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News Archive: Michigan Oncology Journal Spring 98

PSA Screening, Surgery and Recombinant Vaccine Gene Therapy: A Strategy to Reduce Prostate Cancer Mortality

-Martin G. Sanda, M.D.,
Assistant Professor of Urology and Oncology

With the advent of widespread prostate specific antigen (PSA) screening, most prostate cancers are diagnosed at an early stage amenable to ablative local-regional therapy (1). The long-term efficacy of radical prostatectomy in younger men, with a 15-year or greater life expect-ancy, is becoming increasingly evident despite the recognition that many prostate cancers may not be lethal in older men (2,3,4,5). Although patients who recur represent a minority of those undergoing surgery, the high prevalence of prostate cancer causes even a minority of surgical failures to comprise more than 30,000 annual cases of minimal recurrent disease (biochemical relapse evidenced by rising PSA). This setting provides impetus for developing effective therapy for post-surgical residual or recurrent disease. One such strategy under development at the University of Michigan Comprehensive Cancer Center is the use of gene therapy in the form of recombinant prostate cancer vaccines.

Natural History of Prostate Cancer and the Rationale for PSA Screening
It is well documented that not all prostate cancers are lethal (4,5). Conversely, a significant proportion of prostate cancers are deadly, and prostate cancer is the second leading cause of cancer deaths in American men. This provides impetus for screening and intervention.

The paradox of a lethal cancer in the background of endemic indolent disease in the elderly has raised controversy regarding the utility of screening and intervention (6). PSA screening has been both advocated and condemned. The paradox can be resolved, however, by approaching the issue of screening on an individualized basis with consideration given to the patient’s life expectancy and grade of the diagnosed cancer. The most complete data regarding the natural history of untreated localized prostate cancer were derived by a population-based analysis from the Connecticut Tumor Registry by Albertsen and colleagues (Table 1). Also frequently cited as the basis for prostate cancer natural history data is a meta-analysis that is flawed because its principal component study was a series of 309 patients of which a large proportion (79) had been excluded from analysis for unclear reasons (5,7). The data from the Connecticut Tumor Registry demonstrate the pivotal role of cancer grade and life expectancy in prostate cancer mortality. This analysis focused on patients of 65 to 75 years of age; disease-specific mortality in men younger than 65 years of age can be expected to be higher due to lower rates of competing causes of death. Clearly, some prostate cancers may have an indolent clinical course, and low-grade cancers (Gleason score <5) are especially prone to fall in this category. This setting has raised question as to whether screening efforts detect indolent disease only or a sufficient proportion of potentially lethal cancers to justify the screening efforts.

Evidence suggests that screening efforts lead to detection of a significant number of lethal cancers. First, although use of PSA testing is associated with a shift in stage at diagnosis, this change has predominantly consisted of an increase in diagnosis of treatable cancers at stage T1 to T2, and reduced numbers of T3 cancers (1). A grade shift to lower grades, as would be expected if more indolent disease were being diagnosed, has not occurred. For example, low-grade cancers continue to comprise less than 15% of diagnosed prostate cancers following screening at the U-M Comprehensive Cancer Center. Second, if screening efforts led principally to diagnosis of indolent disease, then prevalence of cancer diagnosis with screening would be expected to significantly exceed prevalence of prostate cancer mortality. Population-based screening studies using PSA testing and digital rectal exam (DRE) in young men detect cancers in 3% of screened individuals. Similarly, the prevalence of prostate cancer deaths among American men is 3%, while the prevalence of prostate cancer is 9%. The prevalence of cancers in screened men (3%) mimics the prevalence of prostate cancer mortality in the general population, suggesting that screening efforts in younger men may be detecting significant, rather than indolent, carcinomas. However, patients benefit from screening and early detection principally if an effective local therapy is available. Circumstantial evidence is mounting that radical prostatectomy provides such effective therapy, particularly in younger men.

