Carcinoma of the Prostate in the Elderly: The Therapeutic Ratio of Definitive Radiotherapy

0022-534 7/86/1366-1238$02.00 /0

Vol. 136, December

THE JOURNAL OF UROLOGY

Copyright© 1986 by The Williams & Wilkins Co.

Printed in U.S.A.

CARCINOMA OF THE PROSTATE IN THE ELDERLY: THE THERAPEUTIC RATIO OF DEFINITIVE RADIOTHERAPY JEFFREY D. FORMAN,* STANLEY E. ORDER, EVA S. ZINREICH, DING-JEN LEE AND MOODY D. WHARAM From the Division of Radiation Oncology, The Johns Hopkins Oncology Center, Baltimore, Maryland

ABSTRACT

Withholding or reducing the intensity and aggressiveness of treatment for elderly cancer patients is a widespread tenet lacking substantiation in the literature. To assess the potential value of definitive external beam radiotherapy in the elderly, an analysis of the therapeutic ratio between local regional control and complications was performed in 34 prostatic cancer patients more than 75 years old. Median followup was 5 years (range 2 to 8 years). The 5-year actuarial local regional control rate was 91 per cent. The 5-year actuarial survival rate was 81 per cent and the 5-year survival rate free of disease was 63 per cent. There were no severe complications. Mild to moderate chronic complications occurred in 3 patients (9 per cent). This treatment resulted in an excellent therapeutic ratio, which demonstrates that external beam radiation can be given to elderly patients with acceptable morbidity and gratifying results. The risk-benefit ratio of curative therapy in elderly patients with prostatic cancer is not well defined. Suggested treatments for elderly patients have included observation,1 transurethral resection with or without hormonal therapy2- 7 and definitive radiotherapy. 8 The choice of therapy often is guided by concern for patient tolerance and/or longevity. 9 • 10 However, disease progression may occur rapidly, and may cause morbidity and/ or mortality." The choice of therapy should be based on an analysis of the natural history of the tumor, life expectancy of the patient, and therapeutic ratio between local regional control and treatment-related morbidity. To determine the role of external beam radiation in elderly men with localized prostatic cancer we reviewed our experience in the management of 34 patients more than 75 years old.

rad, mean 6,400 rad). Six patients believed to be at higher risk for the development of complications received radiation to the prostate only. Determination of outcome. Patients were evaluated 1 month after treatment, quarterly for 3 years, twice yearly for 2 years and yearly thereafter. Local tumor control was estimated clinically by serial digital rectal examination and serum acid phosphatase determination, and pathologically by transurethral resection or needle biopsy after progressive prostatic enlargement or obstructive urinary symptoms. Distant metastases were detected clinically or radiographically on followup examinations, which included radiographic and/or radionuclide procedures. Elevated serum acid phosphatase levels alone were not scored as evidence of recurrent disease. All 34 patients were followed

METHODS AND MATERIALS

Patient characteristics. Between 1975 and 1983, 34 patients more than 75 years old with localized carcinoma of the prostate received definitive radiotherapy at our oncology center (table 1). Mean patient age was 78.3 years, with a range of 75 to 86 years. All tumors were assigned a clinical stage according to the system of Whitmore as modified by Jewett. 12 Pathological diagnosis was established by needle biopsy (16 patients) or transurethral resection (18). The tumors were graded by a modification of the Broders system, 13 as well as the Gleason grading system. 14 All patients had normal bone roentgenograms and/or radioisotopic bone scans. Serum acid phosphatase levels were obtained in all patients and were elevated in 1. Six patients had negative lymphadenectomy results, with an average of 21 lymph nodes removed. Three patients had had hormonal therapy before referral. Radiotherapy technique. All patients received radiotherapy according to a previously reported split-course technique. 15 After simulation, all patients had ultrasonography or computerized tomography scans to assess the accuracy of the treatment fields. The entire pelvis was irradiated in 28 patients (4,500 rad). The patients then had a 2-week treatment rest followed by an additional 2,000 rad to the prostate. The total dose to the prostatic tumor volume was 6,500 rad (range 3,960 to 6,700 Accepted for publication May 21, 1986. Supported by National Institutes of Health-National Cancer Institute Grant No, CA-06973-21. * Requests for reprints: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave., New York, New York 10021. 1238

TABLE

1. Distribution of characteristics in 34 patients 75 to 86 years old (mean age 78.3 years) No.(%) Stage: A2

9 (26)

Bl B2

3 (9)

C Grade:

