Neoplasia
Renal Transplantation and Prostate Cancer: Guidelines for Screening and Treatment M. Whang, S. Geffner, Z. Khachikian, A. Kumar, L. Bonomini, and S. Mulgaonkar
P
ROSTATE CANCER has become the most commonly diagnosed cancer in American men, and it is the second most common cause of cancer death among American men. In fact, over 198,000 men are expected to be diagnosed with prostate cancer, with 31,500 estimated deaths from prostate cancer in 2001.1 Between 1976 and 1994, prostate cancer rates doubled and mortality increased by 20%.2 The cause of this is unclear but it is most likely associated with an increased awareness and detection of prostate cancer.3 As more Americans (“baby boomers”) get older and live longer, prostate cancer is affecting more men and has become a major public health issue. It is estimated that 1 in 10 men will suffer from prostate cancer sometime in his life. Recently, with advances in immunosuppression, older patients are receiving kidney transplants. As men over 50 undergo kidney transplantation, the issue of prostate cancer has become significant in this population. Should men over 50, who are candidates for transplant, undergo screening for prostate cancer? Should patients with a history of prostate cancer be allowed to undergo kidney transplant? If so, how long should they be disease-free? Because only a few transplant patients are currently at risk to develop prostate cancer, there are no studies that show the risk of prostate cancer in transplant patients. Thus, it is critical that guidelines be established regarding screening and treatment of prostate cancer for patients who are candidates for kidney transplantation.
age 50.4 With early detection techniques, patients in their 40’s have also been found to have prostate cancer. Although the etiology of prostate cancer is unknown, there is evidence of both environmental and genetic influences in the pathogenesis of prostate cancer. An environmental effect in the pathogenesis of prostate cancer is seen in the incidence of prostate cancer among the Japanese living in the United States and in Japan. The Japanese in Japan have a lower incidence5 of prostate cancer compared to the Americans, while the second-generation Japanese who were born and raised in the United States have the same incidence of prostate cancer as their American counterparts. It is assumed that in this case, something in the environment, such as a diet rich in fat, is responsible for the increase in the incidence of prostate cancer.6 In addition, a deficiency of Vitamin D has also been implicated in the development of prostate cancer.7 Voting for the genetic effect in the pathogenesis of prostate cancer is the familial form of prostate cancer. It has been found that when a patient has one first-degree relative (ie, father, brother, or son) with prostate cancer, his risk of prostate cancer is increased two to three times the general population. When he has two or three first-degree relatives with prostate cancer, this risk is increased 5- to 11-fold.8 It is imperative that when a patient has prostate cancer, his family should be counseled to start screening all male first-degree relatives for prostate cancer starting at
EPIDEMIOLOGY
Prostate cancer incidence appears to increase with increasing age. Though rare before the age of 50, the incidence and mortality rates both increase almost exponentially starting
From the Division of Transplantation, St Barnabas Medical Center, Livingston, NJ, USA. Address reprint requests to Shamkant Mulgaonkar, 94 Old Short Hills Road, Livingston, NJ 07039.
0041-1345/02/$–see front matter PII S0041-1345(02)03463-X
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
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Transplantation Proceedings, 34, 3196 –3199 (2002)
RENAL TRANSPLANTATION AND PROSTATE CANCER
age 40. Another evidence of genetic effect in the pathogenesis of prostate cancer is the fact that African-Americans seem to develop prostate cancer more frequently and have a worse prognosis than white Americans.9 It is recommended that African-Americans also start screening for prostate cancer at age 40. Renal transplant patients are at a higher risk for posttransplant lymphoproliferative disorder.10 At the moment, there is no evidence of increased risk for prostate cancer after transplant. In fact, prostate cancer in this population has been reported to occur less frequently than in the general population.11 As more patients over 50 undergo kidney transplantation, the incidence of prostate cancer in these patients is expected to increase. Currently, renal failure patients with a history of cancer must have a 2-year disease-free interval prior to being allowed to receive kidney transplant.12 It is not clear if the same should apply to prostate cancer patients as prostate cancer is a relatively slow-growing cancer and may recur at a later date than 2 years. SYMPTOMS AND SIGNS
Unfortunately, prostate cancer does not have significant early symptoms that alert a patient to seek help. Often prostate cancer is an incidentally discovered condition thanks to the use of a blood test, prostate-specific antigen (PSA), or by rectal examination performed during a routine physical examination. Many patients who are over 50 experience symptoms of benign prostatic hyperplasia (BPH) and seek medical attention. It is often during evaluation for BPH that prostate cancer is discovered. The symptoms of BPH include frequency and urgency of urination, nocturia, urge incontinence, sensation of incomplete emptying, and decreased force of urinary stream. If a patient complains of these symptoms, he should be evaluated for both BPH and prostate cancer. When a patient complains of back pain or bone pain it may indicate the presence of metastatic prostate cancer.
