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The aim of this study was to assess the efficacy of consolidation therapy with hexamethylmelamine (HMM) in patients with advanced epithelial ovarian cancer (EOC). Patients treated at our hospital between January 1997 and November 2006 and in documented clinical complete response from advanced ovarian cancer following front-line platinum-based therapy were retrospectively analyzed. The patients treated with HMM were compared to the patients of matched counterpart without consolidation therapy. Of 102 patients enrolled, 49 were treated with HMM and 53 received no consolidation treatment. For patients with HMM and observed patients, the mean age were 54.6 and 55.6 yr; the distribution of stage was similar (P=0.977); the optimal surgery was performed in 36 (73.5%) and 44 (83%) (P=0.336); the recurrence rate were 27 (55.1%) and 33 (62.3%) (P=0.463); and the median progression-free survival were 38 months and 21 months for patients with HMM and observed patients (P=0.235). No treatment-related adverse events were reported during the follow-up period. Although this study failed to show the significant survival benefit of consolidation therapy with HMM in patients with advanced EOC, we consider that our study can contribute data to investigate the effectiveness of consolidation therapy in epithelial ovarian cancer.

Objective: To evaluate the activity of oral Altretamine in women with epithelial ovarian carcinoma who responded (PR or CR) to first line chemotherapy but relapsed within 6 months. The protocol was later amended to include patients with relapse within 12 months., Methods: A multicentric phase II trial. The patients had to have measurable disease. No more than one prior chemotherapy regiment was allowed. The patients were treated with 260 mg/m(2)/day of Altretamine in four divided doses for 2 weeks, repeated every 4 weeks. The response was evaluated after every two courses., Results: Thirty-one eligible patients were treated with a median of 3 courses of Altretamine (range 1-12). Hematological toxicity was minimal. Gastrointestinal toxicity was common. Response evaluation was possible for 26 patients. Three patients (9.7% intent-to-treat) achieved a partial response. Eight patients had stable disease, and 15 patients had progressive disease after two treatment courses. The median time to progression was 10 weeks (range, 5-51 weeks). Medial survival was 34 weeks (range, 7-112+)., Conclusion: Altretamine should not be chosen as standard treatment in patients with platinum-resistant recurrent ovarian cancer. However, Altretamine represents a useful alternative in patients who prefer oral treatment or when socioeconomic considerations are an important issue.

Objective: The aim of this study was to evaluate the 2-year survival rate in a group of women in complete clinical remission (cCR) from Stage III ovarian cancer following front-line therapy who were then treated with a 6-month course of altretamine., Methods: Patients were documented to be in cCR by physical examination, computed tomography or magnetic resonance imaging scan, and serum CA-125. Treatment consisted of altretamine (Hexalen) 260 mg/m(2)/day po divided into four doses taken after meals and at bedtime for 14 of 28 days for six cycles. Based on previous experience in the Southwest Oncology Group, the treatment would be considered promising if the 2-year survival rate was > or = 65% as measured from study registration., Results: From 9/1/93 and 7/1/97, 112 patients were registered and 97 were fully evaluable. The majority of patients had optimally debulked (< or = 1 cm: 63%), high-grade (Grade 3: 82%) tumors. The 2-year survival rate in this study was 75% (95% CI: 66-84%). For those patients with optimal disease, the 2-year survival rate was 82% (95% CI: 72-92%) and for those with suboptimal disease it was 64% (95% CI: 48-79%). Four patients (4%) experienced Grade 4 and 21 patients (22%) experienced Grade 3 toxicities consisting primarily of nausea/vomiting, neutropenia, fatigue, anxiety, and paresthesias., Conclusions: The 2-year survival rate in this study warrants further evaluation of consolidation therapy for women in clinical complete remission following front-line chemotherapy for Stage III ovarian cancer. Caution is advised in the interpretation of these data, however, because of the nonrandomized nature of the trial and the unknown contribution of front-line use of paclitaxel to the durability of clinical complete response., (Copyright 2001 Academic Press.)

