Prognosticfactors in Patientswith Advancedstage Prostatecancer1

[CANCER RESEARCH 45, 5173-5179, October 1985] PrognosticFactorsin Patientswith AdvancedStage ProstateCancer1

Lawrence J. Emrich, Roger L. Priore, Gerald P. Murphy, Mark F. Brady,2 and the Investigators of the National Prostatic Cancer Project3

Department of Biomathematics [L J. E, R L P.], the National Prostatic Cancer Project Headquarters Office [G. P. M.Â¡,and the National Prostatic Cancer Project Statistical Office [M. F. B.], Roswell Park Memorial Institute, Buffalo, New York 14263

ABSTRACT protocols since 1973 (Table 1). Details concerning the treatment regi mens used in these protocols, together with comparisons of the various The relationships of 13 potential prognostic factors to objective regimens, have been discussed previously (2-11). response to treatment and survival time were investigated, using Information gathered on the patients at the time of entry into group data gathered on 1,020 patients with advanced stage prostate protocols included the factors listed in Table 2. These 13 variables were cancer who have participated in the clinical trials of the National thought to be among the most important prognostic factors for advanced Prostatic Cancer Project. Multivariate statistical analyses re stage disease. One thousand, six hundred one (83%) of the patients vealed that previous hormone response status, analgesics, pain, were Ã©valuablefor objective response to treatment, and 1020 (64%) of these 1601 patients had information recorded for all 13 of the factors elevated acid phosphatase, and anemia were the important, (Table 1). This report is restricted to these 1020 patients. independent prognostic factors for objective response to treat Definition of Prognostic Variables and End Points. Each of the ment. For survival time, the significant prognostic factors were potential prognostic variables listed in Table 2 was treated as a categor previous hormone response status, anorexia, elevated acid ical variable in all analyses, with categories defined as follows. Previous phosphatase, pain, elevated alkaline phosphatase, obstructive hormone response was classified as a failure if the disease was in symptoms, tumor grade, performance status, anemia, and age progression after hormonal or ablative therapy (3-5, 7-11), as stable if at diagnosis. It is recommended that future treatment protocols the disease had been stabilized by orchiectomy or hormone therapy for for advanced stage prostate cancer take into account hetero at least 3 mo (2), or as previously untreated. Performance status was geneity of the treatment groups with respect to these factors, classified as normal activity, symptomatic but ambulatory, in bed less than 50% of the time, in bed more than 50% of the time, or 100% either through the design of the protocol, or at the time of bedridden. Pain was classified as no pain, mild (occasional use of analysis. analgesics), moderate (controlled use of analgesics), or severe (uncon trollable pain). Tumor grade was classified as I, II, III, or IV, according to INTRODUCTION published criteria (12,13). Age of the patient was classified as less than or equal to 60, 61-65, 66-70, or greater than 70. The remaining factors Prostatic carcinoma is one of the most common forms of listed in Table 2 were classified as either yes or no according to whether cancer and a leading cause of cancer deaths of males in the the condition was present or absent, respectively. United States (1). Prognosis, as measured by objective response NPCP response criteria (2) were used to evaluate objective response to treatment and survival time, is known to be particularly poor to treatment as being either objective progression (treatment failure), for patients with advanced (Stage Oil) disease, as compared objectively stable, partial response, or complete response (treatment with patients with early stage disease. However, little is known success). about which factors within the former group of patients are most Survival time was measured from the time of randomization to death from any cause. important with regard to prognosis. Such knowledge is invaluable Statistical Methods. The prognostic importance of the 13 variables for planning and analyzing the results of future clinical trials with respect to objective response to treatment was assessed using a involving advanced stage patients and for assessing the prog linear logistic regression model (14). First, each variable was assessed nosis of individual patients. separately for its prognostic importance (univariate analyses). Then, to This paper presents the results of a detailed, mult ivariate study the relative prognostic importance of the variables, a forward statistical study of prognostic factors in patients with advanced selection procedure was used to develop a multivariate model which stage prostate cancer. included all prognostic factors which, after adjusting for the effects of all factors entered into the model previously, were found to be significantly (P value less than 0.05) related to objective response. MATERIALS AND METHODS The prognostic importance of the 13 factors with respect to survival time was assessed using Cox's proportional hazards regression model Patient Population. One thousand, nine hundred forty patients with advanced stage prostatic carcinoma have been entered into NPCP4 (15). Again, each factor was assessed separately for its prognostic importance, and then a forward selection procedure was used to develop 1This work was supported in part by Research Grants CA16056, CA37010, a multivariate model. and CA34903 awarded by the National Cancer Institute. Estimates of survival time distribution curves were obtained by the 2 To whom requests for reprints should be addressed. 3 Investigators of the National Prostatic Cancer Project include Edson Pontes, method of Kaplan and Meier (16). Roswell Park Memorial Institute; Raju Thomas, Tulane Medical Center; Robert P. All P values correspond to likelihood ratio tests of hypotheses for Gibbons, The Mason Clinic; Stefan A. Loening, University of Iowa Hospitals and regression coefficients of zero. A P value of 0.05 or less was considered Clinics; David G. McLeod. Walter Reed Army Medical Center; Jean B. deKemion, to be statistically significant. University of California at Los Angeles; James M. Pierce, Jr., Wayne State Univer sity; George R. Prout, Jr., Massachusetts General Hospital; Peter T. Scardino, Baylor University; Joseph D. Schmidt, University of California at San Diego; William W. Scott, Johns Hopkins Hospital; Mark S. Sotoway, University of Tennessee; RESULTS Patrick GuiÃ±an,Cook County Hospital; Robert C. Ranigan, University of Kentucky Medical Center; Hugh Fisher, Albany Medical College Hospital; and Douglas E. Objective Response. The results of the univariate analyses Johnson, M. D. Anderson Hospital. 4 The abbreviation used is: NPCP, National Prostatic Cancer Project. of the prognostic importance of the 13 factors with respect to Received 1/22/85; revised 4/25/85; accepted 7/11/85. objective response to treatment are summarized in Table 3. With