I II III Other Gleason grade: 2-5 6 7

8-10

None Symptoms: Yes No Method of biopsy: Needle Transurethral prostatic resection Acid phosphatase level: Normal Elevated Lymphadenectomy: Yes No Pelvic radiation: Yes No

4 (12) 18 (53)

3 (9)

24 (71) 6 (18) 1 (3) 11 (32) 6 (18) 8 (24) 6 (18)

3 (9) 27 (79)

7 (21) 16 (47) 18 (53) 33 (97)

1 (3) 6 (18) 28 (82)

28 (82) 6 (18)

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CARCINOMA OF PROSTATE IN ELDERLY

for at least 2 years after treatment, with a median followup of 5 years and a maximum of 8 years. Data analysis. Survival was calculated from the day of first treatment. The time-dependent nature of treatment failure in subgroups of patients was computed with Kaplan-Meier actuarial methods. 16 The Kaplan -Meier curves were compared by a log-rank test with a 2-tailed significance level. 17 RESULTS

Survival. The 5-year actuarial survival rate was 81 per cent and the 5-year survival rate free of disease was 63 per cent. The corresponding figures corrected for death of intercurrent disease were 90 and 70 per cent, respectively. The uncorrected survival rates of these 34 elderly patients are demonstrated graphically in figure 1. Pattern of failure. The absolute local regional control rate was 94 per cent. The 5-year actuarial local regional control rate was 91 per cent (fig. 2, A). Disease recurred locally in 1 patient who did not complete therapy (3,960 rad) because of proctitis, and in 1 who had local and distant failure. Local failure occurred in 1 patient (11 per cent) with stage A2 and in 1 (6 per cent) with stage C disease. Distant metastases developed in 9 patients

A

B

(34)

1.0

(27 per cent). Distant metastases rates by stage were 33 per cent for stage A2, 33 per cent for stage Bl and 28 per cent for stage C cancer. The 5-year actuarial risk of distant metastases was 27 per cent (fig. 2, B). Treatment-related morbidity. Mild to moderate treatmentrelated reactions, including diarrhea and cystitis, occurred in 29 patients (85 per cent) but only 1 (3 per cent) failed to complete the prescribed treatment course. This patient had proctitis at 3,960 rad that did not resolve after a treatment rest. Acute post-treatment reactions were defined as occurring within 6 months of treatment (table 2). The gastrointestinal reactions consisted of tenesmus (1 patient) and nonbloody diarrhea (2), while genitourinary symptoms included frequency (2) and nocturia (2). Moderate acute gastrointestinal and genitourinary complications occurred in 6 and 6 per cent of the patients, respectively. Chronic complications. Chronic complications were defined as occurring more than 6 months after treatment. Severe chronic complications, which required surgical intervention, did not occur in the elderly population. Moderate chronic complications caused persistent symptoms that required prolonged medical treatment (table 3). The chronic gastrointestinal complication consisted of proctitis (chronic diarrhea as-

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Fm. 1. Actuarial survival rates for 34 patients more than 75 years old. Parentheses indicate number of patients at risk. A, over-all. B, free of disease.

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75

1240

FORMAN AND ASSOCIATES

Post-treatment reactions (at 6 month:3) in 34 patients 75 or more years old who were treated with definitive external beam radiotherapy

TABLE 2.

No.(%) Gastrointestinal: Nonbloody diarrhea Tenesmus Genitourinary: Frequency Nocturia Genital or lower extremity edema

2 (6) 1 (3) 2 (6) 2 (6) 0 (0)

Chronic complications (more than 6 months) in 3 of 34 patients (9 per cent) 75 or more years old who were treated with definitive external beam radiotherapy

TABLE 3.

Complication Proctitis Urinary outlet obstruction Urinary frequency Lower extremity edema

Moderate No.(%) 1 1 2 2

(3) (3) (6) (6)

No patient suffered severe chronic complications.

sociated with tenesmus) in 1 patient (3 per cent). Chronic genitourinary complications included urinary outlet obstruction in 1 patient (3 per cent) and nocturia with urinary frequency in 2 (6 per cent). No elderly patient experienced small bowel obstruction, rectal stricture, fecal incontinence, urethral stricture, hemorrhagic cystitis or urinary incontinence. Two patients (6 per cent) had lower extremity edema following irradiation. DISCUSSION

