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The effect of advanced age on the efficacy of radiation therapy for early breast cancer, local prostate cancer and grade III–IV gliomas
Inr J. Radramn Oncoio~y Bmi Phy.7, Vol. 26, pp. 539-544 Printed in the U.S.A. All nghts reserved.
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0360.3016/93 $6.W + .OO 0 1993 Pergamon Press Ltd.
??Special Feature
THE EFFECT OF ADVANCED AGE ON THE EFFICACY OF RADIATION THERAPY FOR EARLY BREAST CANCER, LOCAL PROSTATE CANCER AND GRADE III-IV GLIOMAS RICHARD E. PESCHEL, M.D., PH.D.,’ LYNN WILSON, M.D.,’ BRUCE HAFFTY, M.D.,’ DIMITRIOS PAPADOPOULOS, M.D.,’ KEN ROSENZWEIG, M.D.’ AND MICHAEL FELTES, M.D.2 ‘Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 065 10; ‘Uncas on Thames Hospital-University of Connecticut Health Center, Norwich, CT and Travelers Center for Aging, University of Connecticut Health Center Purpose: This study was undertaken to determine the effect of advanced age on radiation therapy outcomes for early breast cancer, local prostate cancer and Grade 3-4 gliomas of the brain. Methods and Materials: Radiation therapy outcomes for three malignancies (N = 1,401) were determined for a geriatric cancer population defined as 70 years of age or older and compared to a non-geriatric cancer population defined as less than 70 years of age. The three patient groups studied were: (a) primary breast cancer patients with clinical Stage I or II disease treated with lumpectomy and radiation therapy (N = 994), (b) local prostate cancer patients with Stage A2, B, or C disease treated with radical radiation therapy (N = 294), and (c) patients with Grade 3-4 gliomas of the brain treated with high dose radiation therapy (N = 113). Results: For Stage I and II breast cancer, there was no statistically significant difference in the overall IO-year survival rates (63% vs. 73%), IO-year cause-specific disease-free survival rates (70% vs. 63%), and IO-year local breast recurrence free survival rates (76% vs. 79%) comparing the geriatric cancer population to the non-geriatric cancer population. For local prostate cancer, there was no statistically significant difference in the lo-year survival rates (38% vs. 41%) or in the IO-year cause-specific disease-free survival rates (58% vs. 52%) in the geriatric population compared with the non-geriatric population. On the other hand, the use of high dose radiation therapy for malignant gliomas resulted in statistically significant inferior l-year (18% vs. 38%) and 2-year (0% vs. 10%) survival rates for the geriatric population versus the non-geriatric population. Conclusion: This study strongly supports the use of standard radiation therapy programs for early breast and prostate cancer patients age 70 years or more. However, our study raises questions about the efficacy of radiation therapy in patients over the age of 70 years with Grade 3-4 gliomas. External beam radiation, Geriatric cancer population, Breast cancer, Prostate cancer, Malignant gliomas.
INTRODUCTION
Many authors have stressed the need for long-term studies on the efficacy of cancer therapy for specific disease sites in geriatric populations (2, 25). Unfortunately, it is a fact that older patients are frequently undertreated or excluded from cancer therapy trials (6,7, 11). This exclusion of the elderly from conventional cancer treatment practices is often based on “ad hoc” decisions and assumptions by physicians rather than on sound scientific data. In most published papers where potential distinctions in the treatment of the elderly cancer population have been addressed, the emphasis has been primarily on the treatment outcomes for surgery or chemotherapy with little or no discussion of external beam radiation therapy results in the geriatric population (2, 15, 24). This study was undertaken to compare the external beam radiation therapy treatment outcomes for a variety
Cancer in the geriatric population is a major public health problem in the United States today. Fifty percent of all cancers occur in the age group over 65 years even though this population represents only 11% of the general population (14). In addition, the treatment of malignant diseases in the geriatric population will become increasingly important over the next 40 years because of two factors: (a) The elderly population will have the fastest growth rate of any subgroup in the United States population reaching 22% of the entire population by the year 2030; and (b) The cancer incidence rates increase dramatically after age 50 years (19). The magnitude of this increase is exemplified by a cancer incidence rate of over 2,000 per 100,000 individuals by age 70 years (25).