Table 1 Patient population summary

NPCP treatment entered used protocol100TreatmentregimensCyclophosphamide responseFailureYractivated1973Yrclosed1975No.on protocol125No.in analyses57 (6f 5-Fluorouracil Standard treatmentHormone

200 Estramustine phosphate Failure 1974 1976 125 59(6) Streptozotocin Standard treatment

300 imidazole-carboxamide Failure 1975 1977 165 78(8) Procarbazine Cyclophosphamide

400 Prednimustine Failure 1976 1977 135 63(6) Prednimustine + estramustine

500 Diethylstilbestrol or orchiectomy Newly 1976 1980 301 131 (13) Diethylstilbestrol + cyclophos- diagnosed phamide Estramustine phosphate

600 Diethylstilbestrol Stable 1976 1982 188 100(10) Diethylstilbestrol + Cyclophos phamide Diethylstilbestrol + estramustine phosphate

700 Hydroxyurea Failure 1977 1979 125 66(6) Methyl-chloroethyl-cyclohexy- nitrosourea Cyclophosphamide

800 Estramustine phosphate Failure 1977 1979 121 56(5) Vincristine Estramustine phosphate + vincristine

1100 Estramustine phosphate Failure 1979 1981 189 130(13) Methotrexate cis-Platinum

1200 Estramustine phosphate Failure 1979 1981 149 96(9) c/s-Platinum Estramustine phosphate + c/s- platinum

1300 Diethylstilbestrol or orchiectomy Newly 1980 1983 317 184(18) Estramustine phosphate diagnosed Diethylstilbestrol or orchiectomy + 5-fluorouracil + Cyclophos phamide

Totals 1940 1020(53) " Numbers in parentheses, percentage used in analyses. the exception of tumor grade and age of the patient, each of the categories of the factors in the model are listed in Table 5. As variables considered was found to be of prognostic importance. expected, the most important prognostic factor is previous hor Patients who are stable on hormones and patients who have mone response status (Table 4). After adjusting for the effect of failed previous hormone therapy have a poorer prognosis (i.e., a this factor, the next most important prognostic factor is whether smaller probability of a treatment success, as defined above) or not a patient requires analgesics. The remaining factors which than newly diagnosed patients, as evidenced by the negative were included in the multivariate model, in order of importance, coefficients for the "stable" and "failure" categories shown in are pain, elevated acid phosphatase, and anemia. Table 3. Prognosis improves with improved performance status Estimates of the probability, P, of an objective treatment and with decreasing pain, as evidenced by the increasingly success for various types of patients can be obtained from Table negative coefficients for these variables. Similarly, prognosis is 4 by substitution into the equation better for patients who do not have anemia or anorexia, for P = exfXX)/[1 + exp(X)] patients who do not require analgesics, and for patients who do not experience weight loss, obstructive symptoms, bone metas where X is the appropriate linear combination of regression tasis, elevated acid phosphatase, or elevated alkaline phospha- coefficient estimates for the type of patient of interest. For tase. example, the estimated probability of a treatment success for a The final multivariate logistic model is displayed in Table 4; the newly diagnosed patient with mild pain and no anemia, and who observed percentages of treatment successes for the various is not using analgesics but has an elevated acid phosphatase

