperatively and to decrease the distance between probes, some physicians treat prostates greater than 40 cm3 with 3 months of preoperative ADT.56 Others, including Dr. Lugg, use saline injections into Denonvilliers fascia to separate the rectum from the prostate. He advocated careful placement of thermosensors at the neurovascular bundles, Denonvilliers space, and apex (the last sensor to protect the sphincter from damage). Urethral warming of catheters to prevent slough has been used since 1994.57 Cryotherapy is currently indicated in low-risk patients as an alternative to prostatectomy or radiotherapy, in higher-surgical-risk patients as primary therapy, and in patients who have not responded to radiation therapy as a salvage procedure.55 Cryotherapy’s safety profile is similar to those of other local therapies. Major complications include Table 3 Complications of Contemporary Third-Generation Cryotherapy Units Han et al55 Patients (n) De La Taille et al57 Primary Cryotherapy Salvage Cryotherapy Primary Cryotherapy Salvage Cryotherapy 104 18 16 19 Urethral sloughing 5/102 (5) 2/18 (11) 0 0 Urge incontinence, no pads 5/99 (5) 1/18 (5.6) NR NR Incontinence pads 3/99 (3) 2/18 (11) 0 2 (11) Penile tingling 2/100 (2) 1/17 (5.9) NR NR Impotence 83/95 (87) 12/14 (86) NR NR Pelvic pain 6/100 (6) 1/18 (5.6) 2* (12) 7* (37) Swelling 5/101 (5) 2/18 (110) 2 (12) 2 (11) Urethral fistula 0 0 0 0 Data are presented as n (%). NR, not reported. * Combines both penile and pelvic pain. S62 VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY RIUS0005(Watson)_04-24.qxd 24/4/06 12:37 Page S63 Treatment and Complications urethral sloughing leading to retention, rectal fistula, incontinence, and erectile dysfunction, which are more common in older patients. When considering the complications of cryotherapy, surgeons must assess the results of the later third-generation machines. Several contemporary series with third-generation units have been published with acceptable complication rates. Complication rates do increase when salvage cryotherapy for radiation failure is performed. Table 3 outlines contemporary complication rates from third-generation units for primary and salvage cryotherapy that compare favorably to other primary treatments for prostate cancer.55,57 Han and colleagues report on a multicenter experience in which experienced cryotherapists, experienced brachytherapists, and novices to both techniques had acceptable morbidity when their data were combined.55 Complications of Radiotherapy Dr. Roach reviewed the body of literature on systematically designed trials to improve efficacy and decrease morbidity in radiation treatment for prostate cancer. Radiation Therapy Oncology Group (RTOG) protocols 7506 and 7706 (N  1020) established the incidence of toxicity from standard radiation therapy for prostate cancer, and these data are the standard from which to compare toxicities for further dose escalation.58 The analysis of RTOG 7506 and 7706 used the Radiation Therapy Oncology Scoring scheme (grade 1 through 559) and reported a 7.7% incidence of grade 3 or greater urinary complications, with 0.5% of cases requiring laparotomy, cystectomy, or prolonged hospitalization. Gastrointestinal toxicity grade 3 or greater occurred in 3.3% of patients, with 0.6% experiencing bowel obstruction or perforation.60 The understanding that prostate cancer is dose responsive to radiation has been long recognized.58 Thus, a phase I trial, 3D Oncology Group (3DOG)/RTOG 9406, for 3-dimensional conformal dose escalation was undertaken to determine the maximum tolerated radiation dose with a less than 20% chance of grade 3 or 4 toxicity and no grade 5 toxicity. Michalski and colleagues reported on toxicity in 3DOG/RTOG 9406 for the first 2 dose escalations, 68.4 Gy and 73.8 Gy.61 They reported no grade 4 (hematuria requiring transfusion) or 5 (death) toxicities. The number of grade 3 toxicities was significantly lower than expected as calculated from the historical control subjects of RTOG 7506 and 7706, as well as the number of men experiencing no toxicity. Thus, the objective of decreasing grade 3 toxicity may have been offset by higher incidence of grade 1 and 2 toxicities.61 Ryu