Long-term survivorship in small-cell anaplastic lung carcinoma.
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[Chemotherapy testing for human ovarian cancer using in vitro colony assay].
The in vitro evaluation of anticancer drug efficacy was performed using the human tumor clonogenic assay developed by Hamburger and Salmon, and correlation between the in vitro and clinical efficacy was analyzed retrospectively. The in vitro colony assay method used in this study was a minor modification of the above method. Thirty-two out of forty-eight samples from patients with ovarian cancer formed more than five colonies per plate on in vitro colony assay. The median plating efficiency was 0.06% (range 0.02-1.3%) and the median colony count per plate was 279 (range: 8-4,000). With regard to colony formation of ovarian cancer according to the source of the specimen, the colony-forming rate of solid tumor was high (72%) as compared with 63% for ascites and 43% for pleural effusion. In vitro chemosensitivity was defined as more than a 50% decrease in colony formation and the rates for standard drugs on ovarian cancer were as follows: adriamycin (0.04 micrograms/ml) 29%, bleomycin (0.1 micrograms/ml) 24% cisplatin (0.2 micrograms/ml) 31%, 5-FU (1.0 micrograms/ml) 22%, hexamethylmelamine (1.0 micrograms/ml) 19%, L-PAM (0.4 micrograms/ml) 44%, mitomycin C (0.1 micrograms/ml) 38% and THP-adriamycin (0.5 micrograms/ml) 36%. A group of patients who had not been exposed to any anticancer drug showed higher sensitivity in vitro as compared with a group of patients who had received prior chemotherapy (35% vs 22%, p less than 0.05). Correlation between in vitro drug sensitivity and clinical responses in patients treated with the same drugs were analysed retrospectively. In all twenty cases, two were true positive cases (29%), while in ten cases, the results were true negative (77%), The overall predictive accuracy was 60%. In conclusion, ovarian cancer cells can form colonies well when the soft agar method is used and this assay method is suitable for the evaluation of various anticancer drugs in vitro.
Altretamine↗
[Palliative chemotherapy of endometrial cancer. Value of combinations with doxorubicin and cisplatin].
The study of a series of 21 consecutive cases of adenocarcinomas of the endometrium requiring chemotherapy, has permitted to demonstrate the superior efficacy of an association of doxorubicin and cisplastin as compared to other plans containing only anthracyclin (45% of partial and complete remissions versus 20%); this difference, however, is not statistically significant. Intolerance reactions were similar in both groups. Confirming recent data from the literature, the results conclude in favor of: the determinant contribution of cisplastin to chemotherapy, the need of a strict selection of the patients intended for chemotherapy, the usefulness of induction chemotherapy trials, prior to pelvic radiotherapy in locally advanced forms, to improve their distant prognosis.
Adult↗
[Scintigraphic follow-up of osteosarcoma during neoadjuvant chemotherapy. Results of the cooperative osteosarcoma study of the Society for Pediatric Oncology].
The response of osteosarcomas to preoperative chemotherapy as measured by quantitative 99mTc-diphosphonate scintigraphy was compared with the amount of tumor cell destruction found histologically in the resected specimens. 3-phase bone scintigraphy, with determination of tumor/non-tumor (T/NT) ratios, allowed accurate prediction of tumor response in 28 of 30 tumors (accuracy = 93%) after completion and in 10 of 12 osteosarcomas (83%) at the half-way stage of preoperative chemotherapy, when only those tumors were evaluated which showed convergent changes of T/NT ratios in the perfusion and the mineral phase. At the half-way stage, however, evaluation of chemotherapy effects was complicated in 12 of 23 osteosarcomas by diverging T/NT ratios. In contrast, quantification and mapping of the tumor plasma volume and 99mTc-diphosphonate clearance on parametric images predicted correctly the histological tumor response to chemotherapy in 10 of 11 tumors (91%) after completion and in all 11 cases (100%) at the half-way stage.
Adolescent↗
Modulation and intensification of a cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin ovarian cancer regimen.
For 61 patients with stage III-IV carcinoma of the ovary, chemotherapy consisted first of cisplatin 50 mg/m2 on day 1, cyclophosphamide 500 mg/m2 on day 3, doxorubicin 50 mg/m2 on day 3, and hexamethylmelamine 100 mg/m2 on days 4-15 every 4 weeks. The dosages of doxorubicin and hexamethylmelamine were increased by 60 and 100%, respectively, until the nadir white blood cell counts fell to 1.0 x 10(9)/L. This regimen was less neurotoxic and nephrotoxic than other intensive treatments and produced better therapeutic effects than did the immediate preceding Mount Sinai regimens: 1) The overall median survival was 43 months and progression-free survival was 25 months; 2) the greatest benefit occurred among patients under 50 years of age; 3) regression of large tumors increased in frequency, with 33% of tumors 2-6 cm and 16% of tumors larger than 6 cm converted to either pathologically proved remission or microscopic disease; and 4) for the first time, partial surgical debulking producing residual tumors less than 6 cm in size improved early survival.