CANCER RESEARCH VOL. 45 OCTOBER 1985 5174

Table 2 Table 3 Potentialprognostic factors studied Summaryof univahateanalysesof objective response Categories" Factor regression rÃ©gression Newly diagnosed (315), stable on Previous hormone response FactorPrevious coefficient-0.6981'-2.3788a-0.86626-1.53496-2.0687*-2.69806-0.6322e-1.8532e-2.0804e0.2695"0.2158o0.3650"0.0912e0.0613e-0.0990e-0.8275'-0.6992'-1.2234'coefficient0.25560.16850.15540.21000.25000.62830.17500.18290.23990.43660.42150.44730.18000.17830.17860.19710.14290.1314 hormones (100), hormone fail ure (605) responseStableFailurePerformancehormone Performancestatus Normal (334), ambulatory (386), in bed <50% (153), in bed >50% (123), in bed 100% (24) Pain None (289), mild (294), moderate statusAmbulatoryIn (300), severe (137) Tumor grade I (24), II (209), III (647), IV (140) bed<50%In Age <60 (243), 61-65 (252), 66-70 bed>50%In (262), >70 (263) bed100%PainMildModerateSevereTumor Anemia No (883), yes (137) Anorexia No (727), yes (293) Analgesics No (482), yes (538) Wt loss No (749), yes (271) Obstructive symptoms No (723), yes (297) Bone mÃ©tastases No (55), yes (965) gradeIIIIIIVAge61-6566-70>70AnemiaAnorexiaAnalgesics Elevated acid phosphatase No (253), yes (767) Elevated alkalinephosphatase No (418), yes (602) " See text for more detailed definitions. 6 Numbers in parentheses, number of patients. level, is found by substituting

X = 2.1848 - 0.0971 - 0.5240 into the above equation, giving the estimate P = 0.83. Similarly, WtlossObstructive -0.64050.4674'-1.1324'-0.7120'-0.2737'SDof0.14610.13880.30960.14800.1277/Â»value<0.0001<0.0001<0.00010.84400.7320<0.0001â€¢cO.0001<0.0001â€¢cO.0001<0.0001â€¢cO.0001<0.0001<0.0001 the estimated probability of a treatment success for a stable symptomsBone patient with no pain and no anemia, but who is using analgesics mÃ©tastasesElevated phosphataseElevatedacid and has a normal acid phosphatase level, is found by substituting alkalinephosphataseEstimated * A positive rÃ©gressioncoefficientimplies that the probability of a treatment X = 2.1848 - 1.0523 - 0.2274 success for patients in this category is greater than for newly diagnosed patients, while the relationshipis reversed for a negativecoefficient. 6 A positive regression coefficient implies that the probability of a treatment into the equation, giving the estimate P = 0.71. The logistic score, X, can take on values in the range -1.9891 success for patients in this category is greater than for patients with a normal performancestatus, while the relationshipis reversed for a negative coefficient. (for hormone failures with severe pain and anemia, who require c A positive regression coefficient implies that the probability of a treatment success for patients in this category is greater than for patients with no pain, while analgesics, and who have an elevated acid phosphatase level) the relationshipis reversed for a negativecoefficient. to 2.1848 (for newly diagnosed patients with no pain or anemia, "A positive regression coefficient implies that the probability of a treatment who do not require analgesics, and who have a normal acid success for patients in this category is greater than for patients with a tumor grade of I, while the relationshipis reversed for a negative coefficient. phosphatase level). By dividing this range into quarters, patients e A positive regression coefficient implies that the probability of a treatment can be classified into one of four prognostic groups ranging from success for patients in this category is greater than for patients less than or equal poor to good. Patients in the first group (with logistic scores to 60 yr of age, while the relationshipis reversed for a negative coefficient. between -1.9891 and -0.9456) have less than a 28% chance A positive regression coefficient implies that the probability of a treatment success for patients with the condition is greater than for patients without the of having a successful response to treatment; patients in the condition, while the relationshipis reversed for a negative coefficient. second group (with logistic scores between -0.9456 and 0.0979) have a 28% to 52% chance of having a successful response; diagnosed patients, as evidenced by the positive coefficients for patients in the third group (with logistic scores between 0.0979 the stable and failure categories shown in Table 6. Survival time and 1.1413) have a 52% to 76% chance of having a successful improves with improved performance status and with decreasing response; and patients in the fourth group (with logistic scores pain, as evidenced by the increasingly positive coefficients for between 1.1413 and 2.1848) have a 76% to 90% chance of these variables. Similarly, prognosis is better for patients who having a successful response to treatment. Chart 1 depicts the do not have anemia or anorexia, for patients who do not require observed percentages of treatment successes for patients falling analgesics, and for patients who do not experience weight loss, into these four groups. The excellent agreement between the bone metastasis, elevated acid phosphatase, or elevated alkaline actual percentages of successes and the ranges for the esti phosphatase. mated percentages indicates that the model fits the data well. The final multivariate proportional hazards model is displayed Survival Time. The results of the univariate analyses of the in Table 7; the estimated median survival times for the various prognostic importance of the 13 factors with respect to survival categories of the factors in the model are listed in Table 8. Again, time are summarized in Table 6. With the exception of tumor the most important prognostic factor is previous hormone re grade, age of the patient, and obstructive symptoms, each of sponse status (Table 7) followed, in order of importance, by the variables considered was of prognostic importance. As found anorexia, elevated acid phosphatase, pain, elevated alkaline above for objective response, patients who are stable on hor phosphatase, obstructive symptoms, tumor grade, performance mones, and patients who have failed previous hormone therapy, status, anemia, and age at diagnosis. have a poorer prognosis (;'.e., a shorter survival time) than newly Interestingly, although obstructive symptoms, tumor grade,

