PROSTATE CANCER: EXPERIENCE WITH DEFINITIVE IRRADIATION IN THE AGED NATHAN GREEN, M.D. HENRY BODNER, M.D. EUGENE BROTH, M.D. OTHERMEMBERS OF STUDY GROUP* From the Depw tments of Urology, and Radiation Therapy, LACKJSC Medical Center, L 3s Angeles; the Department of Urology, Loma Linda Medical Center, Loma Linda; and the Division of Radiation Therapy, the Valley Presbyterian Hospital, Van Nuys, California ABSTRACT- When considering therapeutic options for localized prostate cancer, stage and grade of disease have been the most important determinants. In the elderly, the nominal age has assumed increasing importance in the final decision. A balanced judgment must be reached between the patient’s normal life expectancy and the rapidity with which the cancer may be expected to express its malignant potential. By careful attention to patient selection and the details,of treatment, defini- tive irradiation can improve quality of life and survival. Of 63 patients aged seventy-three to ninety years referred for irradiation, 56 were found medically suitable for definitive treatment. A review of our experience is presented. There is perhaps no greater dilemma confront- ing the urologist than the decision with regard to the optimal management of a patient with clinically localized prostate cancer. Over the past twenty years the therapeutic options have been expanded from observation, removal of the testes, estrogens, and radical prostatectomy to include external beam and interstitial irra- diation, The choice usually has been based on an estimate of the biologic behavior of the can- cer as determined by the stage and grade of the disease and the expectation that a specific form *Ching Chiang, M.D., Jerry Garrett, M.D., Abrahacfn Goldstein, M.D., Harvey Goldberg, M.D., Vincent Gual- tieri, M.D., Robert Gray, M.D., Jack Jaffe, M.D., Ronald Kaplan, M.D., Richard Onofrio, M.D., Donald McCannel, M.D., Sanford Polse, M.D., Stanley Ross, M.D., Leonard Skaist, M.D., Dale Treible, M.D., Arthur Vatz, M.D., and Harvey Wallack, M.D. of therapy would ameliorate that behavior.1-9 In the elderly, the nominal and physiologic age assumes major importance in the final decision, Elderly patients usually have been considered for palliative procedures because life expec- tancy may be short, the prostate cancer more indolent, and complications from definitive ir- radiation more frequent and more severe.6,9-15 It is our impression that elderly patients with prostate cancer could benefit from definitive ir- radiation. Life expectancy has been increasing. Prostate cancer can behave aggressively and be a frequent cause of death.15Js If the treatment regimen is carefully tailored to physiologic tol- erance, definitive irradiation can be well- tolerated.17 Local disease can be controlled in a majority of patients. Both quality of life and survival may improve. r8~19 A review of our expe- rience is described. 228 UROLOGY / MARCH 1985 i VOLUME XXV, NUMBER 3
Transcript
PROSTATE CANCER: EXPERIENCE WITH
DEFINITIVE IRRADIATION IN THE AGED
NATHAN GREEN, M.D. HENRY BODNER, M.D. EUGENE BROTH, M.D. OTHER MEMBERS OF STUDY GROUP*
From the Depw tments of Urology, and Radiation Therapy, LACKJSC Medical Center, L 3s Angeles; the Department of Urology, Loma Linda Medical Center, Loma Linda; and the Division of Radiation Therapy, the Valley Presbyterian Hospital, Van Nuys, California
ABSTRACT- When considering therapeutic options for localized prostate cancer, stage and grade of disease have been the most important determinants. In the elderly, the nominal age has assumed increasing importance in the final decision. A balanced judgment must be reached between the patient’s normal life expectancy and the rapidity with which the cancer may be expected to express its malignant potential. By careful attention to patient selection and the details,of treatment, defini- tive irradiation can improve quality of life and survival. Of 63 patients aged seventy-three to ninety years referred for irradiation, 56 were found medically suitable for definitive treatment. A review of our experience is presented.
There is perhaps no greater dilemma confront- ing the urologist than the decision with regard to the optimal management of a patient with clinically localized prostate cancer. Over the past twenty years the therapeutic options have been expanded from observation, removal of the testes, estrogens, and radical prostatectomy to include external beam and interstitial irra- diation, The choice usually has been based on an estimate of the biologic behavior of the can- cer as determined by the stage and grade of the disease and the expectation that a specific form
*Ching Chiang, M.D., Jerry Garrett, M.D., Abrahacfn Goldstein, M.D., Harvey Goldberg, M.D., Vincent Gual- tieri, M.D., Robert Gray, M.D., Jack Jaffe, M.D., Ronald Kaplan, M.D., Richard Onofrio, M.D., Donald McCannel, M.D., Sanford Polse, M.D., Stanley Ross, M.D., Leonard Skaist, M.D., Dale Treible, M.D., Arthur Vatz, M.D., and Harvey Wallack, M.D.
