Prostate Cancer Management: A Data Analysis

Educational Objectives

The goal of this program is to improve the management of prostate cancer. After hearing and assimilating this pro­gram, the clinician will be better able to:

1.   Distinguish between watchful waiting and active surveillance (AS) in prostate cancer patients.

2.   Employ the AS approach in patients with prostate cancer.

3.   Analyze the risk for radiation-induced secondary malignancy after prostate irradiation.

4.   Discuss the results of studies comparing the relative risks for secondary malignancy from external beam radia­tion therapy with other modalities.

5.   Recognize the pathologic features that predict durable response from radiation after prostatectomy.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committe to disclose relevant financial relationships within the past 12 months that might create any per­sonal conflicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Sylvester is a consultant for Oncura and has received a research grant from IsoRay. Drs. Moul and Stock and the planning committee reported nothing to disclose.

Acknowledgements

Dr. Moul was recorded at the 41st Annual Duke Urologic Assembly, held March 7-9, 2009, in Las Vegas, NV, and sponsored by the Duke University School of Medicine. Drs. Stock and Sylvester were recorded at the 14th Annual Scottsdale Prostate Cancer Symposium, held March 5-8, 2009, in Scottsdale, AZ, and sponsored by Diversified Con­ference Management, Inc. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Active Surveillance

Judd W. Moul, MD, Professor and Division Chief of Urologic Surgery, and Director, Duke Prostate Center, Duke University Medical Center, Durham, NC

Watchful waiting (WW) vs active surveillance (AS): WW  — terminology applied ad hoc in pre-prostate-specific an­tigen (PSA) era for stage A1 prostate cancer after transurethral resection of prostate (TURP); limited success not standardized; many older men not informed of cancer diagnosis; AS  —  newer terminology, for patients with low-risk, low-volume, low-PSA, and low-Gleason score prostate cancer; standardized follow-up; patients well in­formed; usually involves periodic repeat prostate biopsies; AS in context of prostate imaging  —  if better imaging of prostate becomes available, better acceptance of AS option likely

Background studies on WW: Scandinavian study  —  pre-PSA era; mean age of participants 72 yr; all had stage T2 disease and 96% classified as World Health Organization (WHO) grade 1 or 2 (many diagnosed by needle aspira­tion cytology); mean follow-up 21 yr; cancer death rate 20% by 10 yr and increased to 80% at >15 yr; poor results seen with grade 3 tumors; concluded that local control translated into survival benefit; observation not recom­mended for patients with intermediate- or high-risk and palpable disease if life expectancy >5 yr, nor for patients with low risk and palpable disease if life expectancy >10 yr; Department of Defense (DOD) Center for Prostate Disease Research (CPDR) study  —  at 5-yr follow-up, »50% remained on AS (ad hoc WW), and remainder pro­gressed to treatment; similar study showed that after 4 yr, only 27% of patients remained on WW; key teaching point  —  WW ineffective when nonstandardized and without education or repeat biopsies

Background study on modern AS (Klotz et al):  8-yr follow-up, with 85% overall survival at 8 yr; most deaths due to other causes; cancer-specific survival 99% at 8 yr; 2 prostate cancer deaths, each at 5 yr after study entry (both had PSA doubling time [DT] <2 yr)

Surveillance Therapy Against Radical Treatment (START) trial: treatment vs AS; participants randomized to radical prostatectomy or radiotherapy (external beam radiation therapy [EBRT] or brachytherapy) based on patient and physician preference (arm A) or AS with selective intervention based on clinical progression (arm B); inclusion criteria  —  stage T1 or T2 disease; biopsy Gleason score £6, with no pattern 4; PSA <10 ng/mL; speaker recom­mends using same criteria in clinical practice when selecting patients for AS; defining progression — rapid PSA DT; PSA performed every 3 mo for 2 yr, then every 6 mo; in most patients, decision to intervene at 2 yr based on PSA DT <3 yr; estimated that 20% of patients treated for rapid PSA DT; Gleason grade progression to predominant pattern 4 or worse on biopsy (»5% of patients); patient choice in absence of other criteria (»10% of patients); ex­pected one-third of participants to drop out (ie, progress to treatment) by yr 3 to 4; AS successful in two-thirds