The choice of treatment in patients with carcinoma of the prostate should be based on an analysis of the therapeutic ratio between local regional control and complications. 15 In the elderly patient specific problems, including diminished tolerance, slow recovery and limited life expectancy, also must be considered. 9·10 We analyzed the therapeutic ratio of external beam radiation in elderly men with localized prostatic cancer and demonstrated that concern for potential radiation-induced complications does not justify withholding definitive radiotherapy in the elderly. No severe complications occurred in our series and the incidence of moderate complications was similar to those reported with curative radiation in younger patients.15, is-20 In addition to the low morbidity of treatment 94 per cent of the patients benefited from local tumor control. This figure is comparable to the reported experience with definitive radiotherapy in prostatic cancer patients of all ages. Bagshaw and associates reported an 89 per cent local control rate, 18 while Neglia19 and Perez 20 and their associates reported rates of 86 and 85 per cent, respectively. These data are superior to the 75 per cent local recurrence rate reported in patients with stage C disease treated by transurethral resection with or without hormonal therapy. 21 Therefore, definitive radiotherapy in the elderly can achieve local tumor control without significant morbidity. Despite the low morbidity and excellent local control some elderly patients may not be referred for radiotherapy owing to a presumably limited life expectancy secondary to mortality from a nonneoplastic cause. 4 • 22 However, several studies have shown that local progression and dissemination may cause significant morbidity within the 9-year average life expectancy of a 75-year-old man. 5·23 Our 82 per cent 5-year survival rate is evidence that prolonged survival is possible in elderly patients. These results appear to be superior to those of Hanash and associates, who reported a 37 per cent 5-year survival rate in 76 patients more than 70 years old who were treated by transurethral resection,7 and the approximately 50 per cent 5-year

survival for patients treated conservatively in the Veterans Administration study. 1 In that study the 338 patients with stages C and D disease more than 75 years old had a markedly increased risk of cardiovascular death owing to estrogen therapy. 24 Because of the inherent biases in interpreting data retrospectively and the lack of an adequate control population matched for stage and age in the present analysis, we cannot conclude that radiotherapy increased the probability of survival in these elderly patients. However, we can conclude that radiotherapy is an acceptable choice of treatment in the elderly based on an analysis of the natural history of the tumor, life expectancy of the patient and therapeutic ratio of treatment. In our series the treatment of 34 elderly men with carcinoma of the prostate resulted in an excellent therapeutic ratio, which demonstrates that external beam radiation may be given to elderly patients with acceptable morbidity and gratifying results. REFERENCES

1. Veterans Administration Co-Operative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg., Gynec. & Obst., 124: 1011, 1967. 2. Gee, W. F. and Cole, J. R.: Symptomatic stage C carcinoma of prostate. Traditional therapy. Urology, 15: 335, 1980. 3. Barnes, R. W. and Ninan, C. A.: Carcinoma of the prostate: biopsy and conservative therapy. J. Urol., 108: 897, 1972. 4. Rosenberg, S. E.: Is carcinoma of the prostate less serious in older men? J. Amer. Geriat. Soc., 13: 791, 1965. 5. Whitmore, W. F.: Hormone therapy in prostatic cancer. Amer. J. Med., 21: 697, 1956. 6. Herr, H. W.: The patient, disease status, and treatment options for prostate cancer: stages Bl and B2. Prostate, 4: 447, 1983. 7. Hanash, K. A., Utz, D. C., Cook, E. N., Taylor, W. F, and Titus, J. L.: Carcinoma of the prostate: a 15-year followup. J. Urol., 107: 450, 1972. 8. Green, N., Bodner, H. and Broth, E.: Prostate cancer: experience with definitive irradiation in the aged. Urology, 25: 228, 1985. 9. Badib, A. 0., Kurohara, S.S. and Webster, J. H.: Radiotherapy of carcinoma of the uterine cervix in the aged. Geriatrics, 25: 108, January 1970. 10. Webster, J. H.: Radiotherapy of malignant disease in the aging. Geriatrics, 23: 117, May 1968. 11. Whitmore, W. F., Jr.: The natural history of prostatic cancer. Cancer, 32: 1104, 1973. 12. Jewett, H.J.: The present status of radical prostatectomy for stages A and B prostatic cancer. Urol. Clin. N. Amer., 2: 105, 1975. 13. Broders, A. C.: The grading of carcinoma. Minn. Med., 8: 726, 1925. 14. Gleason, D. F., Mellinger, G. T. and The Veterans Administration Cooperative Urological Research Group: Prediction of prognosis for prostatic adenocarcinoma by combined histological grading and clinical staging. J. Urol., 111: 58, 1974. 15. Forman, J. D., Zinreich, E. S., Lee, D.-J., Wharam, M. D., Baumgardner, R. A. and Order, S. E.: Improving the therapeutic ratio of external beam irradiation for carcinoma of the prostate. Int. J. Rad. Oncol. Biol. Phys., 11: 2073, 1985. 16. Kaplan, E. L. and Meier, P.: Nonparametric estimations from incomplete observations. J. Amer. Stat. Ass., 53: 457, 1958. 17. Peto, R. and Peto, J.: Asymptotically efficient rank invariant test procedures. J. Roy. Stat. Soc., 135: 185, 1972. 18. Bagshaw, M.A., Ray, G. R., Pistenma, D. A., Castellino, R. A. and Meares, E. M., Jr.: External beam radiation therapy of primary carcinoma of the prostate. Cancer, 36: 723, 1975. 19. Neglia, W. J., Hussey, D. H. and Johnson, D. E.: Megavoltage radiation therapy for carcinoma of the prostate. Int. J. Rad. Oncol. Biol. Phys., 2: 873, 1977. 20. Perez, C. A., Walz, B. J., Zivnuski, F. R., Pilepich, M., Prasad, K. and Bauer, W.: Irradiation of carcinoma of the prostate localized to the pelvis: analysis of tumor response and prognosis. Int. J. Rad. Oncol. Biol. Phys., 6: 555, 1980. 21. Tomlinson, R. L., Currie, D. P. and Boyce, W. H.: Radical prostatectomy: palliation for stage C carcinoma of the prostate. J. Urol., 117: 85, 1977. 22. Cook, G. B. and Watson, F. R.: Twenty single nodules of prostate cancer not treated by total prostatectomy. J. Urol., 100: 672, 1968.