and colleagues reported on the higher dose, 79.2 Gy, used in 3DOG/RTOG 9406; they also found lower toxicity rates than those in historical control subjects. At a median of 3.3 years of follow-up, 4 patients (2.4%) had grade 3 toxicity.59 tients, with set-up errors, not prostate motion, the cause for positioning errors.65 His group is a proponent of implanted fiducial markers with electronic portal imaging devices for daily monitoring.66 Hormonal therapy may increase both gastrointestinal and genitourinary morbidity.67,68 Zelefsky and colleagues reported that hormonal therapy increased the risk of permanent impotence.69 Brachytherapy side effects have been more extensively studied with quality-of-life measurements.1 Gelblum and colleagues looked at the genitourinary toxicity of brachytherapy with both iodine and palladium. Using a modified toxicity score in their series of 693 men, they found that at 6 months 21% had grade 1 (nocturia), 12% grade 2 (requiring -blockers), and 3% grade 3 (catheter-dependent or needed transurethral resection of the prostate [TURP]) toxicity. Of the 28 men who had TURP, 17% developed stress incontinence.70 Size and preoperative American Urological Association score were significant variables Hormonal therapy may increase both gastrointestinal and genitourinary morbidity. Rectal side effects have been reported to be greater with higher doses of radiation in other studies. Pollack and associates reported greater rectal side effects with 78 Gy.62 Teshima and associates reported higher doses as the variable associated with rectal bleeding,63 whereas Boersma and colleagues reported that doses greater than 74 Gy might increase rectal bleeding.64 Dr. Roach stressed that to minimize radiation’s effect on surrounding tissues, accurate knowledge of the prostate’s location is essential. Reports have documented the inaccuracy of skin markings in obese pa- for toxicity. Kollmeier and colleagues reported that 18% (7/38) of men who underwent TURP after brachytherapy developed stress incontinence.71 Kang and colleagues reported that 88% had genitorurinary toxicity, mostly grade 2, per the RTOG definition. Median duration was 12 months. Prostate size and number of seeds correlated with toxicity; type of seed did not.72 Laparoscopic Versus Open Radical Prostatectomy Dr. Eastham began his comparison of laparoscopic and open radical prostatectomies by reviewing the claims VOL. 8 SUPPL. 2 2006 REVIEWS IN UROLOGY S63 RIUS0005(Watson)_04-24.qxd 24/4/06 12:37 Page S64 Treatment and Complications continued Table 4 Comparison of Laparoscopy and Open Surgery: Advantages and Disadvantages Laparoscopy Claimed Advantages Magnification improves visualization Rebuttal by Open Surgery Same effect achieved with loupes Less blood loss Transfusion rates are similar More precise dissection of neurovascular bundle and apex No advantage demonstrated Less pain and quicker recovery Results are comparable Earlier catheter removal No differences have been noted Open Surgery Critiques of Laparoscopy Rebuttal by Laparoscopy Lack of proprioception increases positive surgical margins Surgical margin rates are equivalent Higher complication rate Complications decrease with time Cautery, used in laparoscopy to mobilize the neurovascular bundle, leads to injury Potency rates are similar Significant learning curve Proctoring helps Longer operating room times and higher costs No rebuttal Adapted, with permission, from Lepor H. Open versus laparoscopic prostatectomy. Rev Urol. 2005;7:115-127. made for each technique and the areas where they can be compared. Table 4 outlines specific claims for and rebuttals to each technique. He outlined the published literature, particularly where prospectively collected and randomized trials were available for data comparison. The focus was on convalescence, continence, potency, and cancer control, specifically in regard to surgical margins. In gallstone disease, an overview of prospective randomized trials of minimally invasive surgery versus open surgery demonstrated no differences in quality of life.73,74 For colon cancer, 1 study demonstrated no difference, and two studies showed marginal favor for laparoscopy.75-77 No randomized trials in genitourinary surgery have been published to date. Webster and colleagues reviewed 314 open and 154 robotic prostatectomy cases and found similar pain scores and narcotic use.78 Another study, a S64 VOL. 8 SUPPL. 