Co-Morbidities and Survival of Men with Localized Prostate Cancer Treated with Surgery or Radiation Therapy

~7/ss/1565-1714$03.00/0 -JOURNAL

vol. 156,1714-1718.November 1996

OF UROLOGY

Printed in U.SA.

copyright 0 1996 by AMERlcm UROLOGICAL ASS~CIATION, hc.

CO-MORBIDITIES AND SURVIVAL OF MEN WITH LOCALIZED PROSTATE CANCER TREATED WITH SURGERY OR RADIATION THERAPY JACKSON E. FOWLER,

JR., FREDDIE L. TERRELL AND D. LAND RENFROE

From the Division of Urology, University of Mississippi Medical Center and Veterans m a i r s Medical Center, Jackson, Mississippi

ABSTRACT

Purpose: We determined the impact of preexisting co-morbidities on survival of men with clinical stages T l b and T2NXMO prostate cancer treated with surgery or radiation therapy. Materials and Methods: A weighted co-morbidity score was determined for 276 consecutive men treated with surgery (138) or radiation therapy (138) at a Veterans Affairs medical center and was correlated with actuarial freedom from death due to co-morbid disease. Results: After a median potential followup of 7.0 years 91 patients (33%) died of co-morbid disease and 20 (7%) died of cancer related causes. There were highly significant correlations between actuarial survival and weighted co-morbidity (p
Approximately 70% of men with prostate cancer present with tumors that are clinically confined to the prostate.1 Although optimal treatment of these malignancies is controversial, surgery or radiation therapy generally is recommended if the estimated malignant potential of the cancer and estimated longevity of the host suggest a high risk of metastatic tumor progression during the remaining lifetime. Among patients with well or moderately differentiated cancers the chance of metastatic tumor progression within 10 years of diagnosis is approximately 2O%2.3 and anticipated longevity is the dominant variable in therapeutic decision making. The expected remaining life of an individual can be estimated from life tables4 and from the presence and severity of co-morbid conditions that may alter anticipated longevity. Albertsen et a1 showed that patient co-morbidities are nearly as potent predictors of survival as tumor grade in men 65 to 75 years old with localized prostate cancer treated with immediate or deferred hormonal therapy 0nly.5 However, the impact of co-morbidities on survival of men treated with surgery or radiation therapy for localized prostate cancer who are likely to be more healthy than those treated with immediate or deferred hormonal therapy has not been stud-

ied. We report the co-morbidities and survival of 276 men with stages Tlb and T2NXMO prostate cancer treated with surgery or radiation therapy at a Veterans Affairs medical center. MATERIALS AND METHODS

Study patients. From January 1, 1980 to December 31,

1991, 276 men with clinical stages T l b and T2 prostate cancer were treated with radical prostatectomy (138) or radiation therapy (138) at a Veterans Affairs medical center. Data concerning other men with localized cancer who were not treated with surgery or radiation therapy during the entire study period were incomplete. However, between 1985 and 1991 less than 10% of patients were treated with primary or deferred hormonal therapy. Median patient age was 66 years (range 45 to 82) and median age of those undergoing surgery and radiation therapy was 64.5 and 69.0 years, respectively (p 0.05) groups. All men had clinical stages Tlb to TZNXMO tumors,6 a normal serum acid phosphatase level (less than 0.08 IUA. thymolphthalein hydrolysis method) and a radionuclide bone scan that was not suspicious for osseous metastases. Tumors were graded using the system of Gaeta et a17 and included 36 grade 1,168 grade 2, 61 grade 3 and 11 grade 4 adenocarci-

Accepted for publication May 3, 1996. The opinions expressed are those of the authors and do not necessarily represent opinions or policies of the Department of Veterans Affairs. 1714