Altretamine↗
Tumor pharmacokinetics of hexamethylmelamine in CDF1 mice bearing P388 leukemia.
The pharmacokinetics and metabolism of hexamethylmelamine (HMM) have been studied in CDF1, mice bearing P388 leukemia. The results obtained for this tumor, which is naturally resistant to HMM, were compared with data on HMM sensitive RC tumor and plasma. The pharmacokinetic parameters, estimated by an original algorithm (FADHA), indicated that HMM Cmax and AUC were very high in RC and P388 tumors as compared to plasma values, but could not be directly correlated with HMM activity. Hydroxymethylpentamethylmelamine (HMPMM), a potentially anticancer metabolite of HMM, was easily detected in P388 leukemia while very poorly detected in RC tissue. This finding led us to make the hypothesis that HMM activity could correlate with HMPMM ability to interact irreversibly with DNA and proteins in tumors.
Altretamine↗
The area under the curve of metabolites for drugs and metabolites cleared by the liver and extrahepatic organs. Its dependence on the administration route of precursor drug.
The venous equilibrium model (or well-stirred model) is used to determine the area under the blood concentration vs. time curve of a metabolite formed from a precursor drug. It will be shown that the AUC of a metabolite will change according to the route of precursor drug administration(whether intraarterially, intravenously, via the portal vein, or orally) when the drug and/or metabolite is eliminated by more than one organ. Elimination includes hepatic and extrahepatic metabolism and renal excretion. The validity of the model is probed by using literature data for drug and metabolite areas. Finally, the use of metabolite areas for evaluating the complete/incomplete absorption or orally administered precursor drug is discussed.
Altretamine↗
Intensive alternating chemotherapy regimen in small cell carcinoma of the lung.
Fifty-five patients with small cell carcinoma of the lung (SCCL) were treated with alternating courses of CAV (cyclophosphamide, doxorubicin, and vincristine) and VHM (etoposide, hexamethylmelamine, and methotrexate) at 21-day intervals. One regimen contained high-dose cyclophosphamide (2400 mg/m2 iv), while the second contained an increased dose of etoposide (250 mg/m2 iv on Days 1-3). Patients achieving a complete response (CR) received a minimum of six cycles of therapy or two cycles beyond the achievement of CR. These patients as well as those with partial response with disease limited to the lung then received radiotherapy to the lung primary (5100 rads in 300-rad fractions) as well as prophylactic cranial radiotherapy (3000 rads in 300-rad fractions). All therapy was subsequently stopped until relapse. There were no deaths during the aplastic periods induced by the intensive chemotherapy. CR was achieved in 57% of the patients and partial response was achieved in 38%. The actuarial median survival for the 27 patients with extensive disease was 13.5 months and for the 28 patients with limited disease was 13 months. Survival at this point appears comparable to less intensive regimens in which maintenance therapy was given. We conclude that prolonged intensive induction chemotherapy in SCCL is well-tolerated. Studies are needed to examine in a randomized trial the role of alternating combinations and maintenance therapy in SCCL.
Actuarial Analysis↗
No response improvement after sequential chemotherapy for small cell lung cancer.
In a phase II study in patients with small cell lung cancer (SCLC) the combination of cyclophosphamide, cisplatinum and etoposide was found to be active, the response rate was 91% (30% CR, 61% PR) in the whole group. In 40 limited disease patients 19 CR (48%) and 20 PR (50%) were seen, whereas in 30 extensive disease patients only 2 CR (7%) and 23 PR (77%) were reached. Adding a second combination of doxorubicin, vincristine and procarbazine resulted in response improvement in only two patients. Median response duration was 41 weeks in CR patients and 30 in PR patients (p less than 0.01). Median survival was 66 in CR and 45 weeks in PR patients (p less than 0.002). Performance score and disease stage were found to be good prognostic factors. Four patients (6%) are disease-free at 2 1/2 years. The value of sequential chemotherapy for SCLC is probably minimal in view of the lack of response improvement.
Adult↗
Phase II trial of mitomycin, vindesine, and hexamethylmelamine in metastatic non-small cell bronchogenic carcinoma.
