The Importance of Prognostic Factors in Advanced Prostate Cancer

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1 The Importance of Prognostic Factors in Advanced Prostate Cancer MarkS. Soloway, MD Three factors were identified in a multivariate analysis of prognostic factors in men with metastatic prostate cancer as significantly associated with their progressionfree survival: 1) extent of disease on the bone scan, 2) pretreatment serum testosterone, and 3) performance status. Men with less than six bone metastases, a pretreatment testosterone > 300 ng/100 ml, and an excellent performance status will have a progression-free survival much longer than a man with more extensive bone metastases, a low testosterone prior to androgen deprivation, and a poor performance status. This information should be used to ensure proper stratification in randomized trials. It may also be helpful in identifying the patient unlikely to be helped by our current treatment. Such patients should be considered for alternative approaches with the aim of improving survival. Cancer 66: , P ROST ATE CANCER is a major cause of morbidity and mortality for men older than the age of 50 years in the United States. Approximately 103,000 new cases of prostate cancer were diagnosed in The combination of greater emphasis on early diagnosis and new techniques to detect early prostate cancer, such as transrectal ultrasound, may lead to a higher percentage of men being diagnosed when the cancer is localized and potentially curable. Currently, the majority of men with prostate cancer do not have organ confined disease when diagnosed. Androgen deprivation remains the primary mode of therapy once metastases have occurred. Although androgen deprivation provides a clinical response in 70-80% of men, most will relapse in 18 to 36 months. Evaluation of new treatment techniques for men with advanced prostate cancer requires prospective, randomized trials to determine their relative efficacy compared with traditional therapy. Unless the number of patients entering into each trial is sufficiently large, stratification is used to ensure equivalency among prognostic factors. Thus, it is necessary to determine the most important predictors of a Presented at the American Cancer Society Workshop on Combined Castration and Androgen Blockade Therapy in Prostate Cancer, Atlanta, Georgia, September 18-20, From the Department of Urology, University ofteimessee, and Baptist Memorial Hospital, Memphis, Tennessee. Address for reprints: MarkS. Soloway, MD, Department of Urology, 956 Court Avenue, Box 10, Memphis, TN Accepted for publication February 13, longer survival. Knowledge of prognostic factors is also valuable in a retrospective analysis of any clinical trial to determine the outcome of treatment according to these various factors. Indeed, it is possible that a given treatment will only provide a benefit for a subset of patients receiving that treatment. In addition, accurate comparison among various trials will also require information on prognostic factors within each trial to demonstrate that similar patients have indeed been treated. Performance status on entry is an important, if not the most important, prognostic factor. 2 This has been used for stratification in most randomized trials. Attempts to stratify by the extent of disease among patients with metastatic prostate cancer have been used, but the method for estimating the extent of disease has been rather crude. 3 Other prognostic factors of variable significance include absence or presence of pain, extent of the primary tumor, and the level of acid and alkaline phosphatase. 4 5 In dealing with prostate cancer, most patients with advanced disease do not have bidimensionally measurable disease according to the usual criteria for chemotherapy trials. The most common sites of metastases from prostate cancer are lymph nodes and bone. Bone is the only site of distant metastases in 65% of patients who present with metastatic prostate cancer. 6 Thus, the extent of bone involvement must be monitored to evaluate response. Before the bone scan became the standard method to identify bone metastases, a Veterans Administration Cooperative Group indicated that the extent of disease, based 1017

2 1018 CANCER September 1 Supplement 1990 Vol. 66 upon plain radiographs, provided prognostic importance. 7 Some had suggested the use of quantitative bone scans, 8 9 but this technique is practiced in few nuclear medicine departments. Thus, there is a need for a simple method to grade the extent of disease on the bone scan. Soloway et a/. 10 suggested a schema to grade the extent of disease (EOD) observed on the bone scan. Thus, the patient's EOD was correlated with response to androgen deprivation and survival. Patients with fewer than six metastatic deposits had a significantly better 2-year survival than those with more metastases. Men with a superscan or its equivalent had a significantly poorer 2-year survival than those with less metastatic sites. In this initial analysis, 166 \ FIG. 2. EOD II bone scan: 6-20 metastases. men with metastatic prostate cancer were treated with various forms of androgen deprivation. Prior to initiation of therapy, they had bone scans performed by either a whole body Omega 500 or a Raytheon camera. On the basis of the number of metastases, the scans were divided into the five EOD categories as follows: 0, normal or abnormal due to benign bone disease; I, number of bone metastases less than six, each of which is less than 50% of the size of a vertebral body (one lesion about the size of vertebral body would be counted as two lesions); 2, number of bone metastases between six and 20; 3, number of metastases more than 20 but less than a superscan; 4, superscan or its equivalent, i.e., more than 75% of the ribs, vertebrae, and pelvic bones. If there were a question whether an area of increased uptake was due to benign disease or metastatic prostate cancer, spot radiographs or a FIG. I. EOD I bone scan: 1-5 metastases.