CO-MORBIDITIES AND SURVIVAL AFTER SURGERY OR RADIOTHERAPY FOR PROSTATE CANCER

1715

TABLE1. Co-morbid conditions included in the Charlson in@ nomas. Gaeta grades 1 to 4 are considered equivalent to and specific co-morbidities of the study patients Gleason grades 2 to 4,5 and 6,7 and 8 to 10, respectively. The distribution of tumor grades in the surgery and radiation Wt. of &:s No. Radiation Total therapy groups was not significantly different. Condition Condition Pta, Therapy Pts. No. Pta. Treatments. The techniques of surgery and radiation ther27 17 1 10 apy have been detailed previously.8 During the study period Myocardial infarct 16 16 0 men with clinical stages Tlb and T2 tumors who had an Congestive heart failure 11 8 3 vascular disease anticipated life expectancy of 10 years or longer were gener- Peripheral 17 12 5 Cerebrovascular disease ally treated with surgery, whereas those with an anticipated Dementia 5 5 0 21 5 16 life expectancy of less than 10 years underwent radiation Chronic pulmonary disease 1 1 0 therapy. Suspected or biopsy proved tumor recurrence usu- Connective tissue disease 16 7 9 disease ally prompted androgen deprivation therapy, although in Ulcer 2 1 1 Mild liver disease recent years some patients with documented local recur- Diabetes 26 7 19 0 0 0 2 rences and minimal prostate specific antigen (PSA) elevation Hemiplegia 4 9 0 Moderate or severe renal have been observed. disease Followup and cause of death. Patients were generally seen Diabetes with end organ 7 6 1 by a urologist at 3 t o 6-month intervals during the first 2 damage 25 15 10 years after treatment and at 6 to 12-month intervals there- Any tumor 0 0 0 after. Digital rectal examination, serum acid phosphatase Leukemia 0 0 0 determination and, during the last 9 years, PSA meas- Lymphoma 3 3 3 0 Moderate or severe liver urement were performed at each visit. Bone scans were usudisease 0 0 6 0 ally obtained every 1to 2 years before 1990 but more recently Metastatic solid tumor 0 0 0 they have been obtained only when there was progressive Acquired immunodeficiency svndrome elevation of PSA. Since 1991,228 of the 276 patients, including 64 of 111(58%)who died, have been monitored by 1of us (J.E. F., Jr.) in a prospective manner. Median potential followup was 7.0 years (range 5.1 to 15.4) means was unequal. Actuarial survival analyses of all paand median observation period was 6.1 years (range 0.2 to tients, and of the surgery and radiation therapy groups strat15.4). Of the patients 158 (57%) were alive at last followup ified by weighted co-morbidity scores were calculated by the within 6 months of data analysis, 91 (33%) died of co-morbid methods of Kaplan and Meier. In our study deaths attributed disease, 20 (7%)died of cancer related causes and 7 (3%)were to co-morbid conditions were the outcome of interest. For this lost to followup a t 2.2 to 4.7 years (median 3.7)after treat- reason cancer related deaths were censored and the analyses ment. reflected freedom from death due to co-morbid disease. The 7 All patients considered to have died as a direct result of patients lost to followup were considered to have died from cancer had distant metastases. Of 12 patients who died co-morbid disease. Differences among actuarial plots were of cancer related causes before 1991 and who were not mon- determined with the generalized Wilcoxon test of Gehan. itored prospectively the medical record documented progresCox proportional hazards regression analyses were used to sive debility from the malignancy. No patient who was con- assess the influence of patient age and race on freedom from sidered to have died of causes other than cancer had known death due to co-morbid disease and to assess the age adjusted metastatic disease at death. Of 35 patients who died before risk of co-morbid death in various patient groups. In most 1991, 30 had normal serum acid phosphatase or PSA less actuarial and regression analyses patients with a weighted than 4.0 ng./ml. within 12 months of death. Many of these co-morbidity score of 3 to 5 were combined because the numPatients died of well-defined co-morbid disease a t our hospi- bers of patients with scores 4 and 5 were limited. A value of tal or at an affiliated nursing home. Of the remaining 5 p <0.05 was considered statistically significant. Patients 3 died of well-defined causes at affiliated facilities and 2 died elsewhere. Death certificates in the latter 2 cases RESULTS did not identify metastatic prostate cancer as a contributing The characteristics of the study patients stratified by cause of death. Co-morbidity index. The hospital records of all patients weighted co-morbidity score are shown in table 2. There were were reviewed to determine the nature of co-morbid disease highly significant correlations among weighted co-morbidity at surgery or radiation therapy. In 12 cases data were de- score, median age and method of treatment. Univariate prorfved from discharge summaries only. Each patient was as- portional hazards analyses showed that actuarial survival signed a weighted co-morbidity score using the index devel- did not correlate with age (p = 0.15, hazards ratio 1.03,95% oped by Charlson et al, which provides each co-morbid confidence interval 0.99 to 1.07) or race (black relative to diagnosis an empiric rating derived from the 1-year mortality white race, p = 0.96, hazards ratio 1.01, 95% confidence experience of a cohort of hospitalized patient^.^ The score for interval 0.67 to 1.51). However, because of the significant each diagnosis is added to give a sum of ratings for each association between age and weighted co-morbidity score the Patient. The index was validated in a population of women hazards analyses of co-morbidity scores were adjusted for mth carcinoma of the breast, and has been used to demon- age. Actuarial plots of freedom from co-morbid death for all strate that the higher mortality of patients undergoing transurethral resection of the prostate compared to open prosta- patients, and for the surgery and radiation therapy groups kctomy probably is due to variability of health status among stratified by weighted co-morbidity scores are shown in the figure. There were significant associations between weighted men receiving the 2 treatments.10 Table 1 shows the co-morbid conditions included in the co-morbidity score and actuarial survival in all patients (p Charlson index,9 weight assigned to each condition, and CO- <0.00001), and in the surgery and radiation therapy groups morbidities of all patients and those treated with surgery or (p = 0.02 and 0.002, respectively). Actuarial plots of the radiation therapy. The weighted co-morbidity scores were 0 surgery and radiation therapy groups with a co-morbidity score of 1were significantly different (p = 0.003) and favored 148 patients, 1in 62,2 in 4 0 , 3 in 1 8 , 4 in 5 and 5 in 3. Statistical methods. The characteristics of patient groups the surgery group but the plots of both groups with cowere compared with the chi-square test or Student's t test. morbidity scores 0 and 2 were not significantly different. ' h e Man-Whitney U test was used ifthe variance of sample Actuarial survivals at 5 and 10 years relative to the co-