Reprint requests to: Richard E. Peschel, M.D., Ph.D. Accepted for publication 14 January 1993. 539
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of malignant diseases in the geriatric patient versus the non-geriatric patient. Early breast cancer, local prostate cancer, and malignant brain tumors were selected for this study for several reasons: First, the efficacy of primary radiation therapy has been documented in the general population for each of these tumors (10, 13, 16,2 I). Second, the mortality rates for breast and prostate cancer continue to increase and the incidence of primary brain tumors has nearly doubled in the geriatric population during the last 10 years (5). Over the next several decades, radiation oncologists will see a rapidly growing number of geriatrics patients with breast cancer, prostate cancer, and malignant brain tumors. Therefore, it will be important to have a substantial data base which documents the radiation therapy outcomes for these geriatric cancer populations. METHODS
AND MATERIALS
The radiation therapy charts (N = 1,401) of three patient groups treated within the Yale University School of Medicine Therapeutic Radiology Program (Yale-New Haven Hospital and Uncas on Thames Hospital) were retrospectively reviewed. The three patient groups reviewed were: (a) Primary breast cancer patients with AJC/ UICC clinical Stage I or II disease treated with lumpectomy and primary radiation therapy (N = 994) from 1960-1987; (b) Prostate cancer patients with American Urological clinical Stage A2, B, or C disease treated with radical radiation therapy (N = 294) from 1975- 1990; and (c) Patients with malignant gliomas of the brain (Grade 3-4) treated with primary radiation therapy (N = 113) from 1968-1989. Within each of the three major patient groups, outcomes were determined based on the age at presentation of each patient. We selected 70 years of age or older to define a geriatric cancer population (GCP) versus less than 70 years of age to define a non-geriatric cancer population (NGCP). For each of the patient groups, the outcomes for the NGCP treated during the same era served as a control group with which to compare the results for the GCP. Seventy years of age was chosen to distinguish GCP versus NGCP for three reasons. First, 70 years of age or more is often used to exclude cancer patients from entering prospective clinical trials (8, 22). Second, in prospective clinical trials which include cancer patients of all ages (9), the results for patients over 70 years are usually not reported separately. Third, in prospective and retrospective cancer studies where the results for patients age 70 years or greater are reported, these studies generally do not include long term follow-up data at 10 years (12, 17). Table 1 summarizes the clinical characteristics of the 994 Stage I & II breast cancer patients (834 NGCP vs 160 GCP) treated with primary radiation therapy from 1960 to 1987. Prior to 1982, an axillary node dissection was not routinely performed. After 1982, more NGCP un-
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Table 1. Comparison of the clinical Stage I and II breast cancer patients treated with primary radiation therapy in the NGCP group vs. the GCP group NGCP
Number (N) Average age (years) Clinical stage I II Axillary dissection Adjuvant therapy
834
160 14
51 550 284 450 233
GCP
(66%) (34%) (53%) (27%)
94 (59%) 66 (41%) 58 (36%) 31(23%)
NGCP = Cancer patients less than 70 years of age; GCP = Cancer patients 70 years of age or more.
derwent axillary node sampling (53%) compared to the GCP (36%). However, the fraction of NGCP receiving either adjuvant chemotherapy or hormonal therapy (27%) was similar to the fraction of GCP receiving adjuvant therapy (23%). In general, adjuvant systemic therapy was recommended only for axillary node positive patients during the years of this study. The radiation therapy treatment program (RT) was identical for both NGCP and GCP groups. Following lumpectomy, RT consisted of external beam treatment to the entire breast to a total dose of 4600 cGy followed by an electron boost to the site of the original tumor to a total tumor dose of 6400 cGy. Appropriate lymph node regions were also treated to a total dose of 4600 cGy. The details of the primary radiation therapy program for Stage I & II disease have been described previously (10). Table 2 summarizes the clinical characteristics of the 294 localized prostate cancer patients ( 157 NGCP vs 137 GCP) with Stage A2, B, or C disease treated with external beam radiation therapy. Clinically, the GCP and the NGCP were quite comparable. The radiation treatment program for both GCP and NGCP was similar and generally consisted of treating a pelvic field to a total dose of 4500 cGy followed by a boost treatment to the prostate to a total dose of 6500-7000 cGy. A small number of patients also received para-aortic radiation to a dose of 4500 cGy in the early years of this study. None of the patients received hormonal therapy as part of their initial treatment. The details of the external beam radiation therapy program for prostate cancer have been described elsewhere (13, 16). Table 2. Comparison of the localized prostate cancer patients treated with primary radiation therapy in the NGCP vs. the GCP group NGCP Number (N) Clinical stage A2 B C Average age (years)
157 20 (13%) 66 (42%) 71 (45%) 63
GCP 137 12 (9%) 74 (54%) 51 (37%) 73
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Effect of age ??R. E. PESCHEL et al.
A total of 113 patients with the diagnosis of Grade 34-malignant gliomas of the brain were treated with primary radiation therapy. Nineteen patients were 70 years of age or older at presentation (GCP) versus 94 patients in the NGCP group. Both treatment groups were equivalent in terms of the distribution of tumor grade. Table 3 summarizes the clinical characteristics of the entire group. Following attempted surgical resection or biopsy, all patients were treated with either a whole brain field with subsequent generous cone down field or with a partial brain field with generous margins around the tumor volume to a total dose of 6,000-6,600 cGy. The details of the radiation program for malignant gliomas were similar to several previously published reports (20, 2 1). The life table method (4) was used to calculate the actuarial overall survival rates, cause specific disease-free (NED) survival rates, and local control rates with associated standard errors (t- standard error). The statistical significance (p-values) for the differences in the outcomes for various treatment groups was determined using the standard z-test.
Table 4. Radiation outcomes for NGCP vs. GCP for breast cancer (combined Stages I and II), prostate cancer (combined Stages A2, B, C), and malignant brain tumors NGCP Breast cancer 5-year survival 5-year LCR 1O-year survival 1O-year NED survival 1O-year LCR Prostate cancer S-year survival 5-year NED survival 1O-year survival 1O-year NED survival Malignant gliomas 1-year survival 2-year survival
GCP
p-values
83% + 2% 94% f 2% 73% f 4%
78% + 98% + 63% f
3% 2% 8%
N.S.