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shown that if PSA is below 4 ng/mL, the chance of finding prostate cancer is less than 5%. If PSA is between 4 and 10 ng/mL, the chance of finding prostate cancer is 17%. If PSA is greater than 10 ng/mL, the risk of prostate cancer is over 50%.17 It is obvious, then, that any patient with PSA greater than 10 ng/mL must have a prostate biopsy and a patient with PSA less than 4 ng/mL probably does not need a biopsy. What is unclear is what to do with the patients whose PSA is between 4 and 10 ng/mL. To help with this dilemma, there have been many new tests designed to help increase the accuracy of PSA. They include PSA density,18 PSA velocity,19 age-specific PSA,20 and percent free PSA.21 PSA density is defined as serum PSA divided by the volume of the gland. If PSA density is greater than 0.15, a biopsy is recommended due to a high risk of malignancy among these patients. PSA velocity measures the change in PSA on a yearly basis. If PSA increases by more than 0.75 ng/mL in 1 year, it is suggestive of the presence of prostate cancer and a biopsy is indicated. PSA velocity is also useful in risk assessment in men with lower PSA levels. In those with PSA levels between 2 and 4 ng/mL, an increase of 0.1 ng/mL per year or more suggest an increased risk for prostate cancer during the next 10 years.22 The age-specific PSA aims to readjust PSA cutoff values based on patient’s age. It is being used to decrease biopsies in older patients and to increase biopsies in younger patients. The percent free PSA is based on the fact that PSA can exist in serum in a form bound to protein or free form. In patients with prostate cancer, the percent free form is lower than in patients with BPH. If percent free PSA is less than 20%, the patient should undergo a biopsy. In addition to PSA, a digital rectal examination (DRE) is an essential part of screening for prostate cancer. Unfortunately, neither PSA nor DRE alone is sufficient to diagnose prostate cancer. However, if both are used, the detection rate is significantly improved. If either or both PSA and DRE are abnormal, the next step is a transrectal ultrasound (TRUS) guided biopsy. TRUS allows accurate visualization of the prostate and facilitates the biopsy of the prostate.
DIAGNOSIS
The discovery of PSA by Wang et al in 1979 marked the beginning of a new era in the management of prostate cancer.13 PSA is a protein that is produced only by the prostate gland in the human body, and therefore it is prostate-specific. Unfortunately, it is not cancer-specific. PSA can be elevated by prostatitis, BPH, prostate cancer, prostate biopsy, urinary retention, or ejaculation.14 Because of its nonspecificity for cancer, there is debate among the medical community whether PSA should be used as a screening test. However, many believe that PSA should be used as a screening test because if prostate cancer is discovered early, it can be cured and it could improve survival.15 Several studies have shown that renal failure and dialysis do not affect the serum PSA level.16 The normal value of PSA is between 0 and 4 ng/mL by the Hybritech assay. A study involving a large number of patients have
STAGING TESTS
If prostate cancer is found, the patient should have staging tests, which in the past included a computed axial tomography (CAT) scan of pelvis or a magnetic resonance imaging (MRI) of pelvis and a bone scan to rule out metastases.23 Some authors feel that if PSA is less than 10 ng/mL and Gleason’s score is less than 7, there is little chance of metastatic disease and staging tests are unnecessary.24 The ProstaScint study has been recently reported to have an increased sensitivity and specificity for detecting metastatic cancer. ProstaScint binds to prostate-specific membrane antigen located in the prostate as well as sites of metastasis.25 A new technique known as fluorinated deoxyglucose positron emission tomography imaging has been found have increased sensitivity compared to CT and MRI in detecting metastatic bone lesions.26
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TREATMENT OPTIONS
When a patient has the diagnosis of prostate cancer, he has four major options available to him. These include observation, surgery, radiation therapy, and hormonal therapy. The choice of the treatment must be individualized based on the patient’s age, health, and stage of the cancer. However, for renal failure patients who are candidates for renal transplant, a more aggressive treatment should be considered because it is not known whether immunosuppression will increase the risk of recurrence or metastatic disease. Observation is also called “watchful waiting.”27 This is a valid option when the patient is elderly or has significant illnesses such as coronary artery disease, stroke, or other major malignancies. In general, patients with life expectancy