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CO-MORBIDITIES AND SURVIVAL AFTER SURGERY OR RADIOTHERAPY FOR PROSTATE CANCER TABLE2. Characteristics of study patients relative to co-morbidity score &-Morbidity Score

1

0 No. pta. (9%) Median age (range)* No. whiteMack pts.7 No. treatment*

3

62 (22) 67 (54-82) 37/25

40 (14) 68 (45-77) 22/18

18 (7) 71 (61-77) 12/6

(2) 5 66 (62-71) 4/1

3 (1) 73 (62-76) W1

26 (9) 70 (61-77) 1819

95 53

27 35

13 27

3 15

0 5

0 3

3 23

99 30 13

35 22

1 2

1

4 13 1 0

0

6

19 19 2 0

5 20 1 0

SUtgerY

Radiation No. current status: Alive Co-morbid death Ca death Lost to followup * p <0.0001. t p = 0.66.

0

25

50

75

100

125

150

4

4

3-5

2

148 (54) 66 (5&81) 89/59

5

5 0

0 0

0

775

Yam

Actuarial freedom from death due to co-morbid disease stratified by co-morbidity score in men with stages Tlb and T2 prostate cancer. p Value indicates significanceof differencesbetween actuarial plots as determinedby generalized Wilcoxon test. Numbers next to plots indicate co-morbidity score. A, 276 patients treated with surgery or radiation therapy. B , 138 patients treated with radical prostatectomy. C, 138 patients treated with radiation therapy.

morbidity scores for all patients, and for the surgery and radiation therapy groups are shown in table 3. Table 4 shows the age adjusted risk ratio for death from co-morbid disease relative to the weighted co-morbidity score for all patients, and for the surgery and radiation therapy groups. The risk ratios for death from co-morbid disease among all patients with a weighted co-morbidity score of 1 , 2 and 3 to 5 were 1.7,2.6 and 5.7 times greater, respectively, than that of patients with a weighted co-morbidity score of 0. The age adjusted risk of death from co-morbid disease was significantly greater in the radiation therapy than in the surgery patients with a co-morbidity score of 1 (p = 0.025, hazards ratio 3.81, 95% confidence interval 1.19 to 12.23). Among patients with a score of 0 or 2 the risk of death was TABLE3. Five and 10-year actuarial freedom fiorn co-morbid death by co-morbidity score in all patients and in those treated with surgery or radiation therapy Co-Morbidity Score

0 1 2 3-5

0 1 2 3 0 1 2 3-5

Total No. Pts. All pts. 148 62 40 26 Surgery group 95 27 13 3 Radiation LheMpY group 53 35 27 23

% Actuarial Survivals

5 Yrs.

1OYrs.

86 17 62 40

66 47 24 9

93 88 62 67

68 77 38 67

82 65 63 40 -

64 27 0 9

TABLE4. Multivariate proportional hazards analyses for freedom from co-morbid death in all patients and in those treated with surgery or radiation therapy by co-morbidity score adjusted for patient age Co-Morbidity Score

Total No. pts.

p Value

All pts. 62 0.49 40 0.001 18 0.000002 5 0.000001 3 0.03 26 CO.000001 Surgery group 1 27 0.27 2 13 0.01 3 0.58 3 Radiation therapy group 1 35 0.01 2 27 <0.05 3 15 0.00005 5 0.00002 4 5 3 0.06 3-5 23 0.000002 * Relative to men with a co-morbidity score of 0.

