Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy.

Localized lymphomas of diffuse and aggressive histology sometimes undergo early hematogenous dissemination such that local therapies (surgery alone or followed by radiation therapy) are not curative in 100% of cases. We have treated 47 clinical stage I or IE patients with aggressive lymphoma histologies (diffuse large-cell, diffuse mixed, diffuse immunoblastic, follicular large-cell, diffuse small-non-cleaved cell) with four monthly cycles of an eight-drug combination chemotherapy program consisting of cyclophosphamide, etoposide, doxorubicin, nitrogen mustard (mechlorethamine), procarbazine, high-dose methotrexate with leucovorin rescue, and prednisone (Pro-MACE-MOPP) administered systemically followed by 40 Gy involved-field radiation therapy. Forty-five (96%) patients achieved a complete remission and no patient has relapsed with a median follow-up time of 42 months (range, 8 to 90). Both patients failing to achieve a complete remission died of lymphoma, and one patient died free of lymphoma 45 months after diagnosis during coronary artery bypass surgery unrelated to lymphoma or its treatment. Hospital admissions were necessary to manage complications on nine of 188 (5%) cycles of treatment. There were no treatment-related deaths. ProMACE-MOPP plus involved-field radiation therapy is safe and effective treatment for localized aggressive lymphoma.

High-dose carboplatin with diethyldithiocarbamate chemoprotection in treatment of women with relapsed ovarian cancer.

Diethyldithiocarbamate (DDTC) has been found to protect the bone marrow, kidneys, and gastrointestinal tract from the toxic effects of cisplatin and carboplatin (CBDCA) in animal models. In an attempt to minimize the toxic effects of high-dose CBDCA (800 mg/m2), a pilot study was undertaken in which women with relapsed or refractory epithelial ovarian cancer were treated with high-dose CBDCA, which was followed 3 hours later with DDTC (4 g/m2). There were four partial responses and no complete response in 21 patients who could be evaluated (overall response rate, 19%). Significant toxic effects, including three treatment-related deaths, were associated with the regimen. This study suggests that while high-dose CBDCA plus DDTC may be active in relapsed or refractory ovarian cancer, it is associated with clinically significant hematologic and autonomic toxic effects.

Adjuvant chemotherapy in males with cancer of the breast.

Analysis of recurrence rates in male breast cancer (MBC) has suggested that tumor size and degree of axillary lymph node involvement carry the same prognostic implications as for breast cancer in women. A similar spectrum of antineoplastic agents appears active in both females and males. Based on reports of active adjuvant chemotherapy of women with breast cancer, we initiated a trial of adjuvant chemotherapy of MBC in July 1974. Twenty-four patients have been treated with cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). All patients had nodal involvement (median three nodes positive; seven patients had a single positive lymph node). All patients began adjuvant therapy within 4 weeks of either a radical or modified radical mastectomy. No postoperative radiotherapy was given. Median potential follow-up is 46 months. Four patients have recurred, one each at 15, 45, 61, and 65 months following mastectomy; two are dead of metastatic disease. The five-year survival rate projected by actuarial means is in excess of 80% (95% confidence interval: 74-100%). Based on these data, this treatment is highly encouraging when compared to other forms of treatment reported in the literature in which 5-year disease-free survival rates are less than 30%. We conclude that adjuvant therapy of MBC with a CMF regimen is feasible and may be associated with substantial improvement in disease-free survival and overall survival.

Activity of tricyclic nucleoside 5'-phosphate in model systems of human ovarian cancer.

Tricyclic nucleoside 5'-phosphate (TCN-P) was evaluated in two models of human ovarian cancer. TCN-P reduced both colony number and volume in clonogenic assays employing human ovarian cancer cell lines. TCN-P cytotoxicity depended on the concentration, exposure duration and cell line studied, but not on cell line plating efficiency or growth rate in soft agarose. Comparison of experimental IC50 concentrations for 1 hour or continuous TCN-P exposure with reported clinically relevant concentrations suggests that therapeutic TCN-P levels are more likely to be achieved by continuous infusions. Cell lines and sublines with resistance to several standard chemotherapeutic agents acquired both in vivo and in vitro were at most 2.6-fold cross-resistant to TCN-P with 1 hour drug exposure. Cross-resistance was not evident with continuous TCN-P exposure. Intermittent bolus TCN-P (100 mg/kg/d X 5) was ineffective in an in vivo xenograft model of human ovarian cancer. These data suggest that TCN-P is most likely to be clinically effective against ovarian cancer, and may be non-cross-resistant with several standard agents, if administered by continuous infusion. Preclinical evaluation of new agents, such as TCN-P, in these experimental models may provide information useful in subsequent clinical trials.