63% + 3% 79% + 3%
70% + 10% 76% f 10%
N.S. N.S.
73% f 4%
81%+
4%
N.S.
80% f 4% 41% xk 6%
89% f 3% 38% z!z 8%
N.S.
52% + 6%
58% k
N.S.
38% rf: 5%
18% + 8.8% 0%
10% -t 3%
N.S. N.S.
8%
N.S.
< .05 < .Ol
N.S. = Not statistically significant; LCR = Local breast cancer control rate.
RESULTS Table 4 summarizes the radiation therapy outcomes for the three treatment groups. For the combined Stage I and II breast cancer patients, the actuarial 5-year and loyear survival rates, NED survival rates, and local breast cancer control rates (LCR) were all equivalent in the GCP group compared to the NGCP group. Table 5 compares the results for the GCP versus NGCP by clinical stage. At 5 years, both the NED survival rate and the LCR were superior in the GCP with Stage I disease versus the NGCP with Stage I disease. After 10 years of follow-up, there was no statistically significant difference in outcome by stage of disease. For localized prostate cancer patients with all stages combined, there was no statistically significant difference in the S-year and IO-year overall survival rates or NED survival rates for the GCP versus the NGCP. Table 5 compares the NED survival rates by clinical stage for the GCP versus the NGCP. Stage A2 and B patients were combined for this analysis. There are no statistically significant differences in the treatment outcomes by stage of disease comparing the GCP with the NGCP.
Table 3. Clinical characteristics of the 113 patients with malignant gliomas treated with radiation therapy Number Males Females Complete surgical resection Partial resection or biopsy NGCP GCP
of patients 73 40 20 93 94 19
For patients with malignant gliomas, the l-year and 2year survival rates were statistically significantly inferior in the GCP compared to the NGCP.
DISCUSSION Although age has been recognized prognostic factor for external beam
as an important radiation therapy
Table 5. Radiation outcomes for NGCP vs. GCP by stage of disease for breast and prostate cancer NGCP Breast cancer 5-year NED Stage I Stage II 1O-year NED Stage I Stage II 5-year LCR Stage I Stage II 1O-year LCR Stage I Stage II Prostate cancer 5-year NED Stage A2/B Stage C IO-year NED Stage A2/B Stage C
GCP
a-value
survival 86% t 2% 72% + 4%
94% + 80% k
67% + 4% 55% f 7%
63% + 13% 73% + 10%
N.S. N.S.
94% zk 1% 94% + 2%
98% f 97% f
< .Ol N.S.
78% + 4% 80% + 6%
66% f 14% 89% + 8%
N.S. N.S.
88% t 5% 74% + 6%
89% + 87% +
4% 6%
N.S. N.S.
68% f 9% 42% + 8%
69% -+ 10% 42% f 14%
N.S. N.S.
3% 8%
< .05 N.S.
survival
1% 2%
survival
survival
N.S. = Not statistically significant; LCR = Local breast cancer control rate.
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outcomes by many authors ( 11, 12, 20), very few studies have specifically addressed radiation therapy outcomes in patients who are 70 years of age or more (GCP). This study was undertaken to add to the paucity of data for radiation therapy outcomes in GCP. The survival rates and NED survival rates for the three groups of NGCP in our study are consistent with the results reported in many other radiation therapy series (9, 12,2 1). Therefore, our NGCP groups represent reasonable control populations with which to compare the outcomes in our GCP groups since each of the groups was evaluated and treated during the same time interval and with the same radiation therapy program.
Breast cancer Breast conservation therapy with segmental resection (lumpectomy) followed by external beam radiation therapy for clinical Stage I and II breast cancer produces equivalent results to mastectomy in the general population (9). The number of patients aged 70+ years already constitutes a significant fraction of the patients referred for primary radiation therapy and will become an increasingly important group in the future. In our study, the GCP represented 16% of our entire primary breast cancer patient population treated from 1960 to 1987. In another large series of 680 early breast cancer patients treated with primary radiation at the Princess Margaret Hospital from 1958 to 1978, 10% of the patients were age 70 years or more (3). Therefore, based on projections that the geriatric fraction of the total population will double over the next 40 years ( 19) one can predict that the GCP will constitute at least 20-32% of all primary breast cancer patients referred for radiation therapy. Another important issue in the treatment of the elderly patient with early breast cancer is the lower rate of appropriate referrals to a radiation center. At the University of Rochester, Kantorowitz et al. (11) reported that only 24% of women age 70 years or more who underwent lumpectomy for early breast cancer were referred for primary radiation therapy compared to 82% of women less than 59 years of age. More important, Kantorowitz et al. (11) stated that referral decisions for elderly women over the age of 70 years appeared to be based on a variety of theoretical assumptions about breast cancer in older women and not on any substantial database. The most critical element in the Rochester study was that even if co-morbidity was accounted for in the treatment of age 70+ patients, “. . . even healthy elderly women are treated less aggressively” (1 1). The results of our study and a review of the literature document that elderly patients with Stage I & II breast cancer will have equivalent or superior results with radiation therapy compared to younger age groups. For example, the University of Rochester study reported a trend toward superior local control with radiation therapy in 5 1 patients age 60 years or more and concluded that radiation therapy may be more beneficial for elderly patients
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compared to younger patients ( 11). This study also showed a trend toward enhancement of survival in elderly women treated with lumpectomy plus radiation therapy compared to elderly women treated with lumpectomy alone (11). Clark et al. (3) at the Princess Margaret Hospital (PMH) reported their results on 68 women age 70-75 years with Stage I and II breast cancer treated with primary radiation therapy. The IO-year relative survival rate (adjusted by the expected survival for this age group) for these 68 patients was 8 1% and was superior to all other age groups in the PMH study (3). Our study of 160 women age 70 or more represents one of the largest reviews of elderly women with Stage I & II breast cancer treated with primary radiation. Our study documents that the GCP had similar IO-year NED survival rates (70% vs. 63%) and lo-year LCR (76% vs. 79%) compared to the NGCP. It can be concluded from our study that there is no rational reason based solely on IO-year results to exclude patients who are 70 years of age or more from standard breast conservation radiation therapy programs.
