radiation therapy of the older patient

CANCER IN THE ELDERLY 0889%3588/00 $8.00 + .OO

RADIATION THERAPY OF THE OLDER PATIENT

Babu Zachariah, MD, and Lodovico Balducci, MD

Cancer in the geriatric population is a significant public health issue in the United States today. Currently, 60% of all malignant tumors occur in individuals aged 65 years and older. Nearly 70% of all cancer deaths occur in this age group. Currently about 12% of the population is over 65 years old, and this figure will rise to 20% in the year 2030.

As age advances, the incidence of cancer increases dramati~ally '~~ in both men and women (Fig. 1). The effect of aging is more apparent in certain cancers. Thrty-five percent of all colon cancers occur in women aged 80 or older; the median age at diagnosis is 75 years. By age 90, 90% of men will have prostate cancer. The distribution of cancer incidence in persons aged 65 years and older is given in Table 1.

Currently, older patients with cancer are evaluated and treated less aggressively than their younger ~ounterparts.5~ Older patients are less likely to receive combined-modality therapy.118 There are few clinical trials for patients over the age of seventy-five years. Older patients are excluded from the existing trials because of concerns regarding the toxicity and lack of benefit from treatment.67, 195

As an alternative to surgery and to systemic chemotherapyz3 radiotherapy is of particular benefit to older and frail cancer patients. It is widely used with curative and palliative intent. The information concerning the effectiveness and tolerance of radiation in the older patients is limited, however. Few books or publications have dealt with this aspect of oncology. Many older patients are either not treated or are undertreated because of the fear of treatment-related toxicities.40, 55, 70, 116, 156 Approximately two thuds of younger patients are managed by multimodality therapy, as compared with only one third of patients more than 75 years This article reviews the current information regarding the effectiveness and toxicity of radiotherapy in older individuals and presents the available data specific to major cancer sites.

From the Department of Radiology, Division of Radiation Oncology (BZ) and the Division of Medical Oncology and Hematology, Department of Internal Medicine (LB), Univer- sity of South Florida College of Medicine; and the Senior Adult Oncology Program, H. Lee Moffitt Cancer Center and Research Institute (BZ, LB), Tampa, Florida

HEMATOLOGY / ONCOLOGY CLINICS OF NORTH AMERICA ~~ ~

VOLUME 14 * NUMBER 1 * FEBRUARY 2000 131

132 ZACHARIAH & BALDUCCI

4500

4000

3500

3000

2500

2000

1500'

1000

500

0 20 30 40 50 60 70 80

Age in Years

Figure 1. Cancer incidence rates for males and females. (From Yancik R: Epidemiology of Cancer in the Elderly: Current status and projections for the future. Rays 22(suppl 1):3, 1997; with permission.)

Table 1. DISTRIBUTION OF CANCER INCIDENCE IN PERSONS AGED 65 YEARS AND OLDER

Cancer Site Percentage of All Diagnosed Cases Occurring

in Persons Aged 65 Years and Older

Colon Rectum Lung Pancreas Stomach Bladder Non-Hodgkin's lymphoma Prostate Breast Ovary

75 66 64 73 69 71 51 80 48 47

Adapted from National Cancer Institute Surveillance, Epidemiology and End Results Program 1989-1993, in Yancik R Epidemiology of cancer in the elderly: Current status and projections for the future. RAYS 22(supp):3, 1997; with permission.

RADIATION THERAPY OF THE OLDER PATIENT 133

CANCER BIOLOGY IN THE ELDERLY

Cancer is primarily a disease of aging. Longevity is associated with prolonged exposure of somatic cells to environmental carcinogens leading to carcinogenesis in these aging cells. The tissue stem-cell reserve is also progressively depleted with age. To restore the waning cell population, the stem cells undergo proliferation and so become highly vulnerable to carcinogenesis. These tissue stem cells may give rise to neoplasms that are resistant to most forms of treatment. The depletion of stem cells in normal tissue may impair the ability of normal tissue to recover from radiation injury.

Sensitivity of tumor cells to radiation therapy depends on tumor proliferation and oxygenation. The H3-thymidine labeling index (TLI), a measure of cell proliferation, is decreased in several tumors in older patients compared with their younger counterparts, suggesting that the sensitivity of tumors to radiation may be decreased in the older patients.’”lS, 22 Age-related decrease in circulation could cause tissue hypoxia that results in decreased tumor sensitivity. As age advances, the functional reserve of many organs declines, causing increased toxicity from treatment. A reduction in stem-cell reserve in bone marrow and in the mucosa and the associated reduced rate of cell repopulation lead to increased damage to normal tissue during radiotherapy.

RADIOTHERAPY IN THE OLDER PATIENT

Older patients with cancer should be evaluated thoroughly, with particular attention to the comorbid conditions and performance status. Their disease should be properly staged so that appropriate treatment can be prescribed. Curative or palliative therapy may be offered, depending on the stage of the disease, with special attention to the quality of life and emotional needs of the patient. Multimodality therapy should not be withheld on the basis of age

199, 2oo Mortality from radiotherapy is rare. Organ and function preservation is an advantage of radiotherapy. A clear disadvantage of radiotherapy, especially for the older population, is the long duration of therapy (about 6-7 weeks for curative therapy and 2 4 weeks for palliative treatment).

TOLERANCE OF RADIOTHERAPY BY OLDER PATIENTS

One of the reasons for the obvious difference in cancer treatment of elderly and younger patients is the fear that advanced age may be associated with reduced tolerance of treatment. Progressive reduction of functional reserve may enhance the damage of normal tissues and the risk of therapeutic complications. Another reason for undertreatment of older patients is the belief that tumors are more indolent in the elderly than in younger patients and have a lesser effect on the life expectancy. Analyses of tumor stage distribution by age194 and of survival rates of older patients who received less aggressive therapy do not support this contention.68 Inadequate radiation doses may compromise the chances of cure for older patients.

Does age per se affect the sensitivity of normal tissues to radiation and lead to increased radiation reactions? So far, only limited data addressing this issue are available. Results from animal studiess6, 154 do not show an increase in radiosensitivity with increasing age. Several clinical studies show no increased radiation toxicity of normal tissues with advancing age. Radiotherapy results of

134 ZACHANAH & BALDUCCI

breast cancer patients showed no increased incidence of telangiectasia, subcutaneous fibrosis, arm edema, or lung fibrosis in patients over the age of 60 years," 25 and no excess of other early or late skin reactions was noted.178

The effect of age on acute and late reactions during and after radiotherapy was reported by Pignon et al.l4O The investigators reviewed data of 1208 patients participating in five different European Organization for Research and Treatment of Cancer (EORTC) studies who received chest irradiation as monotherapy or in conjunction with surgery or chemotherapy. Acute radiation reactions (nausea and vomiting, dyspnea, esophagitis, weakness, weight loss, and change in performance status) and late side effects (radiologically detected changes, dysphagia, esophagitis, weakness, spinal cord damage, and heart damage) were compared in six age groups rangmg from less than 50 years to more than 70 years old. Acute normal-tissue reactions were not higher in the older patients than in the younger patients (Table 2). A trend towards higher weight loss was noted in older patients. The mean time for development of late complications, 13 months, was similar in all age groups. Forty percent of patients were free of late complications at 4 years, with no sigruficant difference among age groups. Although serious esophagitis (higher than grade 2) appeared to occur more frequently in older patients, this difference disappeared after adjustments were made for doses, treatment fields, treatment duration, and combination with chemotherapy. Two previous reports by the same authors on patients with head and neck and pelvic malignancies treated according to several EORTC protocols showed similar

although older patients appeared less tolerant of mucositis than younger individuals. Locoregional tumor control and survival rates were also similar. Some complications of pelvic radiotherapy, such as nausea, deterioration of performance status, and skin reactions were more pronounced in younger patients,l" whereas sexual dysfunction was more common in older patients.

The strength of these studies is that all data were recorded prospectively, and no dose adjustment was made for age. These patients had good performance status with little functional impairment. Other investigators have reported similar results in older patients receiving radiotherapy.=, 159

The available data on the sensitivity of normal tissues to radiation therapy in elderly patients strongly suggest that older patients with good functional status tolerate radiotherapy as well as younger patients, with tumor response and suwival rates that are comparable with those of younger patients? Aggres- sive radiotherapy should not be withheld from older patients because of chronological age alone.