Thirty patients with advanced renal cell carcinoma were treated on a phase 11 trial with altretamine. Altretamine was administered orally at a dosage of 260 mg/m2 days 1 through 14 with cycles repeated every 28 days. Nausea and vomiting were the most common toxicities. Ten percent (3 of 30) experienced Grade 3 gait abnormalities. None of the thirty evaluable patients achieved a complete or partial response. In summary, altretamine did not show antitumor activity in the treatment of advanced renal cell carcinoma.

Combination chemotherapy with hexamethylmelamine (hexalen, altretamine, hexastat), 100 mg, thrice a day, per os, 14 days (out of a 28-day course) and sarcolysin, 15 mg, per os, during the first 5 days of the course, was received by 24 patients with primary advanced tumors of the ovaries, prior to or after cytoreductive surgery. Total apparent response to chemotherapy among 19 patients of the study group was 47.2%, clinically significant (plus stabilization)--94.5%, without significant untoward side-effects (vomiting--19%; leukopenia degree II-III--33% and thrombocytopenia--19%). The drug proved an active component of combination therapy for advanced ovarian carcinoma.

Objectives: In an effort to critically examine the antitumor activity of altretamine (hexamethylmelamine) as salvage therapy of platinum-refractory ovarian cancer, the Gynecologic Oncology Group initiated a Phase II trial of the agent administered in this clinical setting., Methods: Altretamine was administered at a dose of 260 mg/m2 orally for 14 days in a 28-day course. Treatment was continued until disease progression or unacceptable side effects prevented further therapy. A total of 36 patients (median age: 56.5) were treated on this trial, of whom 33 were evaluable for toxicity and 30 for response. All patients had previously received either cisplatin or carboplatin and paclitaxel., Results: The major side effect was emesis (grade 3-4, 7/33, 21%). The objective response rate was 10% (one complete response, two partial responses)., Conclusion: We conclude that altretamine has limited activity in platinum-refractory ovarian cancer.

From December 1982 to December 1986, 52 patients with recurrent ovarian cancer were treated with single-agent HMM. Chemotherapy was given for a period of 1 year unless progression of disease or toxicity was noted. Survival was determined from the time of diagnosis to the date of death or September 30, 1992. The regimen was well tolerated with only one case of severe gastrointestinal toxicity. Nine patients were found to be clinically free of disease following completion of HMM treatment; they had initially responded to cisplatin-based therapy (i.e., potentially cisplatin-sensitive) and subsequently recurred. Four were found to have gross disease at the time of reassessment laparotomy. Three of these 9 patients are alive 81-92 months since diagnosis, having maintained disease-free intervals of up to 6 years. The median survival for the 9 patients without evidence of disease at the end of therapy was 75 months versus 9 months for the nonresponders. No patient who had progressive disease on first-line cisplatin-based combination chemotherapy (i.e., primary cisplatin-resistant) responded to second-line single-agent oral hexamethylmelamine. With a follow-up close to 10 years, our data show that hexamethylmelamine, with reasonable toxicity, can provide an extended, disease-free interval to a selected group of patients.

1. The N-(hydroxymethyl) melamines are analogs of the antitumor agent hexamethylmelamine (HMM) which do not require bioactivation to exert their antitumor effects. 2. Trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine; TM) was developed as a water-soluble antitumor agent for intravenous administration. 3. Phase I and II trials of TM showed promising activity versus platinum-refractory ovarian cancer, but unfortunately further clinical development was halted due to formulation difficulties. 4. Stable analogs of TM were synthesized in an effort to overcome this shortcoming and these were evaluated in a number of in vitro and in vivo studies. 5. While the stable analogs showed good in vitro cytotoxicity in tumor cell lines, only one analog, CB7646 [bis-N-(hydroxymethyl)trimethylmelamine], showed comparable in vivo antitumor activity to that seen for TM. 6. Both TM and CB7646 were curative in human ovarian and breast cancer xenograft models, including the HX110P ovarian cancer xenograft with acquired resistance to carboplatin. 7. As CB7646 possesses favorable formulation characteristics, relating to its superior stability over that for TM, it is currently being developed for phase I clinical trial. 8. The N-(hydroxymethyl) melamines are capable of overcoming many forms of drug resistance, based on data obtained in in vitro and in vivo studies, and thus show promise as agents in the treatment of heavily pretreated, refractive tumors.