Prostate cancer External beam radiation therapy is an accepted local therapy for Stages A2, B, and C prostate cancer (12, 13, 16, 17). Patients over the age of 70 years already constitute a significant fraction of all patients referred for curative radiation therapy. In the RTOG 77-06 prospective clinical trial comparing elective pelvic radiation to local prostate therapy only in Stage A2 and B prostate cancer, 36% of the 445 patients were 7 1 years or older (1). With the increasing geriatric population, patients over the age of 70 years may constitute more than 50% of the patients referred for radiation in the next 20-40 years. A few large studies have specifically reported the radiation therapy results for elderly patients. Unfortunately, these studies have either reported only 5-year results or included patients under the age of 70 years. The RTOG 77-06 study included the results of 160 patients with Stage A2 and B disease who were age 7 1 years or more treated with radiation (1). The 5-year NED survival rate in the 7 1+ age group (76%) was equivalent to all of the younger age groups analyzed (78-83%) (1). In the Patterns of Care Study (POC) on 682 patients with Stages A2, B, and C cancers, 279 patients were age 66 years or more (12). The 66+ year group had a lower overall recurrence rate (33%) compared to patients who were age 60 years or less (43%). Our study includes data on 137 patients aged 70 years or more and extends the follow-up period to 10 years. Our data are consistent with both the RTOG and POC studies and indicate that the GCP with clinical Stage A2, B, or C disease have equivalent 5-year and 1O-year overall and NED survival rates compared to the NGCP. It can be concluded from our study that one should not exclude elderly (70+ years) prostate cancer patients from primary radiation therapy programs based solely on the age of the patients.
Effect of age 0 R. E.
Malignant brain tumors The diagnosis of primary brain tumors has doubled in the geriatric population over the last 20 years and the incidence of these tumors continues to increase (5). The increasing rate (doubling every lo-20 years) of CNS tumors in the elderly combined with the doubling of the geriatric population in the next 40 years will produce an enormous number of elderly patients with brain tumors referred for radiation therapy in the future. The Brain Tumor Study Group has documented that high doses of external beam radiation (6,000 cGy or more) increases the survival of patients with malignant gliomas (Grade 3-4) in the general population (23). However, several studies have documented a lower survival rate with increasing age despite the use of radiation therapy. Salazar et al. (20) found the median survival for radiation patients over 45 years of age to be significantly lower compared to patients less than 45 years for both Grade 3 (52 weeks vs. 133 weeks) and Grade 4 tumors (39 weeks vs. 72 weeks). Prados et al. (18) found a very strong negative correlation between age and survival in 357 patients with anaplastic astrocytomas treated with radiation. Our study shows a statistically significant (p < .05) decrease in the l-year and 2-year survival rates using RT in the GCP compared to the NGCP. These results raise questions
PESCHEL et al.
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about the efficacy of RT in elderly brain tumor patients. However, the number of elderly patients with Grade 34 gliomas in our GCP is relatively small. Therefore, we recommend prospective clinical trials in this age group to compare supportive care only versus standard radiation therapy to better define the role of high dose radiation. This study is one of the largest geriatrics radiation therapy studies ever reported and demonstrates the diversity of outcomes which are possible when general radiation oncology strategies are applied to elderly cancer patients. The conclusions of our study must be viewed with some caution because the results of our study are influenced by multiple patient selection factors and referral patterns which are difficult to quantify. Clearly, many geriatric cancer patients with multiple co-morbidities are not referred to radiation oncologists. However, our study does document that for early breast and localized prostate cancers, the fraction of the geriatric population which is currently being referred to radiation centers have equivalent IO-year results using standard external beam programs compared to the general population. For these subgroups of patients, it is not a rational policy to withhold radiation therapy based solely on age. However, for malignant gliomas, the use of primary radiation in patients over 70 years of age should be tested in prospective clinical trials.