RESULTS OF TREATMENT OF CANCER IN THE OLDER POPULATION

Lung Cancer

Older patients with lung cancer are often referred for radiotherapy because the surgical mortality is sigruficantly higher in the geriatric population.115 Very few older patients receive a radical course of therapy. Patients with early-stage cancer (T1 and T2) referred for curative therapy are often medically inoperable because of poor cardiac or pulmonary conditions. Noordijk et al reported the results of radiotherapy in a group of 50 older patients who had peripherally located T1 and T2 lung lesions.128 Forty patients were over 70 years of age, and all of them received a full course of radiotherapy, a total of 60 Gy in 6 weeks, to the primary site alone. Complete response was achieved in 50% of patients with


tumors smaller than 4 cm. Overall survival was 56% at 2 years and 16% at 5 years. Five-year survival of patients who had a complete response was 42%. These results were comparable with those achieved in the same hospital by surgical treatment of lung cancer patients aged older than 70 years. There were no serious early or late side effects of radiotherapy. Radiation fibrosis was noted frequently in chest radiographs but was never symptomatic. The authors concluded that radiation therapy was a reasonable alternative to surgery for patients older than 70 years who had resectable lung cancer with a largest diameter of 4 cm or less. Coy et ale reported a 5-year survival rate of 17% among 50 patients older than 70 years and with Karnofsky performance scale (KPS) status greater than 70. The morbidity of treatment was comparable with that of younger patients: the most common acute reaction was dysphagia, and two patients developed esophageal stricture. Aristizabal et a17 also showed that age may not have an unfavorable influence on the outcome of radiation therapy in older patients, whether a split regimen or continuous regimen is used.

Furuta et a1,62 from Japan, recently reported their experience in treating patients who were medically inoperable. Thirty-two patients aged over 75 years received definitive radiotherapy for stage I and I1 non-small cell lung cancer. All patients completed the planned therapy without complications. The 2-year and 5-year cause-specific survival rates were 57% and 3670, respectively. These authors concluded that elderly patients with stage I and stage I1 non-small cell lung cancer can expect to have a long survival in spite of having concurrent medical problems. Kusumoto et al?5 also from Japan, showed that patients older than 70 years of age with good performance status have survival rates similar to those of younger patients when irradiated with or without chemotherapy.

The largest radiotherapy series for lung cancer in patients aged 70 years and older was reported by Gava et al, from Italy.@ One hundred ninety-six patients, most with squamous cell carcinoma, were treated with curative intent with a dose ranging from 50 to 70 Gy. Ninety-one percent of patients completed the planned course of radiotherapy. Palliative radiotherapy was given to seventy- three patients, 78% to 86% of whom obtained substantial symptomatic relief. Forty patients (22%) had treatment interruptions. No differences in assessed general and functional conditions were found before and after radiotherapy. Acute toxicity of treatment was comparable with that observed in younger patients.

Older patients with small cell carcinoma of the lung and those with comorbid illnesses are not usually considered for standard combination chemotherapy. In these patients, intensive treatment is associated with substantially increased toxicity without significant survival ad~antage.5~ Evans et a1 used a less toxic regimen of oral etoposide, 100 mg/m2 for 7 days, and carboplatin, 150 mg/m2 on day 1, repeated every 3 to 4 weeks for 6 cycles, in patients older than 65 years. Seventy-one percent responded, and 29% had a complete response. Me- dian survival was 46 weeks. Patients who had complete response were given thoracic and prophylactic cranial irradiation. Treatment was generally well- tolerated except for neutropenia. The results are similar to the previously reported trials of combination chemotherapy?, 53* 153 A retrospective analysis of older patients who received chemotherapy with or without radiotherapy at the Ottawa Regional Cancer Center showed that the response rate (overall response of 70%) and survival rate were similar to those of younger patients.”

Prostate Cancer

Several investigators have shown that by careful selection of patients and with judicious modification of treatment regimens, most elderly patients can be

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rendered free of prostate cancer without causing significant complications. Re- cently, Zachariah et al reported the results of treatment of 105 patients with prostate cancer, aged 70 years or older, who received external beam radiother- a p ~ . ' ~ ~ All patients except 1 completed the treatment. Eighty-five percent of patients had complete clinical response with 77% achieving biochemical control. The 4-year survival rate of 53 patients treated in 1994 and earlier was 96%. Eighty-seven percent of those patients were free of disease. The overall 5-year actuarial survival rate was 92%. No grade 3 or grade 4 acute lower intestinal side effects were observed. Grade 3 and grade 4 acute genitourinary (GU) reactions occurred in 4% and 2% of patients, respectively. Late grade 3 lower intestinal reactions were noted in 6% of patients. Late grade 3 and 4 GU reactions were noted in 5% and 2% of patients, respectively. These results are comparable with those of Forman et a1,'j0 who demonstrated the absence of severe complications in elderly patients with prostate cancer. The incidence of moderate complications was similar to that reported with curative irradiation in younger patients. The 5-year survival rate was 82%, which is better than the 37% survival reported by Hanash et a175 and the 50% survival rate reported in the Veterans Administra- tion study of patients aged more than 70 years.182 Forman reported 94% locoregional control, comparable with the reported experience with definitive radiotherapy of prostate cancer in patients of all ages.'"

Patterns-of-care studies in the United States by Hanks et a1 showed similar treatment outcomes in patients aged younger than 70 years and those aged 70 years and older who received a full course of radiotherapy for prostate cancer. No differences in Radiation Therapy Oncology Group (RTOG) grade 3 and grade 4 late complications were noted between older and younger patients. A reduction in acute and late radiation reactions was obtained with three-dimen- sional (3-D) conformal radiotherapy, compared with conventional external beam radiotherapy, despite an 8% increase in radiation

138

Bladder Cancer

The optimal treatment of bladder cancer in older patients is not well- established. Some older patients with invasive bladder cancer are medically unfit for cystectomy. Sengelov et alls9 from Denmark have recently reported the results of curative radiotherapy of 94 patients aged 75 years or older who had bladder cancer. The total dose given was 57.6 to 62.6 Gy in 24 to 30 fractions in 6 weeks. Seventy-six patients had a planned 2-week break in the treatment. Twenty-nine percent of patients survived for 2 years, and 7% survived for 5 years. Median survival was 13.9 months. Patients aged over 75 years had a shorter survival than patients younger than age 75 years, but the difference was not statistically significant. Fifty percent of patients were hospitalized during or after treatment because of gastrointestinal or GU side effects. Patients with low- stage cancer and good performance who had a 2-week treatment break had a better outcome. The study suggests that curative radiotherapy treatment for bladder cancer is feasible in otherwise healthy elderly patients.

Response to radiotherapy was dose-dependent.I6* Patients who received doses of 55 Gy or more showed a significantly higher response rate than those who received a lower dose. Important predictors of survival included complete clinical response, short time between diagnosis and beginning of therapy, a second transurethral resection (TUR), and good KPS status. Orihuela and Cube- lli134 showed in their series that patients with low KPS rating had poor survival.

Bloom et al,30 in a randomized trial of preoperative radiation and elective


cystectomy versus radical radiotherapy for stage T3 bladder carcinoma, found no statically significant difference in the 5-year survival rates in patients aged 65 and those aged 70 years. They found a superior survival rate in patients aged less than 65 years. They concluded that for patients over the age of 65 years, radical radiotherapy with the possibility of salvage cystectomy in selected cases is the treatment of choice.

Several investigators have evaluated aggressive therapy with combination chemotherapy and radiotherapy for invasive bladder cancer. Housset et a1,8z from France, reported the results of treatment of 54 patients (mean age, 66 years) with stage T2 to T4 operable invasive bladder cancer. All patients had TUR of the tumor followed by 5-fluorouracil-cisplatin combination chemotherapy with concomitant bifractionated split-course radiotherapy. Patients with persistent tumor had cystectomy. Patients with a complete response were treated by either additional chemoradiotherapy or cystectomy. At follow-up cystoscopy, 74% had histologically documented complete response. The disease-free survival rate at 3 years was 62%, which was significantly better in responding patients (77%) than in nonresponding patients (23%). No difference in survival rate was noted between patients receiving cystectomy and those receiving chemoradiotherapy. The neoadjuvent chemotherapy was well-tolerated by elderly patients.

have reported an objective response rate of 93% after combined radiotherapy and intravenous (IV) cisplatin for elderly patients with high-grade bladder carcinoma. Median survival was 22 months, with four patients surviving 3 years or longer. No excessive acute or late reactions were noted in this group of patients (i.e., no World Health Organization [WHO] grade 4 toxicity was noted).

Arias et a16 also have reported that combined chemoradiotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) is feasible in patients aged over 70 years. Complete tumor response was observed in 55% of patients after a dose of 45 Gy to the pelvis. Overall survival rates were 34% at 3 years and 27% at 5 years. Patients who had complete response had a 5-year survival rate of 48%. No life-threatening toxicity was noted in this group of patients. The most frequent RTOG grade 3 and 4 toxicities were leukopenia (10%) and cystitis (10%) (Tables 3 and 4).