of therapy would ameliorate that behavior.1-9 In the elderly, the nominal and physiologic age assumes major importance in the final decision, Elderly patients usually have been considered for palliative procedures because life expec- tancy may be short, the prostate cancer more indolent, and complications from definitive ir- radiation more frequent and more severe.6,9-15
It is our impression that elderly patients with prostate cancer could benefit from definitive ir- radiation. Life expectancy has been increasing. Prostate cancer can behave aggressively and be a frequent cause of death.15Js If the treatment regimen is carefully tailored to physiologic tol- erance, definitive irradiation can be well- tolerated.17 Local disease can be controlled in a majority of patients. Both quality of life and survival may improve. r8~19 A review of our expe- rience is described.
228 UROLOGY / MARCH 1985 i VOLUME XXV, NUMBER 3
Material and Methods
Between 1975 and 1980, a total of 196 pa- tients with proved adenocarcinoma of the pros- tate were seen in the division of radiation therapy at Valley Presbyterian Hospital. The age range was fifty-two to ninety years. A total of 63 patients were age seventy-three and older. These 63 patients comprise the study group for this report. The study group was highly select. All patients were in good health with no signifi- cant medical disorders other than prostate can- cer. The patients were staged according to the extent of tumor spread as judged by rectal ex- amination, operative findings, blood acid phos- phatase, liver function studies, chest roentgeno- grams, skeletal survey, and isotope bone scan. The lymph nodes were evaluated in 35 patients, 17 by lymphangiography, 17 by computerized axial tomogram, and 1 by both. Gross lymph node metastases were suspected if the lymph nodes were markedly enlarged with large filling defects as shown by lymphangiogram, or if the lymph nodes were 2 cm or more in diameter as shown by computerized axial tomogram. Re- gression of the lymph nodes in patients who received estrogen therapy was considered presumptive confirmation of lymph node me- tastases. A total of 4 patients had Stage BI, 9 Stage BII, 14 Stage CI, 31 Stage CII, 3 patho- logic Stage C, and 2 local recurrence after a radical prostatectomy. Eight patients had sus- pected gross lymph node metastases; 1 Stage BII, 2 Stage CI, and 5 Stage CII. Histologic confirmation of malignancy was obtained in 31 patients by needle biopsy and 32 patients by transurethral resection. All slides were re- viewed by one pathologist. The histopathology was categorized as well-differentiated, moder- ately differentiated, or poorly differentiated cancer according to the predominant glandular pattern and cellular characteristics.
Fifty-three patients received definitive irra- diation and 3 patients adjuvant irradiation. Forty-nine patients were aged seventy-two to seventy-nine, and 7 patients were eighty to ninety years. In 49 patients, irradiation was de- livered to the whole pelvis, 170 rad/day, two fields/day, five days/week to a total of 4,800 rad. A boost of 1,700 to 1,900 rad was delivered to the prostate by small field rotation therapy. In 7 patients, irradiation was delivered to the prostate by small field rotation therapy, 180 rad/day, five days/week to a total of 6,500 rad to 6,700 rad. Three were aged seventy-three to
seventy-nine and 4 aged eighty to ninety. Seven patients were excluded from definitive irradia- tion. Four were too fragile. Three had sus- pected periaortic lymph node metastases. It was anticipated extended field irradiation to in- clude the periaortic lymph nodes would not be tolerated. The 7 patients received palliative ir- radiation. A total of 2,000 rad was delivered to the whole pelvis.
A total of 25 patients had received estrogen therapy. Thirteen patients with bulky Stage C disease and/or gross lymph node metastases re- ceived 3 mg of diethylstilbestrol for two months prior to irradiation and were maintained on es- trogen throughout irradiation. Estrogen was discontinued within six months. Ten patients re- ceived irradiation after the prostate cancer had become refractory to long-term estrogen use. Thirty-nine patients received radiation therapy alone.
The subjective response, objective response, complications, survival, and mechanism of death were analyzed according to age, stage of disease, and treatment regimen. The response of the primary tumor was evaluated by serial digital examination done at approximately six- month intervals. A complete response was com- plete regression of the prostate to normal size and consistency or the development of an empty prostate fossa. A partial response was partial regression of the prostate with persistent areas of firmness and nodularity, At each follow-up, a prostate acid phosphatase was ob- tained. Needle biopsy and bone scan were ob- tained if indicated by the clinical findings. Sur- vival was analyzed from onset of treatment. Patients were followed from eighteen to seventy-two months with a median of forty- eight months. The impact of tumor grade, tu- mor size, and tumor response on disease-free survival was evaluated. Patterns of treatment failure and mechanisms of death were catego- rized as local failure, distant metastases, or both. Irradiation complications were assessed from those signs and symptoms that persisted for six months or longer or had onset six months after completion of irradiation.
