Oils and cancer.

Epidemiologic evidence on the relationship between mineral oil exposure and cancer is reviewed. The review is restricted to occupations involving substantial dermal and inhalational exposure and for which an epidemiologic literature exists: metal machining, print press operating, and cotton and jute spinning. Mineral oils are complex mixtures of aliphatic hydrocarbons, naphthenics, and aromatics, the relative distribution of which depends on the source of the oil and the method of refinement. End-use products contain a variety of additives, and contamination by other agents generally occurs during use. Suspect agents include polycyclic aromatic hydrocarbons (PAH) (particularly benz[a]pyrene), nitrosamines, chlorinated paraffins, long-chain aliphatics, sulfur, N-phenyl-2-naphthylamine, and formaldehyde. The heterogeneity of this exposure makes epidemiologic study difficult and meta-analysis inappropriate. Nonetheless, several associations emerge from the literature with varying degrees of support. There is clear evidence that early formulations of mineral oils used in cotton and jute spinning and in metal machining were carcinogenic to the skin. Associations of mineral oil exposure with laryngeal and rectal cancer have received some support in the literature, particularly with respect to straight oils. Evidence is suggestive that grinding operations (which can entail either mineral oil-based or ethanolamine-based fluids) are associated with excess risk of cancer of the esophagus, stomach, and pancreas. A number of bladder cancer case-control studies have noted an association with work as a machinist. There is limited evidence of an association with cancer of the colon, prostate, and sinonasal region. Several studies of printers have yielded positive findings for lung cancer, whereas studies in metal machinists have been generally negative. The PAH and nitrosamine content of current formulations is lower than in the past and the implications of these changes in composition to the carcinogenicity of the formulations are not yet known.

Aclacinomycin A and etoposide (VP-16-213): an effective regimen in previously treated patients with refractory acute myelogenous leukemia.

Thirty-five patients with acute myelogenous leukemia were treated with aclacinomycin A (60 mg/m2/day for 5 days) and VP-16-213 (100 mg/m2/day for 5 days). All were previously treated and had relapsed or were refractory to primary treatment. Most patients (28) had received prior DAT (daunorubicin, cytosine arabinoside, and 6-thioguanine) induction therapy followed by one or more courses of high-dose cytosine arabinoside (HD-Ara C) as consolidation therapy or as treatment for relapse. One patient was in her fourth relapse, one had relapsed acute megakaryoblastic leukemia (following remission with DAT and HD-Ara-C), one had a treatment-induced leukemia, and four patients were treated for primary treatment failures following two induction courses with DAT or a similar regimen. Fourteen patients had infections at start of therapy. Ten patients died within 14 days of treatment, all from sepsis or bleeding, before their marrow could be evaluated for leukemic response. Fourteen patients (40%) responded; 12 (34%) entered complete remission and two (6%) a partial remission (PR). Two of the four patients who were treated for primary treatment failures went into CR. The median CR duration was 99 days (range 30 to 455 days). Side effects from this treatment were similar to the conventional DAT regimen, although the gastrointestinal toxicity and mucositis appeared to be more severe. In addition, two of the patients had severe but reversible ventricular arrhythmias. The overall response (40%) and CR rate (34%) in this group of previously treated AML patients is encouraging, and further studies are needed to evaluate these preliminary findings.

Rodorubicin, a new tetraglycosidic anthracycline.

Rodorubicin is a new tetraglycosidic anthracycline, which was detected because of its activity against human tumors in a human tumor based screening system. Rodorubicin is not active in the typical animal transplantation tumors and might therefore be a new leading structure with preferential activity against slow proliferating human tumors. In spite the fact that Rodorubicin is a chemical anthracycline, the drug has an untypical spectrum of activity and toxicity when compared to standard anthracyclines. The drug is not toxic to bone marrow in animals or humans, however, the dose limiting toxicity is delayed nephrotoxicity in all species, starting with proteinuria and finally clearance reduction. Rodorubicin might be an interesting new candidate for further clinical evaluation and is the first drug being developed clinically in spite its inactivity in animal transplantation tumor systems.

Anthracyclines in the treatment of malignancy in pregnancy.

This article reports two cases and reviews the literature regarding chemotherapy using anthracyclines during pregnancy. Twenty-six additional cases using this class of agents to treat malignancy during pregnancy are summarized from 18 reports for a total of 28 pregnancies. Final outcome of pregnancy is analyzed with regard to the following factors: diagnosis, gestational age at start of therapy, total dose of anthracycline, number and type of agents used, neonatal pathologic findings and months of follow-up of infants. Final outcome of 28 pregnancies resulted in 24 normal infants including a set of twins in the current report. Limited pharmacokinetic information is inconclusive with regard to the appearance of anthracyclines and their known metabolites in placental or fetal tissue.

Assessment of left ventricular diastolic function in patients receiving anthracycline therapy.

Abnormalities in left ventricular filling have been described as an early finding in coronary artery disease and in cardiomyopathy. The present study was undertaken to determine whether impaired diastolic function may be an early sign of anthracycline cardiotoxicity. Radionuclide left ventricular curves of 30 treated patients were compared with the curves of 17 normal, agematched, volunteers. The curves were analyzed for ejection fraction, peak filling rate (normalized for end diastolic counts and for stroke counts), time to peak filling rate and filling fraction in the first third of diastole normalized for cycle length. In 20 patients (Groups A and B), we analyzed the radionuclide ventriculography preceding the decrease of systolic function or a clinical congestive heart failure. In ten patients (Group C) who ended a treatment regimen without systolic dysfunction or clinically evident cardiotoxicity, we analyzed the ventriculography at the end of the therapy. Among the diastolic indexes, only the first third filling fraction was abnormal in a minority of the patients (6/20 in Groups A and B). Our findings suggest that diastolic dysfunction is uncommon in anthracycline treated patients prior to systolic dysfunction.

