Treatment of breast cancer in elderly patients.
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Age Factors↗
Biomedical subjects
R S Gelman
Publications and source records attributed to R S Gelman.
Myelodysplastic syndrome and acute nonlymphocytic leukemia secondary to mitolactol treatment in patients with breast cancer.
One thousand four hundred sixty patients with 2,590 patient-years of follow-up were treated on 15 protocols for metastatic breast cancer with dibromodulcitol (mitolactol; DBD)-containing regimens since 1976. Twenty-three patients developed myelodysplastic syndrome (MDS) and/or acute nonlymphocytic leukemia (ANLL). The overall risk of developing MDS or ANLL per person is 1.6%. In patients who had received more than 16,000 mg of DBD the risk per person is 6%, and in the high-dose subsets of patients who received no prior radiation or alkylator therapy, it is 7.9%. The risk per person increases to a maximum by 30 to 36 months (5.3%). The high risk was seen despite a study population of metastatic breast cancer patients with a median survival of 16 months. This analysis strongly suggests that DBD is one of the most potent of the reported leukemogenic-inducing agents. Further use of this drug in both the adjuvant and metastatic situation should be reconsidered.
Adult↗
Mammography in symptomatic and asymptomatic patients.
It is now generally accepted that screening mammography at 1- to 3-year intervals can decrease mortality from breast cancer. Three randomized trials, involving a total of 238,000 women, have reported mortality results. In two trials (HIP and S2C), there was a significant reduction in breast cancer mortality (22 per cent at 18 years and 27 per cent at 8 years). One trial (Mälmo) showed a nonsignificant reduction in mortality at year 9 (5 per cent) and nonsignificant increases in mortality at earlier years. There are little data from randomized trials to support a benefit of mammographic screening in women under 50 years old. The two Swedish studies at last follow-up had 26 and 29 per cent more breast cancer deaths in young women in the group randomized to screening. The HIP study had 25 per cent fewer breast cancer deaths at 18 years in women under age 50 at the start of the trial, but because only 12 patients under age 50 had mammographically detectable tumors (out of 89 cancers diagnosed in the screened group), most of the benefit must be due to physical examinations or increased awareness of breast cancer symptoms. The as yet unpublished results of the Canadian trial in women under age 50 should elucidate the benefit of mammography in this age group. American centers report a malignant biopsy rate of 20 to 30 per cent for clinically occult lesions. This rate should increase as the proportion of women who have had prior mammography increases. High-quality mammography, including magnification technique for evaluation of suspicious lesions, proper localization and excisional biopsy techniques with pathologic correlation, and potentially, fine-needle aspiration, may improve the yield of screening mammography-induced open-biopsy procedures. Magnification technique can improve mammographic assessment of the extent of the tumor and guide re-excision for patients being considered for breast-conserving therapy. In the irradiated breast, in our experience, mammography alone detected 35 per cent of recurrent cancers in the irradiated breast. We recommend routine mammographic follow-up of the irradiated breast, including magnification of the local excision site, at 6 months, 1 year, and annually thereafter.
Adult↗
A quality-of-life-oriented endpoint for comparing therapies.
An endpoint, time without symptoms of disease and toxicity of treatment (TWiST), is defined to provide a single measure of length and quality of survival. Time with subjective side effects of treatment and time with unpleasant symptoms of disease are subtracted from overall survival time to calculate TWiST for each patient. The purpose of this paper is to describe the construction of this endpoint, and to elaborate on its interpretation for patient care decision-making. Estimating the distribution of TWiST using actuarial methods is shown by simulation studies to be biased as a result of induced dependency between TWiST and its censoring distribution. Considering the distribution of TWiST accumulated within a specified time from start of therapy, L, allows one to reduce this bias by substituting estimated TWiST for censored values and provides a method to evaluate the "payback" period for early toxic effects. Quantile distance plots provide graphical representations for treatment comparisons. The analysis of Ludwig Trial III evaluating toxic adjuvant therapies versus a no-treatment control group for postmenopausal women with node-positive breast cancer illustrates the methodology.
Antineoplastic Agents↗
Time-course of local recurrence following conservative surgery and radiotherapy for early stage breast cancer.