Table 4 100V)Ã•3 Multivariate logistic regression model lor objective response

regression regression so3* Factor*ConstantPrevious coefficient2.1848*-1.0523ecoefficient0.23000.2732 o o (/)601/5 hormone response Stable -2.0132eSDof FailureEstimated 0.1832 540Â£ Analgesics -0.2274e 0.1771 20n-18%41%70%82% Pain -0.0971c Mild -0.8142e 0.2099 Moderate 0.2338 -0.9149e Severe 0.2951 Elevated acid phosphatase -0.5240e 0.1788 LOGISTIC SCORE -0.4944e Chart 1. Observed percentages of treatment successes for patients in four Anemia 0.2287 prognostic groups defined by the logistic score derived from the final multivariate * Factors are listed in order of entry into the model (i.e., in order of importance). logistic regression model. The logistic model is: X = 2.1848 - 1.0523 stable - " A constant term was included in every modelto allow for unequal probabilities 2.0132 failure - 0.2274 analgesics - 0.0971 mild - 0.8142 moderate - 0.9149 of treatment success and failure for the base-line group of patients; i.e.. newly severe - 0.5240 elevatedacid phosphatase- 0.4944 anemia. diagnosed patients with normal performance status, no pain, tumor grade = I, 60 yr old or younger, and with none of the conditions listed in Table 2. e See footnotes to Table 3 for further explanation of these values. grade of I, normal performance status, no anemia, and 60 yr old or younger. Estimates of the probability, S(f), of surviving beyond Tables any time, f, for various types of patients can be obtained from Observed response rates tor factors included in the final logistic regression model this chart and Table 7 by substitution into the equation

no. with treatment FactorPrevious size315100605482538289294300137253767883137Observedsuccess253 where S0 (f) is the ordinate value for f from Chart 2, and Y is the responseNewlyhormone appropriate linear combination of regression coefficient estimates (80)"67 diagnosedStableFailureAnalgesicsNoYesPainNoneMildModerateSevereElevatedfor the type of patient of interest. For example, the estimated (67)166(27)305 probability of surviving beyond 1 yr (i.e., t = 52) for a patient who is stable on hormones and who is anorexic, but has normal (63)181 acid phosphatase and alkaline phosphatase levels, no pain or (34)205(71)166(57)83 obstructive symptoms, has a tumor grade of III, is in bed less than 50% of the time, has no anemia, and is 75 yr old, is found by substituting (28)32 y = 1.0110+0.3352+0.3034+0.3203+0.0660 (23)154(61)332 phosphataseNoYesAnemiaNoYesSampleacid and S0 (52) = 0.94 (from Chart 2) into the above equation, giving the estimate S(52) = 0.62. (43)444 The proportional hazards score, Y, can take on values in the range -0.2726 (for newly diagnosed patients with no anorexia (50)42(31) or pain, normal acid phosphatase and alkaline phosphatase, no * Numbers in parentheses, percentage with treatment success. obstructive symptoms, a tumor grade of I, normal performance status, no anemia, and age between 66 and 70) to 5.0583 (for and age at diagnosis were not found to be significantly related hormone failures with anorexia and severe pain, with elevated to survival time when examined individually (Table 6), they were acid phosphatase and alkaline phosphatase, and with obstructive found to be significant in the multivariate analysis (Table 7). This symptoms, a tumor grade of IV, anemia, 100% bedridden, and phenomenon occurs because the univariate analyses of these age greater than 70). By dividing this range into quarters, patients factors did not take into account the fact that patients are not can be classified into one of four prognostic groups ranging from homogeneous with respect to the other prognostic factors. By poor to good, just as was done with the logistic score above. The Kaplan-Meier estimates of the survival time distributions for adjusting for this heterogeneity (i.e., by estimating the effect of each factor with the other factors in the model held constant) in the four groups are shown in Chart 3. Once again, the model the multivariate analyses, the true prognostic importance of appears to fit the data well, as evidenced by the obviously distinct obstructive symptoms, tumor grade, and age at diagnosis was estimated distributions. discerned. Chart 2 depicts the base-line survival time distribution esti DISCUSSION mated using the multivariate model of Table 7, that is, the estimate of the survival time distribution for newly diagnosed Several studies of prognostic factors in patients with prostate patients with no anorexia, normal acid phosphatase, no pain, cancer have been reported previously. Berry ef al. (17) investi normal alkaline phosphatase, no obstructive symptoms, a tumor gated the importance of 25 potential prognostic variables, includ-