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Volume 26, Number 3, 1993 22. Veronesi, U.; Saccozzi, R.; Del Vecchio, M.; Banfi, A.; Clemente, C.; De Lena, M.; Gallus, G.; Greco, M.; Luini, A.; Marubini, E.; Muscolino, G.; Rilke, F.; Salvadori, B.; Zecchini, A.; Zucali, R. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N. Engl. J. Med. 305:6-l 1;1981. 23. Walker, M. D.; Strike, T. A.; Sheline, G. E. An analysis of the dose-effect relationship in the radiotherapy of malignant gliomas. Int. J. Radiat. Oncol. Biol. Phys. 5:17251731;1979. 24. Walsh, S. J.; Begg, C. B.; Carbone, P. P. Cancer chemotherapy in the elderly. Sem. Oncol. 16:66-75;1989. perspective 25. Yancik, R.; Ries, L. G. An epidemiologic treatment issues. Cancer 68:2502-25 10; 199 1.
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??Special Feature
THE EFFECT OF ADVANCED AGE ON THE EFFICACY OF RADIATION THERAPY FOR EARLY BREAST CANCER, LOCAL PROSTATE CANCER AND GRADE III-IV GLIOMAS RICHARD E. PESCHEL, M.D., PH.D.,’ LYNN WILSON, M.D.,’ BRUCE HAFFTY, M.D.,’ DIMITRIOS PAPADOPOULOS, M.D.,’ KEN ROSENZWEIG, M.D.’ AND MICHAEL FELTES, M.D.2 ‘Department of Therapeutic Radiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 065 10; ‘Uncas on Thames Hospital-University of Connecticut Health Center, Norwich, CT and Travelers Center for Aging, University of Connecticut Health Center Purpose: This study was undertaken to determine the effect of advanced age on radiation therapy outcomes for early breast cancer, local prostate cancer and Grade 3-4 gliomas of the brain. Methods and Materials: Radiation therapy outcomes for three malignancies (N = 1,401) were determined for a geriatric cancer population defined as 70 years of age or older and compared to a non-geriatric cancer population defined as less than 70 years of age. The three patient groups studied were: (a) primary breast cancer patients with clinical Stage I or II disease treated with lumpectomy and radiation therapy (N = 994), (b) local prostate cancer patients with Stage A2, B, or C disease treated with radical radiation therapy (N = 294), and (c) patients with Grade 3-4 gliomas of the brain treated with high dose radiation therapy (N = 113). Results: For Stage I and II breast cancer, there was no statistically significant difference in the overall IO-year survival rates (63% vs. 73%), IO-year cause-specific disease-free survival rates (70% vs. 63%), and IO-year local breast recurrence free survival rates (76% vs. 79%) comparing the geriatric cancer population to the non-geriatric cancer population. For local prostate cancer, there was no statistically significant difference in the lo-year survival rates (38% vs. 41%) or in the IO-year cause-specific disease-free survival rates (58% vs. 52%) in the geriatric population compared with the non-geriatric population. On the other hand, the use of high dose radiation therapy for malignant gliomas resulted in statistically significant inferior l-year (18% vs. 38%) and 2-year (0% vs. 10%) survival rates for the geriatric population versus the non-geriatric population. Conclusion: This study strongly supports the use of standard radiation therapy programs for early breast and prostate cancer patients age 70 years or more. However, our study raises questions about the efficacy of radiation therapy in patients over the age of 70 years with Grade 3-4 gliomas. External beam radiation, Geriatric cancer population, Breast cancer, Prostate cancer, Malignant gliomas.
INTRODUCTION
Many authors have stressed the need for long-term studies on the efficacy of cancer therapy for specific disease sites in geriatric populations (2, 25). Unfortunately, it is a fact that older patients are frequently undertreated or excluded from cancer therapy trials (6,7, 11). This exclusion of the elderly from conventional cancer treatment practices is often based on “ad hoc” decisions and assumptions by physicians rather than on sound scientific data. In most published papers where potential distinctions in the treatment of the elderly cancer population have been addressed, the emphasis has been primarily on the treatment outcomes for surgery or chemotherapy with little or no discussion of external beam radiation therapy results in the geriatric population (2, 15, 24). This study was undertaken to compare the external beam radiation therapy treatment outcomes for a variety
Cancer in the geriatric population is a major public health problem in the United States today. Fifty percent of all cancers occur in the age group over 65 years even though this population represents only 11% of the general population (14). In addition, the treatment of malignant diseases in the geriatric population will become increasingly important over the next 40 years because of two factors: (a) The elderly population will have the fastest growth rate of any subgroup in the United States population reaching 22% of the entire population by the year 2030; and (b) The cancer incidence rates increase dramatically after age 50 years (19). The magnitude of this increase is exemplified by a cancer incidence rate of over 2,000 per 100,000 individuals by age 70 years (25).