Mitomycin (10 mg/m2 iv on Day 1), vindesine (3 mg/m2 iv on Days 1 and 8), and hexamethylmelamine (100 mg/m2/day orally on Days 1-14) was administered to 32 patients with metastatic non-small cell bronchogenic carcinoma. No patient had been previously treated with chemotherapy and Eastern Cooperative Oncology Group (ECOG) performance status was 0-1 in 21 of 32 patients. Eleven partial responses (34%) were observed, with a median duration of 9 weeks. No complete responses were observed in this group of patients, whose median survival duration was 22 weeks. Moderate leukopenia (median leukocyte count nadir, 2500/mm3) was the major toxic effect. Although this regimen is active and relatively nontoxic, it will not be utilized in future ECOG trials because it has not produced an apparent improvement in survival duration.
Adult↗
Phase II trial evaluating continuous infusion of etoposide, cisplatin, and hexamethylmelamine in extensive-disease small cell carcinoma of the lung.
A total of 27 untreated and 24 previously treated patients with extensive-disease small cell lung cancer (SCLC) were treated with a combination chemotherapeutic regimen of continuous-infusion etoposide for 5 days, cisplatin, and hexamethylmelamine. of 25 evaluable patients with untreated SCLC, three (12%) achieved a complete response and 16 (64%) achieved a partial response. Among 23 evaluable patients with relapsed SCLC there were no complete responses and nine (39%) achieved a partial response. Median survival times were 252 and 109 days for the above groups, respectively. Myelotoxicity, especially thrombocytopenia, was moderately severe. Other toxic effects, including renal and neurologic, were minimal. These results compare favorably with other regimens including etoposide and cisplatin. Our results further confirm the activity of etoposide and cisplatin as both initial therapy and as a salvage regimen in the management of patients with extensive-stage SCLC.
Adult↗
Pentamethylmelamine: review of an aqueous analog of hexamethylmelamine.
The s-triazine derivatives have shown preclinical antitumor activity against several histologic types. The most widely used compound of this class in the clinic, hexamethylmelamine, has been largely restricted to oral use because of its low solubility and lack of stability in solutions suitable for parenteral administration. New analogs were sought which were soluble and stable and retained antitumor activity. Pentamethylmelamine (PMM), the monodemethylated derivative, showed these promising characteristics. Preclinical toxicology studies of PMM in mice, dogs, and monkeys showed toxic manifestations that involved the hematopoietic, lymphatic, renal, male reproductive, gastrointestinal, and nervous systems; these changes were both infusion-rate- and dose-dependent. Clinical phase I trials of PMM were performed using a variety of infusion durations and frequency schedules. The dose-limiting toxic effect common to all of these trials was protracted nausea and vomiting. In addition, some studies reported dose-limiting central nervous system manifestations in the form of agitation, drowsiness, somnolence, and even coma. Mild to moderate hematologic changes were noted. Because of the severity and frequency of the gastrointestinal and central nervous system toxic effects observed in the completed trials, no new clinical trials of PMM sponsored by the National Cancer Institute are planned. However, the interest in finding a clinically useful parenteral triazine continues.
Altretamine↗
Effect of phenobarbital pretreatment on the metabolism and antitumor activity of hexamethylmelamine.
The effect of phenobarbital (PB) pretreatment on the N-demethylation and antitumor activity of hexamethylmelamine (HMM) was investigated in mice. In mice pretreated with PB, the levels of HMM in plasma, liver, and M5076 tumor were much lower than in mice treated with HMM alone. Plasma area under the curve (AUC) values were 15 +/- 4 versus 37 +/- 28 micrograms/ml X min, liver AUC values were 43 +/- 13 versus 246 +/- 5 micrograms/g X min, and tumor AUC values were 37 +/- 14 versus 109 +/- 24 micrograms/g X min. All of the N-demethylated metabolites except N2N4 dimethylmelamine in plasma, liver, and tumor also reached much lower levels in mice pretreated with PB. The antitumor activity of HMM was significantly antagonized by PB treatment in both M5076 reticular cell sarcoma and PC6 plasmocytoma of the mouse.
Altretamine↗
[Chemotherapy in 143 advanced epithelial cancers of the ovary. Experience at the Hôtel-Dieu of Quebec and Hôpital Saint-Antoine (Paris)].