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Tablee Table7 Summary oÃun/VarÃateanalysesof survival time Multivariateproportional hazards model tor survival time

coefficient''1.00101.58400.33520.24000.02120.38100.50820.25170.29100.0248 FactorPrevious coefficient0.6484a1coefficient0.16410.10880.1005value<0.0001<0.0001<0.0001>0.90000.5724<0.0001 coefficient0.17170.12010.08650.09740.13360.14440.17320.08180.09160.2487 responseStableFailurePerformancehormone responseStableFailureAnorexiaElevatedhormone .7050a0.8721*

statusAmbulatory 1.295061.6210o1.9340"0.6183e1.2660e In bed<50%In 0.11970.12580.23030.11310.1076 phosphatasePainrainMildModerateSevereElevatedacid bed>50%In bed100%PainMildModerate

1.5700e-0.0331" phosphataseObstructivealkaline SevereTumor 0.12700.2434 symptomsTumor gradeII 0.0408" grade III 0.2349 0.0129"-0.0242e-0.0935e II 0.25330.10680.1063 IVAge61-6566-70 IIIIVPerformance 0.30340.46320.29130.24310.26200.1253

statusAmbulatory 0.0464e0.6272' 0.10630.1049 >70Anemia In bed<50%In 0.32030.3828 0.15240.1737 bed >50% In bed100%AnemiaAge61-6566-70>70Estimatedregression1.03200.2870-0.0540-0.27260.0660SDofregression AnorexiaAnalgesicsWt 0.71110.8408'0.5736'-0.1050'0.9041'0.4659'0.3095'SDofrÃ©gression0.07920.07780.08140.08480.20470.09020.0772P<0.0001<0.0001<0.0001>0.9000Â«cO.0001<0.0001<0.0001Factor8Previous 0.25370.11080.10980.11090.1093

lossObstructive symptomsBone mÃ©tastasesElevated phosphataseElevatedacid alkaline phosphataseEstimatedregression * A positive regression coefficient implies that the hazard (instantaneous risk of 3 Factors are listed in order of entry into the model (i.e., in order of importance). death) for patients in this category is greater than for newly diagnosed patients, " See footnotes to Table 6 for further explanation of these values. while the relationship is reversed for a negative coefficient. h A positive regression coefficient implies that the hazard (instantaneous risk of death) for patients in this category is greater than for patients with a normal performance status, while the relationship is reversed for a negative coefficient. survival time and eight potential prognostic factors (pain due to c A positive regression coefficient implies that the hazard (instantaneous risk of cancer, acid phosphatase, ureteral dilatation, metastasis, per death) for patients in this category is greater than for patients with no pain, while formance status, weight, hemoglobin, and age). Studying only the relationship is reversed for a negative coefficient. " A positive regression coefficient implies that the hazard (instantaneous risk of the regression model with all factors included, they found that death) for patients in this category is greater than for patients with a tumor grade the only factor which was not significantly related to survival time of I, while the relationship is reversed for a negative coefficient. " A positive regression coefficient implies that the hazard (instantaneous risk of was pain due to cancer. death) for patients in this category is greater than for patients less than or equal to In contrast to these studies, the present study investigated 60 yr of age, while the relationship is reversed for a negative coefficient. both objective response to treatment and survival time, using A positive regression coefficient implies that the hazard (instantaneous risk of death) for patients with the condition is greater than for patients without the univariate and multivariate nonparametric statistical methods, condition, while the relationship is reversed for a negative coefficient. and used a forward selection procedure to determine the relative importance of several potential prognostic variables. ing various demographic factors, prior therapy, symptoms, ex It was found that, in order of importance, previous hormone tent of disease, and laboratory parameters, with respect to response status, analgesics, pain, elevated acid phosphatase, survival time, using 88 patients with hormone-resistant Stage IV and anemia were the factors significantly related to objective prostate cancer studied between 1973 and 1977. Using univar response to treatment when studied simultaneously in the mul iate statistical methods only, they found that age, bone pain, tivariate models (Table 4). For survival time, the significant prog performance status, sites of mÃ©tastases,malignant pleural effu nostic factors were, in order of importance, previous hormone sion, elevation of serum lactic dehydrogenase, serum glutamic response status, anorexia, elevated acid phosphatase, pain, oxaloacetic transaminase, alkaline and acid phosphatase, albu elevated alkaline phosphatase, obstructive symptoms, tumor min, and prolactin were significantly related to survival time. grade, performance status, anemia, and age (Table 7). Lepor et al. (18) studied the influence of hormonal therapy on The fact that previous hormone response status was found to survival of patients with advanced prostatic cancer seen between be the most important prognostic factor for both objective re 1937 and 1944, while adjusting for the effects of stage of sponse to treatment and survival time is not surprising, since disease, age at diagnosis, and date of diagnosis. They found newly diagnosed patients can be expected to have a more that none of these factors was significantly related to survival favorable response to treatment and survive longer from the time, although the overall model fit was found to be significant. beginning of study than patients diagnosed previously. It was of Byar ef al. (19) used an exponential regression model and data upmost interest, however, to obtain as precise estimates as from 1824 patients with Stages III and IV disease, entered in a possible for the prognostic importance of the remaining factors clinical trial begun in 1960, to study the relationship between listed in Table 2 for all patients with advanced stage prostate