Increasing the response rate to cytotoxic chemotherapy by endocrine means.

Cloned cell lines of human breast cancer can be growth inhibited by tamoxifen and this inhibition can be reversed by estrogen. We wondered whether tamoxifen inhibition of breast cancer followed by estradiol reversal would increase the efficacy of chemotherapy by increasing the fraction of rapidly cycling cells. We describe a clinical trial in which 110 patients were prospectively randomized to chemotherapy consisting of cytoxan 750 mg/m2 and adriamycin 30 mg/m2 on Day 1 plus 5-FU 500 mg/m2 and methotrexate 40 mg/m2 on Day 8 vs the same chemotherapy plus tamoxifen 20 mg/m2 Days 2-6 and premarin 0.625 mg Q 12-H X 3 on Day 7. Chemotherapy was given in 21-day cycles. 108 patients were evaluable. No difference exist for any important prognostic variables. The first 55 patients were randomized to a regimen in which 5-FU preceded methotrexate by 24 h; thereafter, all patients received methotrexate followed in 1 h by 5-FU. No difference in any response parameter was seen between these two 5-FU methotrexate schedules. No differences in percent of protocol chemotherapy administered or observed toxicity was seen between the 2 regimens. Objective response rate was nearly identical--57% without and 64% with additional hormones. Prior adjuvant chemotherapy with L-PAM had no observable effect on response rate, response duration or survival. In a limited number of patients with inflammatory breast cancer we saw a significantly higher response rate (93 vs 61%; P = 0.03) than in patients with recurrent metastatic disease. Time to progression (13 vs 17 months) and survival (17 vs 23 months) of responders significantly favored the treatment arm including tamoxifen and premarin. Greater benefits of additional tamoxifen and premarin were seen in partial vs complete responders. This may have resulted from lower doses of chemotherapy given to patients achieving a complete remission. An additive effect of hormones plus chemotherapy cannot be entirely excluded as the explanation for the improved results seen with the addition of tamoxifen for 4 days plus 1 day of premarin. We believe that our results suggest that further efforts to increase the efficacy of chemotherapy by perturbing tumor growth rates may be worthwhile.

Iatrogenic nutritional deficiencies.

PIP: This article catalogs the nutritional deficiencies inadvertently introduced by certain treatment regimens. Specifically, the iatrogenic effects on nutrition of surgery, hemodialysis, irradiation, and drugs are reviewed. Nutritional problems are particularly frequent consequences of surgery on the gastrointestinal tract. Gastric surgery can lead to deficiencies of vitamin B12, folate, iron, and thiamine, as well as to metabolic bone disease. The benefits of small bowel bypass are limited by the potentially severe nutritional consequences of this procedure. Following bypass surgery, patients should be monitored for signs of possible nutritional probems such as weight loss, neuropathy, cardiac arrhythmias, loss of stamina, or changes in mental status. Minimal laboratory tests should include hematologic evaluation, B12, folate, iron, albumin, calcium, phosphorus, alkaline phosphatase, transaminases, sodium, potassium, chloride, and carbon dioxide levels. Roentgenologic examination of the bone should also be obtained. Loss of bone substance is a major consequence of many forms of treatment, and dietary supplementation with calcium is warranted. Patients undergoing hemodialysis have shown carnitine and choline deficiencies, potassium depletion, and hypovitaminosis, as well as osteomalacia. Chronic drug use may alter intake, synthesis, absorption, transport, storage, metabolism, or excretion of nutrients. Patients vary markedly in the metabolic effects of drugs, and recommendations for nutrition must be related to age, sex, reproductive status, and genetic endowment. Moreover, the illness being treated can itself alter nutritional requirements and the effect of the treatment on nutrient status. The changes in nutritional levels induced by use of estrogen-containing oral contraceptives (OCs) are obscure; however, the effects on folate matabolism appear to be of less clinical import than previously suggested. Reduction in pyridoxine and serum vitamin B12 levels has been reported among OC users, and requirements of thiamine and riboflavin may be increased. In cases where the therapy is justified, the nutritional consequences can often be justified. However, every effort should be made to identify nutritional side effects by proper assessment procedures and to manage them by oral or parenteral supplementation where feasible.^ieng

Treatment of osteogenic sarcoma. I. Effect of adjuvant high-dose methotrexate after amputation.