A Phase II trial was conducted by the Gynecologic Oncology Group to determine the activity of altretamine in previously treated patients with squamous cell carcinoma of the cervix. Thirty-two women with advanced or recurrent squamous cell carcinoma of the cervix were entered. The starting dose was 260 mg/m2/day for 21 days every 4 weeks. Twenty-six patients were evaluable for response and 29 were evaluable for toxicity. Among the 26 evaluable patients, 21 had received prior radiotherapy and 24 had received prior chemotherapy. A median of two courses were given (range, 1-6). Grade 3 or 4 gastrointestinal toxicity, occurring in 17%, was the most common complication (grade 3, 13.8%; grade 4, 3.4%). Grade 3 anemia was slightly less common occurring in 13.8%. Grade 3 peripheral neurotoxicity occurred in 3.4%. There were no objective responses, demonstrating that this agent is useful in previously treated squamous cell carcinoma of the cervix.

Using an 'intelligent' tablet bottle which, unknown to the patient, electronically records the times of opening, we have assessed the compliance of patients with prescribed oral altretamine for ovarian cancer. During the periods of compliance monitoring the physical and mental state of the patients was also monitored by means of self-assessed diary cards. 11 patients were assessed over 21 monitoring periods, each of 14 days, representing a total of 294 days. The Overall Compliance (OC), which we define as the number of bottle openings in a monitoring period as a percentage of that number expected on the assumption of perfect compliance, had a mean (SD) of 97.4 (6.9)% over the 21 periods. The OC was not related to any of the diary card measures, or to the cycle number (range 1-5) of the treatment. The high level of compliance is encouraging and is in line with our previous reports in patients with lymphoma and with small cell lung cancer.

After a remarkable improvement of the very poor prognosis of small cell lung cancer with very simple therapy such as iv and oral cyclophosphamide the role of oral therapy has become minimal. However, since more than a decade results of combination chemotherapy are at a plateau and it is necessary to reconsider the role of simple therapy in patients without the prospect of cure. Oral therapy might be worthwhile because it is probably less effecting the quality of life of the patient and makes it unnecessary to visit the hospital frequently. All drugs available for oral use with known activity against small cell lung cancer are reviewed. The best example of the success of oral therapy is etoposide, other candidates that need to be tested in a modern way are oral cyclophosphamide and hexamethylmelamine. New concepts of prolonged chemotherapy and dose-intensity are easier evaluated by using oral drugs. The discovery of the activity of prolonged oral etoposide is an excellent example how to test a new concept in a very simple way.

Altretamine (hexamethylmelamine) is a cytotoxic antineoplastic agent which appears to require metabolic activation. Metabolic intermediates may act as alkylating agents; however, altretamine is not directly cross-resistant with classical alkylating agents. Objective response rates to orally administered altretamine as salvage therapy in patients with advanced ovarian cancer were 0 to 33%, with disease stabilisation in a further 8 to 78% of patients. Response rates appear to be higher in patients who have responded to previous alkylating agent or cisplatin-based therapy. There is some evidence that addition of altretamine to platinum-based combination regimens used for induction therapy of advanced ovarian cancer may improve long term survival, particularly in patients with limited residual disease. Although altretamine displays some activity in small cell lung cancer, it is unlikely to have any clinical role in the management of non-ovarian cancer. Altretamine appears to be relatively well tolerated, with gastrointestinal, neurological and haematological toxicities being the main dose-limiting adverse effects. However, assessment of accurate incidence rates for these effects is complicated by the use of altretamine with cisplatin. On the basis of the emerging body of clinical evidence, altretamine appears to have a limited role in the treatment of persistent or recurrent advanced ovarian cancer, primarily in patients who are potentially platinum sensitive yet intolerant of platinum analogues. Additionally, altretamine may be added to platinum-based regimens for induction therapy of advanced ovarian cancer. At the doses currently recommended, altretamine offers a reasonably well tolerated regimen that can be administered orally and is suitable for use on an outpatient basis.