Phase I study of pirarubicin.

A Phase I trial of pirarubicin (4'-O-tetrahydropyranyl-doxorubicin) was undertaken to study its toxicity and to gain preliminary knowledge of its efficacy. The dose was escalated by increments of 10 from 30 to 70 mg/m2. Out of 20 patients, 19 were evaluable for toxicity and response to treatment. Hematologic toxicity was dose limiting and dose related. Other adverse effects included nausea and vomiting, hair loss, and stomatitis. No acute cardiotoxicity was encountered. In 2 patients with metastatic breast cancer who had not been pretreated with cytostatic agents, a partial remission was achieved lasting for 5 months. In 6 patients, tumor parameters did not change for a median of 3 months, and 11 patients suffered progressive disease.

Phase II study of aclarubicin in acute myeloblastic leukemia.

Aclarubicin is a new anthracycline antibiotic that produces substantially less cardiotoxicity in animals that does doxorubicin. Based upon prior Phase I and II trials in leukemia, a Phase II study in acute myeloblastic leukemia was developed to assess the response rate and toxicity in previously treated patients. Forty patients received aclarubicin 100 mg/m2 per day X 3 with repeated course on days 14-16 if marrow hypoplasia was not produced. Complete responses were achieved in 27.5% (11/40) with durations of 1.5, 2, 2, 2, 3, 3+, 4, 5+, 32+, 33+, and 34+ months. Toxic effects of this therapy included severe neutropenia and thrombocytopenia, nausea/vomiting, mucositis, and diarrhea. No patient developed significant changes in the left ventricular ejection fraction, as measured by radionuclide angiography, or any clinical cardiac symptoms. Alopecia was minimal. Aclarubicin can produce a significant response rate in previously treated patients with acute myeloblastic leukemia and should be considered for study in initial therapy.

Phase II evaluation of aclacinomycin-A in advanced ovarian carcinoma.

Sixteen women with advanced epithelial ovarian carcinoma were treated with Aclacinomycin-A 40 mg/M2 given as a weekly infusion for four consecutive weeks followed by a two week rest period. All had failed prior chemotherapy. No responses were observed. Nausea and vomiting were the most frequent side effect. Myelosuppression was minimal. This dose and schedule of Aclacinomycin-A are not recommended for further trials in ovarian carcinoma.

Aclacinomycin A. Phase II evaluation in bronchogenic squamous-cell carcinoma.

Aclacinomycin A (ACLA-A) was administered to 22 patients with metastatic measurable bronchogenic squamous-cell carcinoma in a Phase II trial of the drug. Sixteen patients were fully assessable for response and toxicity. The initial dose of ACLA-A was 85 mg/m2 weekly for 4 consecutive weeks; however, due to severe myelosuppression, the weekly dose was reduced to 65 mg/m2. Fifteen patients were previously untreated. Toxicity was primarily hematological. Complete or partial responses were not observed on this treatment schedule. ACLA-A administered on this schedule lacks therapeutic efficacy in the treatment of patients with advanced bronchogenic squamous-cell carcinoma.

Aclacinomycin A. Phase II evaluation in advanced soft tissue sarcoma.

Aclacinomycin A (ACLA-A), an anthracycline antibiotic, was administered in a Phase II study to 20 patients with advanced, measurable soft tissue sarcomas. The dose schedule consisted of 85 mg/m2 intravenous ACLA-A given weekly for 4 weeks followed by a 2-week rest. Because of severe myelosuppression in the initial patients, the weekly dose was reduced to 65 mg/m2. Seventeen patients were fully evaluable for toxicity and response to the drug. Complete or partial responses were not identified. Toxicity was primarily hematological. ACLA-A administered in the above schedule demonstrated no therapeutic efficacy in patients with advanced soft tissue sarcomas.

[Scalp hypothermia as a preventive of alopecia in patients receiving combined chemotherapy including anthracyclines]. / Gipotermiia volosistoi chasti golovy kak profilaktika alopetsii u bol'nykh, poluchaiushchikh kombinirovannuiu khimioterapiiu s ispol'zovaniem antratsiklinov.

Scalp cooling to prevent alopecia was used in 47 patients treated with anthracyclines for various tumors. Good results were obtained though the course included cyclophosphamide which also causes alopecia. Total beneficial (good + satisfactory) effect was recorded in 36 patients (74.4%) who did not need a wig.

Phase I-II trial of aclacinomycin A given in a four-consecutive-day schedule to patients with solid tumours. A South-East European Oncology Group (SEEOG) Study.

Aclacinomycin A (ACM) in a daily dose of 30 mg/m2 was infused over 1 h on 4 consecutive days to 50 patients. Myelotoxicity was acceptable, nausea and vomiting was frequent, hair loss was mild. Grade 1-2 cardiac rhythm abnormalities were observed in 12% of the patients. Between days 1 and 4 the heart rate and the corrected Q-T interval increased while the amplitude of the T wave decreased significantly, cardiac contractility remained unchanged. In 24 evaluable breast cancer patients 1 complete remission (4%) and 2 partial remissions (8%) lasting for only 2-3 months were seen. None of the 8 patients suffering from ovarial cancer benefitted from ACM therapy.