of 10 year or less should undergo observation. In addition, patients with very low-grade prostate cancer may elect to undergo observation. Surgery is the single best chance at a cure from prostate cancer, and it should be reserved for patients with at least 15 years of life expectancy.28 Since surgery has significant complications including impotence, incontinence, pulmonary embolism, and blood loss, the surgery should be reserved for healthier patients who are less than 70 years old. Operating on patients over 70 is strongly discouraged unless the patient has family history of longevity or the patient is in excellent physical condition. Radiation therapy is another option for treatment of prostate cancer. There are two forms of radiation commonly used in treatment of prostate cancer: conformal radiation therapy (XRT)29 and brachytherapy (radioactive seed implant).30 The XRT is the most common form of radiation therapy for prostate cancer, and it involves about 35 treatments over a 7-week course. Side effects include frequency and urgency of urination, diarrhea, urge incontinence, and dysuria. Long-term complications include proctitis and impotence. Brachytherapy is a relatively new form of radiation therapy for prostate cancer. Usually radioactive Iodine or Palladium is implanted into the prostate under ultrasound guidance. Although it has had a relatively short experience, the results indicate that it is as good as if not superior in efficacy to the standard XRT, and it may even parallel the efficacy of surgery. Brachytherapy can be performed as an outpatient procedure. The hormonal therapy is reserved for patients in whom the prostate cancer has metastasized, and it is not a curative therapy. Previously, the hormonal therapy involved surgical removal of both testes (bilateral orchiectomy). Since most patients abhorred the idea, medical castration has replaced the surgery in majority of cases. Now most patients receive complete androgen blockade using an injection of luteinizing hormone-releasing hormone analogue each month and take androgen tablets daily.31 There is no effective chemotherapy for prostate cancer at this time. It is thought that
WHANG, GEFFNER, KHACHIKIAN ET AL
prostate cancer is resistant to chemotherapy due to its relatively slow doubling time. Cryosurgery is a relatively new treatment modality for prostate cancer. In cryosurgery, needles are placed in the prostate and the prostate is frozen with liquid nitrogen via these needles. It is fraught with complications including urethral necrosis, fistula formation, incontinence, and impotence.32 In addition, it has been available only for a short time. Therefore, it is not considered a standard therapy for prostate cancer. For renal failure patients, who are candidates for transplant, surgical therapy is recommended if the patient is under 70 years old and the cardiac status if good enough to undergo a major operation. If the patient is over 70 or has inadequate cardiac reserve, radiation therapy is recommended. Regardless of treatment, currently a patient should have a 2-year disease-free interval prior to receiving a kidney transplant. For surgical patients, PSA should be 0 or undetectable for 2 years. For radiation patients, the PSA never reaches 0 and should be stable for 2 years prior to receiving transplant. When a patient develops prostate cancer after a kidney transplant, again, aggressive treatment is indicated because it is not known if immunosuppression will increase the risk of metastatic disease. In general, if the patient is less than 70 years old and has the cardiac reserve, a radical prostatectomy is performed. The lymph node dissection is limited to the side contralateral to the transplanted kidney so that the transplant is not injured inadvertently during the node dissection. If a patient is over 70 years old or does not have the cardiac reserve, brachytherapy is recommended. Although XRT is feasible, the risk of radiation toxicity to the transplant kidney is greater than with brachytherapy.
THE ST BARNABAS EXPERIENCE
Between 1992 and 2000, 1144 patients underwent kidney transplant. Among them, 678 (59.3%) were men. The ages ranged from 1 to 78 years and the average age was 46 years. Among them, 276 (40.7%) were over age 50. Among the 276 male patients over 50 years old, nine (3.3%) had prostate cancer. Among the nine patients, two had prostate cancer diagnosed before transplant and seven had prostate cancer diagnosed after the transplant. Of the two patients with prostate cancer before transplant, one underwent a radical prostatectomy and the other underwent external beam radiation therapy. Both of these men were able to wait 2 years of disease-free interval and ultimately received kidney transplant. Currently, they have no evidence of disease and are doing well. There were seven patients who were diagnosed with prostate cancer after transplant. The diagnosis was made 2 months to 6 years (mean 37 months) after transplant. Three patients underwent a radical prostatectomy, and four underwent radiation therapy. Among the four patients who received radiation therapy, one had seed implant alone, two