The antitumor activity of hexamethylmelamine (HMM) was evaluated using four human tumor xenografts serially transplanted in nude mice. HMM was dissolved in 0.2 ml of 1% hydroxypropyl cellulose per mouse and administered perorally daily, except on Sunday, for 4 weeks, giving an estimated maximum tolerated dose (MTD) of HMM of 75 mg/kg. The MX-1 cell line showed dose-dependent sensitivity to HMM and was completely eradicated by treatment at the MTD. The minimum effective dose of HMM against MX-1 was calculated to be 22.1 mg HMM/kg, resulting in the chemotherapeutic index of 3.4. The demethylated derivatives of HMM, pentamethylmelamine and tetramethylmelamine, were also effective against MX-1, whereas trimethylmelamine was ineffective. The effect of HMM was more marked when the drug was administered on day 1 after tumor inoculation, compared with administration during the exponential growth phase. HMM is thought to be a promising agent for the treatment of several types of human carcinoma, producing active metabolites in vivo after peroral administration.

By combining paclitaxel and cisplatin in treatment schedules for the initial treatment of advanced ovarian cancer, new hope has been engendered that we can further improve survival. With premedication, paclitaxel can be administered safely as a short infusion. The combination of paclitaxel and carboplatin is recognized as an alternative to the combination of cisplatin and paclitaxel, and is now under study to define its role in future treatment programs. Other new drugs have been recognized as active in platinum-resistant disease, including docetaxel and gemcitabine. Renewed interest arose for a chronic low dose of oral etoposide in platinum-refractory ovarian cancer. The results obtained with chemotherapy in cervical cancer have always been modest, and no combinations have been shown to result in improved survival rates as compared with single drugs. The novel biologic regimen, using retinoids and interferon, was confirmed to be active in locally advanced cervical cancer. In trophoblastic disease, the Charing Cross scoring system is a relevant pretreatment scoring system compared with the International Federation of Gynecology of Obstetrics staging. Careful recognition of prognostic subgroups can prevent under- or overtreatment.

The purpose of this report was to review second-line hexamethylmelamine (HMM) chemotherapy of epithelial ovarian cancer to determine if HMM was active in cisplatin-resistant disease. Forty-four women with measurable disease received 100-300 mg/day HMM for 14 days, courses repeated every 4 weeks. There were 6 complete and 3 partial responses for an objective response rate of 20%. Among responding patients disease-free survival was 55% and overall survival was 88% at 3 years. Five of the 6 patients with a complete response remained disease-free at 10-117 months. Only 7/35 (20%) nonresponding patients were alive with mean follow-up of 16 months, and all had persistent cancer. Five women manifesting disease progression during cisplatin or carboplatin were subsequently treated with HMM, and none responded. Seventeen patients developing progressive cancer while receiving HMM were subsequently treated with cisplatin or carboplatin and objective responses occurred in 5 (29%). HMM was an active drug against epithelial ovarian cancer previously treated with cisplatin, but further study is needed to determine its activity against cisplatin-resistant ovarian cancer.

Between March 1985 and December 1987, 34 women who had advanced adenocarcinoma of the ovary with macroscopic residual disease entered in a phase II trial of chemotherapy. Treatment consisted of a 3-month induction with monthly ifosfamide combined with 5-fluorouracil and high-dose cisplatin, and a maintenance treatment with ifosfamide, 5-fluorouracil, cisplatin and hexamethylmelamine in monthly cycles. At the end of the treatment patients with complete remission were evaluated by surgery. Neurotoxicity was a limiting factor, and treatment had to be prematurely withdrawn in 10 patients. The above treatment was found to be effective with a 94 percent objective response rate, a 54-month median survival and a 51-month median relapse-free survival. Because of the neurotoxicity, a shorter therapy and the use of neuroprotective agents may be envisaged.