Radical Prostatectomy in the Management of Localized Prostate Cancer: Cancer Control
In the absence of conclusive data from prospective randomized clinical trials, evidence of surgical efficacy is based on circumstantial evidence. Disease-specific mortality data from a multi-institutional analysis by Gerber and colleagues, and the largest, most recently updated single institution series from Johns Hopkins by Pound and colleagues indicate that less than 20% of patients die of prostate cancer by 10 years after prostatectomy (Table 2). Noteworthy is the better survival rate in the single institution cohort (93% at ten years) compared to the multi-institution study (80%). Clinical stage distribution of the two studies was similar, with two-thirds of each study comprised of T2 cancers with the remainder principally T1. However, two issues may account for the discrepant results. First, the multi-institutional analysis of Gerber et al included series utilizing a perineal oper-ation, as well as those using retropubic prostatectomy, while Pound et al used retropubic prostatectomy exclusively. Second, different pathologists determined the Gleason score in these studies, raising the possibility that differences in grade distribution may be present.

Direct comparison of the natural history data from Albertsen and surgical outcomes data is clearly problematic due to selection bias. Nevertheless, comparison deserves comment. In comparing different series of prostate cancer cohorts, a pivotal issue is uniformity of the pathological staging and grading. The Connecticut Tumor Registry cohort reported by Albertsen and the Johns Hopkins surgical cohort reported by Pound have both been staged by the same pathologist (who was blinded to outcome), excluding this issue when these two cohorts are considered. Moreover, the clinical stage distribution in these two cohorts is similar, with a trend toward more favorable stage in the untreated cohort (51% T1) compared to the surgical series (31% T1). Finally, the untreated cohort was older at diagnosis (71 years) compared to the surgical cohort (59 years), with higher co-morbidity in the untreated group reducing the observed disease-specific mortality. Despite a comparison where the principal biases (age and stage differences) would favor lower disease-specific mortality in the untreated cohort, the surgical outcome appears favorable (7% versus 24% disease-specific mortality for moderate grade cancers). These findings would be difficult to reconcile in the absence of significant surgical therapeutic efficacy.

Radical Prostatectomy in the Management of Localized Prostate Cancer: Quality of Life
The efficacy of radical prostatectomy has to be viewed in context of intervention-related side effects. The operation can be performed safely and expe-diently. In our hands, operative time is usually two to three hours, the procedure is performed under epidural anesthesia, transfusion is required in less than 10% of cases, and patients are ready to return home on the second post-operative day. Morbidity such as wound infection or deep venous thrombosis occurs in less than 5% of cases, and mortality is rare (less than 0.5%).

Sexual and urinary function may often be adversely affected following radical prostatectomy, whether performed using nerve-sparing or non-nerve sparing approaches, albeit the effects on urinary function are typically temporary. Of interest, elderly men may be willing to compromise some aspects of urinary function for cancer therapy (8), and global measures of health-related quality of life (HRQOL), such as the RAND short-form 36, have not detected significant long-term adverse effects on overall patient-reported HRQOL in patients who have undergone surgery compared to those undergoing radiation or no therapy (9). However, prospective longitudinal analyses of HRQOL following surgery, stratified by nerve-sparing and compared to baseline are scant. We implemented a pilot prospective study to investigate longitudinal urinary and sexual function related to radical prostatectomy.

A questionnaire concerning urinary and sexual function and bother was completed by 462 patients undergoing radical prostatectomy preoperatively and at three-month intervals thereafter by an objective third party (Table 3). The proportion of men self-reporting leaking/dripping urine and those reporting erections were compared to preoperative baseline, and sexual function and bother were stratified by nerve-sparing versus non-nerve sparing surgery. Of interest, many men (13%) had some urinary leakage at pre-operative baseline, which was rarely perceived as a problem. Most men (58%) experienced incontinence three months after surgery, and although many men (37%) continued to occasionally leak urine one year after surgery, the severity of incontinence was minimal and was problematic for only 3% of patients. In contrast to a recently reported small series in which patient-reported erectile function did not differ between similar groups (10), recovery of erections in our cohort was better in those undergoing nerve-sparing surgery than those who did not have nerve-sparing.