AS plus: aggressive dietary and lifestyle modification; 5-a reductase (finasteride, dutasteride); complementary alter­native medications; oral antiandrogens; novel future agents; trial by Ornish et al  —  randomized to standard diet or intensive lifestyle intervention; difficult for patients to maintain 10% dietary fat and vegan diet; includes yoga and meditation; 4% had decreased PSA in experimental arm, while 6% had increased PSA in standard arm

Radical prostatectomy (RP): most common treatment for prostate cancer; potential for side effects; achieves cancer control; Duke Prostate Center RP and short-term surveillance  — average time from biopsy to RP  »3 mo; 75% of patients had RP within 3.2 mo; patients who delayed >6 mo had lower PSA recurrence-free survival than patients who underwent surgery within 6 mo; results not stratified by multivariable analysis; men >70 yr of age affected to greater degree by delay; age itself probably adverse factor for prostate cancer; in patients with Gleason sum <7, those with longer delay had higher PSA recurrence-free survival; first-pass analysis suggested delay in diagnosis had greater impact on black men; in men with PSA of 10 to 20 ng/mL, delay has impact on recurrence-free sur­vival; length of WW period has no significant effect on recurrence-free survival in men diagnosed after 2000

Summary: AS remains debated due to lack of randomized trials; lack of robust imaging hinders use; modern AS strategies preferred over  pre-PSA approach; social and economic factors affect use of AS; studies of delayed active treatment (eg, RP) important  

Secondary Malignancy After Prostate Irradiation

John E. Sylvester, MD, Director of Research, Seattle Prostate Institute at Swedish Medical Center, Seattle, WA

Radiation-induced second primary cancer: tumor that develops >5 yr after radiation therapy (RT), with histopath­ologic features differing from treated primary tumor; literature reports varying estimates of risk; data from atomic bomb survivors and medically exposed individuals show increased risk for cancer of gastrointestinal (GI) tract, thy­roid, breast, and bladder after exposure to radiation; lower risk with fractionated radiation (eg, from RT); data show incidence of secondary malignancies increases with £4 gray (Gy), then levels off and decreases; no increase in rates with extremely high and low (<1 Gy) doses; carcinomas seen within and distant from radiation field; radiation-in­duced sarcomas only occur within radiation field; risk for secondary malignancy varies with age; young individuals (ie, teenagers) have higher risk than middle-aged individuals; risk reduced if smaller tissue volume treated and dose fractionated; competitive risk model — takes into account dose delivered and full-dose distribution of normal tissue in irradiated organ; study  —  found that EBRT techniques exposed larger volumes of rectum and bladder to poten­tially carcinogenic dose than low-dose rate radiation, brachytherapy, or high dose-rate monotherapy

Intensity-modulated radiation therapy (IMRT): increases number of fields (treating greater volume of tissue with lower doses); theorized that relative risk (RR) of radiation-induced malignancy increased by 0.5%, compared to standard 4-field irradiation; machine runs longer, compared to standard irradiation, with leakage of radiation from head of machine, resulting in total body dose exposure (theorized to increase RR by 0.25%); predicted that  IMRT increases risk for radiation-induced malignancy by 0.75% (or perhaps 100%) over standard 4-field irradiation to same target volume; providing >10 megavolts of energy to normal tissues more carcinogenic than standard x-rays; increased risk only in theory (follow-up inadequate)