Results The prostate cancer was well-differentiated
in 9 patients, moderately differentiated in 21 patients, and poorly differentiated in 25 pa- tients. One patient had a utricle cancer. The histologic grade was not determined in 7 pa- tients.
Thirty-three patients had urinary outlet ob- structive symptoms, 3 urinary frequency and burning, 10 hematuria, and 1 pelvic pain. A transurethral resection was of benefit in 19/32 (59 % ) . Sixteen of 22 (73 % ) had alleviation of obstructive symptoms and 3/10 (70 % ) hematu- ria. Two patients required permanent catheter drainage. In 20134 (59%) with symptomatic disease improvement followed sequential estro- gen and irradiation or irradiation alone. Im- provement was observed in 12123 (52%) ob- structive symptoms, 8110 (80 % ) hematuria, and O/l (0%) pain.
Tumor control
Following irradiation, a complete tumor re- sponse was observed in 38153 (72 % ), partial tu- mor response in 9153 (17 % ), and no tumor re- sponse in 6153 (11% ) (Table I). Tumor regrowth occurred in 2138 (5 % ) complete responders (1 Stage BII, 1 Stage CI) and 819 (89%) partial responders. The time to recurrence ranged from six months to four years. In 9110 (90%) recur- rence occurred within three years. Tumor re- sponse was found to correlate with tumor stage.
TABLE III. Survival following definitive irradiation
&+---- Status 73-79 (%) 80-90 (%)
Alive free of disease 28/49 (58) 517 (72) Alive with disease 10/49 (20) 117 (14) Died free of disease 5/49 (10) 017 (0) Died with disease 6/49 (12) 117 (14)
Local tumor control was observed in 90 per cent of Stage B disease and 65 per cent of Stage C disease (Table II). The frequency of tumor control was comparable with small field irra- diation, 5/7 (71%) as compared with large field irradiation, 33146 (72%). Tumor control was observed in 10114 (71%) treated with sequen- tial estrogen and irradiation, 3/4 (75 % ) irradia- tion for estrogen refractory cancer, and 25135 (71%) irradiation therapy alone. Because of the small number in the study group, the results in patients treated with sequential estrogen and ir- radiation could not be analyzed according to the presence or absence of estrogen response.
Survival Forty-four/56 patients (78 %) who received
definitive or adjunct irradiation are alive: 33/56 (58 %) without evidence of disease and 11/56 (20%) with disease. Twelve patients died: 7 of disease and 5 of unrelated causes (Table III). Failure occurred in 18/52 (32%): 9/56 (16%) local, 7156 (13%) local and distant, and 2156 (4 % ) distant (Table II). Undoubtedly had rou- tine bone scans been obtained at follow-up, a greater number of patients might have been shown to have distant metastases. Disease-free survival was substantially better for Stage B dis- ease. Analyses of patients at risk four years or longer showed 819 (89%) Stage B and 6/88 (33%) Stage C were alive without evidence of disease; 4118 (22%) alive with disease, 5118 (28 % ) died of disease, and 3118 (50 % ) died of unrelated causes. Of the 18 Stage C patients at risk four years or longer, 15 had poorly differen- tiated bulky (Stage CII) prostate cancer. The patient age and histologic differentiation were not found to influence survival. Twenty-eight/ 49 (57%) aged seventy-three to seventy-nine and 5/7 (72 % ) aged eighty and older were alive and well. Five/9 (56%) with well-differ- entiated cancer, 10120 (50 % ) moderately dif- ferentiated cancer, and 11122 (50 % ) poorly differentiated cancer have remained free of
bowel movement Rectal fissure Phimosis Penile edema Scrotal edema Leg edema Painful prepubic
skin edema
l/7 1;49 . * 2149 . . 4149 . . 1149 . . 1149 . .
TOTALS 15/49 (31) 2/7 (29)
disease. Because of the small number of pa- tients, the impact of treatment volume, estro- gen therapy, and lymph node metastases on sur- vival could not be assessed. Six/7 (86%) who received palliative irradiation died. One is alive with disease. In total, 13/63 (21% ) died of can- cer: 5 of local disease, 6 of local disease and dis- tant metastases, and 2 of distant metastases.