Results of initial chemotherapy in 143 patients with advanced epithelial ovarian cancer are presented. Twenty-five patients were treated with alkylating agents, their median survival was 13 months and 15% were alive at 4 years. Nineteen received Cyclophosphamide-Methotrexate-5 Fluorouracil with or without Hexamethylmelamine, median survival was 22 months and 4 years survival was 20%. Forty-eight were treated with Adriamycin and Cisplatinum, their objective response rate proven by second-look laparotomy was 54.4% (26.1% complete response), median survival was 23 months and 35% were alive at 4 years. Thirty-one received Hexamethylmelamine, 5 Fluorouracil, Adriamycin and Cisplatinum with a median survival of 18 months and 4 years survival of 15%. Twenty had various other chemotherapy regimens, their median survival was only 8 months. Recent advances in the therapy of ovarian carcinoma are also discussed.
Altretamine↗
Role of hexamethylmelamine in the treatment of ovarian cancer: where is the needle in the haystack?
Hexamethylmelamine (HMM) was selected for development as an antineoplastic agent because it demonstrated activity in a variety of preclinical tumor models. Its mechanism of action is unknown. It has been used in clinical trials since 1964. The clinical toxic effects have consisted of signs and symptoms involving the following systems: gastrointestinal (nausea, vomiting, anorexia), hematologic (leukopenia, mild anemia), and neurologic (critical depression, hallucinations, peripheral motor and sensory deficits). Antitumor activity against advanced ovarian cancer was demonstrated in phase I trials and the drug was quickly incorporated into trials which utilized drug combinations. The majority of these have consisted of phase II trials without an identified control population. As might be predicted, all of the HMM-containing combinations are active. However, the contribution of HMM to the antitumor activity of the combination remains conjectural. Thus, in spite of greater than 15 years of clinical trials with a drug that has single-agent activity, the questions regarding the role of HMM in the treatment of ovarian cancer remain unanswered.
Altretamine↗
Effect of cimetidine and ranitidine on the metabolism and toxicity of hexamethylmelamine.
In a rat model, doses of 20-120 mg/kg of cimetidine prolonged in a dose-related manner the half-life of hexamethylmelamine by 29%-80%, while doses of 1-25 mg/kg of ranitidine did not. Administration of 120 mg/kg of cimetidine with a single 350-mg/kg dose of hexamethylmelamine increased toxicity from LD30 to LD75 (P = 0.005). When combined with 25 mg/kg of ranitidine, a statistically insignificant (P = 0.16) 15% increase in hexamethylmelamine toxicity was noted. These studies indicate that cimetidine but not ranitidine increases the toxicity of hexamethylmelamine through inhibition of microsomal metabolism.
Altretamine↗
Prognostic factors: cisplatin regimens for patients with ovarian cancer after failure of chemotherapy.
For 129 ovarian cancer patients failing prior chemotherapy, overall clinical response rates were: 21% with cisplatin, 36% with cisplatin plus doxorubicin, 52% with cyclophosphamide added to the two drugs, and 44% with hexamethylmelamine added to the three drugs. Median survival was six or seven months in each trial. Twenty-five percent of the patients survived nine months with cisplatin and 14 to 16 months with each of the three combinations. Characteristics associated with best rate of response included: performance status 1 (completely ambulatory), age greater than or equal to 50, residual tumor less than or equal to 5 cm, and two or less prior cytotoxic drugs. In multivariate analyses, performance status dominated, although age and possibly treatment (cisplatin versus others) were significant. With performance status removed from the model, all of the remaining factors became significant. Factors associated with best survival included: performance status 1, tumor size less than or equal to 5 cm, and complete or partial response. In a multivariate analysis for survival, performance status entered the model. In a series of analyses with performance status removed, tumor size or response entered the model. These findings provide reasons to study both treatment with cisplatin before disease progression reduces the number of favorable characteristics and systematic second attempts at debulking surgery.
Adult↗
Second-line chemotherapy of stage III-IV ovarian carcinoma: a randomized comparison of melphalan to melphalan and hexamethylmelamine in patients with persistent disease after doxorubicin and cisplatin.
A total of 205 women with stage III or IV ovarian cancer who had persistent disease after initial treatment with doxorubicin and cisplatin were randomized to receive melphalan (8 mg/m2 orally for 4 days) or the combination of melphalan (6 mg/m2 for 4 days) and hexamethylmelamine (120 mg/m2 for 14 days) every 4 weeks. Only one of 64 patients with measurable disease had an objective response. The major determinants of survival after randomization were the amount of residual disease after initial chemotherapy and the type of response to initial chemotherapy. There was no overall difference in survival between the two chemotherapy regimens, but the small group of patients whose disease progressed on initial chemotherapy survived significantly longer when treated with the two-drug combination. Neither of these regimens provided effective therapy for women whose disease was not eliminated by first-line treatment. However, the superior results obtained in one subgroup with the addition of hexamethylmelamine suggest that the place of this agent in treating ovarian cancer should be carefully evaluated.
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