Reprint requests to: Richard E. Peschel, M.D., Ph.D. Accepted for publication 14 January 1993. 539
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of malignant diseases in the geriatric patient versus the non-geriatric patient. Early breast cancer, local prostate cancer, and malignant brain tumors were selected for this study for several reasons: First, the efficacy of primary radiation therapy has been documented in the general population for each of these tumors (10, 13, 16,2 I). Second, the mortality rates for breast and prostate cancer continue to increase and the incidence of primary brain tumors has nearly doubled in the geriatric population during the last 10 years (5). Over the next several decades, radiation oncologists will see a rapidly growing number of geriatrics patients with breast cancer, prostate cancer, and malignant brain tumors. Therefore, it will be important to have a substantial data base which documents the radiation therapy outcomes for these geriatric cancer populations. METHODS
AND MATERIALS
The radiation therapy charts (N = 1,401) of three patient groups treated within the Yale University School of Medicine Therapeutic Radiology Program (Yale-New Haven Hospital and Uncas on Thames Hospital) were retrospectively reviewed. The three patient groups reviewed were: (a) Primary breast cancer patients with AJC/ UICC clinical Stage I or II disease treated with lumpectomy and primary radiation therapy (N = 994) from 1960-1987; (b) Prostate cancer patients with American Urological clinical Stage A2, B, or C disease treated with radical radiation therapy (N = 294) from 1975- 1990; and (c) Patients with malignant gliomas of the brain (Grade 3-4) treated with primary radiation therapy (N = 113) from 1968-1989. Within each of the three major patient groups, outcomes were determined based on the age at presentation of each patient. We selected 70 years of age or older to define a geriatric cancer population (GCP) versus less than 70 years of age to define a non-geriatric cancer population (NGCP). For each of the patient groups, the outcomes for the NGCP treated during the same era served as a control group with which to compare the results for the GCP. Seventy years of age was chosen to distinguish GCP versus NGCP for three reasons. First, 70 years of age or more is often used to exclude cancer patients from entering prospective clinical trials (8, 22). Second, in prospective clinical trials which include cancer patients of all ages (9), the results for patients over 70 years are usually not reported separately. Third, in prospective and retrospective cancer studies where the results for patients age 70 years or greater are reported, these studies generally do not include long term follow-up data at 10 years (12, 17). Table 1 summarizes the clinical characteristics of the 994 Stage I & II breast cancer patients (834 NGCP vs 160 GCP) treated with primary radiation therapy from 1960 to 1987. Prior to 1982, an axillary node dissection was not routinely performed. After 1982, more NGCP un-
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Table 1. Comparison of the clinical Stage I and II breast cancer patients treated with primary radiation therapy in the NGCP group vs. the GCP group NGCP
Number (N) Average age (years) Clinical stage I II Axillary dissection Adjuvant therapy
834
160 14
51 550 284 450 233
GCP
(66%) (34%) (53%) (27%)
94 (59%) 66 (41%) 58 (36%) 31(23%)
NGCP = Cancer patients less than 70 years of age; GCP = Cancer patients 70 years of age or more.
derwent axillary node sampling (53%) compared to the GCP (36%). However, the fraction of NGCP receiving either adjuvant chemotherapy or hormonal therapy (27%) was similar to the fraction of GCP receiving adjuvant therapy (23%). In general, adjuvant systemic therapy was recommended only for axillary node positive patients during the years of this study. The radiation therapy treatment program (RT) was identical for both NGCP and GCP groups. Following lumpectomy, RT consisted of external beam treatment to the entire breast to a total dose of 4600 cGy followed by an electron boost to the site of the original tumor to a total tumor dose of 6400 cGy. Appropriate lymph node regions were also treated to a total dose of 4600 cGy. The details of the primary radiation therapy program for Stage I & II disease have been described previously (10). Table 2 summarizes the clinical characteristics of the 294 localized prostate cancer patients ( 157 NGCP vs 137 GCP) with Stage A2, B, or C disease treated with external beam radiation therapy. Clinically, the GCP and the NGCP were quite comparable. The radiation treatment program for both GCP and NGCP was similar and generally consisted of treating a pelvic field to a total dose of 4500 cGy followed by a boost treatment to the prostate to a total dose of 6500-7000 cGy. A small number of patients also received para-aortic radiation to a dose of 4500 cGy in the early years of this study. None of the patients received hormonal therapy as part of their initial treatment. The details of the external beam radiation therapy program for prostate cancer have been described elsewhere (13, 16). Table 2. Comparison of the localized prostate cancer patients treated with primary radiation therapy in the NGCP vs. the GCP group NGCP Number (N) Clinical stage A2 B C Average age (years)
157 20 (13%) 66 (42%) 71 (45%) 63
GCP 137 12 (9%) 74 (54%) 51 (37%) 73
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Effect of age ??R. E. PESCHEL et al.
A total of 113 patients with the diagnosis of Grade 34-malignant gliomas of the brain were treated with primary radiation therapy. Nineteen patients were 70 years of age or older at presentation (GCP) versus 94 patients in the NGCP group. Both treatment groups were equivalent in terms of the distribution of tumor grade. Table 3 summarizes the clinical characteristics of the entire group. Following attempted surgical resection or biopsy, all patients were treated with either a whole brain field with subsequent generous cone down field or with a partial brain field with generous margins around the tumor volume to a total dose of 6,000-6,600 cGy. The details of the radiation program for malignant gliomas were similar to several previously published reports (20, 2 1). The life table method (4) was used to calculate the actuarial overall survival rates, cause specific disease-free (NED) survival rates, and local control rates with associated standard errors (t- standard error). The statistical significance (p-values) for the differences in the outcomes for various treatment groups was determined using the standard z-test.