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CARCINOMA OF PROSTATE IN ELDERLY 23. Nesbit, R. M. and Baum, W. C.: Endocrine control of prostatic carcinoma: clinical and statistical survey of 1,818 cases. J.A.M.A., 143: 1317, 1950. 24. Bayard, S., Greenberg, R., Showalter, D. and Byar, D.: Comparison of treatments for prostatic cancer using an exponential-type life model relating survival to concomitant information. Cancer Chemother. Rep., 58: 845, 1974. EDITORIAL COMMENT The authors report on 34 elderly patients treated with external beam radiation therapy for carcinoma of the prostate. The discussion focuses on a consideration of the therapeutic ratio between local regional cancer control and treatment complications. The authors do not provide data that compare directly the efficacy of radiation therapy to that of endocrine therapy in this elderly patient population. However, they suggest that their results with radiation therapy are superior to those reported in 1972 by Hanash and associates, and by the Veterans Administration Cooperative Urological Research Group in 1967 (references 1 and 7 in article). This comparison is not valid since these groups of patients actually were treated in different eras. The complications associated with radiation therapy include an 85 per cent incidence of diarrhea and cystitis. In 1 patient the toxicity was so severe that treatment had to be stopped. However, despite discontinuation of treatment, diarrhea and cystitis persisted. In addition, 1 patient suffered urinary outlet obstruction and 2 had chronic urinary frequency. Two patients also had lower extremity edema. Overall, 9 per cent of the patients had chronic complications. The authors state that this complication rate is acceptable but clearly it is in excess of what would be anticipated from orchiectomy. The authors claim that their treatment results are gratifying. It is noteworthy, however, that they did not consider an elevated acid phosphatase titer alone as evidence of treatment failure. More than a

quarter of the patients had distant metastases within 5 years. This high cancer progression rate is striking if one considers that 16 of the 34 patients treated had clinical stage A or B tumors, and would suggest that these patients may have been treated more appropriately with endocrine therapy from the outset. The authors conclude that the concern for irradiation complications does not justify withholding radiation therapy in elderly patients. My interpretation of their data is different. The complications from radiation therapy are in excess of what would be expected from orchiectomy and the therapeutic benefit in the group of patients is questionable. The data presented fail to demonstrate that radiation therapy is preferable to endocrine therapy in prostatic cancer patients more than 75 years old.

William J. Catalona Division of Urology Washington University Medical Center St. Louis, Missouri REPLY BY AUTHORS This study demonstrates a favorable therapeutic ratio between local regional control (94 per cent) and chronic complications (O per cent severe and 9 per cent moderate). These data suggest that the results of curative external beam radiation therapy are superior to those of palliative treatments. A randomized trial comparing definitive radiotherapy and a more conservative treatment, such as orchiectomy, would be necessary to prove this conclusion. We believe that local-regional recurrence of the tumor is the most severe complication. To compare a 9 per cent incidence of rectal irritation and frequent urination with a more than 50 per cent incidence of recurrent cancer and its sequelae is a judgment that urologists and informed patients may make for themselves.