3 No. 5 PROGNOSTIC FACTORS. Soloway cantly different (P = 0.37). These differences were also demonstrated by analyzing the 2-year survival. The 2year survival rates calculated by the direct method were 0.944, 0.739, 0.682, and 0.4 for EOD I, II, III, and IV, respectively. The 2-year survival rate calculated by Kaplan and Meier are 96%, 76%, 62%, and 43% for EOD I, II, III, and IV, respectively. Another factor that seems to be predictive of response and duration of response is the level of serum testosterone prior to initiation of androgen deprivation. Adlercreutz et a!. 11 investigated 32 patients with prostate cancer and found that the mean plasma testosterone was significantly higher for patients who had a "good" response than those who did not. FIG. 3. EOD Ill bone scan: 21 + metastases. a computed tomography (CT) scan was obtained. The method of grading each patient's scan was thus relatively simple. Figures 1 to 4 illustrate examples of each of the EOD categories. Patients were seen monthly. A bone scan was performed every 3 months to monitor response to therapy. Survival curves were calculated by the method of Kaplan and Meier. Survival curves were compared by using the Lee and Desu statistic. The survival rates varied significantly by the initial EOD. EOD I and IV were significantly different from the other categories (I vs. II, P = ; I vs. III, P = 0.005; I vs. IV, P = 0.003; II vs. IV, P = ; III vs. IV, P = 0.05), but EOD II and III were not statistically signifi FIG. 4. EOD IV bone scan: superscan.

4 1020 CANCER September 1 Supplement 1990 Harper et a/. 12 studied more than 200 men with prostate cancer and observed that those who died within I year of treatment had significantly lower levels of serum testosterone prior to initiation of androgen deprivation therapy than those who survived longer than I year. Hickey et a/. 13 also noted that patients with a high serum testosterone prior to androgen deprivation were more likely to have objective regression of their disease than those who had a serum testosterone below normal prior to initiation of androgen deprivation therapy. In an effort to determine the relative significance of a variety of prognostic factors, a multivariate analysis was performed; 110 patients with metastatic prostate cancer had their clinical course reviewed from the initiation of androgen deprivation until progression of their disease was documented by the National Prostatic Cancer Project criteria. 14 The pretreatment bone scans were reviewed and the extent of disease graded. Patients received a variety of forms of androgen deprivation, including luteinizing hormone-releasing hormone (LH-RH) analog, 46; diethylstilbestrol (DES) 33; bilateral orchiectomy 21; megesterol acetate 7; and estramustine phosphate 3. Current data would indicate that all of these forms of androgen deprivation are equally effective. Patients ranged in age from 47 to 92 years with a mean age of 68 years. A total of 48 patients had a performance status of 0, 51 a performance status of I, and 11 had a performance status of 2. The median follow-up was 21 months (4-89 months). Before beginning treatment all patients had a thorough history, physical examination, and laboratory data, including determination of the serum prostatic acid phosphatase, which was determined by an enzymatic assay in 1? patie.nts and a radioimmunoassay in 91. The upper limits of normal with the radioimmunoassay (RIA) differed among the three hospitals in which these patients were followed. To compare the values from different laboratories, an index was developed by dividing the actual value by the mean value of the normal range. Thus, the index was equivalent to a 11?-ultiple of the mean normal value at each treatment location. Patients were classified into four groups according to the index: Group I, the actual PAP was within normal range; Group 2, the index was between 2 and 15; Group 3, the index was 15-40; and Group 4, the index was greater than 40. The pretreatment testosterone level was determined in 79 patients. The blood for measurement of serum testosterone was drawn at 8 A.M. (normal ng/100 ml). The univariant survival analysis.of interval to progression resulted in three significant associations: pretreatment testosterone (P = ), extent of bone metastasis (P = ), and performance status (P = ). The remaining covariants of age, race, and prostatic acid phosphatase were not significantly associated with the intervals to progression (P > 0.05 ). The patients who had a pretreatment testos- Vol. 66 terone level that was less than 300 ngj 100 ml had a shorter interval free of progression than those patients whose level was greater than 300 prior to androgen deprivation. The median intervals were 14 and 31 months, respectively. The proportion of patients who did not have progression at 24 months was 26% and 57% respectively. Patients who had the longest intervals free of progression were those with an EOD on the bone scan ofl. Patients with an EOD of II- IV had shorter intervals free of progression, and differences among these grades, in this particular analysis, were not statistically significant. The median interval free of progression was greater than 89 months for those whose EOD was I but was 17, 16, and 15 months, respectively, for those whose bone scans were II, III, and IV; 76% of the patients who had an EOD I were free of progression in 2 years compared with only 34% of those who had an EOD II, 28% with an EOD III, and 34% of those who had an EOD of IV. Patients with the best performance status had the longest median interval free of progression, i.e., 39 months. Fifty-nine percent of those with a 0 performance status were free of progression at 2 years. Patients with a performance status of 1 or 2 had median progression free intervals of 16 and 22 months, respectively, and 38% and 35% were free of progression at 2 years. Cox's proportional hazards model identified the pretreatment testosterone level and the extent of disease on the bone scan as the only two covariants significantly as. sociated with the interval to progression. The association of performance status with bone scan and testosterone level was examined by means of the chi-square statistic for contingency tables. The performance status was significantly associated with the EOD of the bone scan (P = ). The percentage of patients with more than six bone metastases was 53% if the performance status was 0, but it was 80% if the performance status was either I or 2. There was also an association between the performance status and testosterone, although it was not statistically significant (P = ). In conclusion, androgen deprivation will remain the primary treatment for patients with advanced prostate cancer until there is major progress in finding an effective alternative, e.g., chemotherapy, biologic modifier. A number of new approaches to optimizing androgen deprivation have been explored. These include the LH-RH analogs, which provide an effective medical castration, thus giving the patient a choice between surgical castration and a monthly injection for the purpose of lowering the seru.m testosterone. Antiandrogens have been combined with both surgical castration and LH-RH analogs with the hope of providing a longer progression free survival and overall survival. Some studies suggest an advantage, whereas others do not indicate a clear benefit. As more control trials are performed, we are learning more about subsets of patients within the broad category