Surveillance, Epidemiology, and End Results (SEER) database: RR for second cancer 6% greater in patients re­ceiving EBRT, compared to surgery at any point in time, with maximum RR of »34% at 10 yr; at   ³  10 yr, EBRT-treated patients had higher risk for bladder cancer, rectal cancer, and sarcoma than surgically treated patients; also showed that RR for bladder cancer increased 1.5-fold at 8 yr, compared to surgically treated or nonirradiated pa­tients (RR of 1.0); no increase in rectal carcinomas or leukemias (conflicting reports); reasons for increased risk  —  radiation causing secondary malignancies; failure of studies to correct for age of patient; radiation patients usually  in poorer health and more likely heavy smokers and/or obese relative to surgical patients (have increased risk for malignancy independent of history of EBRT); bladder tumors diagnosed earlier in radiation patients due to pres­ence of radiation cystitis and microscopic hematuria; relative risk vs actuarial risk  —  actuarial risk of secondary malignancy (bladder tumor) 0.19%/person-year without radiation (0.26%/person-year with radiation; lower than risk for complications from RP); data show only 29 bladder cancers developed in patients treated with brachyther­apy plus EBRT (however, median follow-up only 3 yr; not definitive proof of lower bladder cancer risk); majority of bladder malignancies treated with transurethral resection of bladder tumor (TURBT) with or without intravesic­ular therapy; speaker’s study  —  considered any tumor occurring >5 yr after treatment in rectum or bladder radia­tion-induced; found 15 secondary cancers fitting definition (2 after  iodine monotherapy and 13 after combination therapy); of 11 transitional carcinomas of bladder, >50% had history of heavy smoking; 3 patients who developed rectal cancer had significant risk factors; general risk of man 60 to 70 yr of age for developing bladder cancer over 10 yr, 2.42%; average age of study subjects, 69 yr; data translate to 1.6% incidence of bladder cancer after iodine monotherapy and 3.6% after EBRT plus seed implantation (ie, no evidence of increased risk in monotherapy pa­tients); no increase in observed cases to expected cases ratio in 5-yr brackets followed; study  — looked at risk for primary malignancy after RT or brachytherapy or combination therapy, compared to surgery; excluded malignan­cies occurring within 1 yr of treatment; unable to demonstrate that brachytherapy alone or in combination with EBRT increased risk for secondary malignancy (however, study had short follow-up); article by Baxter  —  showed that RR for secondary rectal carcinomas after RT greater than that after surgery; also states that relative risk based on age significantly higher than RR based on radiation; adjusting for age important, as age-adjusted evaluation found no increased risk in radiation-treated patients; study  —  using age-adjusted rates, found EBRT had higher risk for secondary malignancy than brachytherapy; in late, age-adjusted, second primary malignancies, risk associated with EBRT greater than no treatment, but not significantly greater than in those receiving brachytherapy; age-ad­justed incidence of early secondary malignancies (not likely radiation-induced) vs late secondary malignancies greater in EBRT, compared to other treatments; for primary tumors occurring within pelvis, higher risk seen with EBRT and brachytherapy; however, no information on patient’s other risk factors for cancer); overall incidence of late secondary malignancies in patients who received no RT or surgery, 28.5% (baseline population risk); risk with EBRT 40.4%, brachytherapy 20%, and brachytherapy plus EBRT 25%; conclusions  —  SEER and institutional re­ports show mixed results; theoretically, volume-treated with 2 to 4 Gy increases risk for secondary malignancy; for individual patient, actual risk 0.07%/yr greater than surgical patient; if bladder cancer occurs, usually treated suc­cessfully with TURBT with intravesicular therapy; if increased risk from radiation exists, possibly statistically sig­nificant, but not clinically significant; more likely that patients who receive EBRT have higher risk than patients treated to smaller volume; possible that IMRT has higher risk than standard EBRT

Adjuvant/salvage Radiotherapy After Prostatectomy

Richard G. Stock, MD, Professor and Chair, Department of Radiation Oncology, Mount Sinai School of Medi­cine, New York, NY

RT after prostatectomy: issues to address  —  are outcomes different with adjuvant vs salvage RT; may overtreat per­centage of patients with no residual microscopic local disease; with adjuvant RT, local recurrence possibly present, despite lack of evidence; with salvage RT, some evidence of local recurrence; adjuvant RT treats smaller number of cancer cells (too small for detection by PSA assay), while salvage RT treats larger number of cancer cells (detect­able PSA); pathologic features that predict presence of residual disease  —  positive margins; invasion through cap­sule; invasion of seminal vesicle; detectable PSA

Factors that predict durable response to RT after prostatectomy: PSA that never reduces to zero poor prognostic sign (disease outside prostate contributing to PSA level likely); data show that the lower the PSA value before RT, the better the outcome; higher Gleason scores (8-10) have poorer prognosis than lower scores; poorer prognosis with invasion of seminal vesicles; patients with positive margins have better outcomes than those with negative margins (more likely to have residual disease for which RT effective)

Retrospective data: trial — participants received salvage RT for recurrent prostate cancer; outcomes suboptimal; at 5 to 8 yr, only 35% of patients obtain durable response; likelihood of curing patient for second time with salvage RT relatively low; study of prostate cancer-specific survival — patients who received salvage RT with or without hormones had better outcomes than those with no treatment; concluded that salvage RT administered within 2 yr of biochemical recurrence associated with significant increase in prostate cancer-specific survival among patients with PSA DT <6 mo