The time-course of local failure following conservative surgery and radiotherapy (S+RT) for early breast cancer is not well established. We therefore examined the time-course and patterns of breast recurrence as a first site of treatment failure in a group of 607 AJCC clinical Stage I or II invasive breast carcinomas treated from 1968-81. Sixty-seven patients had a breast failure (11%), corresponding to 5- and 10-year actuarial rates of 10% and 16%. The hazard rate (i.e., the risk per unit time of a failure) for any breast failure increased over the first 2 years, was fairly constant at about 2.5%/year over the period from 2 to 6 years after treatment, and then decreased to about 1%/year at 8 years. The majority of failures were at or near the primary tumor site (33 true recurrences (TR) and 15 marginal misses (MM). In addition there were 12 failures at sites at least several cm from the boosted volume (E), 6 recurrences in the skin without a parenchymal mass (S), and 1 patient with an unclassifiable failure. Recurrences at or near the primary site (TR/MM) occurred earlier (median 38.5 mo, range 12-87 mo) than recurrences at distant sites in the breast (E) (median 64.5 mo, range 26-90). The hazard rate for TR/MM increased over the first 2-1/2 years to reach approximately 2%/year, remained at that level till about 5 years after treatment, and then decreased to about 0.5%/year at 8 years following RT. By contrast, the hazard rate for E increased slowly with time to approximately 1%/year at 5 years, with little change in the rate after that time. We conclude that the time-course of the development of local recurrence after S+RT is protracted. The majority of failures appear at or near the primary tumor site; these are seen mainly in the first 7 years following RT. Recurrences at distant sites in the breast have an even more protracted time-course. Such recurrences are rare in the first 4 years following RT. Our results emphasize the need to obtain long follow-up in these patients, both to detect these recurrences promptly and to properly evaluate the results of S+RT.
Adult↗
Is mammography painful? A multicenter patient survey.
Anecdotal reports of pain experienced during mammography have been a source of anxiety and concern for some women considering screening. To determine what asymptomatic women actually experience during mammography, a survey of 1847 women was performed at seven breast-imaging centers. Women recorded their experience on a six-point scale ranging from no discomfort to severe pain. Eighty-eight percent of the women experienced no discomfort (49%) or mild discomfort (39%). Only 9% experienced moderate discomfort; 1%, severe discomfort; and 1%, moderate pain. No woman had pain so severe that it would make her reconsider having a mammogram again. The degree of discomfort was slightly greater in women who complained of breast tenderness within three days prior to the mammogram but was not strongly related to age, menstrual status, or week of the menstrual cycle. We conclude that in a vast majority of women mammography causes no or mild physical discomfort and that actual pain is an uncommon occurrence.
Adult↗
Cardiac disease after mediastinal irradiation for seminoma.
One hundred twenty-four patients with seminoma (119 primary testis, five primary extragonadal) were treated between 1968 and 1984 at the Joint Center for Radiation Therapy. Fifty-seven of the 124 patients were treated with irradiation to the mediastinum as well as to an infradiaphragmatic field. One patient received supradiaphragmatic radiotherapy only. The remaining patients had radiation treatment limited to the infradiaphragmatic field only. Median dose to the mediastinum among the 58 patients was 2400 cGy. Four patients developed heart disease (one fatal myocardial infarction, one uncomplicated myocardial infarction, one constrictive pericarditis resulting in permanent total body anasarca, and one patient requiring aortic valve replacement and coronary artery bypass grafting for atherosclerotic disease) and two died suddenly. The two sudden deaths were thought to be cardiac in origin by the patient's primary physicians. All six complications occurred in the group that received mediastinal irradiation. No cardiac disease was manifested in the group not treated with mediastinal irradiation. This difference in the incidence of cardiac disease between the two groups is statistically significant (two sided, P = 0.019). Neither group had a statistically significant difference in cardiac disease rate from a normal population (Framingham study), although the ratio of observed to expected cardiac disease was 1.97 in the group receiving mediastinal radiation. Further experience from this and other institutions is necessary to confirm this finding.
Adult↗
Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group Study.
One hundred thirty-one premenopausal women with metastatic breast cancer who had received no prior systemic treatment for metastases were entered on study. Patients without prior chemotherapy with estrogen receptor (ER)-positive and ER-unknown disease were randomized to receive cyclophosphamide, Adriamycin (Adria Laboratories, Columbus, OH), and 5-fluorouracil (CAF) or surgical oophorectomy followed directly by CAF (O + CAF). ER-negative patients without prior chemotherapy were directly assigned to treatment with CAF. Among randomized patients 83% have responded, and 37% have achieved a complete remission. Among ER-negative patients the complete response rate was 38%, and the complete plus partial response rate was 70%. Characteristics significantly associated with a longer time to treatment failure were age 45 or over, one or two organ sites, and performance status O. The median survival time of ER-positive patients treated with CAF is 29 months, and with O + CAF it has not yet been reached, whereas for ER-unknown patients the equivalent survival times are 41 months and 43 months respectively. For ER-negative patients treated with CAF the median survival time is 17 months. Characteristics associated with significantly longer survival among randomized patients were age 35 or over (P = .009) and only one or two organ sites involved (P = .02). Neither treatment (P = .33) nor ER status (P = .70) was significant.
Adenocarcinoma↗
Actual versus ideal weight in the calculation of surface area: effects on dose of 11 chemotherapy agents.
This study of 2382 breast, 182 rectal, 817 colon, and 351 lung cancer patients treated with combination chemotherapy on eight phase III Eastern Cooperative Oncology Group protocols indicates that 69% would receive a higher dose of at least one drug if surface area were calculated from actual weight rather than from the minimum of actual and ideal weight. Forty-eight percent of the patients would have at least a 10% increase in drug dose based on actual weight. Only on the premenopausal adjuvant breast cancer protocol and among women on the rectal adjuvant study do the differences in dose based on actual rather than ideal weight increase significantly with age. On the postmenopausal adjuvant breast study and on the lung cancer study, the differences in dose decrease significantly with age. For all age decades and both sexes within each protocol, the mean differences between dose based on actual and dose based on ideal weights were on the same order as the rounding factors for the 11 drugs studied. From the literature on the effect of doses of common chemotherapies on leukopenia, it appears that the percent of hematologic toxicity would not be raised to unacceptable levels by using actual weight to set doses.
Adult↗
Age as a prognostic factor in recurrent breast cancer.
The effect of age as a prognostic factor in recurrent breast cancer was studied in 1,168 patients treated on Eastern Cooperative Oncology Group (ECOG) protocols. Survival was significantly shorter in patients less than 35 years of age (P = .03). This was true even when other good prognostic factors were present. Eighteen prognostic factors were analyzed, and the effect on survival in each of six age groups was studied. Patients with better performance status, less than three sites of metastases, and without visceral or nodal metastases had a better survival time. A Cox proportional hazards model of survival showed that younger age groups, irrespective of menopausal status, had shorter survival times. The predicted median survival times after the first recurrence were 491 days for patients less than 35 years of age, 590 days for patients 36 to 45 years of age, and 700 days for those greater than 45 years of age.
Adult↗
Combination chemotherapy compared to tamoxifen as initial therapy for stage IV breast cancer in elderly women.
In a randomized crossover study, 181 patients over the age of 65 with recurrent breast cancer received either tamoxifen or cyclophosphamide, methotrexate, and fluorouracil (CMF). After progression on tamoxifen, a hormone withdrawal period was required. Because of altered pharmacokinetics with aging, creatinine clearance was used in calculating the dose of CMF. Response rates were 45% on tamoxifen and 38% on CMF, with median durations of 10.4 and 7.9 months, respectively. Survival rates tended to favor tamoxifen as the initial treatment even in estrogen-receptor-negative patients. Additional disease control with hormone withdrawal occurred in 23% of patients, and this benefit was highly correlated with prior hormone response. We conclude that initiation of hormone therapy rather than CMF chemotherapy is justified in almost all situations in elderly patients, and combination chemotherapy, is safe and useful after hormone failure if modified on the basis of renal dysfunction.
Aged↗
Duration of therapy in adjuvant chemotherapy trials.
Almost all the adjuvant chemotherapy regimens that have been established as effective in prolonging the survival of patients with early breast cancer have been administered for 1 to 2 years. If equally effective, shorter courses of therapy would result in less overall toxicity and allow early introduction of non-cross-resistant regimens. The efficacy of 2 regimens differing only in duration was compared in 5 randomized trials that have been conducted. None have shown an overall survival advantage for a longer course of therapy, and only 1 has shown an advantage in time to recurrence for a longer course. There has been a nonsignificant trend in some of the trials in favor of the shorter arms of therapy. It must be concluded at the present time that regimens that utilize 4 to 6 months of therapy are likely to be as effective and are probably preferable to 12 or more months of therapy.
Antineoplastic Combined Chemotherapy Protocols↗
The Eastern Cooperative Oncology Group experience with cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer.
Data on 162 women (90 premenopausal and 72 postmenopausal) with metastatic breast cancer randomized to receive cyclophosphamide, Adriamycin (doxorubicin) and 5-fluorouracil (CAF) on two Eastern Cooperative Oncology Group (ECOG) protocols were analyzed. Twenty-three percent had complete remission; 39% had partial remission; 28% had no change; and 3% had disease progression. Of those patients in whom receptors were known, response rates were 65% for estrogen (ER)-receptor positive and 70% for ER-negative patients. The median duration of response was 11.4 months. The median survival time from the start of CAF was 20.2 months. The response rate, time to treatment failure (TTF), and median survival time were superior in the premenopausal women. These differences ceased, however, to be statistically significant in logistic models. Factors significantly associated with longer TTF and longer survival were as follows: one or two organs with metastases (TTF, P less than 0.0001; survival, P less than 0.0001); dominant site other than soft tissue (TTF, P less than 0.0001; survival, P = 0.05); and an initial good performance status (TTF, P = 0.007; survival, P = 0.02). Patients with ER-positive disease had a significantly longer median survival time (P = 0.003).
Antineoplastic Combined Chemotherapy Protocols↗
Analysis and interpretation of the comparison of survival by treatment outcome variables in cancer clinical trials.
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Adult↗
Clinical comparison of two radiocolloids for internal mammary lymphoscintigraphy.
Recent studies suggest that 99mTc-labeled radiocolloid (SC) compounded with hydrogen sulfide can be used to visualize lymph channels and nodes. Our study prospectively compared SC with 99mTc antimony sulfide (SbS) colloid, in 28 patients undergoing internal mammary lymphoscintigraphy. Images were recorded on a scintillation camera and computer at 0.5, 1.0, and 3.0 hr. Quantitative analysis included assessment of percent (%) injected dose in nodes, the percent remaining at the injection site, and the relative intensity of the most cephalad node compared to a 57Co standard. The mean (means) % injected dose of both radiocolloids within visualized nodes was less than 1% at each time interval, with no significant differences between means's. The means % injected dose remaining at the injection site at 3.0 hr was 83 for SbS and 76 for SC not statistically significant (N.S.). The means of the ratio of counts within the most cephalad node at 3.0 hr to counts within a 57Co standard was 0.98 for SbS and 1.03 for SC (N.S.). Clinical assessment of number of nodes visualized and extent of radiocolloid migration showed no difference between the two agents. The biological and clinical parameters for the two colloids appear similar when used for internal mammary lymphoscintigraphy.
Adult↗
Traits that influence longevity in mice.
Analysis of genetic interactions in the segregating backcross [(C57BL/6 X DBA/2)F1 X DBA/2] mice revealed influences of genetic and environmental factors on life span. Using determinants of coat color (brown locus of chromosome 4 and dilute locus of chromosome 9), serologically determined H-2 antigens (chromosome 17) and sex as genetic markers, we studied the effects of these genes on longevity. The results suggested that genes in the brown locus (b) segment of chromosome 4, genes in a segment of the sex chromosomes and, to a more limited extent, genes in the segment of chromosome 17 which contains the H-2 haplotype all influenced longevity. The coat color (b locus) segment of chromosome 4 was associated with life span predominantly in females, whereas the chromosome 17 (H-2 haplotype) segment was associated with longer life primarily in males. The dilute locus d segment on chromosome 9 did not affect life span. Longevity appears to be influenced by interactions between genes in the chromosomal segment carrying H-2, those in the b segment, gender and the month of birth. Greater heterozygosity at the loci studied was associated with longer life span. Histopathological findings on mice that died at or after 28 months of age were comparable for all genetic combinations except that there was an increased frequency of lymphoma in females and an increased frequency of amyloidosis in males. Our analysis emphasizes the need for comprehensive studies of aging and longevity that would simultaneously determine the effects of several genetic regions and their interactions with the environment with respect to possible causes of death.
Animals↗
Pulmonary uptake of technetium 99m macroaggregated albumin: a predictor of gastrointestinal toxicity during hepatic artery perfusion.
Hepatic artery infusion of 5-fluoro-2-deoxyuridine (5-FUdR) provides high hepatic drug levels but little systemic toxicity, since, by this route of administration, the drug is detoxified by the hepatocytes. Slow infusion of technetium 99m- (99mTc) labeled macroaggregated albumin (MAA) through the hepatic artery is an aid in catheter placement, in predicting response of liver metastases to therapy, and in identifying extra-hepatic flow in the gastroduodenal or splenic arteries as an indicator of systemic toxicity. Marked pulmonary uptake of this tracer after slow radionuclide hepatic angiography was noted in four patients who showed major gastrointestinal (GI) toxicity. A retrospective examination of pulmonary accumulation of 99mTcMAA as a predictor of GI toxicity is the subject of this paper. Two groups of patients were evaluated. The first group consisted of 14 consecutive patients in whom continuous infusion of drug was administered by an external pump by way of a percutaneous catheter. Patients received baseline and follow-up (seven to 27 days) slow-infusion tracer studies (2 to 4 mCi 99mTcMAA at 10 to 21 mL/h). The second group included 14 consecutive patients who were receiving intraarterial chemotherapy by a totally implantable pump system. All received baseline slow-infusion studies (2 to 4 mCi 99mTcMAA at approximately 0.5 to 1.0 mL/min). The percentage of the injected dose in the lung was determined. Patients with greater than 20% of tracer in the lung after radionuclide hepatic angiography had significantly greater severe GI toxicity than patients with baseline values of less than 20%. Our findings support the existence of hepatic arteriovenous (A-V) communications in some patients and suggest that they are present pretherapy. Presence of these A-V communications, which can result in a vascular bypass of normal hepatic parenchyma and the subsequent decrease in hepatic detoxification of chemotherapeutic agents, is the likely cause of GI toxicity. Pulmonary uptake of tracer injected in the hepatic artery may be useful in quantifying the degree of shunting and facilitate the monitoring of potential systemic toxicity.
Antineoplastic Agents↗
Cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy in women more than 65 years old with advanced breast cancer: the elimination of age trends in toxicity by using doses based on creatinine clearance.
Ninety-two patients with advanced breast carcinoma and no prior chemotherapy from 65 to 90 years old were treated with the combination cyclophosphamide (C), methotrexate (M), and 5-fluorouracil (F) (CMF). Because of the primary renal excretion of the first two drugs, their initial doses were calculated using a linear function of creatinine clearance. 5-Fluorouracil was given at 2/3 of the usual dose. These doses resulted in no significant age trends in almost all toxicity, response, time to failure, or cycle by cycle percentages of calculated dose actually received. There was significantly less nausea and vomiting as age increased (P less than .001) and patients greater than 80 years had a significantly shorter survival (P = .01) than patients aged 65 to 79 years. The toxicity results are in marked contrast to the experience of 126 patients aged 24 to 65 years treated with usual doses of CMF on earlier protocols. Among these younger patients there was a significant upward trend with age in diarrhea (P less than .001) and noticeable upward trends with age in hematologic toxicity (P = .06), infection (P = .06), and severe mucositis (P = .09). Patients greater than 65 years had their doses decreased less quickly than did patients less than 65 years; hence by the sixth cycle, the young and elderly patients were receiving almost the same amount of M and F.
Aged↗