Seventeen/56 (30 % ) sustained radiation com- plications. The frequency of complications were comparable in patients aged seventy-three to seventy-nine and aged eighty to ninety (Table IV). After definitive irradiation, urethral stric- ture was found in 4/25 (16%) who had under- gone a transurethral resection and l/26 (4%) who had not. Of 5 patients with scrotal leg edema, 4 had persistent local disease that may have been a contributory factor.
Comment The absolute and physiologic age of the
patient with prostate cancer has been an impor- tant index of suitability for definitive ir- radiation. Temporizing measures such as observation, estrogen therapy, bilateral orchiec- tomy, and transurethral resection have been ad- vocated for the management of prostate cancer in the elderly. There has been the perception that elderly patients cannot tolerate the rigors of definitive irradiation and usually die of un- related causes.20-24 On the other hand, the probability of dying of prostate cancer has been shown to increase with age.‘O,” Irrespec- tive of age, survival from untreated Stage C dis- ease may be as short as three years. Survival from bulky Stage C disease may be less.10.24.25
There has been no substantial benefit observed from transurethral resection or estrogen therapy. 1.5.7.10.19
We believe the absolute age of a patient should not be a contraindication to definitive irradiation. Life expectancy of a male aged seventy without prostate cancer is ten years and aged eighty, five years. Accordingly, judg- ment should be reached by balancing normal life expectancy against the rapidity with which the prostate cancer can be expected to express its malignant potential. 26-28 We have found that by careful attention to patient selection and by judicious modification in the treatment regi- men, the majority of elderly patients can be rendered free of disease without causing undo complications. Excluded from definitive irra- diation were patients in poor health and pa- tients with suspected or proved periaortic lymph node metastases. The survival of patients in poor health may be short. The tolerance to definitive irradiation is poor. Extended field ir- radiation has been used to treat periaortic lymph node metastases. The value of extended field irradiation has been uncertain and the tol- erance in the elderly poor.r8 We tailored the treatment volume according to an estimate of the patient’s tolerance to irradiation. Pelvic ir- radiation was delivered in patients less than eighty years of age. Irradiation was usually con- fined to the prostate in patients aged eighty and older. By tailoring the treatment volume, acute reactions were minimized and irradiation could be delivered in a scheduled and uninterrupted fashion. Local control was thereby enhanced. We also used estrogen for two months prior to and concurrent with irradiation in patients with bulky Stage C disease or gross lymph node metastases. The tumor burden was reduced in those patients who had estrogen-responsive can- cer. Irradiation could be delivered to a smaller volume. Although a total dose of 7,000 rad or more has been advocated for Stage C disease, we found the lower and safer dose of 6,500 rad to be efficacious for patients with estrogen re- sponsive cancer. 17mrg Tumor control was substan- tially higher in patients with estrogen respon- sive cancer as compared with patients with estrogen resistant cancer and patients treated with irradiation alone.2g
Control of the local disease has been the most effective parameter of response to irradiation. Local control was observed in over 90 per cent of our patients with Stage B disease and 65 per cent with Stage C disease. Irradiation can lead
UROLOGY ! MARCH1985 1 VOLUMEXXV,hWMBER3 231
to improved survival by delaying or preventing death from aggressive local disease and distant metastases. Persistent local disease can act as a source for distant metastases.18~2e-28 Seventy-five per cent of our patients have remained alive, 60 per cent without evidence of disease. The me- dian follow-up of four years was relatively short. Survival benefit was most clearly ob- served in patients with bulky poorly differen- tiated prostate cancer. Untreated, this disease has an aggressive behavior. Fifty per cent of pa- tients with bulky prostate cancer have re- mained alive, 33 per cent without evidence of disease.
Overall, in 30 per cent of patients complica- tions did develop. Fortunately most were mild. Less than 2 per cent sustained serious complica- tions. In 10 per cent urethral stricture devel- oped. The frequency of urethral stricture was significantly higher in patients who had under- gone a transurethral resection. However, even in those patients, control of the local disease was of benefit. Obstructive symptoms caused by urethral stricture were usually easily managed with urethral dilatation. Obstructive symptoms caused by uncontrolled cancer often require repeat transurethral resections.
Our series is small and select. The median follow-up of four years is relatively short. Ac- cordingly, the results may not be applicable to all elderly patients. On the other hand, we have shown that definitive irradiation can be de- livered in the elderly by careful tailoring of the irradiation therapy according to the tolerance of the patients, Quality of life and survival can be improved in most patients without causing undo morbidity.
Van Nuys, California 91405 (DR. GREEN)
ACKNOWLEDGMENT. To Harley Wishner, M.D., Steven Kugler, M.D., Marcel Horowitz, M.D., and Isidor Schlossberg, M.D., for their advice.
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