Table 8 Â« 100 Estimated median survival times for factors included in the final proportional hazards regression model > 90 -O 2726 iY<(06OI 1.0601 i Y<2 3929 Estimated > median DC 80 2 3929 SY<37256 o 3.7256 Ã•YÃ•5.O583 Factor (wk) 70 PreviousresponseNewly hormone diagnosedStableFailureAnorexiaNoYesElevated z 60 UJ ocU 50 lu Ã›. 4O o LU 30 phosphataseNoYesPainNoneMildModerateSevereElevatedacid 20 (O W lÃ¼ _L j 52 104 156 208 260 312 364 WEEKS ON STUDY

phosphataseNoYesObstructivealkaline Charts. Estimated survival time distributions for patients in four prognostic groups defined by the proportional hazards score (Y) derived from the final multivariate proportional hazards regression model. The proportional hazards score is: y = 1.0110 stable + 1.5840 failure + 0.3352 anorexia + 0.2400 elevated acid symptomsNoYesTumor phosphatase + 0.0212 mild + 0.3810 moderate + 0.5082 severe + 0.2517 elevated alkaline phosphatase + 0.2910 obstructive symptoms + 0.0248 Stage II + 0.3034 Stage III + 0.4632 Stage IV + 0.2913 ambulatory + 0.3203 in bed <50% + 0.3828 in bed >50% + 1.0320 in bed 100% + 0.2870 anemia - 0.0540 61 to 65 yr grade1IIIIIIVPerformance -0.2726 66 to 70 yr + 0.0660 >70 yr.

cancer, while adjusting for imbalances in the current set of data with respect to previous hormone response status. Thus, it was statusNormalAmbulatoryIn decided to include previous hormone response status as a prognostic factor in these analyses, rather than to perform bed<50%In separate analyses (each with fewer patients) for each previous bed>50%In bed100%AnemiaNoYesAges6061-6566-70>70168983572338750124703530704956625766565612454332720643455626256hormone response status category. The current study is based on data gathered on patients entered into 11 NPCP protocols since 1973, and each of these protocols involved two or three treatment regimens (Table 1). Thus, it may be argued that the prognostic significance of some or all of the 13 variables studied might be confounded with the effects of the various treatment regimens used in these proto cols. It was decided, however, not to include treatment group in the analyses for several reasons. Few of the distributions for the prognostic factors differed significantly across the treatment groups within the previous hormone response status categories. (The exceptions were elevated acid phosphatase for the newly diagnosed subjects; elevated alkaline phosphatase for the stable on hormones category; and performance status, pain, tumor 80 grade, anemia, analgesics, and elevated alkaline phosphatase for the hormone failure category.) Furthermore, patients were assigned randomly to treatment group within each protocol. 60 These two facts make it unlikely (although not impossible) that UJ 50 imbalances across the prognostic factor categories with respect Ã› 40 to treatments, beyond the imbalances which are accounted for UJ by adjusting for the effect of previous hormone response status, C 30 2 influenced the results. Finally, and most importantly, one of the principal objectives of this study was to make recommendations Ã¼J10 i i i regarding which pretreatment factors should be taken into ac 52 104 156 208 260 312 364 count when designing and analyzing future treatment protocols WEEKS ON STUDY (as discussed below). Since future protocols will undoubtably Chart 2. Estimated base-line survival time distribution; that is, the estimated involve treatments not used in any of the protocols considered survival time distribution for newly diagnosed patients with no anorexia, normal acid phosphatase, no pain, normal alkaline phosphatase, no obstructive symptoms, here, adjustment for treatment effects was not considered to be a tumor grade of I, normal performance status, no anemia, and 60 yr old or younger. appropriate.