A total of 61 patients with recurrent or persistent clinically measurable platin-resistant epithelial ovarian carcinoma were treated with 260 mg/m2 oral hexamethylmelamine daily for 14 days, repeated at 4-week intervals. Platin resistance was defined as progression or stable disease during cis- or carboplatin treatment (used alone or in combination with other drugs), or relapse within 6 months after the end of that therapy. Fifty patients were evaluable for response and 57 for toxicity. The objective response rate was 14% (3 complete and 4 partial responses). The response rate was higher in patients with relapse within 6 months than in patients with progression or stable disease on platin-based therapy. This observation underscores the importance of defining response and time to progression after first-line chemotherapy. The median duration of response was 8 months and the median survival in responding patients was 9+ months versus 5 months for patients with progression on hexamethylmelamine. Nausea and vomiting requiring antiemetic treatment occurred in 8 (14%) patients and reversible peripheral neuropathy in 3 patients. Two patients developed agitation, insomnia, and depression during hexamethylmelamine therapy. In conclusion, the 14% objective response rate and the occurrence of complete responses with oral hexamethylmelamine treatment in a group of ovarian cancer patients with true platin resistance are noteworthy.

A Phase II trial of an intravenous preparation of Hexamethylmelamine was performed in ovarian cancer. Patients who had received prior Platinum based chemotherapy and had measurable disease were eligible. Among 15 evaluable patients, there were no objective responses. Two patients did show clinical and laboratory evidence of improvement. Toxicity was predominantly nausea and vomiting with minimal other toxicity. This intravenous form of Hexamethylmelamine has not shown meaningful activity in ovarian cancer patients who have failed prior platinum treatment.

Chemotherapy is playing an ever increasing role in the treatment of patients with the common gynecologic malignancies, including ovarian, cervical cancer, and endometrial cancer. Chemotherapy has its most defined role in the treatment of patients with ovarian cancer where virtually all patients will receive cytotoxic chemotherapy. There are four major areas of research in chemotherapy in gynecologic malignancies. In retrospective studies it has been demonstrated that dose intensity is an important factor in maximizing response rates. Clinical studies are now prospectively evaluating the importance of dose intensity, particularly with the new platinum analogue carboplatin. In addition, it has been demonstrated in endometrial cancer and cervical cancer that patients with poor prognostic features such as high grade tumours and large volume disease have a low probability of cure by standard modalities such as surgery and radiation. In this group of patients combined modality approaches are being evaluated. In addition, regional therapy, either in the form of intra-arterial therapy for patients with cervical cancer or intraperitoneal therapy for patients with ovarian cancer, is being investigated. The primary factor limiting the effectiveness of chemotherapy in gynecologic malignancies is the development of drug resistance. It has recently been demonstrated that several drugs such as taxol, ifosfamide, and hexamethylmelamine have activity in patients who have had previous treatment with platinum-based compounds. In addition, the mechanism associated with the development of drug resistance in ovarian cancer have recently been identified. Clinical trials have been initiated with compounds such as buthionine sulfoximine in an attempt to specifically reverse resistance associated with alkylating agents and platinum compounds.

The purpose of this study was to determine the activity and toxicity of hexamethylmelamine chemotherapy in patients with persistent or recurrent epithelial ovarian cancer. Forty-nine women received hexamethylmelamine 100 to 150 mg/day for 14 days, repeated at 4-week intervals. All patients had previously received at least one chemotherapy regimen, and 46 (94%) had received cisplatin. Among 25 patients with clinically measurable disease there were three complete and two partial responses, for an objective response rate of 20%. The mean progression-free interval for responders was 38.6 months versus 9.6 months for nonresponders or patients with nonmeasurable disease (p less than 0.001). Thirteen patients are alive, eight with no clinical evidence for disease. Only four patients discontinued therapy because of toxic reactions. Hexamethylmelamine appears to be a well-tolerated drug with activity against ovarian cancer previously treated with cisplatin.

Hexamethylmelamine, an orally administered substituted melamine, has single agent activity in lymphoma (39% PR + CR), cervical cancer (28% PR), transitional carcinoma of the bladder (27% PR + CR), and Bilharzial bladder cancer (38% PR). Toxicity is mild and reversible and is manifested by myelosuppression, neurotoxicity and gastrointestinal toxicity. The potential role of hexamethylmelamine in combination chemotherapy in the diseases in which it has single agent activity is largely unexplored and should be investigated in clinical trials.