All of these studies suggest that aggressive therapy should not be withheld on the basis of advanced age alone.

Raghavan et

Table 3. TOXICITIES ASSOCIATED WITH NEOADJUVANT MVAC TREATMENT OF BLADDER CANCER IN 20 PATIENTS ,

Grade of Toxicity

Toxicity 0 1 2 3 4

Anemia 17 2 1 0 0 Leukopenia 10 5 3 2 0 Thrombocytopenia 17 2 0 1 0 Nausea/emesis 8 6 4 1 1 Alopecia 2 4 10 4 0 Mucositis 17 2 1 0 0 Renal 15 4 1 0 0

W A C = methotrexate, vinblastine, doxorubicin, and cisplatin Adaptedfrom Arias F, Duenas M, Martinez E, et a1 Radical chemoradiation for elderly patients with

bladder cancer invading muscle. Cancer 80:115, 1997; with permission.


Table 4. TOXICITIES ASSOCIATED WITH CONCOMITANT CISPLATIN AND RADIOTHERAPY TREATMENT OF BLADDER CANCER IN 20 PATIENTS

Grade of Toxicity

Toxicity 0 1 2 3 4

Anemia 16 4 0 0 0 Leukopenia 10 5 5 0 0 Thrombocytopenia 18 1 1 0 0 Diarrhea 4 13 3 0 0 Nausea/emesis 10 6 4 0 0 Bladder 3 12 3 2 0 Renal 14 4 2 0 0

Adaptedfrom Arias F, Duenas M, Martinez E, et al: Radical chemoradiotherapy for elderly patients with bladder cancer invading muscle. Cancer 80:115, 1997; with permission.

Breast Cancer

Breast cancer is the most common cancer in women in the United States and is the second leading cause of cancer-related death among women. Because breast cancer is age-related and because the population is aging, more cases of breast cancer will be detected in the coming years.

The standard local treatment for stage I and stage I1 breast cancer in older patients includes modified radical mastectomy and lumpectomy followed by radiotherapy. The choice of therapy depends on the health status of the patient, her preferences concerning breast preservation, and her willingness to undergo 5 to 6 weeks of radiotherapy. Older women are less likely than younger women to have breast-conserving surgery.97

Even when receiving standard breast-conserving surgery and radiotherapy, women aged 65 and older are less likely to have a re-excision, extensive axillary dissection, chemotherapy, or nodal irradiati~n.~, 9, 11* Despite these treatment differences, some investigations have reported similar local control and 5-year survival rates in patients older than 65 and in their younger counterparts.112 Randomized prospective studies comparing aggressive and less aggressive modes of therapy are needed to reach any conclusion regarding the outcome of therapy.160

The optimal treatment of breast cancer in the older patients is not yet well- established. Some believe that survival of older patients with breast cancer is not significantly affected by treatment.

The number of patients receiving radiotherapy after breast-conserving surgery decreased markedly with age, regardless of comorbidity status and stage of the disease (77% in patients < 70 years versus 24% in patients 2 80 years of age).I4, 26 Women over 75 years of age are less likely to receive adjuvant radiotherapy after mastectomy. More often, these women are given endocrine therapy?6 Wide local excision and other forms of conservative surgical techniques have been used for older patients with breast cancer in an attempt to improve cosmesis and reduce the operative morbidity and mortality. Treatment with breast-conserving surgery alone, however, is associated with a significant rate of local failure, ranging from 6% to 37%.&, 17'

Tamoxifen has been used as a sole therapy in older patients with breast cancer,58 but the local failure rate with tamoxifen monotherapy ranges from 23% to 58%.65, lI9 Because most elderly women tolerate mastectomy or lumpectomy


and radiotherapy well, there is no medical reason to forgo standard treatment in most older women. The choice of therapy is between modified radical mastectomy or breast-conserving surgery plus postoperative radiotherapy. Although the risk of surgical complications increases with increasing age, Turnbull et supported standard surgical procedures in older women. In a retrospective analysis of 4050 operations, they reported a perioperative mortality rate of 4.8% for patients aged 70 compared with 3.4% overall.

Several investigators studied the tolerance and outcome of radiotherapy in older patients with stage I and stage I1 breast cancer following breast-conserving surgery.88,1Ms177 Solin treated 173 women aged 65 years or older and compared the results with those for 385 women aged 50 to 64 years treated during the same period. There were no differences between the two age groups for the rates of 10-year overall survival, relapse-free survival, freedom from distant metastasis, or local failure (Table 5). There was significant difference in the rate of death from intercurrent diseases at 10 years (11Y0 versus 2% respectively). Merchant et aP2 compared the outcome of breast-conserving surgery followed by radiotherapy for women aged 65 years and older with the outcome for women aged 64 years and younger. No differences in the 10-year local failure rate, disease-free survival rate, or overall survival rate were noted. Women over 60 years of age who receive radiotherapy after segmental mastectomy for early breast cancer have a lesser chance of locoregional failure than those who have segmental mastectomy alone. Complications following radiotherapy are modest. Kantorowitz reported that postoperative radiotherapy after segmental mastectomy can be given safely to older patients, resulting in a lower rate of local failure (4%) than in patients younger than 60 years (17%). Similar age-related locoregional response to segmental mastectomy and radiotherapy was noted by other investigator^.^^, 58, 77 Toonkel et reported an actuarial 10-year survival rate of 51% after tylectomy and radiotherapy for stage I and stage I1 breast cancer in patients older than 70 years of age who had multiple medical problems. Their results compared favorably with their previously reported 53% 10-year survival rate for women of all ages similarly treated. In their series, elderly patients tolerated radiotherapy fairly well. All patients developed the expected acute skin reactions, varying from mild erythema to modest desquamation in women with larger and more pendulous breasts. Three percent of patients developed arm edema. Eighty percent of patients who developed breast edema had axillary node dissection.

In a study by Wyckoff et al,192 the toxicity associated with breast irradiation following partial mastectomy among 63 women aged 65 years and older was compared with that of 100 women under the age of 65 years. Total dose, treatment interruptions, and treatment duration were comparable among younger and older women (Table 6). No statistically significant difference in the cutaneous or hematological toxicity was noted between the two groups (Table 7). No mucosal toxicity was noted. Complications were generally mild and infrequent in both groups of patients. No cutaneous toxicity higher than grade 2 was noted. Grade 2 toxicity was experienced by seven patients (11%) older than 65 years and by 21 patients (21%) younger than 65 years. Hematological toxicity was grade 1 in all cases.

In summary, postoperative radiotherapy is well-tolerated by older patients with breast cancer. Advanced age, per se, is not a contraindication for radiation therapy after breast-conserving surgery. Patients with early-stage cancer should not be denied the opportunity for cure by using less aggressive treatment modalities. Several studies have demonstrated that breast conserving surgery

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Table 6. DOSES AND DURATION OF RADIATION THERAPY AND TREATMENT INTERRUPTIONS IN OLDER AND YOUNGER WOMEN WITH BREAST CANCER

Age Groups < 65 2 65 P Value

Total dose of radiation (cGY) 5971 f 344 5662 f 622 0.529 No. of patients with treatment interruptions 10 (9%) 2 (3%) 0.063 No. of patients whose treatment was 40 (35%) 18 (28%) 0.82

Treatment duration (mean average, in days) 53 f 14 51 ? 9 0.78 prolonged beyond 42 days

Adupfedfrom Wyckoff J, Greenberg H, Sanderson R, et al: Breast irradiation in the older woman: A toxicity study. J Am Geriatr SOC 42150, 1994; with permission.

and definitive irradiation in older women achieves good results in terms of survival, freedom from distant metastasis, and local control.

Radiation therapy also has a major role in palliation of advanced breast cancer. Radiation therapy, like chemotherapy, is underutilized in older patients. Fetting et a156 reported that, although 57% of patients under 65 years of age with metastatic breast cancer received radiotherapy, only 46% of patients aged 65 to 74 years and 29% of patients aged 75 years and older received palliative radiotherapy. Symptoms related to metastatic cancer involving brain, bone, and soft tissues can be adequately palliated with a short course of radiotherapy in older women, including those who are frail.

Colorectal Cancer

Radiation therapy plays a major role in the treatment of patients with colorectal cancer. There is little information, however, regarding the tolerance of older patients to radiotherapy and the response of the tumor at this particular site. The survival rate of patients with colon cancer seems to decrease with increasing age.38 This decreased survival rate could be related to the less aggressive therapy received by the older population.11s To reduce local recurrence, radiation therapy, often combined with chemotherapy, is frequently used as an adjuvant to primary surgical resection. Radiation is also used for palliation of unresectable cancer.