2 2006 comparison of 2 surgeons at 1 institution, both in their first year of practice, found no differences in time to oral intake, length of hospital stay, or morphine equivalents use. There were differences favoring laparoscopy in shorter days for catheterization (19 vs 14 days), partial recovery (21 vs 12 days), and full recovery (47 vs 30 days).79 Rassweiler and colleagues also reported shorter full convalescence for laparoscopy (27 vs 52 days).80 They also reported significantly lower blood loss and transfusion rates in the laparoscopy group. Dr. Eastham summarized by noting that for short-term convalescence, laparoscopic prostatectomy had longer operating times, lower blood loss and transfusion rates in most series, less pain medication, and shorter convalescence by 2 to 3 weeks. Dr. Eastham then reviewed functional outcomes of continence and anastomotic stricture between the 2 REVIEWS IN UROLOGY types of procedures. Continence with open procedures ranged from 81% to 92% with a stricture rate of 4% to 16%.80-83 For the laparoscopic series, continence ranged from 84% to 92%, and stricture 0% to 4%.80,84-87 Potency differences between the 2 techniques were reported by Abbou, Roumeguere, and their colleagues. In Abbou’s series, 30% remained potent in the open versus 41% in the laparoscopic group.88 For the Roumeguere series 55% remained potent in the open versus 65% in the laparoscopic group.89 Dr. Eastham’s final comparison was the Memorial Sloan-Kettering experience. From January 2003 to June 2005, 1213 consecutive radical prostatectomies were performed: 485 laparoscopic and 692 open (36 cases were excluded for neoadjuvant therapy). Patients were evenly matched statistically, with the same pathologic stage and Gleason scores. There were some differences in clinical stage, for example, more T1c (72% vs 65%) in the laparoscopic group. The overall margin status was 11% for both techniques. There were no statistical differences for individual stage or when risk was adjusted using the Partin tables to predict probability of organ confinement. Dr. Eastham concluded that most patients diagnosed today are candidates for either technique, and both approaches are technically demanding. Functional and cancer control outcomes depend on surgical skill and experience. Surgical technique rather than surgical approach matters. Patients with higher-risk cancers may be better suited for open prostatectomy, where wider margins are observed on pathology specimens. Panel Discussion During the question and answer session, Dr. Simoneau was asked whether the US Food and Drug Administration should regulate supplements. She RIUS0005(Watson)_04-24.qxd 24/4/06 12:37 Page S65 Treatment and Complications replied in the affirmative. “Yes. There are toxic metals or drugs that contaminate the products, interactions with prescriptions and surgery, doses that may cause cancer, and the rare fatal event, but what is most concerning is that for many consumers of supplements, behaviors proven to be healthy—maintaining ideal body weight, eating a variety of fruits and vegetables, and participating in exercise—are not being chosen, but are being replaced with intakes of supplements—with no proven benefit yet—in an effort to maintain health despite an unhealthy lifestyle. This is where supplements and those who overstate their effects do a disservice to vast numbers of people.” Dr. Eastham was asked where he falls in the debate on performing robotic prostatectomy. He replied that he still prefers open surgery, especially in high-risk cases, but he allowed that he may change his perspective. Dr. Roach was asked about radiation and fistula formation. The key, he stated, is to not get a fistula with careful placement of the posterior row of seeds. “Radiation is the gift that keeps on giving.” He cautioned that the nature of radiation injury is not fixed and, at the point of first identification of an injury, it may still evolve to encompass a larger area. Key points