Paul P. Carbone

Toxicity and response criteria of the Eastern Cooperative Oncology Group.

STANDARD CRITERIA FOR TOXICITY and for response to treatment are important prerequisites to the conduct of cancer trials. The Eastern Cooperative Oncology Group criteria for toxicity and response are presented to facilitate future reference and to encourage further standardization among those conducting clinical trials.

Combination Chemotherapy in the Treatment of Advanced Hodgkin's Disease

Abstract Forty-three patients with advanced, primarily untreated Hodgkins disease were treated with a combination of vincristine sulfate, nitrogen mustard (or cyclophosphamide), procarbazine hydro...

Curability of advanced Hodgkin's disease with chemotherapy. Long-term follow-up of MOPP-treated patients at the National Cancer Institute.

The results of treatment of 198 patients with Hodgkins disease with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) were analyzed. Eighty percent attained complete remission, and 68% of patients achieving a complete remission have remained disease free beyond 10 years from the end of treatment. Results of autopsy on patients who died of other causes while in clinical complete remission did not show evidence of residual tumors except in one patient. Asymptomatic patients and patients with mixed-cellularity or lymphocytic-depleted Hodgkins disease do significantly better than symptomatic patients and those with nodular sclerosing histologic type. Advanced Hodgkins disease appears to be curable by chemotherapy.

Clinical trials and drug toxicity in the elderly. The experience of the eastern cooperative oncology group

Nineteen studies of advanced cancer in 8 disease sites have been examined using data from the Eastern Cooperative Oncology Group. The purpose of the investigation was to determine susceptibility of elderly patients (<70 years of age) to cancer chemotherapy and to compare the results with corresponding figures in control patients (<70 years of age). The results indicate that in general, the elderly patients have identical rates of severe toxicity as their younger counterparts. The only exception is for hematologic reactions in a few of the sites studied. On closer examination, the agents that appear to be responsible for these especially adverse effects are methotrexate and methyl‐CCNU. It is demonstrated that the elderly patients have similar response rates and survival expectancy to the nonelderly patients. Consequently, it is concluded that the apparent discrimination in not treating elderly patients as aggressively as younger patients, and in excluding elderly patients from protocols, does not appear to be justified. Exclusions should be based on physiologic functional parameters, such as measures of renal, liver and marrow function, or performance status, rather than on an arbitrary age limit. Exceptions should only be made for agents which have a clearly demonstrated adverse effect on the elderly. Cancer 52:1986‐1992, 1983.

The health consequences of smoking. Cancer.

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 individuals risk of cancer.

A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy

A prospective randomized trial was conducted comparing the clinical response of 78 previously untreated patients with advanced metastatic breast cancer to a combination of cyclophosphamide, methotrexate, and 5‐fluorouracil (CMF) or to a combination of cyclophosphamide, adriamycin, and 5‐fluorouracil (CAF). Sixty‐two percent of the patients receiving CMF responded to treatment compared to an 82% response rate for the patients receiving CAF. Although within acceptable limits, hematologic and GI toxicity was greater with CAF. There was no significant difference in the duration of response to the two regimens. Therefore, the therapeutic difference between the two therapies is a higher initial response rate to the adriamycin containing regimen.

Elevated antibody titers to Epstein-Barr virus in Hodgkin's disease.

Sera from 63 patients with Hodgkins disease and 42 patients of comparable age with other lymphomas were tested for antibody to Epstein‐Barr virus (EBV) by indirect immunofluorescence. The geometric mean titer (GMT) of EBV antibody in the patients with Hodgkins disease was significantly higher (1:367) than the GMT of the other lymphoma patients (1:132) and 85 normal controls (1:90). Higher EBV titers in untreated patients with Hodgkins disease were associated with a longer duration of symptoms, more advanced disease, shorter survival, and a histologic picture of lymphocyte depletion. Treated patients had significantly higher titers than untreated patients. When the same sera were tested for antibody to 4 other herpes viruses (herpes simplex type I and type II, cytomegalovirus, and varicella), no differences in titer between patient and control groups were found. Although this study associates elevated EBV titers with those factors relating to a poor prognosis in patients with Hodgkins disease, the data do not distinguish between an etiologic role for EBV and that of a passenger virus which produces high titers as a result of the disease process.