Table 7. INCIDENCE OF BREAST CANCER TREATMENT COMPLICATIONS

Age Groups Complication < 65 (%) 2 65 (%) P Value

Cutaneous Anemia Leukopenia Thrombocytopenia

45 (45) 34 (52.3) 0.37 1 (1.5) 0.83

0.07 0.94

2 (2) 14 (14) 4 (7) 1 (1) 0

Adupfed from Wyckoff J, Greenberg H, Sanderson R, et al: Breast irradiation in the older woman: A toxicity study. J Am Geriatr SOC 42150, 1994; with permission.


Colon Cancer

Local recurrence is a major problem after curative resection for colon cancer.190 There are no reported randomized trials of radiotherapy after curative surgery for colon cancer. A retrospective review from Massachusetts General Hospital showed improved 5-year actuarial local control, recurrence-free survival, and overall survival rates after postoperative radiotherapy in stage 83 or C3 colon cancer. Willett et reported acute toxicity of grade 3 and higher in 8% of patients who received postoperative radiotherapy for colon cancer. The incidence was lower in patients who received radiation plus chemotherapy (4% versus 16%, respectively). Long-term toxicity of grade 3 and higher was experienced by 4.5% of patients. With careful treatment techniques, the acute and long-term toxicities of postoperative local and regional radiotherapy, with or without chemotherapy, for colon cancer are comparable with those reported for rectal cancer.94

Anorectal Carcinoma

Prognosis of colorectal carcinoma is determined primarily by the stage of cancer rather than by the age of the patient." Radiation therapy is more widely used as an adjuvant to surgery for rectal carcinoma than for colon carcinoma. More recently, chemotherapy has been added to radiotherapy in the adjuvant setting. Several randomized and nonrandomized trials have shown that radiation therapy is effective in reducing local recurrence of rectal cancer when used after complete surgical resection (Tables 8 and 9)?9, 63, 94, 17*, 183, 188

Several prospective trials in patients with rectal carcinoma have compared a short course of preoperative radiotherapy (500 cGy in a single fraction to 2500 cGy in 5-10 fractions) with surgery alone.79, 147, 158, 166 No survival advantage was

Table 8. COMPARISON OF LOCAL CONTROL IN RANDOMIZED TRIALS OF POSTOPERATIVE ADJUVANT RADIATION IN COMPLETELY RESECTED RECTAL,CANCER PATIENTS

Radiation Trial Dose

(Reference Number) Randomized (GY) Local Control

GITSG (63) Control (n = 58)* - 76% (44/58) Chemotherapy (n = 48) - 73% (35/48) Radiation therapy (n = 50) 4048 80% (40/50) CT + RT (n = 46) 40-44 89% (41/46)

NSABP R-01 (59) Control ( n = 184) - 76% (139/184) Chemotherapy ( n = 187) - 79% (147/187) Radiation therapy ( n = 184) 4647 84% (154/184)

NCCTG (94) Radiation therapy ( n = 100) 45-50 75% (75/100) CT + RT (n = 104) 40-44 86.5% (90/ 104)

'Control = surgery alone. GITSG = Gastrointestinal Tumor Study Group; CT = chemotherapy; RT = radiation therapy;

NSABP = National Surgical Adjuvant Breast and Bowel Project; NCCTG = North Central Cancer Treatment Group.

From Famiok KE, Levitt S H The role of radiation therapy in the treatment of colorectal cancer: Implication for older patients. Cancer 742154, 1994; with permission.


Table 9. NONRANDOMIZED TRIALS OF ADJUVANT POSTOPERATIVE RADIATION IN COMPLETELY RESECTED RECTAL CANCER PATIENTS: RESULTS BY STAGE OF DISEASE

Radiation Trial No. of Dose in Local 5-Year

(Reference) Patients Gy* Stage Recurrence Survival (%)

Tepper (172) 165 45-50 B2 B3 c1 c 2 c 3

Vigliotti (183) 105 40-50 B2 and B3 C1, C2, and C3

Wiggenraad (188) 62 45 B C

Schild (157)$ 139 3.8-64.6 82 and B3 c1 C2 and C3

9% (5/53) 0% (0/7)

21% (16/77) 20% (2/10)

53% (8/15) 14% (5/37)

21% (5/24) 18% (6/34) 19% (7/36)

25% (21/83)

16% (10/62)

10% (2/20)

71 67 90 39 17 55t

NS NS 79 89 42

*Radiation dose delivered to all patients. tSurvival rate is for all patients. $Chemotherapy was added to radiation therapy in 44 patients. NS = not stated. From Farniok KE, Levitt SH: The role of radiation therapy in the treatment of colorectal cancer:

Implication for older patients. Cancer 742154, 1994; with permission.

demonstrated in the group receiving preoperative radiotherapy. One of the reports showed that the postoperative mortality rate related to infections and wound dehiscence was 8% among patients receiving preoperative radiotherapy and only 2% in patients treated with surgery The increase in mortality was greater in patients over 75 years of age (16%) than in younger patients (5%).

Valentini et a1180 examined 17 patients over 75 years of age who received combined chemoradiotherapy for anorectal carcinoma. Patients were well-selected, having good renal and cardiac function. All patients received concomitant chemotherapy (bolus mitomycin C 10 mg/m*, on day 1 and continuous infusion 5-fluorouracil (5-FU), 1000 mg/mz for 24 hours, on days 14). The dose of pelvic radiotherapy ranged from 38 to 45 Gy. Ten patients had rectal carcinoma, and 7 patients had carcinoma of the anus. Valentini reported acute RTOG grade 3 toxicity in 3 of 17 patients (18%). Only 1 patient was unable to complete the planned treatment course. No severe late toxicity was reported. Six patients had complete response to therapy. In 16 of 17 patients, the size of lesion was reduced by more than 50%. All patients with pelvic pain experienced relief after therapy. Five of 6 patients who had rectal bleeding at presentation experienced control of the symptoms after therapy. This report suggests that, in well-selected older patients, chemoradiotherapy can be performed safely.

The feasibility and outcome of radical radiotherapy with or without concomitant chemotherapy of mitomycin C and 5-FU for anal carcinoma in patients aged 75 years and older was studied by Allal et a12 Radiotherapy was given to the pelvis at a mean initial dose of 39.6 Gy followed by a boost with either brachytherapy or external beam radiation (median dose 20 Gy). Ninety-five percent of the patients completed the planned course of therapy. Acute RTOG grade 2 and grade 3 acute reactions were noted in 43% and 54% of patients,


respectively. Sixty-eight percent of grade 3 reactions occurred in the chemoradiotherapy group. Grade 2 and grade 3 leukopenia and fatigue occurred in 25% and 58% of patients, respectively, in the chemoradiotherapy group. Five patients, all from the chemoradiotherapy group, had grade 3 or grade 4 late complications. No significant differences in local control and overall survival rates were noted between the radiotherapy and the chemoradiotherapy groups. This report suggests that sphincter-conserving treatment is feasible in the older patients with anal carcinoma. Acute and late complication rates are similar to those in younger patients.

Another treatment option particularly useful for older patients with small early rectal cancer is local excision followed by external beam radiation therapy. Good local control has been reported in patients who had no gross residual disease after surgery.113, 146, 191 Patients with small (preferably < 3 cm), well- differentiated, and superficial tumors are ideal for this type of therapy. Endocavi- tary radiation therapy, originally described by Papi l l~n, '~~ has shown excellent local control in selected patients. Reported local failure of this modality ranges from 11% to 18%. For older and frail individuals, endocavitary radiation therapy is an attractive option. Lesions with a maximum size of 3 to 5 cm within 10 cm from the anal verge and with no evidence of disease extension outside the bowel wall or anal canal are ideal for endocavitary therapy.

Older patients are at a higher risk for radiation enteritis because of pre- existing conditions such as hypertension, vascular disease, diabetes and prior abdominal surgery. No differences in side effects from radiotherapy were noted, however, between younger and older patients in clinical trials.54 By limiting the volume of the bowel irradiated with the help of radiographs, positioning patients prone with full bladder, and using multiple fields, the occurrence of side effects from radiotherapy can be reduced to nearly 5%.