Several conclusions can be drawn from a review of HMM preclinical and clinical pharmacology data. The drug is extensively metabolized by animals and by man. The drug is well absorbed following oral administration to animals, but oral bioavailability is low due to first pass metabolism. Based on limited human data and more complete animal data, absorption of HMM following oral administration may be quite high in man. We do not yet know the oral bioavailability of HMM in patients, but again based primarily on animal studies, oral bioavailability is most likely low and variable due to extensive first pass metabolism. Systemic exposure to HMM and demethylated metabolites following oral administration varies greatly from patient to patient and is sometimes quite low. Most patients are, however, exposed to a substantial fraction of the administered dose when determined by urinary recovery of the total dose (based on parent drug and metabolites or total radioactivity) or by the total plasma AUC of parent drug and all metabolites. Systemic exposure to HMM following intravenous administration is clearly greater and less variable than following oral administration. An unresolved question is whether the highly variable and often low systemic exposure after oral administration compromise antitumor activity when compared to intravenous administration. A key issue is whether or not one accepts the hypothesis that metabolism is a prerequisite for antitumor activity. The metabolic activation studies do not rule out other mechanisms of HMM antitumor activity. Modest activity of HMM was observed after prolonged exposure to cells which did not metabolize the drug. However, most of the accumulated data are consistent with the metabolic activation hypothesis. Certainly HMM has clinical activity when administered by mouth. If metabolism is required, then exposure to the total dose (parent drug and metabolites) could be of significance even when exposure to HMM is low, since every demethylated metabolite must have come ultimately from the initial HMM demethylation. We do not know whether the initial metabolic reaction (occurring in the liver rather than in the tumor) provides sufficient exposure of tumor to reactive species. Specifically, does the variable HMM plasma AUC seen after oral administration lead to variable delivery of potentially reactive species to tumor (by rapid breakdown and/or further metabolism of MPMM before it leaves the gut and/or liver) or are quantities of MPMM delivered to tumor comparable to those delivered following intravenous administration. The issue of rate of MPMM formation compared to rate of breakdown and ultimate delivery to tumor has been noted by Judson and Rutty.(ABSTRACT TRUNCATED AT 400 WORDS)

Hexamethylmelamine has been recognized as having useful single-agent activity for the treatment of ovarian cancer for the past 25 years, with some patients surviving disease-free for periods in excess of 12 years. Data from recently analysed and mature trials demonstrate that the addition of hexamethylmelamine to first-line combination chemotherapy results in significant improvements in survival compared to what is achieved with regimens of cisplatin and cyclophosphamide with or without doxorubicin.

Hexamethylmelamine (altretamine, HMM) 260 mg/m2/day p.o. for 14 days followed by a 14-day drug-free interval was administered to 52 outpatients with advanced ovarian cancer who had previously been treated with chemotherapy. Prior to HMM, 92% (48/52) of these patients had received cisplatin and cyclophosphamide with or without doxorubicin. Two more patients received other cisplatin-based regimens. At the completion of HMM therapy, 15% (8/52) displayed no evidence of disease (NED). Of these eight patients, five are still alive 32 to 82 months after altretamine therapy (median follow-up of 46 months). At 41 months, one patient died of intercurrent illness with no clinical evidence of recurrence; the other two patients died of their disease at 21 and 31 months following HMM therapy. The median survival of the total group was 11 months: nine months for patients who did not respond to altretamine and 46+ months for patients with NED after altretamine (p less than 0.05). Intermittent oral administration of single-agent altretamine was well tolerated: eight patients reported moderate gastrointestinal symptoms, and only one patient reported severe gastrointestinal symptoms. Moderate neurologic toxicity was reported by five patients. No WBC fell below 2000 mm3 and platelet counts fell below 100,000 mm3 in only three patients; no patient experienced severe hematologic toxicity. In this series of patients, the overall response (15%) was comparable to or better than those reported for more toxic chemotherapeutic regimens. On the basis of these data and those reported by other investigators, HMM warrants consideration as a reasonable option in the management of recurrent or persistent ovarian cancer.