The knowledge gained in this study should be extremely useful of patients will be reported at a later date, when adequate follow- for the design and analysis of the results of future studies. The up information for these patients is available. NPCP accounts for approximately 75% of all patients with pros tate cancer who are treated on cooperative group protocols, and REFERENCES similar data have been gathered on each patient under similar 1. Silverberg,E. Cancer statistics, 1982. Caâ€”CancerJ. Clin., 32: 15, 1982. conditions since its inception in 1973. Thus, the patients entered 2. Gibbons, R. P., Beckley, S., Brady, M. F., Chu, T. M., deKemion. J. B., on protocols to date and the data gathered from these patients Dhabuwala, C., Gaeta, J. F., Loening, S. A., McKiel, C. F., McLeod, D. G., Pontes, J. E., Prout, G. R., Scardino, P. T., Schlegel, J. U., Schmidt, J. D., can be expected to be reasonably representative of the type of Scott, W. W., Slack, N. H., Soloway, M. S., and Murphy, G. P. The addition of patients and data to be seen in future studies. chemotherapy to hormonal therapy for treatment of patients with metastatic carcinomaof the prostate. J. Surg. Oncol., 23: 133-142,1983. The results of this report suggest that future treatment pro 3. Loening, S. A., Becktey, S., Brady, M. F., Chu, T. M., deKemion, J. B., tocols for advanced stage prostate cancer should take into Dhabuwala, C., Gaeta, J. F., Gibbons, R. P., McKiel, C. F., McLeod, D. G., Pontes, J. E., Prout, G. R., Scardino, P. T., Schlegel, J. U., Schmidt, J. D., account heterogeneity of the treatment groups with respect to Scott, W. W., Slack, N. H., Soloway, M. S., and Murphy, G. P. Comparisonof the important prognostic factors listed above, either through the estramustine phosphate, methotrexate, and c/s-platinum in patients with ad vanced, hormone refractory prostate cancer. J. Ural., 729: 1001-1006, 1983. design of the protocol (e.g., by using a separate randomization 4. Loening, S. A., Scott, W. W., deKemion, J., Gibbons, R. P., Johnson, D. E., scheme for each of the four prognostic groups defined above Pontes, J. E., Prout, G. R., Schmidt, J. D., Soloway, M. S., Chu, T. M., Gaeta. J. F., Slack, N. H., and Murphy, G. P. A comparison of hydroxyurea, methyl- using the logistic regression score, X, or the proportional hazards chloroethyl-cyclohexy-nitrosourea,and cyclophosphamidein patients with ad score, Y) or at the time of analysis (e.g., by using multivariate vanced carcinoma of the prostate. J. Urol., 725: 812-816,1981. 5. Murphy, G. P., Gibbons, R. P., Johnson, D. E., Prout, G. R., Schmidt, J. D., models which include the prognostic factors along with treatment Soloway, M. S., Loening, S. A., Chu, T. M., Gaeta, J. F., Saroff, J., Wajsman, group indicators). Z., Slack, N., and Scott, W. W. The use of estramustine and prednimustine versus prednimustinealone in advanced metastatic prostatic cancer patients It should be emphasized that the multivariate analyses pre who have received prior irradiation.J. Urol., 727: 763-765,1979. sented above took into account the interdependence of the 6. Murphy, G. P., Beckley, S., Brady, M. F., Chu, T. M., deKemion, J. B., Dhabuwala, C., Gaeta, J. F., Gibbons, R. P., Loening, S. A., McKiel, C. F., prognostic factors with respect to their effect on the end points McLeod, D. G., Pontes, J. E., Prout, G. R., Scardino, P. T., Schlegel, J. U, of interest. Hence, they revealed the prognostic importance of Schmidt, J. D., Scott, W. W., Slack, N. H., and Soloway, M. S. Treatment of newly diagnosed metastatic prostate cancer patients with chemotherapy certain factors (e.g., obstructive symptoms) which were not agents in combination with hormones versus hormones alone. Cancer(Phila.), revealed in the univariate analyses and demonstrated the lack of 57:1264-1272,1983. 7. Murphy, G. P., Gibbons, R. P., Johnson, D. E., Loening, S. A., Prout, G. R., independent prognostic importance of other factors (e.g., weight Schmidt,J. D., Brass, D. S.. Chu, T. M., Gaeta,J. F., Saroff, J., and Scott, W. loss) which were significant in the univariate analyses. W. A comparison of estramustine phosphate and streptozotocin in patients with advanced prostatic carcinoma who have had extensive irradiation. J. However, other potentially important interdependencies Urol., 778:288-291,1977. among the variables, which may influence their relationships with 8. Schmidt, J. D, Scott, W. W., Gibbons, R. P., Johnson, D. E., Prout, G. R., Loening, S. A., Soloway, M. S., Chu, T. M., Gaeta, J. F., Slack, N. H., SarÃ²Â«, objective response to treatment and