Head and Neck Cancer

Cancer of upper aerodigestive tract is quite common in the elderly population. More than 50% of the patients are older than 65 years at diagnosis. The most commonly involved sites are the larynx, oropharynx, and oral cavity.102 Because of coexisting illnesses and poor performance status, radiotherapy is often the treatment of choice in these elderly patients. The special advantages of radiotherapy include the possibility of preserving the organ and function and avoiding mutilating surgery that has a deleterious effect on the social and emotional well-being of older patients. Only a few reports in the literature focus on radiotherapy in older patients with head and neck neoplasm.4°, Io2, 133, 174

Results of radiotherapy of 446 patients aged 70 years and older with carcinoma involving the larynx, oropharynx, and oral cavity were recently reported from the University of F10rence.I~~ All patients were treated exclusively with radiotherapy with a curative intent. The radiotherapy techniques used were very similar to those used for younger patients. Laryngeal cancers were mostly early stage, whereas most oral cavity and oropharyngeal lesions were locally advanced. Cervical node involvement was mostly NO or N1 by the Union Internationale Contre le Cancer (UICC) 1978 staging system. Locoregional extent of the cancer was comparable in patients younger than 70 years and those older than 70 years. No differences in 5-year actuarial local control or survival with no evidence of disease (NED) were noted between the two age groups for patients


Table 10.5-YEAR ACTUARIAL LOCAL CONTROL AND SURVIVAL WITH NO EVIDENCE OF DISEASE (NED) IN A SERIES OF PATIENTS CONSECUTIVELY TREATED AT UNIVERSITY OF FLORENCE

Local Control NED Survival

Cancer Patients Aged Patients Aged Patients Aged Patients Aged Site < 70 Years > 70 Years < 70 Years > 70 Years

Larynx 86% 87% 83% 86% Oral cavity 50% 28% 38% 27% 0 r o p h a ry IW 41% 45% 37% 38%

From Olmi F, Ausili-Cefaro G, Loreggian L: Radiation therapy in the elderly with head and neck cancer. Rays 22(suppl 1):77, 1997; with permission.

with laryngeal or oropharyngeal cancer (Table 10). For patients with cancer of the oral cavity, local control was better in the younger patients than in those aged 70 years and older (50% versus 28%, P = 0.04). There was no statistically significant difference in the NED survival between the two groups. Acute or late reactions from radiotherapy in older patients were not different from those observed in the younger patients.

Lusinchi et al,'OZ from Institut Gustave Roussy, Paris, have reported their results of treatment of 331 patients over age 70 years who had radiotherapy for upper aerodigestive tract carcinoma from 1978 to 1983. The site of primary cancer was the larynx in 28% of patients, the oropharynx in 27%, and the oral cavity in 16% of patients. Two hundred forty-nine patients received curative radiotherapy, and 54 had palliative therapy. Local control was achieved in 71% of patients treated for cure and in 19% of patients treated for palliation of symptoms. Immediate and long-term tolerance to radiotherapy was good. Grade 3 toxicity of the skin and mucous membranes occurred in 1% and 17% of patients, respectively.

The Italian Geriatric Radiation Oncology Group (GROG) prospectively studied 103 older patients with laryngeal cancer. Most had early-stage cancer. Mean age was 76.3 years. Most patients received a curative dose of radiotherapy (mean dose, 63.4 Gy). Analysis of acute toxicity showed good mucosal and cutaneous tolerance, with toxicity ranging from RTOG grade 0 to grade 2. The details of this study are given in the

Treatment of 103 Patients with Larynx Cancer in Geriatric Radiation Oncology Group Study 1994

Patient Characteristics

Primary disease (MO) Age: 70-88 years; mean, 76.3 years Gender ratio: 83 men to 8 women (1O: l ) Performance status: mean value 1.07 Stage: I and II

Data not available Recurrent or distant (Ml) disease

111 and IV

91 patients

56 patients 31 patients 4 patients 2 patients

Box continued on following page


Therapy for Patients with Recurrent or Distant Disease

Surgery alone 1 patient Radiotherapy (RT) alone 68 patients

Curative RT 65 patients Palliative RT 3 patients

Surgery plus curative RT 21 patients No therapy 1 patient Curative Radiation Therapy

Dose of curative RT: 36-72 Gy; mean dose, 63.4 Gy Conventional fractionation Toxicity by Radio Therapy Oncology Group

(RTOG) classification Skin Mucosa 0 and 1 87 patients 48 patients 2 10 patients 35 patients 3 and 4 1 patient 5 patients no data for 3 patients

Adapted from Olmi P, Ausili-Cefaro G, Loreggian L: Radiation therapy in the elderly with head and neck cancer. Rays (suppl 1):77, 1997; with permission.

Thompson et reported two series of patients aged 75 years and older with head and neck cancer. The first series included 68 patients with laryngeal cancer, of whom 45 were treated radically with radiotherapy. (Patients with stage I11 and stage IV disease were excluded.) The second series included 33 patients with hypopharyngeal cancer, of whom 10 were treated with radiotherapy and 7 received surgery. The actuarial survival rate was 57% in the patients with laryngeal carcinoma, including some patients with stage I11 cancer. The 3- year actuarial survival rate in the hypopharyngeal carcinoma series was only 22%.

Chin et a140 have reported their results on treatment of oropharyngeal cancer in elderly patients. Older patients were prescribed and received lower doses of radiation. The report showed that age was not related to the risk of local failure, and there was a trend towards locoregional failure with increasing age up to 70 years. The risk of failure for patients over the age of 70 years, however, was equal to that of the youngest group. Older patients had longer hospital stays than younger patients, but age was not related to the duration of treatment interruption or to the severity of toxicity.

Malignant Gliomas

During the past decade, the incidence of primary brain tumors has increased dramatically in patients aged 65 years and 47, 71 Consequently, oncologists are more frequently faced with complex medical decisions involving rapidly lethal neoplasms and highly morbid treatments that may overtax the limited functional reserve of the aged patient. This section focuses on the treatment of older patients with brain tumors using radiotherapy.

Following surgery, radiation remains the most effective treatment for malignant gliomas.81 The benefit of postoperative radiotherapy was established by the multicenter randomized trial of the Brain Tumor Cooperative Group (BTCG)l= and the Scandinavian Glioblastoma Study Group (SGSG).93 The BTCG trial dem-


onstrated a significant survival advantage for patients who received radiotherapy alone or with 1-3 bis (2-chloroethyl) 1-nitrosourea (BCNU) compared with those treated with resection and supportive care or with BCNU alone. In the SGSG trial, patients who received radiotherapy had a twofold improvement in median survival rate compared with those who received only conservative management.

The current treatment of anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) consists of surgical resection, whch is often incomplete, followed by radiotherapy and chemotherapy?8, 93, With more precise radio- graphic definition of tumor margin, most patients are now treated with partial brain irradiation, avoiding progressive diffuse necrotizing encephalopathy that previously had affected as many as 50% of long-term survivors, especially among those over 65 years of age.

Major prognostic factors in brain tumors include hstology, location of the tumor, performance status, and age.lZ4 Anaplastic astrocytoma appears to have a better outcome than GBM. Levin et a1 have demonstrated that combination chemotherapy with lomustine l-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU), procarbazine and vincristine (PCV) is superior to treatment with a single agent and almost doubles the survival of patients with AA (Table 11).

Performance status is an independent prognostic factor in virtually all malignancie~.~~ Performance of the activities of daily living (ADL) may constitute a more reliable prognostic index in older patients affected by disabling chronic condition^.'^

The prognostic implications of age are universally recognized (Table 12). Frankel and German studied the natural history of high-grade gliomas and found that survival decreased markedly for those aged 50 years and older.61 In several clinical trials, older patients appeared to benefit less from the combination of surgery, radiotherapy and chemotherapy?6, 50, The distinction between AA and GBM becomes irrelevant for patients aged 60 years and older, because the outcome of therapy for either type of neoplasm was poor in these

The poor outcome in older persons with brain tumors may be caused by several factors, some of which are tumor-related or tumor-host-related, whereas others are related to external conditions. Brain tumors may be more aggressive in older patients than in younger patients.I5 Changes in the inner milieu of the aging tumor host may favor a more rapid growth of the tumor.51 It is also

Table 11. INFLUENCE OF BRAIN TUMOR HISTOLOGY ON SURVIVAL

Median Survival in Weeks

Author Anaplastic Glioblastoma (Reference) Treatment astrocytoma multiforme

Levin et a1 (100) Surgery + radiotherapy + 82.1 57.4 BCNU 157.1 50.4

PVC

regimens

regimens

Surgery + radiotherapy + Shapiro et a1 (161) Comparable treatment 111 + 51

Chang et a1 (36) Comparable treatment 134 38

BCNU = 1-3 bis(2-chloroethyl) 1-nitrosurea; PVC = procarbazine and vincristine and CCNU. From Zachariah SB, Zachariah B, Wang T, et al: Primary brain tumors in the older patient: An

annotated review. J Am Geriatr SOC 401265, 1992; with permission.