Table 4. Radiation outcomes for NGCP vs. GCP for breast cancer (combined Stages I and II), prostate cancer (combined Stages A2, B, C), and malignant brain tumors NGCP Breast cancer 5-year survival 5-year LCR 1O-year survival 1O-year NED survival 1O-year LCR Prostate cancer S-year survival 5-year NED survival 1O-year survival 1O-year NED survival Malignant gliomas 1-year survival 2-year survival
GCP
p-values
83% + 2% 94% f 2% 73% f 4%
78% + 98% + 63% f
3% 2% 8%
N.S.
63% + 3% 79% + 3%
70% + 10% 76% f 10%
N.S. N.S.
73% f 4%
81%+
4%
N.S.
80% f 4% 41% xk 6%
89% f 3% 38% z!z 8%
N.S.
52% + 6%
58% k
N.S.
38% rf: 5%
18% + 8.8% 0%
10% -t 3%
N.S. N.S.
8%
N.S.
< .05 < .Ol
N.S. = Not statistically significant; LCR = Local breast cancer control rate.
RESULTS Table 4 summarizes the radiation therapy outcomes for the three treatment groups. For the combined Stage I and II breast cancer patients, the actuarial 5-year and loyear survival rates, NED survival rates, and local breast cancer control rates (LCR) were all equivalent in the GCP group compared to the NGCP group. Table 5 compares the results for the GCP versus NGCP by clinical stage. At 5 years, both the NED survival rate and the LCR were superior in the GCP with Stage I disease versus the NGCP with Stage I disease. After 10 years of follow-up, there was no statistically significant difference in outcome by stage of disease. For localized prostate cancer patients with all stages combined, there was no statistically significant difference in the S-year and IO-year overall survival rates or NED survival rates for the GCP versus the NGCP. Table 5 compares the NED survival rates by clinical stage for the GCP versus the NGCP. Stage A2 and B patients were combined for this analysis. There are no statistically significant differences in the treatment outcomes by stage of disease comparing the GCP with the NGCP.
Table 3. Clinical characteristics of the 113 patients with malignant gliomas treated with radiation therapy Number Males Females Complete surgical resection Partial resection or biopsy NGCP GCP
of patients 73 40 20 93 94 19
For patients with malignant gliomas, the l-year and 2year survival rates were statistically significantly inferior in the GCP compared to the NGCP.
DISCUSSION Although age has been recognized prognostic factor for external beam
as an important radiation therapy
Table 5. Radiation outcomes for NGCP vs. GCP by stage of disease for breast and prostate cancer NGCP Breast cancer 5-year NED Stage I Stage II 1O-year NED Stage I Stage II 5-year LCR Stage I Stage II 1O-year LCR Stage I Stage II Prostate cancer 5-year NED Stage A2/B Stage C IO-year NED Stage A2/B Stage C
GCP
a-value
survival 86% t 2% 72% + 4%
94% + 80% k
67% + 4% 55% f 7%
63% + 13% 73% + 10%
N.S. N.S.
94% zk 1% 94% + 2%
98% f 97% f
< .Ol N.S.
78% + 4% 80% + 6%
66% f 14% 89% + 8%
N.S. N.S.
88% t 5% 74% + 6%
89% + 87% +
4% 6%
N.S. N.S.
68% f 9% 42% + 8%
69% -+ 10% 42% f 14%
N.S. N.S.
3% 8%
< .05 N.S.
survival
1% 2%
survival
survival
N.S. = Not statistically significant; LCR = Local breast cancer control rate.
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outcomes by many authors ( 11, 12, 20), very few studies have specifically addressed radiation therapy outcomes in patients who are 70 years of age or more (GCP). This study was undertaken to add to the paucity of data for radiation therapy outcomes in GCP. The survival rates and NED survival rates for the three groups of NGCP in our study are consistent with the results reported in many other radiation therapy series (9, 12,2 1). Therefore, our NGCP groups represent reasonable control populations with which to compare the outcomes in our GCP groups since each of the groups was evaluated and treated during the same time interval and with the same radiation therapy program.