Altretamine is a National Cancer Institute-designated group C antineoplastic agent used in the treatment of advanced ovarian cancer. Altretamine is a highly lipid-soluble drug available only for oral administration as a capsule. The drug is activated through metabolic oxidation to intermediate methylol derivatives and formaldehyde. It is unclear which metabolite is the major species responsible for cytotoxicity or the primary mechanism of cytotoxicity. As a single agent in the treatment of ovarian cancer, altretamine demonstrates a response rate similar to other active agents in this disease (21-39 percent). The major utility of altretamine is in combination with other agents such as cyclophosphamide, doxorubicin, fluorouracil, melphalan, and cisplatin. However, few randomized trials have evaluated the contribution of altretamine in these multiagent combinations. Dose-limiting toxicities include gastrointestinal (nausea, vomiting, anorexia), hematologic, and neurotoxic (peripheral neurotoxicity). The therapeutic role of altretamine is limited because of a toxicity profile similar to that of cisplatin, one of the more active agents in ovarian cancer. Its use should be reserved for patients who are not candidates for more standard platinum-based regimens.

The lack of decisive progress in ovarian cancer chemotherapy in recent years led the ARTAC "Ovary" group to initiate a study based on the hypothesis of collateral sensitivities. In this phase I-II trial, NHO-88, the V-H combination (associating vinorelbine (VNB) and hexamethylmelamine (HMM) was studied in patients with advanced ovarian adenocarcinomas, most of which had become resistant to previous chemotherapy. The aim of the study was to find an active combination without complete cross resistance with first-line platinum salt based combinations, such as CAP, FAP or CACb-300. A pilot feasibility study was first carried out to determine the maximum tolerated weekly dose (MTWD) of VNB (20 mg/m2/week), HMM being administered per os on days 1-14 of every 28-day cycle at a standard dose of 250 mg/m2/day. An open phase II-A study was further carried out according to a 2-step sequential analysis method for phase II clinical trials. We observed: 1), a good tolerance of the V-H combination apart from frequent neutropenia; 2), a response rate of 35% (95% confidence interval: 23-47%); 3), a median response duration of 4 months (range: 1-7 months); 4), in some cases, the absence of a complete cross-resistance between the V-H regimen and the previously administered platinum-based combinations. These results, which are currently being validated (phase II-B ongoing), constitute the first step in the search for active systems of sequential or alternate chemotherapeutic regimens for the treatment of advanced carcinomas.

The data on 914 patients enrolled in four randomised trials in advanced ovarian cancer, consecutively conducted by the same cooperative group between 1978 and 1986, were analysed with the aims of: (1) determining the impact of selected prognostic variables on survival; (2) finding, from the interaction of favourable prognostic factors and treatment, an approximate estimate of the magnitude of the survival advantage associated with the use of platinum-based combination chemotherapy. The overall 3-year survival in this series of patients is twice that reported historically (22%; 95% CL 18.7-25.4). The proportional hazard regression model was used to perform the analysis on survival. Residual tumour size, age, FIGO stage and cell type were all independent determinants of survival. Differences in survival from the various prognostic groups were impressive with 5-year survival rates ranging from 7 to 62%. However, these differences were not qualitative (i.e. the kinetics of survival were similar for the best and the worst groups) suggesting that current prognostic factors are of little use for selecting 'biologically' different sub-populations. Platinum-based regimens were associated to an overall prolonged median survival, but this benefit was not observable in the subgroup with most favourable prognosis (less than 2 cm residual tumour size). The implications of these observations for clinical research and ovarian cancer patients care are discussed.

Fifty-two patients with advanced ovarian cancer were treated with single-agent hexamethylmelamine (HMM), 260 mg/m2 po per day for 14 days followed by 14 days off drug. All patients had been previously treated with chemotherapy. Of these patients, 92% (48/52) received cisplatin and cyclophosphamide +/- doxorubicin prior to hexamethylmelamine. Two additional patients received other cisplatin-based regimens. Fifteen percent (8/52) were found to have no evidence of disease (NED) at the completion of treatment with HMM. Five of these patients are alive at 12 to 65 months (median follow-up of 32 months); one patient died at 41 months of an intercurrent illness with no clinical evidence of recurrence; two patients died of recurrent tumor at 21 and 31 months. The median survival of the series of 52 patients is 11 months: 9 months for patients who did not respond versus 41 months for patients with NED post-HMM (P less than 0.05). The regimen was well tolerated: moderate gastrointestinal toxicity was reported by 8 patients; only one patient reported severe gastrointestinal toxicity. Moderate neurologic toxicity (primarily sensory) was reported by 5 patients, 3 patients experienced white counts less than 2000 or platelet counts less than 100,000, and no patient sustained severe hematologic toxicity. This moderate-dose intermittent regimen was associated with moderate toxicity and was well accepted by patients. The overall response is comparable to or higher than that reported for more toxic chemotherapy regimes. Based on these data and those recently reported by other authors, hexamethylmelamine should be considered in the treatment of recurrent ovarian cancer.