Table 12. INFLUENCE OF AGE ON OUTCOME

Median Survival in Weeks

Anaplastic Glioblastoma Author (Reference) Age Groups astrocytoma multiforme

Frankel and German (61) < 30 3049 2 50

EORTC (50) < 50 2 50

Shapiro et a1 (161) 1 5 4 4 45-54 5564 65 + < 40 40-60 > 60

Chang et a1 (36)

54 52 24 59 31

116 + 78 58 39

184 74 131 41 23 27

EORTC = European Organization for Research and Treatment of Cancer. From Zachariah SB, Zachariah 8, Wang T, et al: Primary brain tumors in the older patient: An

annotated review. J Am Geriatr SOC 401265, 1992; with permission.

possible that older cancer patients present with more advanced disease and are usually treated less aggressively than younger patients. Tumor resection may be less extensive for patients aged 60 years and older, probably because their tumors are larger and more often inoperable.&

studied the effect of age on patients with malignant gliomas. Nineteen patients aged 70 years and older with malignant glioma were compared with 94 younger patients with similar tumor characteristics. All nineteen of the older patients received radiotherapy alone after biopsy. A total dose of 60 to 66 Gy was given to the tumor. One-year and 2-year survival rates for patients over age 70 years were statistically significantly inferior to those of patients younger than 70 years.

Because of the poor outcome of radiotherapy reported in older patients with glioma, several investigations have treated older patients with short courses of radiotherapy.20, lz7, 173 Bauman et alZo irradiated 29 patients with pathologically confirmed glioblastoma, aged 65 years or older or with a KPS status of 50 or less to a dose of 3000 cGy in 10 fractions to the whole brain. Postradiotherapy tumor volume (measured using CT scan), dexamethasone requirements, quality- of-life index, and KPS rating were measured 1 month after therapy and compared with historic controls who had received radical treatment or supportive care only. For 60% of the patients in the study, the tumor response indices were stable or improved. The median survival time was 6 months. The median survival times of a similar group of patients receiving radical treatment or supportive care only were 10 months and 1 month, respectively. A survival advantage for the radical versus short-course radiotherapy was observed only in the subset of patients whose KPS rating was greater than 50.

The recursive partitioning analysis of the combined results in three RTOG malignant glioma trials demonstrated that patient's age (<50 or 250) is the most significant variable affecting survival. Among the patients aged 50 years or older, KPS status was the next most significant factor influencing survival. Extent of resection or radiation dose affected outcome only in patients with KPS ratings of 70 or more.46

Peschell et


Newall et allz7 reported their results of treating 18 patients with glioblastoma who received a short course of radiotherapy (3000 cGy in 10 fractions) to the brain. Median survival time of this group was 44 weeks. The median survival time for patients with initial KPS status below 70 was 36 weeks. These results are as good as those reported in the RTOG or Eastern Cooperative Oncology Group (ECOG) studies. The smaller number of patients, the large number of total or subtotal resections (in 17 of 18 patients), and the higher performance status (10 of 18 patients had KPS ratings above 50) might have biased the results.

Older patients with malignant glioma who have a poor KPS rating can receive adequate palliation with short-course radiotherapy. Selected patients with good KPS status may benefit from aggressive surgery followed by a radical course of radiotherapy.

Several new forms of treatment, which may be safer in older patients, are being explored. Stereotactic radiosurgery allows tumor ablation without craniot~my.’~, 98, 99, 165 New techniques of administering radiotherapy might improve the effectiveness of therapy.39, 74, 126, 169 New lines of research are being pursued in the chemotherapy of brain tumors, including the development of

176 A1 so, biological therapy with interleukin and interferon may be effective in primary new

brain tumors.104. 105, 111. 121

34, 49, 143, 196 and of more effective treatment deli~ery.3~. 73, 86,

Non-Hodgkin’s Lymphoma

The incidence of non-Hodgkin’s lymphoma increases with age. Very few studies, however, have been published that address the management of non- Hodgkin’s lymphoma in older patients?, 36, 86, lz3, 136, 175 A report of an EORTC study on non-Hodgkin’s lymphoma by Tirelli et showed that approximately 30% of the total number of patients with non-Hodgkin’s lymphoma are older than 70 years of age. Seventy-three percent of patients had unfavorable (intermediate-grade and high-grade) histology, according to the working formulation, and 60% had localized disease (stage I and stage 11).

In general, patients with intermediate-grade and high-grade lymphoma are treated with combination chemotherapy at reduced Aggressive full- dose combination chemotherapy has produced significantly high treatment- related mortality?, 175 Older patients generally tolerate a reduced dose of combination chemotherapy (50%-70% of full dose) in combination with loco-regional radiotherapy.

Tirelli et a1 reported their experience in treating 137 patients aged 70 years or older with non-Hodgkin’s lymphoma.175 Sixty patients received conservative treatment (one or two antineoplastic drugs or local-field radiotherapy), and 77 patients received aggressive therapy (polychemotherapy regimens or extended- field radiotherapy). Response rates were similar between the two treatment groups, but severe lethal toxicity was significantly higher in the aggressively treated group. A similar observation was made by Carbone et a1 in their analysis of 50 patients with non-Hodgkin‘s lymphoma who were treated aggressively or conservatively based on their general physical condition. No significant difference in response or survival was noted between the two groups. More deaths from toxicity were reported in the aggressively treated gr0up.3~

also supports the use of less aggressive therapy with reduced-dose chemotherapy and locoregional irradiation in older patients with localized non-Hodgkin’s lymphoma. In their study, 38 patients older than 65 years with intermediate-grade or high-grade (based on

A recent report from Japan by Oguchi et


working formulation) non-Hodgkin's lymphoma received involved field radiation (40 Gy) and adjacent lymph node irradiation (30 Gy) and reduced-dose chemotherapy (2 cycles of 50%-70% doxorubicin, cyclophosphamide, vincristine, and prednisone [ACOP]; 70% doxorubicin, cyclophosphamide, vincristine, methotrexate, bleomycin, prednisone [MACOP-B] for 4 weeks). All patients completed the planned course of therapy. No treatment-related deaths were observed. The 5-year local control rate was 98%. The 5-year disease-free survival rate and the 5-year cause-specific survival rates were 70% and 82%' respectively. The serious complication rate was only 3%. It appears that by adjusting the chemotherapy dose schedules and making proper selection of patients, less aggressive therapy could produce better treatment outcome in these older patients with non-Hodgkin's lymphoma. More studies are needed to establish the optimal treatment (aggressive or nonaggressive) in older patients with non- Hodgkin's lymphoma.

Hodgkin's Lymphoma

Older patients diagnosed with Hodgkin's disease have a less favorable outcome than younger patients. Several studies have indicated that age is an independent unfavorable prognostic indicator in Hodgkin's disease.9o, 181, Be- cause older patients may have multiple comorbid illnesses, they are often ineligi- ble for radical therapy. Ths limitation on radical therapy may be one reason for the poor outcome. Older patients with good general health who are fit enough to be managed similarly to younger patients can fare just as well.

Zietman et a1 have examined 29 patients older than 60 years of age with stage I and stage I1 Hodgkin's disease managed by radiation therapy Fourteen of the patients who were optimally managed with adequate staging followed by radical radiation therapy (mantle or inverted Y field) showed no relapse over a median of 4 years of follow-up, but 10 of 15 patients in the group suboptimally treated with limited staging or involved-field radiotherapy experienced relapse.

The actuarial 5-year disease-free survival rate for the optimally managed group was 61%, versus 6% for the suboptimally managed group. The disease- free survival rates were 100% and 39%, respectively. Only 3 patients had acute complications severe enough to warrant an interruption in treatment. This study indicates that, in selected older patients, aggressive treatment can improve the treatment outcome.

BRACHYTHERAPY IN THE OLDER CANCER PATIENT

Brachytherapy (interstitial or intracavitary radioactive seed implantation) is commonly used to treat cancer involving the head and neck, breast, and genitourinary tract. Although several reported brachytherapy series include patients aged over 65 years, age-specific information regarding the tolerance and outcome of the therapy is minimal. A brief review of the available data is presented here.

For elderly patients with prostate cancer with high risk for surgery, interstitial implantation with external beam radiation therapy offers adequate local control with low morbidity and m~rtality.'"~ Prostate cancer is the most common cancer in older men, and several brachytherapy series have included patients aged over 65 years.27, 48, 69, 89, 167, 186 Ragde et a1 have reported the results of brachytherapy in treating 152 patients with clinically proved organ-confined


carcinoma of the The median age of patients in this study was 70 years. The overall 10-year survival rate of the group was 65%. Only 2% of patients died of prostate carcinoma. Sixty-five percent of patients remained clinically and biochemically free of disease at 10 years.