Breast cancer Breast conservation therapy with segmental resection (lumpectomy) followed by external beam radiation therapy for clinical Stage I and II breast cancer produces equivalent results to mastectomy in the general population (9). The number of patients aged 70+ years already constitutes a significant fraction of the patients referred for primary radiation therapy and will become an increasingly important group in the future. In our study, the GCP represented 16% of our entire primary breast cancer patient population treated from 1960 to 1987. In another large series of 680 early breast cancer patients treated with primary radiation at the Princess Margaret Hospital from 1958 to 1978, 10% of the patients were age 70 years or more (3). Therefore, based on projections that the geriatric fraction of the total population will double over the next 40 years ( 19) one can predict that the GCP will constitute at least 20-32% of all primary breast cancer patients referred for radiation therapy. Another important issue in the treatment of the elderly patient with early breast cancer is the lower rate of appropriate referrals to a radiation center. At the University of Rochester, Kantorowitz et al. (11) reported that only 24% of women age 70 years or more who underwent lumpectomy for early breast cancer were referred for primary radiation therapy compared to 82% of women less than 59 years of age. More important, Kantorowitz et al. (11) stated that referral decisions for elderly women over the age of 70 years appeared to be based on a variety of theoretical assumptions about breast cancer in older women and not on any substantial database. The most critical element in the Rochester study was that even if co-morbidity was accounted for in the treatment of age 70+ patients, “. . . even healthy elderly women are treated less aggressively” (1 1). The results of our study and a review of the literature document that elderly patients with Stage I & II breast cancer will have equivalent or superior results with radiation therapy compared to younger age groups. For example, the University of Rochester study reported a trend toward superior local control with radiation therapy in 5 1 patients age 60 years or more and concluded that radiation therapy may be more beneficial for elderly patients
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compared to younger patients ( 11). This study also showed a trend toward enhancement of survival in elderly women treated with lumpectomy plus radiation therapy compared to elderly women treated with lumpectomy alone (11). Clark et al. (3) at the Princess Margaret Hospital (PMH) reported their results on 68 women age 70-75 years with Stage I and II breast cancer treated with primary radiation therapy. The IO-year relative survival rate (adjusted by the expected survival for this age group) for these 68 patients was 8 1% and was superior to all other age groups in the PMH study (3). Our study of 160 women age 70 or more represents one of the largest reviews of elderly women with Stage I & II breast cancer treated with primary radiation. Our study documents that the GCP had similar IO-year NED survival rates (70% vs. 63%) and lo-year LCR (76% vs. 79%) compared to the NGCP. It can be concluded from our study that there is no rational reason based solely on IO-year results to exclude patients who are 70 years of age or more from standard breast conservation radiation therapy programs.
Prostate cancer External beam radiation therapy is an accepted local therapy for Stages A2, B, and C prostate cancer (12, 13, 16, 17). Patients over the age of 70 years already constitute a significant fraction of all patients referred for curative radiation therapy. In the RTOG 77-06 prospective clinical trial comparing elective pelvic radiation to local prostate therapy only in Stage A2 and B prostate cancer, 36% of the 445 patients were 7 1 years or older (1). With the increasing geriatric population, patients over the age of 70 years may constitute more than 50% of the patients referred for radiation in the next 20-40 years. A few large studies have specifically reported the radiation therapy results for elderly patients. Unfortunately, these studies have either reported only 5-year results or included patients under the age of 70 years. The RTOG 77-06 study included the results of 160 patients with Stage A2 and B disease who were age 7 1 years or more treated with radiation (1). The 5-year NED survival rate in the 7 1+ age group (76%) was equivalent to all of the younger age groups analyzed (78-83%) (1). In the Patterns of Care Study (POC) on 682 patients with Stages A2, B, and C cancers, 279 patients were age 66 years or more (12). The 66+ year group had a lower overall recurrence rate (33%) compared to patients who were age 60 years or less (43%). Our study includes data on 137 patients aged 70 years or more and extends the follow-up period to 10 years. Our data are consistent with both the RTOG and POC studies and indicate that the GCP with clinical Stage A2, B, or C disease have equivalent 5-year and 1O-year overall and NED survival rates compared to the NGCP. It can be concluded from our study that one should not exclude elderly (70+ years) prostate cancer patients from primary radiation therapy programs based solely on the age of the patients.
Effect of age 0 R. E.
Malignant brain tumors The diagnosis of primary brain tumors has doubled in the geriatric population over the last 20 years and the incidence of these tumors continues to increase (5). The increasing rate (doubling every lo-20 years) of CNS tumors in the elderly combined with the doubling of the geriatric population in the next 40 years will produce an enormous number of elderly patients with brain tumors referred for radiation therapy in the future. The Brain Tumor Study Group has documented that high doses of external beam radiation (6,000 cGy or more) increases the survival of patients with malignant gliomas (Grade 3-4) in the general population (23). However, several studies have documented a lower survival rate with increasing age despite the use of radiation therapy. Salazar et al. (20) found the median survival for radiation patients over 45 years of age to be significantly lower compared to patients less than 45 years for both Grade 3 (52 weeks vs. 133 weeks) and Grade 4 tumors (39 weeks vs. 72 weeks). Prados et al. (18) found a very strong negative correlation between age and survival in 357 patients with anaplastic astrocytomas treated with radiation. Our study shows a statistically significant (p < .05) decrease in the l-year and 2-year survival rates using RT in the GCP compared to the NGCP. These results raise questions
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about the efficacy of RT in elderly brain tumor patients. However, the number of elderly patients with Grade 34 gliomas in our GCP is relatively small. Therefore, we recommend prospective clinical trials in this age group to compare supportive care only versus standard radiation therapy to better define the role of high dose radiation. This study is one of the largest geriatrics radiation therapy studies ever reported and demonstrates the diversity of outcomes which are possible when general radiation oncology strategies are applied to elderly cancer patients. The conclusions of our study must be viewed with some caution because the results of our study are influenced by multiple patient selection factors and referral patterns which are difficult to quantify. Clearly, many geriatric cancer patients with multiple co-morbidities are not referred to radiation oncologists. However, our study does document that for early breast and localized prostate cancers, the fraction of the geriatric population which is currently being referred to radiation centers have equivalent IO-year results using standard external beam programs compared to the general population. For these subgroups of patients, it is not a rational policy to withhold radiation therapy based solely on age. However, for malignant gliomas, the use of primary radiation in patients over 70 years of age should be tested in prospective clinical trials.
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