Prostate Cancer Gene Therapy: Recombinant Vaccines for Post-surgical Recurrence
Despite favorable surgical outcomes in most patients undergoing radical prostatectomy, some patients develop cancer recurrence. Post-surgical recurrence is typically first apparent as biochemical failure or PSA recurrence, evidenced by a rising PSA in the absence of grossly metastatic disease. The patient with PSA recurrence represents an ideal candidate for novel therapeutic strategies targeting minimal cancer burden. Based on data showing the efficacy of recombinant poxvirus vaccines encoding specific tumor-associated antigens in pre-clinical animal models, we are currently evaluating recombinant poxvirus vaccines for the treatment of such PSA-recurrent prostate cancer. We opened the first prostate cancer gene therapy protocol at the U-M in July 1997, and have completed registration of 21 patients at present. In this trial, performed in collaboration with NCI-CTEP and Therion Biologicals, the recombinant vector vaccinia-PSA (11) is administered to patients in the setting of intermittent androgen deprivation, which is performed in order to maximize sensitivity of detecting biological response and as a tool for attenuating PSA-specific tolerance (Figure 1). The goal of this treatment strategy is to induce PSA-specific T cells capable of eliminating PSA-expressing cancer cells. The unique Phase II design was developed to allow patients’ first cycle of androgen deprivation interruption to be used as a control for gauging any subsequent response to the recombinant vector.

Conclusion
The era of PSA testing has allowed a stage shift such that most patients diagnosed with prostate cancer have surgically curable disease. Concurrently, technical refinements in radical prostatectomy have allowed improvements in post-surgical quality of life without impeding cancer control. The minority of patients who develop post-surgical recurrence can be enrolled in clinical trials developing new therapies, such as genetically engineered vaccines, which rationally target minimal systemic cancer burden.

References

1. Jacobsen SJ, Katusic SK, Bergstralh EJ, Oesterling JE, Ohrt D, Klee GG, Chute CG, Lieber MM. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA. 274:1445-9, 1995.
2. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Urologic Clinics of North America. 24:395-418, 1997.
3. Gerber GS, Thisted RA, Scardina PT, et al. Results of radical prostatectomy in men with clinically localized prostate cancer. JAMA. 276:615-619, 1996.
4. Albertsen PC, Fryback DG, Storer BE, Kolon TF, Fine J. Long-term survival among men with conservatively treated localized prostate cancer. JAMA. 274:626-631, 1995.
5. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med. 330:242-248, 1994.
6. Coley CM, Barry MJ, Fleming C, Fahs MC, Mulley AG. Early detection of prostate cancer. Part II: Estimating the risks, benefits, and costs. Ann Intern Med. 126:468-479, 1997.
7. Johansson JE, Adami HO, Andersson SO, Bertstrom R, Holmberg L, Krusemo UB. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA. 267:2191-2196, 1992.
8. Mazur DJ, Merz JF. Older patients’ willingness to trade off urologic adverse outcomes for a better chance at five-year survival in the clinical setting of prostate cancer. J Am Geriatr Soc. 43:979-984, 1995.
9. Litwin MS, Hays RD, Fink A, et al. Quality-of-life outcomes in men treated for localized prostate cancer. JAMA. 273:129-135, 1995.
10. Talcott JA, Rieker P, Propert KJ, et al. Patient-reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst. 89:1117-1123, 1997.
11. Hodge JW, Schlom J, Donohus SJ, et al. A recombinant vaccinia virus expressing human prostate-specific antigen (PSA): Safety and immunogenicity in a non-human primate. Int J Cancer. 63:231-237, 1995.

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