Wallner et alls6 have reported the results of treating 92 patients with T1 or T2 prostate cancer using iodine 125 (1-125) interstitial implants. Of 56 patients who were potent before therapy, 43 (83%) aged over 60 years maintained their potency. Fourteen percent of the patients had persistent urinary symptoms of RTOC grade 2 or higher. Five patients developed radiation-induced rectal ulcer- ation. The overall actuarial freedom from biochemical failure at 4 years following implantation was 63%, comparable with that of prostatectomy.

Older patients with head and neck cancer have been successfully treated with interstitial radioactive seed implantation. In a retrospective review of re- cords of patients who received brachytherapy boost after external beam radiotherapy for glioblastoma multiforme, Sneed et aP3 showed that age is the most important factor influencing survival. Among young patients (aged 18-30 years) the 3-year probability of survival was 78% +. 14%.

High-dose-rate (HDR) intraluminal radiotherapy is used as a boost after external beam radiotherapy for esophageal cancer. High-dose-rate intraluminal brachytherapy may also be used alone for very small esophageal lesions and for palliation of locally advanced cancer. Superficial spreading cancer of the esophagus has been successfully treated in older patients with external beam radiotherapy and HDR intracavitary irradiation.80 Endocavitary irradiation is also used to treat rectal cancer. Kovalic et a192 have reported their experience in treating rectal adenocarcinoma and villous adenoma, showing satisfactory outcome and tolerance. Endocavitary iridium 192 (Ir-192) implantation and laser treatment can be used for palliative treatment of older patients with inoperable rectal cancer.Il4

Brachytherapy can be used safely to treat anal cancer in older patients. Sandu et alls5 recently reported their experience in the use of interstitial Ir-192 implantation with external beam radiotherapy to treat anal cancer in 79 patients with a median age of 70 years. A few patients also received concurrent chemotherapy. Complete response and local control were achieved in 91% and 78% of patients, respectively. Major complications requiring surgical intervention were reported in only 7.5% of patients.

Brachytherapy is feasible in older breast cancer patients after lumpectomy. Perara et have reported their experience using HDR brachytherapy to the tumor bed in 39 patients with a mean age of 59 years (range, 39-84 years). For 60% of the patients, treatment was given twice daily as an outpatient procedure under local anesthesia. Except for fat necrosis, complications were minimal, and the patient satisfaction rate was high.

In selected cases, interstitial irradiation provides good local control of perineal and gynecologic malignancies, with low morbidity in frail elderly patients.log High-dose-rate afterloading therapy was tried in older patients with carcinoma of the cervix. In a report by Roman et al,lso 87 patients with cervical carcinoma, stage IIA to IIIB, received HDR therapy following pelvic radiotherapy. The median age of the patients was 60 years. The overall survival rate at 5 years was 88% for stage IIA patients, 64% for stage IIB patients, and 32% for stage IIIB patients. Late grade 3 and grade 4 complications of bowel occurred in 12 patients. Results of HDR intracavitary therapy were comparable with those of conventional low-dose intracavitary therapy. Among patients who received combined external beam radiotherapy and HDR intracavitary irradiation for carcinoma of the cervix, age greater than 60 years was a significant favorable prognostic f a~ t0 r . I~~ Perioperative morbidity is more common after intracavitary


therapy in older patients resulting in early removal of the implant in about 5% of High-dose-rate brachytherapy has been used for stage I and stage I1 vaginal cancer in older women. Nanavati et allz reported 100 patients with a complete response and a local control rate of 92%. No acute or chronic grade 3 or grade 4 bowel or bladder toxicity was reported.

High-dose-rate brachytherapy has been used as the primary therapy for endometrial carcinoma for patients who are unfit for surgery and has provided acceptable rates of local control and survival. Available data indicate that older patients tolerate brachytherapy as well as younger patients. In selected patients, the procedure is safe and provides acceptable outcome. More age-specific studies are needed in this area.

UNCONVENTIONAL FRACTIONATION RADIOTHERAPY IN OLDER PATIENTS

The conventional radiotherapy fractionation schedule is one fraction of 180 to 200 cGy/day, 5 days a week, extending to 6 to 8 weeks for curative treatment. To reduce the number of visits to radiotherapy centers and the side effects of treatment, hypofractionated radiotherapy (fewer than 5 fractions/week) has been tried in older and frail patients.

Hypofractionated radiotherapy to the bladder using 6 Gy once a week to a total of 30 to 36 Gy produced palliation of symptoms in 78% of patients; acute grade 3 bowel and bladder toxicities were experienced by 18% and 9% of patients, respectively.110 Once-a-week radiotherapy of 6.5 Gy for 6 weeks was also administered to older women with breast cancer in combination with tamoxifen (20 mg/day).lo6 High rates of locoregional control (86%) and disease- specific survival (88'Yo) were achieved using this regimen in very old patients, without the inconveniences of a protracted course of radiotherapy. Ths regimen is well-tolerated by older patient^.'^^ Very old patients with inoperable rectal cancer can be adequately palliated using hypofractionated radiotherapy. Rodri- guez reported a complete response with once-a-week treatment to a total dose of 30 Gy in 3 weeks. No treatment related toxicity was rep0~ted.I~~

Split-course radiotherapy delivering 31.5 to 57.7 Gy in 10 to 12 fractions in a mean overall time of 48 days was tried for bladder carcinoma in elderly patients with poor general health.184 Complete remission was achieved in 31% of patients. Only 8% patients experienced grade 2 or grade 3 late complications. This regimen is an attractive option for elderly patients who are unsuitable for a prolonged course of radiotherapy. Hypofractionated radiotherapy has been administered for palliative treatment of high-grade gliomas in older patient^.'^^ The treatment was well-tolerated without any acute toxicity. For elderly patients who have epidermoid carcinoma of the face,' hypofractionated radiotherapy is also reported to be highly effective and to have a low local failure rate (4%). Satisfactory cosmetic results were obtained in 90% of the patients.

Accelerated fractionation (fraction size of daily dose > 200 cGy) schedules are used in the palliative treatment of malignant gliomas in older patients to shorten the overall treatment duration. Accelerated fractionation radiotherapy with carboplatin followed by vincristine chemotherapy for GBM showed the worst survival rate in patients aged 60 years or older.'00 Accelerated fractionation is recommended for older patients with GBM, especially those with poor KPS status. Hernandez et a1 reported their experience with accelerated radiotherapy in treating GBM patients who received 54 to 55 Gy in 3 weeks.78 The treatment


was well-tolerated by patients older than 62 years; the median survival time was 30 weeks.

Patients over the age of 70 years are usually excluded from accelerated fractionation schedules for the treatment of upper aerodigestive tract cancers, so the tolerance of these patients to therapy is not well established.l0, In3 Yu et alls7 treated patients with inoperable non-small cell lung cancer with an accelerated fractionation schedule. Patients received 40 Gy to the primary site and mediasti- num and a concurrent boost of 10 Gy to the gross tumor volume during the last 5 days. The rates of local tumor control and overall survival were similar to those resulting from conventional fractionation, without increasing the normal- tissue toxicity. No grade 3 or grade 4 complications were reported. Accelerated fractionation radiotherapy is also well-tolerated by older patients with bladder cancer. When the total duration of therapy was reduced from 6.5 weeks to 5 weeks, no acute bowel or bladder toxicity was rep~rted."~

Hyperfractionated radiotherapy (more than one fraction per day) is also feasible in older individuals. In a randomized comparison of hyperfractionated radiotherapy with conventionally fractionated radiotherapy for bladder cancer, Nuslund et allz9 showed a 10-year survival benefit for the subgroup of patients with T3 disease treated with hyperfractionated radiotherapy. Bowel complications were more common in the group receiving hyperfractionated regimens, although the difference was not statistically significant.

Preoperative hyperfractionated radiotherapy with concurrent 5-FU was used by Movsas et a1*2n for the treatment of rectal cancer in patients aged 61 and older. Significant down-staging was noted in 60% of patients. The authors observed that age greater than 61 years was a significant predictor for improved disease-free survival, even though a trend towards increased postoperative complications was reported in the older patients.