Intestinal Lymphangiectasia: a Protein-Losing Enteropathy with Hypogammaglobulinemia, Lymphocytopenia and Impaired Homograft Rejection

Intestinal lymphangiectasia is a disease characterized by dilated intestinal lymphatics, protein-losing enteropathy, hypoalbuminemia, and edema. The immunologic status of 18 patients with intestinal lymphangiectasia was studied. Concentrations of IgG, IgA, and IgM were measured by immune precipitation and metabolism of these three immunoglobulins was studied using purified radioiodinated proteins. The serum concentration and total body pool of each immunoglobin were greatly reduced. The fraction of the intravascular protein pool catabolized per day was increased to 34% for IgG, 59% for IgA, and 66% for IgM; these are in contrast with control values of 7%, 28%, and 17%, respectively. Synthetic rates of the immunoglobulins were normal or slightly increased. Primary circulating antibody response was tested in five patients with Vi and tularemia antigens. Titers elicited in patients with the Vi antigen were significantly lower than those seen in a control group, whereas no difference was seen between patient and control responses to the tularemia antigen. Lymphocytopenia was noted in patients with intestinal lymphangiectasia. The mean circulating lymphocyte count was 710 +/- 340/mm(3) in contrast to 2500 +/- 600/mm(3) in controls. Cellular hypersensitivity was studied with skin tests and skin grafts. 91% of normal individuals reacted to at least one of the four skin test antigens: purified protein derivative, mumps, Trichophyton, and Candida albicans; in contrast, only 17% of patients with intestinal lymphangiectasia had a positive reaction. Each of three patients tested with dinitrochlorobenzene had a negative reaction. Finally, all four patients who received skin homografts have retained these grafts for at least 12 months. The immunological disorders in patients with intestinal lymphangiectasia appear to result from loss of immunoglobulins and lymphocytes into the gastrointestinal tract secondary to disorders of lymphatic channels. Lymphocyte depletion then leads to skin anergy and impaired homograft rejection.

Pseudomonas pneumonia: A retrospective study of 36 cases

Abstract The clinical course in 36 cases of Pseudomonas pneumonia collected over a 15 year period (1956 to 1970) at the Clinical Center of the National Institutes of Health were reviewed to identify factors which increased the risk of infection and affected prognosis. In all cases, the patients had a serious underlying disease which predisposed to infection, and the majority had neoplastic diseases, particularly acute leukemia; cardiac or pulmonary diseases were less frequent. Pseudomonas related mortality was 81 per cent and was not influenced by type of antibiotic therapy or by the year of occurrence. Many patients were neutropenic, usually subsequent to cytotoxic chemotherapy, and frequently had been treated with steroids or antibiotics just prior to the development of pneumonia. Adequate numbers of circulating granulocytes were essential to survival. No patient with a positive blood culture survived. Possibilities for new means of prevention and treatment of Pseudomonas pneumonia are discussed.

L‐phenylalanine mustard (L‐PAM) in the management of primary breast cancer: An update of earlier findings and a comparison with those utilizing L‐PAM plus 5‐fluorouracil (5‐FU)

In 1972, a prospective, randomized, multi‐institutional, cooperative clinical trial was begun to evaluate the efficacy of prolonged 1‐phenylalanine mustard (L‐PAM) administration following operation in lengthening the disease free interval of patients with primary breast cancer. That protocol using a single agent was the first of a series directed toward evaluating successively more complex chemotherapeutic regimens in an attempt to define subsets of patients which might be responsive to less therapy than others. When it was observed that L‐PAM prolonged the disease free interval, particularly of premenopausal patients, findings were reported and a new evaluation comparing L‐PAM with L‐PAM plus 5‐fluorouracil (5‐FU) was begun. Upon completion of patient accrual in that protocol, an additional trial comparing L‐PAM and 5‐FU with L‐PAM, 5‐FU and Methotrexate was implemented. The present report updates findings from the initial study and presents those from the second. It compares results across the first two protocols as well as between groups within a protocol. While insufficient time has elapsed for determining the ultimate worth of the modalities employed, findings from the second protocol confirm those previously reported indicating that L‐PAM lengthens the disease free interval following mastectomy. The combination of L‐PAM with 5‐FU resulted in a reduction of treatment failure at 12 months which is as good or better than that observed with L‐PAM in the first protocol lending further credibility to the earlier findings. While at the end of the first year following mastectomy there was alomst a 50% reduction in treatment failures in patients aged 50 or over (post‐menopausal), by 18 months the reduction was 23% and at two years, based on small numbers of patients, only 5%. Examination of results from the first protocol (placebo vs L‐PAM) after two years reveals a most highly significant effect of L‐PAM in pre‐menopausal women with one to three positive nodes. There is an 89% reduction of treatment failures. A similar but less striking effect is noted for those under 50 with ≥four positive nodes. In older patients in both nodal categories, the early observed effect for L‐PAM has decreased with time. Inter‐protocol comparisons relative to survival are premature. At two years survival in L‐PAM patients is 36% greater than in those receiving placebo. It is somewhat better in every subgroup for those receiving L‐PAM. Information relative to the effect of these agents on patient toxicity and loco‐regional treatment failures is presented. All of the findings stress the urgency for obtaining results on subsets of patients rather than on a population as a whole and they lend support to the thesis that since breast cancer is an eponym to describe a heterogeneous group of tumors residing in a heterogeneous group of women, it is unlikely that uniformly qualitative and quantitative systemic regimens of therapy will be required for every patient.