RENAL TRANSPLANTATION AND PROSTATE CANCER Table 1. The St Barnabas Guideline for Renal Patients With Prostate Cancer Age and Health Status
⬍70 years, good cardiac reserve ⬍70 years, poor cardiac reserve ⬎70 years
Ca Before Txp
Ca After Txp
Surgery
Surgery
Seed implant or XRT
Seed implant Seed implant
Seed implant or XRT
had XRT alone, and the fourth had combination of seed implant and XRT due to a high Gleason’s score of 8. Currently, only one patient has evidence of recurrent disease. This patient had a Gleason’s score 8 prostate cancer and he seems to be failing despite seed implant and XRT. CONCLUSIONS
Prostate cancer has become the most commonly diagnosed cancer in American men and will cause death of 31,500 men in 2001. If detected early, prostate cancer is curable with an excellent prognosis. There are many factors that affect the survival from prostate cancer including the stage of cancer, aggressiveness of the cancer, health of the patient, and treatment method. Regardless of the treatment option, close follow-up is essential. It is critical to understand the importance of early diagnosis by screening with both DRE and PSA tests. If a patient has an abnormal PSA or DRE, he should undergo a TRUS guided biopsy. Then, depending on the stage and health of the patient, he should be counseled on all treatment options for prostate cancer including observation, surgery, radiation therapy, and hormonal therapy. The American Urologic Association recommends that every man over 50 have a DRE and PSA annually. If there is a family history of prostate cancer or if the patient is an African-American, the screening should start earlier, perhaps as early as age 40. For the renal failure patient who is a candidate for transplant, a more aggressive approach is needed because it is not known whether immunosuppression will increase the risk of metastasis or recurrence. For the transplant patient who develops prostate cancer after transplant, again, more aggressive treatment is indicated. At St Barnabas Medical Center, the guideline in Table 1 is followed. With early diagnosis and aggressive intervention, prostate cancer is curable. Although the St Barnabas experience does not show an increased incidence of prostate cancer than in general population, only time will tell whether renal
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transplant patients are at an increased risk for prostate cancer and or metastatic prostate cancer. Until then, the transplant team members should be aware of the recommendations above and evaluate these patients. REFERENCES 1. Greenlee RT, Hill-Harmon MB, Murray T, et al: CA 51:15, 2001 2. Ries LAG, Kosary CL, Hankey BF, et al: SEER Cancer Statistics Review, 1973–1994 (NIH Pub. No 97-2789). Bethesda, Md: NCI; 1997 3. Haas GP, Sakr WA: CA 47:273, 1997 4. Mettlin CJ, Murphy GP, Ho R, et al: Cancer 77:2162, 1996 5. Brawley OW, Knopf K, Thomsen I: Semin Urol Oncol 16:187, 1998 6. Shimizu H, Ross RK, Bernstein L, et al: Br J Cancer 63:963, 1991 7. Hanchette CL, Schwartz GG: Cancer 70:2861, 1992 8. Spitz MR, Currier RD, Fueger JJ, et al: J Urol 146:1305, 1991 9. Morton RA Jr: Urology 44:637, 1994 10. Penn I: Transplantation 43:32, 1987 11. Penn I: Transplant Science 4:23, 1994 12. Penn I: Ann Transplant 2:14, 1997 13. Wang MC, Valenzuela LA, Murphy GP, et al: Invest Urol 17:159, 1979 14. Tchetgen MN, Oesterling JE: Urol Clin North Am 24:283, 1997 15. Arcangeli CG, Ornstein DK, Keetch DW, et al: l Clin North Am 24:299, 1997 16. Ha R, Jindal RM, Milgrom MM, et al: South Med J 91:847, 1998 17. Cooner WH, Mosley BR, Rutherford CL, et al: J Urol 143:1146, 1990 18. Benson MC, Whang IS, Olsson CA, et al: J Urol 147:817, 1992 19. Carter HB, Pearson JD, Metter JE, et al: JAMA 267:2215, 1992 20. Richardson TD, Oesterling JE: Uron Clini North Am 24: 339, 1997 21. Catalona WJ, Smith DS, Wolfert RL, et al: JAMA 274:1214, 1995 22. Fang J, Metter EJ, Landis P, et al: Urology 59:889, 2002 23. Rees MA, Resnick MI, Oesterling JE: Urol Clin in North Am 24:379, 1997 24. Lee CT, Oesterling JE: Urol Clini in North Am 24:389, 1997 25. Sodee DB, Faulhaber PF, Nelson A et al: Medscape Radiology 2: 2001 26. Morris MJ, Akhurst T, Osman I, et al: Urology 59:913, 2002 27. Chodak GW, Thisted RA, Gerber GS, et al: NEJM 330:242, 1994 28. Zincke H, Oesterling JE, Blute ML, et al: J Urol 152:1850, 1994 29. Zietman AL, Coen JJ, Dallow KC, et al: Int J Rad Onc Bio Phys 32:287, 1995 30. Blasko J, Wallner K, Grimm P, et al: J Urol 154:1096, 1995 31. Crawford ED, Eisenberger MA, McLeod DG, et al: NEJM 321:419, 1989 32. Crawford ED, Cox RL: Urology 45:932, 1995