5 No.5 PROGNOSTIC FACTORS Soloway 1021 of metastatic prostate cancer. Some patients have a relatively long progression-free survival following androgen deprivation, whereas others do not. If there are no significant differences among various forms of androgen deprivation in regard to efficacy, one might try to use the treatment with the fewest side effects. This would place an increasing emphasis on quality oflife. Cost of treatment may also be an important consideration. On the other side of the spectrum, the prognosis for some patients is relatively poor despite single or combination androgen deprivation. If patients who are not likely to respond to androgen deprivation can be identified, this will provide a cohort of patients in which to try experimental therapies. Among those who have studied prognostic factors, performance status at initiation of therapy stands out as a highly significant variable. Unfortunately, the determination of performance status is somewhat subjective. Closely linked to performance status are other variables, such as the presence or absence of pain and the analgesic requirements. Some authors indicate that the level of alkaline phosphatase is predictive of response duration.15 This probably relates to the extent of bone metastases, but this has not been analyzed. In an attempt to semiquantitate the bone scan, the extent of disease was measured by dividing the number of lesions into four categories or grades. Patients with I to 5 lesions have a statistically significant better progressionfree and overall survival than those with more lesions. Possibly one could combine the EOD categories II and III and use a three-grade system. Thus, an EOD ofl would indicate patients who on the bone scan have I to 5 lesions and an EOD of III would be those patients who have more than 75% of the bone skeleton involved or a superscan. Finally, the pretreatment serum testosterone level appears to correlate with response and progression-free survival. A number of authors have also indicated the association between a low testosterone level and a shorter survival following androgen deprivation.''- 13 The mechanism and explanation are uncertain but indicate that further diminishing an already low level is not productive for most patients. REFERENCES I. Silverberg E, Lubera J. Cancer statistics. CA 1989; 39: DeVoogt HJ, Suciu S, Sylvester R, Pavone-Macaluso M, Smith P, DePauw M. Multivariate analysis of prognostic factors in patients with advanced prostatic cancer. J Uro/1989; 141 : Leuprolide Study Group. Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Eng/ J Med 1984; 311 : Sieber PR, Rohner TJ Jr. Importance of acid phosphatase in response criteria for prostate cancer. Urology 1987; 30: Emrich U, Priore RL, Murphy GP, Brady MF. Prognostic factors in patients with advanced stage prostate cancer. Cancer Res 1985; 45: McCrea LE, Karafin L. Carcinoma of the prostate: Metastases, therapy and survival. A statistical analysis of 500 cases. Int Col/ Surg J 1958; 29: Hovsepian JA, Byar DP. Quantitative radiology for staging and prognosis of patients with advanced prostatic carcinoma. Urology 1979; 14: Citrin DL, Cohen AI, Harberg J, Schlise S, Hougen C, Benson R. Systemic treatment of advanced prostatic cancer: Development of a new system for defining response. J Uro/1981; 125: Drelichman A, Decker DA, Al-Sarraf M, Vaitkevicius V, Muz J. Computerized bone scan. Cancer 1984; 53: Soloway MS, Hardeman SW, Hickey D eta/. Stratification of patients with metastatic prostate cancer based on extent of disease on initial bone scan. Cancer 1988; 61: II. Adlercreutz H, Ran nikko S, Kairento AL, Karonen SL. Hormonal pattern in prostatic cancer: II. Correlation with primary response to endocrine treatment. Acta Endocrinol (Copenh) 1981 ; 98: Harper ~E, Pierrepoint CG, Griffiths K. Carcinoma of the prostate: RelatiOnship of pre-treatment hormone levels to survival. Eur J Cancer Clin Onco/1984; 20: Hickey D, Todd B, Soloway MS. Pre-treatment testosterone levels: Significance in androgen deprivation therapy. J Ural : , 14. Slack NH, Karr JP, Chu TM, Murphy GP. An assessment of bone scans for 11_1onitoring osseous metastases in patients being treated for prostate carcmoma. Prostate 1980; 1: Merrick M_V, Ding CL, Chisholm GD, Elton RA. Prognostic sigmfic~nce of alkahne and acid phosphatase and skeletal scintigraphy in carcmoma of the prostate. Br J Uro/1 985 ; 57: