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Background: Despite some evidence that age does not meaningfully influence the efficacy or toxicity of cancer treatment, older patients tend to receive less comprehensive cancer therapies.Purpose: We conducted a population-based study to evaluate the selection of cancer treatment among the elderly.Methods: Between September 1 and November 30, 1990, we interviewed by telephone a sample of 628 female Wisconsin residents recently diagnosed with breast (507) or colorectal (121) cancer. The women, aged 20-74 at the time of diagnosis, were identified through Wisconsin's statewide tumor registry. The approximately 30-minute long telephone interview, part of a larger study of cancer etiology, included questions on treatment history, physician specialty, and reasons for the selection of specific therapies. Analyses compared the proportion of subjects with various treatment characteristics according to age (< 65 and > or = 65 years). In evaluating the effect of age on selected therapies, we adjusted summary proportions for stage of disease using the indirect method. The Mantel-Haenszel chi square statistic was used to evaluate statistical significance of the differences in proportions.Results: After adjusting for stage of disease at diagnosis, substantial variation was observed in cancer treatment according to age for both breast and colorectal cancer. Older women (> or = 65 years) with breast cancer were less likely than younger women (< 65 years) to have received conservative surgery, radiation, and adjuvant therapy. Older women were, in fact, more likely than younger women to accept mastectomy (P = .03). Consultation with a medical or radiation oncologist was less common among older than younger patients (57% versus 73%). Older women were also less likely to have alternative therapies presented to them (19% versus 31%). While older patients were less likely to have been offered adjuvant treatments, like chemotherapy (P < .01), they were also more likely than younger women to reject these treatments when offered (P = .01). These differences were observed in both breast and colorectal cancer patients. Regardless of age, the most common reasons for not selecting treatments were physicians' recommendations and the desire for more comprehensive treatment. Concern about side effects, however, was more frequently reported by older women (P = .07).Conclusion and Implication: Patients' ages influence the choice of treatment. Physicians offer older women with cancer different treatments from those offered to younger women and are less likely to recommend specialist consultation. Physicians' advice and description of toxicity may influence patients' selection of treatment. However, older patients' concerns about the consequences of cancer treatment may also influence treatment choice. [ABSTRACT FROM AUTHOR]

Preclinical studies have shown that the inhibition of ornithine decarboxylase (ODC) by alpha-difluoromethylornithine (DFMO) and resultant decreases in tissue concentrations of polyamines (putrescine and spermidine) prevents neoplastic developments in many tissue types. Clinical studies of oral DFMO at 500 mg/m(2)/day revealed it to be safe and tolerable and resulted in significant inhibition of phorbol ester-induced skin ODC activity. Two hundred and ninety-one participants (mean age, 61 years; 60% male) with a history of prior nonmelanoma skin cancer (NMSC; mean, 4.5 skin cancers) were randomized to oral DFMO (500 mg/m(2)/day) or placebo for 4 to 5 years. There was a trend toward a history of more prior skin cancers in subjects randomized to placebo, but all other characteristics including sunscreen and nonsteroidal anti-inflammatory drug use were evenly distributed. Evaluation of 1,200 person-years of follow-up revealed a new NMSC rate of 0.5 events/person/year. The primary end point, new NMSCs, was not significantly different between subjects taking DFMO and placebo (260 versus 363 cancers, P = 0.069, two-sample t test). Evaluation of basal cell (BCC) and squamous cell cancers separately revealed very little difference in squamous cell cancer between treatment groups but a significant difference in new BCC (DFMO, 163 cancers; placebo, 243 cancers; expressed as event rate of 0.28 BCC/person/year versus 0.40 BCC/person/year, P = 0.03). Compliance with DFMO was >90% and it seemed to be well tolerated with evidence of mild ototoxicity as measured by serial audiometric examination when compared with placebo subjects. The analysis of normal skin biopsies revealed a significant (P < 0.05) decrease in 12-0-tetradecanoylphorbol-13-acetate-induced ODC activity (month 24, 36, and 48) and putrescine concentration (month 24 and 36 only) in DFMO subjects. Subjects with a history of skin cancer taking daily DFMO had an insignificant reduction (P = 0.069) in new NMSC that was predominantly due to a marked reduction in new BCC. Based on these data, the potential of DFMO, alone or in combination, to prevent skin cancers should be explored further.

Purpose: Standard therapies for non-Hodgkin's lymphoma (NHL) are associated with an increased risk of developing treatment-related myelodysplastic syndrome or acute myelogenous leukemia (tMDS/AML). However, there is considerable debate over the incidence or risk of tMDS/AML in NHL patients treated with any particular modality and the factors that contribute to malignant transformation., Design: Conclusions were based on thorough analysis of data reported in the peer-reviewed literature and careful examination of the statistical methodology and methods for identifying cases of tMDS/AML. Unless noted, data are reported only for NHL patients, excluding Hodgkin's disease patients., Results: Despite differences in methods used to identify cases and to estimate the cumulative incidence over time (actuarial v cumulative calculations), up to 10% of NHL patients treated with either conventional-dose chemotherapy or high-dose therapy and autologous stem-cell transplantation may develop tMDS/AML within 10 years of primary therapy. Kaplan-Meier estimates of the actuarial incidence, which are based on censoring of patients who died without developing tMDS/AML, can lead to artificially high estimates with large confidence intervals at later time points. Although there is much debate about the cause(s) of tMDS/AML, there is compelling evidence that alkylating agents, certain other leukemogenic agents, and total-body irradiation (TBI) cause chromosomal damage that can lead to tMDS/AML., Conclusion: Limiting exposure to alkylating agents and eliminating TBI from transplantation conditioning regimens may reduce the relative risk of tMDS/AML.

Background: A phase II study of dacarbazine (DTIC), was conducted to determine the response rate, duration of response, toxicity and overall survival of patients with advanced pancreatic islet cell tumors., Patients and Methods: Fifty patients with advanced pancreatic islet cell tumors, having progressive symptoms or evidence of rapidly advancing disease were entered on this study. DTIC was given by IV infusion at a dose of 850 mg/m2, over 60-90 minutes, repeated every four weeks., Results: The response rate was 33% in 42 patients who had measurable tumor, and 34% in the 50 patients (90% confidence interval (90% CI): 23%-47%). The majority of the responses were seen in patients without prior chemotherapy. Median overall survival was 19.3 months. There were two lethal toxicities on the study, one septic shock and one myocardial infarction. Grade 4 toxicities were, hematological (5 patients), sepsis, neurological (depression and paranoid behavior) and bleeding (1 patient each). The most common toxicity was vomiting, grade 3 in 13% of patients., Conclusions: DTIC has activity in advanced previously untreated pancreatic islet cell tumors.

Individuals who receive life-saving organ transplants and the required immunosuppression often develop secondary cancers. One of the most common secondary cancers is nonmelanoma skin cancer in sun-exposed areas. Attempts to prevent these cancers have not been successful. Difluoromethylornithine (DFMO), a suicide inhibitor of ornithine decarboxylase (ODC), is a known experimental cancer prevention agent that is being evaluated in a number of human cancer prevention trials. This report describes a Phase I trial in 18 organ transplant recipients, randomized to 1.0 and 0.5 g of DFMO or a placebo, designed to look at short-term toxicities over 28 days as well as the impact of DFMO on two biological parameters, skin polyamines and 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ODC activity. Blood levels of DFMO were also measured. The results indicate that DFMO was well tolerated over the 28-day period. The TPA-induced ODC activity in 3-mm skin biopsies was significantly lowered by 80 and 67% at the two dose levels. Polyamine levels were not affected significantly except for putrescine at the 0.5-g level. Blood levels of DFMO were about two times higher than expected, based on our prior pharmacokinetic studies. Our studies indicate that DFMO is a reasonable agent that should be tested further in larger Phase 2b trials in this population as a chemopreventive agent. TPA-induced ODC activity appears to be a relevant intermediate biological assay.

The purpose of this study was to assess the bioavailability of two oral preparations of difluoromethylornithine (DFMO). The current preparation of DFMO is a liquid with a concentration of 0.2 gram/ml that must be drawn up into a syringe and dispensed into a small medicine glass. This form of DFMO causes wastage of the medication. The liquid form also makes compliance and blinding difficult. Recently, a new coated tablet preparation has become available from Ilex Oncology Services (San Antonio, TX). The coated tablets are 0.25 gram and are scored. The tablet form should increase compliance by making it much easier for the subject to take the medication. This report compares the bioavailability of both preparations with the goal of demonstrating equivalence of the preparations. Ten normal subjects entered the cross-over study in which the order in which they would receive the liquid or tablet preparation of DFMO was randomized. The study was designed with the objective of establishing the bioequivalence of a tablet preparation of DFMO at daily dose 0.5 gram/m2 and a liquid preparation of DFMO at the same daily dose. The mean area under the time-by-concentration curves (microM x hours) for the liquid and tablet preparations was 368.2 and 370.4, respectively. The peak concentrations for the liquid and tablet preparations were 47.3 and 48.2 microM, respectively. No statistically significant differences were seen in these parameters, in time to peak concentration, or in serum half-life.

Cancer is a disease of the elderly. More than 50% of all cancers and deaths occur in people over 65 years. Older cancer patients are less likely to be referred to centers or to be given adequate chemotherapy. The elderly are under-represented in Phase I and II trials. Some of this hesitancy to give chemotherapy is related to the increased presence of co-morbid conditions in the elderly. Toxicity is another concern. This review summarizes data from literature on the effectiveness, outcome, and toxicity of chemotherapy in selected tumors. Information is presented on age related effects. In addition, a summary of new agents and biologics is presented that needs to be looked at for age related effects. Some comments are made on the pharmacokinetic impact of physiologic changes in the elderly on chemotherapy drugs. As the world's population ages, we need to include the elderly in trials to get data on age related effects. Most of the information presented shows that effective chemotherapy can be given safely to the elderly and the outcomes and toxicity are equivalent for many of the common solid tumors.

A two-step Phase I study of piroxicam (PXM) and a-difluoromethylornithine (DFMO) alone and in combination was initiated to assess toxicity and the impact of these drugs on several biological markers. In step 1, 12 subjects with a history of skin cancers were assigned to receive PXM 10 mg every day (q.d.) or 10 mg every other day (q.o.d.). The dosage of PXM 10 mg q.o.d. was tolerated. No changes were seen in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase (ODC) or urinary polyamine levels. Steady-state serum levels of PXM were consistent with the oral dose level. In step 2, 31 subjects with stage 0 or I nonmelanoma skin cancers, stage A or B prostate or colon cancer, or stage I breast cancer or who had a family history of cancer were randomized to receive DFMO 0.5 g/m2, PXM 10 mg q.o.d., or the combination of DFMO and PXM. In addition to the biological markers of TPA-induced ODC activity in skin biopsies and urinary polyamine levels, we measured urinary 11-dehydrothromboxane B2, a specific metabolite of thromboxane A2. Of the 12 subjects on DFMO/PXM, 2 dropped out for non-drug-related reasons. Three developed grade-2 drug-related toxicities. One subject developed dyspnea that resolved and was able to continue on the study for 6 months. One subject who developed diarrhea that resolved after 5 days was also able to restart the drug without a recurrence. A third subject described intermittent episodes of tinnitus starting 4 h after taking PXM that lasted only 5 s and did not progress on treatment. Comparing the 6-month measurements with pretreatment, DFMO/PXM or DFMO significantly reduced TPA-induced ODC levels (Ps, 0.03 and 0.05). Urinary polyamine levels of spermidine decreased slightly with the DFMO/PXM or DFMO alone, whereas putrescine decreased with PXM alone. Levels of 11-dehydrothromboxane B2 were depressed by PXM and PXM/DFMO. The doses of DFMO/PXM determined in step 2 are potential starting dosages for Phase IIa and IIb chemoprevention trials.

Seventy-three eligible, chemotherapy-naive, ambulatory patients with advanced pancreatic carcinoma were allocated to one of two treatment regimens: 35 received PALA (1250 mg/m2 daily x 5 every 4 weeks) and 38 were given SAM (streptozotocin 400 mg/m2 i.v. daily x 5, doxorubicin 45 mg/m2 i.v. on day 1 and 22, and methyl CCNU 60 mg/m2 orally on days 1 and 22 every 6 weeks). Doses were modified for myelo-, gi-, or cardiotoxicity. Adequate organ, bone marrow and cardiac function; a measurable lesion; adequate caloric intake; and a life expectancy of 2 months were required for treatment on this trial. One patient on each regimen had a partial response for response rates of 3% (95% confidence intervals, 0.08 to 17%). Median survival on the PALA arm was 5 months and median time to treatment failure was 2.6 months. SAM patients experienced median overall and progression free survivals of 3.4 and 1.9 months, respectively. The severe toxicity observed was almost exclusively myelosuppression on both regimens. One patient receiving SAM had lethal leukopenic sepsis during the first cycle as the only treatment-related death. Neither PALA nor SAM offer any therapeutic utility to patients with advanced pancreatic cancer.

The development of chemotherapy for patients with the major cancers progressed from the initial success attained in the treatment of acute leukemias and choriocarcinoma. Many of the principles of therapy were based on the concepts developed in the experimental laboratories and early clinical studies done at the NIH Clinical Center and other centers around the country. The purpose of this review is to describe some of the early advances in cancer therapy and show how many are based on the efforts of Dr. Emil J Freireich. Over his career, Dr. Freireich has published more than 500 papers and worked on more than 70 different drugs and combinations. The principles defined by Dr. Freireich, namely, the use of intermittent intensive chemotherapy to induce complete remissions (CRs), intensification of therapy in remission, and the use of unmaintained remissions to assess cure, have been important in developing curative chemotherapy programs in patients with acute leukemias. These same principles were applied to combination therapy of Hodgkin's disease as the nitrogen mustard, vincristine, procarbazine, and prednisone combination was developed. This led to the high CR and cure rate for this disease. The treatment of metastatic breast cancer does not produce a high proportion of CRs, and cures of metastatic disease are unlikely with chemotherapy alone. But adjuvant chemotherapy after surgery has resulted in a significant reduction in cancer mortality. Many challenges remain in increasing the cure rate for the major solid tumors. New avenues of controlling cell growth and metastases need to be explored. One approach that is exploitable is the use of drugs or nutrients to prevent cancer. Laboratory approaches are now becoming a clinical reality.

Cancer is primarily a disease of the elderly and the palliation of both disease- and treatment-related symptoms is of importance in the practice of cancer medicine in all patients. Many older patients are treated within community hospitals, in which anticancer therapies are less likely to be given and in which the palliation of symptoms should be of primary importance. Many oncologists struggle with the palliation of symptoms in patients who are near the end of life. This is despite the considerable energies that are spent in palliating symptoms in patients who are receiving anticancer therapies at all disease stages. The management of pain has advanced considerably recently with improvements in pain assessment and pharmacologic interventions. However, elderly patients are less likely than younger patients to receive proper pain management. Elderly patients also are less likely to take opioids for pain because of their attitudes and beliefs. Fatigue, dyspnea, and psychologic issues also are of importance in the management of elderly cancer patients both during anticancer therapy and near the time of death. Some elderly cancer patients die in the care of a hospice, although many are not referred to this service. There are many barriers to the provision of palliative medicine and these may be related to health practitioners, to the patients themselves, or to the health care system of which they are part. The increased educational efforts of health professionals are needed to ensure that all patients, including the elderly, have adequate palliation of their cancer-related symptoms.

Background: Over the past 20 years, considerable progress has been made in the early detection and treatment of cancer. Despite these advances, cancer incidence and mortality rates among Native Americans have not kept pace. Cancer centers are in a unique position to offer technical assistance, resources, and a long term commitment that can help address these concerns within tribal communities., Methods: The University of Wisconsin Comprehensive Cancer Center developed a proactive plan to build collaborative partnerships with Wisconsin Native Americans. This began with an outreach plan that prioritized intervention strategies. A Native American health professional was hired to serve as liaison and advocate. Resources were committed, and staff was assigned to work with the community to develop intervention strategies that would be culturally competent and able to address the concerns of community members., Results: Various collaborative activities resulted from these efforts. These included participation in Native American cancer work groups, conferences, and seminars. Most importantly, these efforts resulted in a partnership with the Native American community that is based on honor and mutual respect., Conclusions: Careful planning, prioritization, allocation of resources, and a commitment to Native Americans can result in partnerships with the community and interventions that address their cancer control needs. Building and sustaining these partnerships takes time and thoughtful exploration of issues and concerns to develop mutual trust and respect. Both cancer centers and tribal communities can benefit by recognizing that shared power, as a reciprocal value, can benefit the whole.

Large numbers of men have an undetected prostate tumor, but in only a small proportion of cases do these lesions ever become clinically significant. That being so, it will take time to demonstrate the PSA screening or any given treatment strategy has benefit. Meanwhile, patients need help deciding whether to undergo screening and, if cancer is found whether to opt for aggressive treatment.

Pain control should be a priority in cancer care. For most patients, the basic strategies are straightforward and pharmacologic: Up to 85% of cancer pain can be managed with oral agents. Barriers arise from misconceptions about opioids. The greatest single problem may be inadequate pain assessment--a deficiency that can be rectified by relying on patients to rate their pain.

Purpose: We studied oncologists' attitudes and behavior with regard to their participation in randomized clinical trials., Methods: We surveyed the 1,737 physician members of the Eastern Cooperative Oncology Group (ECOG) using the Physician Orientation Profile (POP), a self-administered mailed questionnaire. A response rate of 86% was achieved (1,485 of 1,737); each physician's actual patient accrual was recorded., Results: All respondents indicated that they had a systematic pattern of patient preselection for entry onto trials beyond the formal inclusion/exclusion trial criteria. Eighty-nine percent stated that improving patient quality of life rather than prolonging survival was more personally satisfying. Sixty-two percent did not enter a single patient during the 12-month period following the survey, while 10% entered 80% of all patients during that time. Physicians overestimated their accrual rate by a factor of 6. Eighty-three percent defined randomization and adherence to trial protocol as a serious challenge to their ability to make individualized treatment decisions., Conclusion: This study raises questions regarding the following: (1) the perceived generalizability of trial findings, (2) the role of end points other than survival for clinical trials, (3) the consequences of physician overestimation of patient accrual, and (4) the impact of randomized trials on the behavior of clinicians. Further investigation into these critical issues will provide meaningful recommendations to enhance the future design, implementation, and conduct of randomized clinical trials in cancer.

We report a case of a patient with hepatocellular carcinoma (HCC) who has two unusual features. The patient was 95 years old at the time of diagnosis and his excellent response to treatment. The authors briefly review the age distribution of HCC and the treatments used. We concluded that therapy should not be arbitrarily withheld based solely on chronological age. Older cancer patients deserve the right to be treated if they so wish.

Background: alpha-Difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the key enzyme in mammalian polyamine biosynthesis. Levels of ODC are closely related to tumor promotion, and inhibition of ODC is associated with suppression of tumor development in laboratory animals. DFMO has shown a dose-response effect in tumor inhibition in mice., Purpose: A randomized phase I study of DFMO was conducted to determine the lowest daily oral dose that can achieve at least 50% inhibition of ODC activity induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in human skin, with minimal clinical toxicity (grade 1 or lower; Eastern Cooperative Oncology Group [ECOG])., Methods: Cancer patients entered in steps 1 and 2 of the study had been treated and had no clinical evidence of cancer. In step 1, 13 patients received 0.125, 0.25, 0.5, or 0.75 g/m2 DFMO four times a day. In step 2, 13 patients received 0.125 or 0.25 g/m2 four times a day or 0.5 or 1.0 g/m2 every day. The 26 patients treated in steps 1 and 2 (range, < 1-6 months) had colon, prostate, or bladder cancer. In step 3, six cancer-free subjects at risk for colorectal cancer received 0.5 g/m2 every day for 5-12 months. To evaluate the effectiveness of DFMO in reducing TPA-induced ODC activity, we calculated the percent change from pretreatment ODC levels in skin biopsy specimens and the percentage of subjects with at least a 50% reduction in ODC levels., Results: In step 1 of the study, treatment-limiting audiotoxicity was observed at the three highest doses. Because the only dose with no major toxic effects in step 2 was 0.5 g/m2 every day, that dose was administered in step 3, with no major toxic effects. Seven subjects treated with 0.5 g/m2 every day had pretreatment ODC levels in the normal range; five averaged a reduction in ODC activity of at least 50%. DFMO had linear pharmacokinetics over the entire dose range. When 0.5 g/m2 was given every day, the peak plasma concentration was 47.1 +/- 5.1 microM at 3-4 hours (monthly mean +/- SE, 14.5 +/- 5.2 microM); half-life was 3.5 hours; and area under the curve for plasma concentration x time for a single dose of DFMO was 311 +/- 39 microM x hour., Conclusions: These data support phase II chemoprevention studies with DFMO given at a dose of 0.5 g/m2 every day., Implications: Studies investigating prevention of cancers with DFMO are under consideration.

One of a novel series of compounds (AMAPS or arylmethylaminopropanediols), 773U82-HCl has shown significant antitumor activity in in vitro and in in vivo tumor systems, but has less animal CNS toxicity than the lead compound in the same series (crisnatol). This study was designed to evaluate the pharmacokinetics, qualitative and quantitative toxicities of 773U82-HCl and to determine the recommended phase II dose (MTD) of 773U82-HCl given as a short infusion daily for 3 days every 3 weeks. Twenty-nine patients with refractory malignancies received 79 courses over 9 dose levels during this study. Doses ranged from 50 to 1060 mg/m2/d x 3 days. Due to the possibility of local hemolysis with concentrations > 1.5 mg/ml, drug was administered in solutions containing < or = 1.5 mg/ml. Because large volumes were needed at the higher dose levels, the infusion duration was increased from 2 hours to 4 hours. Mild to moderate nausea, vomiting, fatigue, dizziness and headaches were observed. Myelosuppression was the dose limiting toxicity. The recommended phase II dose and schedule was determined to be 800 mg/m2/d x 3d every 3 weeks. 773U82-HCl plasma concentration-time data were analyzed using a two-compartment pharmacokinetic model. The t1/2 beta averaged 6 hours and the total body clearance was 75.9 L/hr/m2. The volume of distribution (Vdss) was large, averaging 470 L/m2.

Background and Methods: Tamoxifen, a synthetic antiestrogen, increases disease-free and overall survival when used as adjuvant therapy for primary breast cancer. Because it is given for long periods, it is important to know whether tamoxifen affects the skeleton, particularly since it is used extensively in postmenopausal women who are at risk for osteoporosis. Using photon absorptiometry, we studied the effects of tamoxifen on the bone mineral density of the lumbar spine and radius and on biochemical measures of bone metabolism in 140 postmenopausal women with axillary-node-negative breast cancer, in a two-year randomized, double-blind, placebo-controlled trial., Results: In the women given tamoxifen, the mean bone mineral density of the lumbar spine increased by 0.61 percent per year, whereas in those given placebo it decreased by 1.00 percent per year (P less than 0.001). Radial bone mineral density decreased to the same extent in both groups. In a subgroup randomly selected from each group, serum osteocalcin and alkaline phosphatase concentrations decreased significantly in women given tamoxifen (P less than 0.001 for each variable), whereas serum parathyroid hormone and 1,25-dihydroxyvitamin D concentrations did not change significantly in either group., Conclusions: In postmenopausal women, treatment with tamoxifen is associated with preservation of the bone mineral density of the lumbar spine. Whether this favorable effect on bone mineral density is accompanied by a decrease in the risk of fractures remains to be determined.

Smoking has now been identified as a definite cause of cancer at many sites (Table 2). Of all cancers in the United States, 30% could be prevented if cigarette smoking were eliminated. Organs in direct contact with smoke--the oral cavity, esophagus, lung, and bronchus--are at the greatest risk of malignancy among smokers. As many as 90% of these cancers are attributable to smoking. Organs and tissues distant from smoke are also at some increased risk. Among smokers, rates of cancer of the cervix, pancreas, bladder, kidney, stomach, and hematopoietic tissue are increased 50% to 200% over rates in nonsmokers. Risk of cancer at all sites increases with increasing exposure to cigarette smoke. Cigarette smoke contains potent carcinogens that influence carcinogenesis at both early and late stages. These carcinogens can interact with other exposures, such as alcohol, to synergistically increase the risk of cancer. The adverse carcinogenic effects of cigarette smoking, however, can be reduced for all smokers if tobacco use is stopped. The prevalence of smoking among the US population as a whole has declined from 40% in 1965 to 29% in 1987. This progress against the epidemic of tobacco use has already produced a decrease in the occurrence of the most common tumor among men, lung cancer. Unfortunately, the decline in smoking prevalence and cancer incidence has not occurred equally across US populations. Death rates of lung cancer in women continue to rise, and, based upon current smoking patterns, these rates will continue to increase into the next century. The challenge to physicians and public health workers is compelling and immediate: Abstaining from smoking is the single most effective way to reduce an individual's risk of cancer.

The Committee on Treatment acknowledged the paucity of information related to the management of cancer in older patients and identified short-term and long-term efforts to study these issues. Short-term efforts should focus on effects of cancer and cancer treatment on survival and quality of life, efficacy and toxicity of antineoplastic therapy, barriers to adequate treatment, alternative settings of cancer care, and special supportive care needs. Long-term efforts should focus on unique features of cancer in older patients, long-term effects of cancer and cancer treatment, and prevention and detection of new primary malignancies. The Committee recognized that our recent advances in cancer treatment including palliative surgery, limited surgery, radiosurgery, and antidotes to drug toxicity may improve the tolerance of antineoplastic therapy by older patients and be beneficial in terms of survival and quality of life.

Because cancer is the number one cause of mortality in Taiwan, a governmental decision was made to develop an experiment in medical oncology education using a United States-style training program in medical oncology in three Taipei, Taiwan, university hospitals. In the past, trainees from developing countries came to the United States or other foreign countries to receive specialty training. In doing so, the training did not necessarily prepare the individuals with skills to treat the indigenous cancers, nor did they work with other related specialists or support staff such as nursing and pharmacy, so important to providing good cancer care. This program involved 13 fellows with significant laboratory experience working with American faculty on-site. The major benefits of this model for oncology training are that the trainees developed important interdisciplinary relationships with local staff at each of the hospitals; they were involved in the treatment of the major cancer diseases of Taiwan such as nasopharyngeal, hepatocellular, and cervical cancers as well as breast, lung, and colon cancers; and they completed a certification process involving written and oral tests by two senior American oncologist examiners. Oncology services have been established at each of the hospitals and most of the fellows have expressed an interest or made arrangements to come to the United States to get additional research experience.

The execution of cancer clinical therapy trials has evolved over the past 45 years and is centered in the Clinical Oncology Group mechanism. The organization, statistical and administrative support, protocol development, and quality control systems have been worked out well and can be described in detail through the Eastern Cooperative Oncology Group. Prevention trials, on the other hand, are larger and fewer and take longer to complete. They involve people who are healthy or not as motivated to take pills or change lifestyle habits as those who are ill. The problems of compliance, toxicity, and costs become major issues. The practice of medicine is organized to take care of sick people and not healthy volunteers. We describe potential roles for Clinical Oncology Groups. These include preliminary tests of prevention agents for safety and toxicity much like Phase 1 trials with cytotoxic agents. A second important possible involvement would be to provide patients at high risk for developing second cancers, treatment- or non-treatment-induced, for prevention trials. A third set of individuals that can be recruited through current group resources are relatives of cancer patients who themselves might be highly motivated to participate in prevention trials. While the Clinical Oncology Groups may not have primary roles in prevention trials, they do represent a resource that has trial discipline and willingness and could facilitate the research efforts in chemoprevention.

Combined modality trials in early breast cancer have been underway since the 1960s and results are available to indicate varying degrees of success in Stage I and II. The trials have involved more than 29,000 women in 61 randomized trials. The recommendations can be summarized by stage, estrogen receptor (ER) status, and menopausal status. In Stage II patients, chemotherapy has an impact on disease mortality for ER-positive and ER-negative premenopausal women and possibly ER-negative postmenopausal patients. In postmenopausal Stage II ER-positive patients, tamoxifen given for more than 2 years has a beneficial effect on survival. In node-negative patients, the major effects have been on improving disease-free survival (DFS) rather than overall survival. Tamoxifen has a positive effect in ER-positive patients while chemotherapy benefits ER-negative patients. In at least one trial chemotherapy benefitted women with ER-positive tumors, both premenopausal and postmenopausal, with lesions larger than 3.0 cm. Ongoing trials are designed to answer questions regarding optimal therapy for varying subsets including those tumors in which ER cannot be measured. New prognostic features used to determine therapy include flow cytometry studies of DNA synthesis and oncogene expression.

We conducted a 2-year, randomized, double-blind, placebo-controlled toxicity trial of therapy with tamoxifen (10 mg twice a day) in 140 postmenopausal women with a history of breast cancer and histologically negative axillary lymph nodes. These women had been treated with surgery with or without radiotherapy. At a 3-month evaluation, tamoxifen-treated women showed a significant decrease in fasting plasma levels of total cholesterol and low-density lipoprotein (LDL) cholesterol, which persisted at 6- and 12-month evaluations. During the first 12 months, plasma triglyceride levels increased; small but significant decreases in high-density lipoprotein cholesterol (HDL) were observed in tamoxifen-treated women, but ratios of total cholesterol to HDL cholesterol and of LDL to HDL cholesterol changed favorably. While data relating lipid/lipoprotein profiles and cardiovascular disease are limited in women, current evidence suggests that total cholesterol and possibly low-density lipoprotein cholesterol are risk factors. We conclude that during the first 12 months of treatment, tamoxifen exerts a favorable effect on the lipid profile in postmenopausal women with early stage breast cancer.

Breast cancer is being diagnosed earlier with about 94% of patients presenting with disease limited to the breast or axilla. Despite this trend, more and more patients are receiving adjunctive therapy. In Stage II disease the results of clinical trials suggest that single agent chemotherapy has little if any role in adjuvant therapy. Polychemotherapy can improve survival in premenopausal women with a gain in outcome of about 26%. The duration of therapy appears optimal when given for 6 months. In postmenopausal estrogen receptor-negative women, chemotherapy also has a major role. Tamoxifen appears to offer approximately a 22% improvement in mortality for postmenopausal women. The longer duration of tamoxifen as adjuvant therapy appears to enhance the effect. Premenopausal women may also benefit using tamoxifen but the gain is less clear. Adding tamoxifen to chemotherapy does not enhance the effect. Patients with more than four positive lymph nodes may require more intensive therapy to show a major benefit. Radiotherapy can be integrated along with chemotherapy as adjunctive therapy.

Metastatic disease is the most common cause of death in breast cancer. Although cardiac involvement has been reported in 12% to 30% of cases, intra-atrial involvement is rare. In this report we describe a 41-year-old woman with metastatic breast cancer whose left atrium was invaded by a metastatic tumor that resulted in intermittent left ventricular in-flow obstruction. Such a presentation has not been described previously in metastatic breast cancer. The pertinent literature is reviewed.

The effective treatment of systemic cancer began in the 1950s on two fronts, i.e., childhood leukemia and choriocarcinoma. These two diseases were successfully treated as a direct result of the use of antifolate methotrexate. The demonstration of complete durable remissions in these diseases quickly led to development of other anticancer drugs, tested using the prospective clinical trials. In the 1960s as the number of active drugs increased, combination chemotherapy was introduced. Other systemic cancers, such as Hodgkin's, large cell lymphoma, and testicular cancer, became curable in the 1970s. For the common low-growth fraction solid tumors, the curability of systemic disease remained elusive until the introduction of adjuvant therapy to treat micrometastases. The past decade of the 1980s has seen improvement in the outcomes for breast cancer, osteosarcoma, and possible colon cancer utilizing adjunctive chemotherapy. The 1980s also saw the introduction of biologic therapies that have further improved the outcomes of several leukemias and produced consistent responses in patients with renal cell and melanoma. The 1990s will undoubtedly see more improvements as the effects of current drugs will be enhanced not only by improved integration of systemic and local therapies but also by utilizing cytokines and biologic response modifiers in concert with cytotoxics. Moreover, as we understand more about the process of cancer induction, promotion, and progression, more specific anti-cancer approaches will be developed to control cancer even before clinical cancer is diagnosed. Underlying and facilitating the improvement in cancer therapy have been not only the experimental results of many laboratory scientists but also the outcomes from many controlled clinical trials, the laboratory of clinical scientists.

The current trial was designed to assess whether the addition of prednisone or prednisone + tamoxifen would enhance the therapeutic effectiveness of 1 year of adjuvant CMF therapy. Premenopausal women with ipsilateral axillary node-positive breast carcinoma and known estrogen receptor (ER) status were randomized to receive 1 year of postoperative treatment with 12 28-day cycles of cyclophosphamide, methotrexate, 5-fluorouracil (CMF), CMF plus prednisone (CMFP), or CMFP plus tamoxifen (CMFPT). There were 553 analyzed cases with 188 receiving CMF, 183 CMFP, and 182 CMFPT. The overall time to relapse (TTR) and survival comparisons between the regimens are not statistically different at a median follow-up time of 7.7 years. The major subgroups currently with a suggestive TTR difference are greater than 3N+ (CMFPT greater than CMF, P = 0.07) and estrogen receptor-negative (ER-) greater than 3N+ (CMFPT greater than CMF, P = 0.03). Patients receiving CMFPT appeared to have a superior survival to CMF in the ER- greater than 3N+ cohort (P = 0.02). The following patient characteristics were associated with a significantly longer TTR: decreasing nodal involvement or tumor size, positive ER status, age greater than or equal to 40 years, and decreasing obesity. The favorable effects of decreasing nodal involvement, positive ER status, age 40 years or greater, and decreasing obesity carried over to survival. Development of amenorrhea was also significantly associated with improved survival (P = 0.001). Toxicity was increased by the addition of prednisone to CMF and by the addition of tamoxifen to CMFP. Overall relapse patterns were similar among the three regimens. The results of the current trial do not currently suggest an overall therapeutic benefit for adding prednisone or only 1 year of tamoxifen to CMF adjuvant treatment.

Adjuvant therapy trials in breast cancer have grown steadily more complex since 1971, when the first long-term adjuvant trial in the United States was initiated. From L-PAM alone or in combination with a few other cytotoxic agents, ECOG protocols have expanded to consider different multidrug combinations with tamoxifen and other endocrine agents, administered for various lengths of time, sometimes alternating between two combinations. Nevertheless, we are still in the gestational stages of adjuvant studies, with many critical questions yet to be answered.

A poorly differentiated adenocarcinoma of the rectum developed in a 43-year-old man 37 years after ureterosigmoidostomy for epispadias with urinary incontinence. The review of literature indicates that patients who have undergone ureterosigmoidostomy have an increased risk for the development of large bowel neoplasia. The median time interval between the procedure and the diagnosis of the neoplasm is 21 years, and the median age at diagnosis is 33 years. The majority of the lesions are malignant and seem to occur at the site of ureteric anastamosis. The suggested etiologic mechanisms and the clinical aspects of colonic neoplasia following ureterosigmoidostomy are discussed.

One-hundred and fifty-one adults with acute non-lymphocytic leukemia (ANLL) were entered into an Eastern Cooperative Oncology Group protocol (EST-1473) comparing twice daily cytosine arabinoside and thioguanine (AT) with weekly cyclophosphamide, cytosine arabinoside, and methotrexate (CAM) for remission induction. Of 111 evaluable patients, 16 treated with CAM and 16 treated with AT entered complete remission (CR) on their initial therapy and 5 additional patients entered CR on crossover for a total of 37 or 33% of the evaluable patients. Of the 71 patients who survived three weeks or longer, the overall CR rate was 52%. Cytochemical studies were performed on 85% of the evaluable cases, Minor disagreements between morphologic subtypes of ANLL occurred in 50% of cases. There was no difference in response rates between the major subtypes of ANLL regardless of whether the investigator's diagnosis or the cytochemical reference laboratory diagnosis was used. The median survival of all evaluable patients was 4.9 weeks; those patients who responded with a CR had a median survival of 60 weeks, while those who did not have a median survival of less than 3 weeks. Age less than 60, ambulatory performance status, or fewer than 50% marrow blasts were also associated with a better response rate and longer survival. CAM had more severe mucositis and vomiting associated with it than did AT, but toxicities were otherwise comparble. Weekly CAM and AT appear to be equally effective regimens in the treatment of ANLL.