survival time, were not J., and Murphy, G. P. Comparison of procarbazine, imidazole-carboxamide, investigated in this report. Specifically, interaction terms were and cyclophosphamidein relapsing patients with advanced carcinoma of the prostate. J. Urol., 727:185-189, 1979. not included in any of the models studied. Such interaction terms 9. Scott, W. W., Gibbons, R. P., Johnson, D. E., Prout, G. R., Schmidt, J. D., reveal situations in which the direction of the effect of a factor Saroff, J., and Murphy, G. P. The continued evaluation of the effects of chemotherapy in patients with advanced carcinoma of the prostate. J. Urol., on the end point of interest depends on the level of another 776:211-213, 1976. factor. Thus, anorexia may imply a poor prognosis for patients 10. Soloway, M. S., Beckley, S., Brady, M. F., Chu, T. M.. deKemion, J. B., Dhabuwala, C., Gaeta, J. F., Gibbons, R. P., Loening, S. A., McKiel, C. F., with severe pain, but a good prognosis for patients with no pain. McLeod, D. G., Pontes, J. E., Prout, G. R., Scardino, P. T., Schlegel, J. U., Knowledge of this type of interaction is important to understand Schmdt, J. D., Scott, W. W., Slack, N. H., and Murphy, G. P. A comparisonof estramustine phosphate versus c/s-platinum alone versus estramustine phos further the disease and the effects of the prognostic factors on phate plus c/s-platinumin patients with advancedhormone refractory prostate prognosis and will be the subject of a future paper. cancer who had had extensive irradiationto the pelvis or lumbosacralarea. J. Urol., 729:56-61, 1983. Finally, it is important to note that the apparent goodness of 11. Soloway, M. S., deKernion,J. B., Gibbons, R. P., Johnson, D. E., Loening, S. fit of the current multivariate models to the data, as depicted in A., Pontes,J. E., Prout, G. R., Schmidt,J. D., Scott, W. W., Chu, T. M., Gaeta, J. F., Slack, N. H., and Murphy, G. P. Comparisonof estramustine phosphate Chart 1 for objective response to treatment and in Chart 3 for and vincristine alone or in combination for patients with advanced, hormone survival time, is likely much better than it would have been had refractory, previously irradiated carcinomaof the prostate. J. Urol., 725: 664- 667,1981. the models been fit to an independent set of data gathered on 12. Gaeta,J. F. Glandularprofiles and cellularpatterns in prostatic cancer grading. Urology,3 (Suppl).-33-37, 1981. similar patients. The current data set could have been partitioned 13. Gaeta,J. F., Asirwatham,J. E., Miller,G., and Murphy, G. P. Histologiegrading into two disjointed subsets, with one being used to develop the of primary prostatic cancer: a new approach to an old problem. J. Urol., 723: multivariate models, and with the second subset being used to 689-693, 1980. 14. Cox, D. R. The Analysisof Binary Data. London: Chapmanand Hall, 1977. test the goodness of fit. However, it was decided that the 15. Cox, D. R. Regressionmodelsand life-tables.J. R. Stat. Soc. Ser. B, 34:187- information which would have been gained by such a procedure 200, 1972. 16. Kaplan, E. L., and Meier, P. Nonparametricestimation from incompleteobser did not justify the decrease in precision of the estimates which vations. J. Amer. Stat. Assoc., 53: 457, 1958. would have resulted from the decreased sample size. Rather, 17. Berry, W. R., Laszlo, J., Cox, E., Walker, A., and Paulson, D. Prognostic factors in metastatic and hormonallyunresponsivecarcinoma of the prostate. the goodness of fit of the models will be assessed further using Cancer (Phila.),44: 763-775,1979. 18. Lepor, H., Ross, A., and Walsh, P. C. The influence of hormonal therapy on data being gathered currently on over 700 patients with ad survival of men with advanced prostatic cancer. J. Urol., 728: 335-340,1982. vanced stage prostate cancer who are entered into ongoing 19. Byar, D. P., Huse, R., Bailar, III, J. C., and the Veterans Administration treatment protocols. The results of this study of the usefulness Cooperative Urological Research Group. An exponential model relating cen sored survival data and concomitant information for prostatic cancer patients. of the models for assessing the prognosis of an independent set J. Nati. Cancer Inst., 2: 321-326,1974.

CANCER RESEARCH VOL. 45 OCTOBER 1985 5179 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1985 American Association for Cancer Research. Prognostic Factors in Patients with Advanced Stage Prostate Cancer

Lawrence J. Emrich, Roger L. Priore, Gerald P. Murphy, et al.

Cancer Res 1985;45:5173-5179.

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