are diversion and repair with nonradiated tissue. Fistulas have been reported for surgery and cryotherapy, and as radiated tissue is not involved, repair with the York Mason procedure can be attempted, as outlined by Dr. Lugg.90-93 For those interested, Mayo Clinic recently reported on their experience with fistulas in radiated men. Treatment is individualized but for fistulas greater than 1.5 cm consideration of immediate fecal and urinary diversion is suggested. Men who received external beam radiation developed nonspecific symptoms at 32 months after radiation and 2 months before frank fistulization. For brachytherapy recipients, symptoms started 22 months after radiation and 16 months before the fistula was apparent.94 An algorithm for stepwise approach in the management of this difficult problem has been published.95 Merrick and colleagues have published information on minimizing brachytherapy morbidity.96 References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. Nilsson S, Norlen BJ, Widmark A. A systematic overview of radiation therapy effects in prostate cancer. Acta Oncol. 2004;43:316-381. Swanson GP, Tangen C, Miller G, et al. Phase III randomized study of adjuvant radiation therapy versus observation in patients with T3 prostate cancer (SWOG 8794). Paper presented at: ASTRO 47th Annual Meeting; 2005; Denver. CO. Kane CJ, Amling CL, Johnstone PA, et al. Limited value of bone scintigraphy and computed tomography in assessing biochemical failure after radical prostatectomy. Urology. 2003;61:607-611. Cher ML, Bianco FJ Jr, Lam JS, et al. Limited role of radionuclide bone scintigraphy in patients with prostate specific antigen elevations after radical prostatectomy. J Urol. 1998;160:13871391. Dotan ZA, Bianco FJ Jr, Rabbani F, et al. Pattern of prostate-specific antigen (PSA) failure dictates the probability of a positive bone scan in patients with an increasing PSA after radical prostatectomy. J Clin Oncol. 2005;23:1962-1968. Stephenson AJ, Slawin KM. The value of radiotherapy for the treatment of recurrent prostate cancer after radical prostatectomy. Nat Clin Pract Urol. 2004;1:90-96. Orwoll ES, Oviatt SK, McClung MR, et al. The rate of bone mineral loss in normal men and the effects of calcium and cholecalciferol supplementation. Ann Intern Med. 1990;112:29-34. Higano CS. Management of bone loss in men with prostate cancer. J Urol. 2003;170(6 Pt 2): S59-S63; discussion S64. Mann T, Oviatt SK, Wilson D, et al. Vertebral deformity in men. J Bone Miner Res. 1992;7:12591265. Smith MR, McGovern FJ, Fallon MA, et al. Low bone mineral density in hormone-naive men with prostate carcinoma. Cancer. 2001;91:22382245. Main Points • A case presentation of a 56-year-old man who underwent radical prostatectomy for T1c prostate cancer and had detectable PSA levels during follow-up with observation illustrated practice variations on when to order a bone scan and what therapeutic options to offer. • Bisphosphonates have become the standard of care to prevent skeletal complications from metastatic bone disease. Consensus has not yet emerged, however, regarding all aspects of their use or appropriate length of therapy. • Despite their widespread perception as benign, supplements have side effects. Commonly used herbal supplements have the potential for interactions during invasive procedures, use of complementary medicine while undergoing chemo- or radiation therapy is not recommended, and heavy metal toxicity should be considered when making differential diagnoses. • Cryotherapy continues to evolve, and it is currently indicated in low-risk patients as an alternative to prostatectomy or radiotherapy, in higher-surgical-risk patients as primary therapy, and in patients who have not responded to radiation therapy as a salvage procedure. • Accurate knowledge of the prostate’s location is essential to minimize radiation’s effect on surrounding tissues. • Most patients with prostate cancer are candidates for either laparoscopic or open radical prostatectomies. Both approaches are technically demanding, with surgical skill, experience, and techniques critical to good functional and cancer control outcomes. 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