Thirty-nine patients with extremity osteogenic sarcoma and no discernible metastases were treated with amputation and postoperative adjuvant high-dose methotrexate with leucovorin rescue. One half of the patients were also randomized to receive bacillus Calmette-Guérin by a multiple-puncture technique. Results have been analyzed with a minimum followup of 10 months and a median followup of 27 months. Actuarial analysis estimates that 38% of current protocol patients remain continuously free of disease for 24 months compared to only 17.4% of historical control patients (P = 0.029; one-sided generalized Kruskal-Wallis test). Bacillus Calmette-Guérin administered by a multiple-puncture technique had no effect on disease-free interval. Minor differences between current protocol and historical control patients with regard to race, age, histologic type, and site and size of primary tumors do not affect the difference in disease-free interval between these two patient groups. However, current patients had somewhat lower grade lesions and consideration of the patients with grade III and IV lesions only, lessens the difference between current and historical control patients (P = 0.11; one-sided generalized Kruskal-Wallis test). High-dose methotrexate was administered with virtually no morbidity and no deaths. The small differences observed in this study between protocol patients treated with surgery plus high-dose methotrexate and historical control patients treated with surgery alone point to the need for a prospective randomized study to establish the role of high-dose methotrexate in the adjuvant treatment of patients with osteogenic sarcoma.

Different behavioral responses to L-DOPA after anterolateral or posterolateral hypothalamic injections of 6-hydroxydopamine.

After bilateral microinjections of 6-hydroxydopamine (6-OHDA) into the anterolateral (AL) or posterolateral (PL) hypothalamus L-DOPA (1,3,4-dihydroxy-phenylalanine) produced running and rearing in AL6-OHDA rats and oral stereotypies in PL 6-OHDA rats. Since the same dose of L-DOPA had no behavioral effect in vehicle injected rats, the responses to L-DOPA of both AL and PL 6-OHDA rats are examples of behavioral supersensitivity. The different forms of behavioral supersensitivity correlated with different patterns of catecholamine (CA) denervation determined by fluorescent microscopy. The major regions of CA denervation in AL 6-OHDA rats were neocortex, hippocampus, limbic forebrain, anteromedial striatum and anterolateral hypothalamus. PL 6-OHDA had these same areas denervated and, in addition, had severe denervation of the entire striatum, parts of the amygdala and thalamus, and of the posterolateral hypothalamus. We conclude that the supersensitive behavioral response to a fixed dose of L-DOPA is determined by the pattern and/or extent of CA denervation.

Abnormal open field behavior after anterolateral hypothalamic injection of 6-hydroxydopamine.

To investigate the importance of forebrain catecholamine terminals in open field behavior, rats were microinjected bilaterally in the medial forebrain bundle at the level of the anteralteral hypothalamus with 6-hydroxydopamine (6-OHDA), a specific catecholaminergic neurotoxin. These 6-OHDA microinjections produced extensive loss of forebrain catecholamine terminals; identical vehicle microinjections did not. When 6-OHDA rats were given 8 open field (OF) tests in the first or the fifth postinjection week, they had a longer latency to enter the OF, crossed fewer squares and reared less than normal rats or rats microinjected with vehicle. The abnormal OF behavior of 6-OHDA rats was not a generalized loss of locomotor activity because 6-OHDA rats were normally active in the home cage. The abnormal OF behavior of 6-OHDA rats was also not a result of a generalized lack of reactivity because the OF test elicited an increase of plasma corticosterone in 6-OHDA rats. The possibility that 6-OHDA rats were abnormal in the OF because they were hyperractive to it was not consistent with the observations that the OF activity of 6-OHDA rats did not change with repetitive testing, 6-OHDA rats did not defecate more than vehicle rats, and 6-OHDA rats did not display freezing behavior. These results suggest, but do not prove, that the abnormal OF behavior of 6-OHDA rats reflects a deficit of exploratory behavior that is correlated with extensive loss of forebrain catecholamine terminals.

Preliminary Results of trials of chemotherapy in advanced ovarian carcinoma.

A search for improved forms of systemic chemotherapy in advanced ovarian carcinoma has resulted in two prospective trials at the Medicine Branch National Cancer Institute. The first trial compared high-dose, split-course intravenous cyclophosphamide with conventional treatment with an oral alkylating agent, melphalan [also called L-phenylalanine mustard (PAM)]. While both regimens were essentially equal in therapeutic efficacy, the former was considerably more toxic and the latter was therefore preferred. The second trial employed a 4-drug combination (5-fluorouracil, methotrexate, cyclophosphamide, and hexamethylmelamine); the results indicated a higher overall response rate (85%) and a higher complete remission rate (31%) with the combination therapy than with the PAM therapy, although the study is short and the observations are preliminary.