Jeremie et a P specifically studied the effect of combined chemotherapy and accelerated hyperfractionated radiotherapy in older patients with limited-stage small cell lung cancer. Seventy-five patients aged 70 years or older with a KPS status of 60 or higher and no major medical problems were given intravenous carboplatin (on da'ys 1 and 29), oral etoposide (on days 1-21 and 2949) , and accelerated hyperfractionated radiotherapy (1.5 Gy twice daily to a total of 45 Gy). Fifty-seven percent of patients achieved complete response, with a median survival of 15 months. The 2-year and 5-year survival rates were 32% and 13%, respectively. Acute grade 3 leukopenia, thrombocytopenia, and esophagitis were observed in 8.370, 11%, and 2.8% of patients, respectively. Only one patient developed grade 4 acute toxicity (thrombocytopenia). No late grade 3 or higher toxicity was noted. The study clearly indicates that, in patients with good performance status, aggressive therapy with combined chemoradiation is feasible and safe. Older patients should not be treated less aggressively on the basis of age alone.

RADIOTHERAPY IN THE OLDEST OLD CANCER PATIENTS

The United States, like other countries in the world, is experiencing changes in the age composition within the older segment of the population. An increasing proportion of persons in the 65-and-over age group is aged 80 years and older. The subset of persons aged 80 years and older is the most rapidly expanding segment of the United States population.1g4* 195 Among the frail elderly patients with cancer, radiotherapy is the most widely used treatment modality. Some- times patients are denied aggressive (curative) therapy because of concerns


regarding treatment-related toxicity. Patients aged 80 years and over are usually excluded from prospective clinical trials despite having good general health and performance status.

In recent years, several investigators have reported the tolerance to and outcome of radiotherapy in patients over the age of 80 years with cancer involving different In the United States the largest series of patients aged 80 years and older with cancer who received radiotherapy was reported by Zachariah et from the H. Lee Moffitt Cancer Center of Tampa, Florida. The authors have examined 203 patients aged 80 years and older who received radiotherapy for cancer involving the head and neck, breast, chest, pelvis, and other sites. Ninety-four percent of patients completed the planned course of therapy. Six percent of patients had interrupted treatment. The causes of interruption included weight loss from diarrhea, dysphagia, and progressive disease (Table 13). Treatment interruptions were more likely in patients treated with large treatment fields. Side effects were comparable with those observed in younger patients. In patients treated for upper aerodigestive tract cancer, grade 3 and grade 4 mucositis was noted in 20% and 2% of patients, respectively. Grade 1 and grade 2 enteritis was noted in 43% of patients treated for pelvic malignancies. Grade 3 dermatitis was noted in only 2% of patients (Table 14). The study also showed that in 6 of 12 patients, the cause of treatment interruption was weight loss. Nutritional support before and during therapy and mainte- nance of body weight seem to improve compliance with the therapy by reducing the treatment

In another large series, from Italy, 2060 patients aged over 70 years received radiation therapy for cancer involving various Four hundred thirty-seven patients were aged 80 years and older. The side effects of radiotherapy were very similar to those observed by Zachariah et al. Most patients had no or only grade 1 toxicity. The rates of grade 3 and grade 4 toxicities of skin, mucous membranes, and gastrointestinal tract were 2%, 3'70, and 2% respectively. The authors concluded that older patients tolerate radiotherapy well and should receive the same treatment as younger patients.

Swanson et aP8 reported the results of treatment of 190 women aged 80 years and older from the Massachusetts General Hospital, Boston. One hundred three patients had mastectomy, and 29 patients had radiotherapy. No patient who received radiotherapy, either as primary therapy or as an adjuvant to

13fl, 168, 193, 199,

Table 13. CAUSES OF RADIOTHERAPY TREATMENT INTERRUPTION

Weight Loss Progressive Other Site (2 5%) Disease Causes Total

2 2

0 0

Head and Neck 1 *(C) 0 1 (PI 1 (PI Lung 0 1 (C)

Pelvis 1 (C), 2 (PI 1 (P) 0 4

Breast 0 0 3

Other

*> 10% wt loss. (C) = curative treatment; (P) = palliative treatment. From Zachariah B, Balducci L, Venkattaramanabalaji GV, et al: Radiotherapy for cancer patients

aged 80 and older: A study of effectiveness and side effects. Int J Radiat Oncol Biol Phys 391125,1997; with permission.

Tabl

e 14

. SID

E E

FFE

CTS

OF

CU

RA

TIV

E A

ND

PA

LLIA

TIV

E R

AD

IOTH

ER

AP

Y B

Y R

TOG

GR

AD

E

~

Gra

de 0

G

rade

1

Gra

de 2

G

rade

3

Gra

de 4

S

ide

Eff

ect.

Site

C

P

T

C

P

T

C

P

T C

P

T

C

P

T M

ucos

itis,

hea

d an

d n

eck

7 12

19

6

1

7 12

1

13

10

0 10

1

0 1

Eso

phag

itus

, lu

ng

9 13

22

10

1

11

4 0

4 0

0 0

0 0

0 E

nter

itis,

pel

vis

16

14

30

13

2 15

7

1 8

0 0

0 0

0 0

RTO

G =

Rad

ioth

erap

y O

ncol

ogy

Gro

up; C

= C

urat

ive

ther

apy;

P =

Pal

liativ

e th

erap

y; T

= T

otal

. Fr

om Z

acha

riah

B, B

aldu

cci L

, Ven

katta

ram

anab

alaj

i G

V, e

t al

: Rad

ioth

erap

y fo

r ca

ncer

pat

ient

s ag

ed 8

0 an

d ol

der:

A s

tudy

of

effe

ctiv

enes

s an

d si

de e

ffec

ts. I

nt J

Rad

iat

Onc

ol B

iol

Phys

39:

1125

, 199

7; w

ith p

erm

issi

on.


surgery, failed to complete the full course of prescribed treatment. Seven patients had treatment interruption, all of which were caused by transient skin reactions that did not require specific therapy. Complications from therapy were generally transient and well-tolerated.

Recently, Oguchi et a1 reported their experiences in treating patients aged over 90 years with cancer involving various sites.130 All 13 patients who received curative radiotherapy completed the planned course of therapy; the local control rate was 62%. Sixty-four percent of patients treated with palliative intent completed the course of therapy; 81% of them adueved palliation. Acute dermatitis, mucositis, pharyngitis, esophagitis, and RTOG grade 2 and 3 cystitis related to radical radiotherapy were tolerable for the patients who had good performance status. No acute grade 4 skin or mucosal reactions were documented. The intensity of acute reactions in patients with a performance status of 0 or 1 on the World Health Organization (WHO) scale was similar to that observed in younger patients. The duration of recovery from acute reactions was longer (4-7 weeks) than that of younger patients. Oguchi et a1 recommend radiotherapy when applicable, even for patients aged over 90 years. They believe patients older than 90 years with good performance status may tolerate acute reactions of radiotherapy administered according to conventional fraction schedules.

Two recent reports from Japan also favor a radical course of radiotherapy for patients aged over 80 years who have esophageal carcinoma.8°, 193 Yamakawa et a1 reported the results of treating 40 patients over the age of 80 years with esophageal cancer.193 Eighty-three percent of these patients received a total dose of more than 60 Gy to the tumor. In 22 patients, old age alone was the reason for selecting radiotherapy as the primary treatment. The 5-year disease-specific survival rate for patients who received curative radiotherapy was 34%. The 5- year disease-free survival rate for patients with a complete response was 64%. Mild esophagitis was noted in most of the patients. No severe complications, such as radiation ulcer, stricture, or fistula, were observed. Hishikawa et also examined 29 patients aged 80 years and older with esophageal cancer who received radiotherapy (external beam and HDR intracavitary irradiation) and compared the results with two other groups with ages ranging 43 to 69 years and 70 to 79 years, respectively. High-dose-rate intracavitary irradiation, with or without external beam irradiation, was performed in 83% of patients aged 80 and older. Complete response was experienced by 34% of patients older than 80 years of age, compared with 24% in the younger age groups. The 5-year survival rate was similar to those of younger patients. No differences in patterns of failure and in radiation injuries were noted in patients aged over 80 years compared with those patients aged less than 80 years.

SUMMARY

Radiotherapy has a major role in the multidisciplinary approach to cancer therapy. It is widely used for curative and palliative treatment of cancer involving various sites. Radiotherapy is of particular benefit to older and frail cancer patients as an alternative to surgery and to systemic therapy. The available data on the sensitivity of normal tissues to radiotherapy in elderly patients strongly suggest that older patients with good functional status tolerate radiotherapy as well as younger patients and have comparable tumor response and survival rates. Aggressive radiotherapy should not be withheld from older patients because of chronological age alone.


ACKNOWLEDGMENTS

Charlotte A. Truitt, MA, and Nancy Bernal, MA, for librarial assistance, and Wanda D. Lane for preparation of manuscript.

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radiation therapy of the older patient

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