Adjuvant RT after prostatectomy: European Organization for Research and Treatment of Cancer (EORTC) trial   —  participants randomly assigned to observation or immediate postoperative RT (60 Gy) delivered over 6 wk; in­cluded subjects with ³1 pathologic risk feature (capsular perforation, positive surgical margins, or invasion of sem­inal vesicle); revised primary end point biochemical progression-free survival; at 8 or 9 yr, significant difference favoring immediate postoperative RT compared to observation; observation group had marked increase in locore­gional failures, compared to postoperative RT group; RT group had slightly increased incidence of toxicity of any grade compared to observation group; for grade 3 toxicity, no significant difference noted; postoperative RT in presence of surgical margin positivity had best outcome (no difference if surgical margins negative); surgical mar­gin positivity without postoperative RT had worst outcome; Southwest Oncology Group (SWOG) trial  —  looked at health-related quality of life (QOL) results; within first 1 to 2 yr, participants who received RT had increased bowel movements (BMs) compared to observation group (after 1-1.5 yr, number of BMs comparable); those who received RT reported frequent urination persisting at 5 yr; no significant difference in erectile dysfunction; overall health-re­lated QOL not affected in RT group; trial by Thompson  —  RT vs observation; for overall recurrence-free survival, RT significantly reduced recurrence; immediate postoperative RT significantly reduced likelihood of hormone ther­apy; no significant difference in overall survival; study by Swanson  —  concluded that pattern of treatment failure predominantly local, with low incidence of metastatic failure; adjuvant RT to prostate bed reduced risk for meta­static disease and biochemical failure at all postsurgical PSA levels;  adjuvant RT also significantly reduced bio­chemical failure, compared to observation; patients with seminal vesicle positivity at high risk of developing local recurrence; significant difference with postoperative RT; update of SWOG trial  —  immediate postoperative adju­vant RT significantly reduces risk for metastatic disease and improves survival; as risk factors increase, RT has greater role in improving survival; need to treat 9.1 men with pathologic T3 disease with adjuvant RT to prevent one death at median follow-up of 12 mo

Suggested Reading

Baxter NN et al: Increased risk of rectal cancer after prostate radiation: a population-based study. Gastroenterology 128:819, 2005; Brooks JP et al: Long-term salvage radiotherapy outcome after radical prostatectomy and relapse predictors. J Urol 174:2204, 2005; Chrouser K et al: Bladder cancer risk following primary and adjuvant external beam radiation for prostate can­cer. J Urol 174:107, 2005; Dall'Era MA et al: Active surveillance for the management of prostate cancer in a contemporary co­hort. Cancer 112:266, 2008; Dewell A et al: A very-low-fat vegan diet increases intake of protective dietary factors and decreases intake of pathogenic dietary factors. J Am Diet Assoc 108:347, 2008; Ercole B et al: Outcomes following active surveillance of men with localized prostate cancer diagnosed in the prostate specific antigen era. J Urol 180:1336, 2008; Hu JC et al: The effect of postprostatectomy external beam radiotherapy on quality of life: results from the Cancer of the Prostate Strategic Urologic Re­search Endeavor. Cancer 107:281, 2006; Kulkarni GS et al: Clinical predictors of Gleason score upgrading: implications for pa­tients considering watchful waiting, active surveillance, or brachytherapy. Cancer 15;109, 2007; Nieder AM et al: Radiation therapy for prostate cancer increases subsequent risk of bladder and rectal cancer: a population based cohort study J Urol 180:2005, 2008; Penson DF et al: 5-year urinary and sexual outcomes after radical prostatectomy: results from the prostate can­cer outcomes study. J Urol 173:1701, 2005; Scholz MC et al: Outcomes of treatment vs observation of localized prostate cancer in elderly men. JAMA 297:1651, 2007; Swanson GP et al: Southwest Oncology Group 8794. The prognostic impact of seminal vesicle involvement found at prostatectomy and the effects of adjuvant radiation: data from Southwest Oncology Group 8794. J Urol 180:2453, 2008; Teh BS et al: Long-term benefits of elective radiotherapy after prostatectomy for patients with positive sur­gical margins. J Urol 175:2097, 2006; Thompson IM Jr et al: Adjuvant radiotherapy for pathologically advanced prostate can­cer: a randomized clinical trial. JAMA 296:2329, 2006.