1 2 3 4 5 3-5

Hazards Ratio (95% confidence interval)* 1.69 (1.00-2.86) 2.58 (1.47-4.54) 4.90 (2.53-9.47) 11.54(4.44-30.00) 4.95(1.18-20.80) 5.73(3.23-10.18) 0.54 (0.1S1.59) 2.97 (1.25-7.02) 1.75 (0.23-13.04) 2.50 (1.254.99) 2.19 (1.014.77) 5.27(2.35-11.80) 9.97(3.50-28.41) 4.28(0.95-19.09) 5.87(2.85-12.11)

also greater in the radiation therapy group (hazards ratios 1.36 and 1.12, respectively) but the differences were not statistically significant, probably due to the small sample size. DISCUSSION

We found that only 7.2% of patients treated with surgery or radiation therapy for localized prostate cancer died of cancer related causes during 5 to 15 years of potential followup, while 33% died of other causes. The actuarial risk of death

CO-MORBIDITIES AND SURVIVAL AFTER SURGERY OR RADIOTHERAPY FOR PROSTATE CANCER from other causes correlated directly with severity of comorbid disease a t treatment. These findings complement the observations of Albertsen et a1 regarding the influence of co-morbidities on survival of men treated with initial or deferred hormonal the rap^.^ However, their patients were derived from a cancer registry and were not considered appropriate candidates for aggressive therapy, whereas ours were derived from a Veterans Affairs medical center and were believed to benefit from potentially curative treatments. For these reasons, and because our therapeutic philosophy favored surgery in men judged to have a good life expectancy, the analyses provide additional insights into the potential value of co-morbidity indexes in the interpretation of survival data in operative and nonoperative treatment experiences and in different patient populations. Albertsen e t a1 speculated that men who undergo surgical treatment for localized prostate cancer may have significantly fewer competing disease hazards, and they cautioned that this phenomenon might bias all cause survivals in various treatment experiences.5 Our general treatment guidelines are not unique and the co-morbidities were significantly less severe in the surgery than in the radiation therapy groups. Although cause specific survival analyses should compensate for variability in the health of patients in case series involving operative and nonoperative treatments, our findings support the intuitive but poorly documented probability that significant co-morbid conditions are more prevalent in patients treated nonoperatively. The significance of the associations between the severity of co-morbidities and actuarial freedom from death due to comorbid disease was less striking in the surgery than in the radiation therapy groups. Also, the age adjusted risk of death from co-morbid disease when stratified by co-morbidity score was uniformly greater in the radiation therapy groups. These differences suggest variability in the impact of different disease processes of an equivalent weight on the longevity of men with localized prostate cancer, and raise the possibility that men with seemingly more severe co-morbidities were excluded from surgical treatment because of concern about perioperative morbidity and mortality. Although this concept cannot be proved, there were notable differences in the nature of co-morbid conditions with a weight of 1 in the 2 patient groups. For example, no patient with congestive heart failure or dementia underwent surgery. Our study also suggests that unquantifiable health factors or co-morbidities that are not included in an index may influence the risk of death from co-morbid disease in different patient populations. Our actuarial survivals reflect freedom from death due to co-morbid conditions and, by definition, they are more favorable than all cause survivals because patients who died of cancer related causes were censored in the calculations. Nonetheless, the survivals of our surgery and radiation therapy patients with no COmorbidities were similar or lower than the all cause actuarial survivals in other experiences with localized prostate cancer. For example, Zincke et a1 reported a 75%, 10-year actuarial all cause survival rate in 3,170 patients who underwent surgery.11 The median age of their patients (66 years) was similar to that in our surgery group. Bagshaw et a1 reported a 60%, 10-year all cause survival rate among 601 patients treated with radiation therapy.12 The median age of their patients (64 years) was also similar to that in our radiation therapy group. Our patients received some or all of their health care at a Veterans Affairs medical center and 39% were black. Both factors could contribute to the disturbingly high incidence of death from co-morbid disease because the estimated age adjusted mortality rate among men 65 years old or older who use Veterans Affairs facilities is approximately 1.6 times greater than that of the general population13 and because the life expectancy of American black men 55 and 75 years old is

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i.2 and 1.4 years less, respectively, than that of American iYhite men.4 These issues are of considerable institutional interest and have led to modifications of treatment strategies For localized prostate cancer. We are now more likely to recommend initial or deferred hormonal therapy rather than surgery or radiation therapy to men with significant comorbidities. The availability of survival data has facilitated patient acceptance of the uncertainties associated with these less morbid but noncurative management strategies. CONCLUSIONS

The inferior survival rates of our patients also raise concern about the interpretation of clinical trials for localized prostate cancer that involve Veterans Affairs patients. For example, prospective, randomized studies conducted by the Veterans Administration Cooperative Urological Research Group showed that hormonal therapy in men with clinical stages T3 and T4 prostate cancer and normal serum acid phosphatase levels produced striking improvement in actuarial progression-free survival compared to patients treated with a p1aceb0.l~However, the all cause survivals in the 2 patient groups were not significantly different. If the risk of death from co-morbid disease among participants in the Veterans Administration Cooperative Urological Research Group studies paralleled that of our patients, potentially important survival benefits derived from hormonal therapy may have been obscured. The outcomes of the ongoing Veterans Affairs Prostate Cancer Intervention Versus Observation Trial, which compares radical prostatectomy and deferred therapy in men with localized prostate cancer, may be influenced by the same phenomenon.15 More specifically, significant differences between cause specific survivals in the 2 treatment groups may not be identified if deaths from comorbid disease are excessive, and the results may not be representative of treatment outcomes in the general population. REFERENCES

1. Mettlin, C. J., Murphy, G. P., McGinnis, L. S. and Menck, H. R.:

The National Cancer Data Base report on prostate cancer. American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer, 7 6 1104,1995. 2. Johanssen, J. E., Adami, H. O., Andersson, S. O., Bergstrom, R., Holmberg, L. and Krusemo, U. B.: High 10-year survival rate in Datients with earlv. untreated urostatic cancer. J.A.M.A.. _

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3. Chodak. G. W.. Thisted. R. A,, Gerber, G. S., Johansson, J. E., Adolfsson, J , Jones, G. W., Chisholm, G. D., Moskovitz, B., Livne, P. M. and Warner, J.: Results of conservative management of clinicallv localized urostate cancer. New End. - J. Med., 330 242,1994. 4. National Center for Health Statistics: Vital Statistics of the United States, 1990,vol. 11, Mortality, Part A. Washington, D. C.: United States Public Health Service, 1994. 5. Albertsen, P. C., Fryback, D. G., Storer, B. E., Kolon, T. F. and Fine, J.: Long-term survival among men with conservatively treated localized prostate cancer. J.A.M.A., 274 626,1995. 6. Beahrs, 0.H., Henson, D. E., Hutter, R. V. P. and Kennedy, B. J.: Manual for Staging of Cancer, 4th ed. American Joint Committee on Cancer. Philadelphia: J. B. Lippincott Co., 1992. 7. Gaeta, J. F., Asirwatham, J. E., Miller, G. and Murphy, G. P.: Histologic grading of primary prostatic cancer: a new approach to an old problem. J. Urol., 123 689,1980. 8. Fowler, J. E., Jr., Braswell, N. T., Pandey, P. and Seaver, L.:

Experience with radical prostatectomy and radiation therapy for localized prostate cancer at a Veterans Affairs Medical Center. J. Urol., part 2,153. 1026,1995. 9. Charlson, M., Pompei, P., Ales, K. L. and MacKenzie, C. R.: A new method of classifylng prognostic comorbidity in longitudinal studies: development and validation. J. Chon. Dis., 40: 373, 1987.

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CO-MORBIDITIES AND SURVIVAL AFTER SURGERY OR RADIOTHERAPY FOR PROSTATE CANCER

10. Concato, J., Horwitz, R. I., Feinstein, A. R., Elmore, J. G. and 13. Fisher, E. S.and Welch, H. G.: The future of the Department of Veterans Affairshealth care system. J.A.M.A., 273: 651,1995. Schiff, S. F.: Problems of comorbidity in mortality after pros14. BY=, D. P. and Corle, D. K.: Hormone therapy for prostate tatectomy. J.A.M.A., 267: 1077, 1992. cancer: results of the Veterans Administration Cooperative 11. Zincke, H., Oesterling, J. E., Blute, M. L., Bergstralh, E. J., Urological Research Group studies. Natl. Cancer Inst. Myers, R. P. and Barrett, D. M.: Long-term (15 years) reMonos., 7: 165, 1988. sults after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J. Urol., part 2, 152: 15. Wilt, T. J. and Brawer, M. K.: The Prostate Cancer Intervention Versus Observation Trial (PIVOT):a randomized trial com1850,1994. paring radical prostatectomy with expectant management for 12. Bagshaw, M. A., Cox, R. S. and Hancock, S. L.: Control of prosthe treatment of clinically localized prostate cancer. Cancer, tate cancer with radiotherapy: long-term results. J. Urol., part 2, 152 1781, 1994. 75: 1963, 1995.