Between June 1980 and December 1984, 88 patients with stage III-IV ovarian carcinoma were entered in a study evaluating the role of debulking surgery and chemotherapy consisting of cyclophosphamide, doxorubicin, and cisplatin intravenously on day 1, every 4 weeks (CAP-1). The results after a median follow-up of 62 months (range 41-93 months) are presented. The median survival of all patients was 24 months (30 alive, 58 dead). The 5-year progression-free survival of all patients was 27% and the overall survival was 33%. Of patients with stage III disease debulked to lesions less than or equal to 1.5 cm before the initiation of chemotherapy (n = 34) the 5-year progression-free survival was 52%. Of 31 patients with a histologically documented complete response the median survival was 55+ months; 9 (29%) of them relapsed as opposed to 8 of 10 achieving microscopic residual disease at second look. Of 22 patients with stage IV disease, 20 died. This report confirms that patients who have undergone surgical removal of of bulk tumor and who achieve a complete remission have an improved survival outcome.

To evaluate the role of hexamethylmelamine (HMM) in the treatment of endometrial cancer, 20 women with metastatic or recurrent endometrial carcinoma received HMM orally at a dose of 8 mg/kg/day. Six patients (30%) showed a partial response, with a median duration of response of 3.5 months and a range of 1 to 7 months. Two patients responded to HMM as a second-line agent following previous treatment with nonhormonal chemotherapy. There were no complete responses. The major toxicities noted with HMM therapy were nausea, vomiting, and neurotoxicity. In 6 patients (30%), therapy with HMM was discontinued because of toxicity. Although HMM is active against endometrial cancer when given at a dose of 8 mg/kg/day, it appears to have limited usefulness because toxicity precludes its prolonged administration.

Curative effects of hexamethylmelamine (HMM, NSC 13875) against intramuscularly or intracerebrally implanted Yoshida sarcoma depend on the schedules. A twice daily oral administration over a 2-week period showed a significant chemotherapeutic advantage over a single daily administration. The observed curative effect depends on the tumour site and on its mass. The Yoshida sarcoma seems to be one of the most suitable test models for HMM or related derivatives.

Hexamethylmelamine (HXM) is one of the substituted melamines derived from cyanuric chloride [1]. Previous studies with HXM have shown activity against small cell carcinoma of the lung, when it was given as a single agent [2, 3]. Because of relatively mild bone marrow toxicity, HXM was subsequently given in combination with other drugs and/or radiation therapy, in order to improve the therapeutic results. In this paper, our experience with HXM in treatment of small cell carcinoma of the lung is summarised.

Twenty-five patients with previously untreated adenocarcinoma of the ovary (International Federation of Gynecology and Obstetrics, stages II, III, and IV) were placed on a six-drug trial (CHAMP-5) for 18 months. This trial consisted of 28-day cycles of hexamethylmelamine, doxorubicin, and cisplatin alternating with hexamethylmelamine, cyclophosphamide, methotrexate, and 5-FU. After a minimum follow-up of 31 months, 14 (56%) of the 25 evaluable patients achieved complete or partial response and nine (36%) achieved complete pathologic response. Although CHAMP-5 is effective in the treatment of ovarian cancer, the results in these patients are not substantially different from those achieved with hexamethylmelamine, doxorubicin, and cisplatin alone.

The M5076 reticulum cell sarcoma is a murine tumour of potential value in experimental chemotherapy. Experiments were conducted to ascertain the growth characteristics and chemosensitivity of this neoplasm in the BDF1 mouse. The intramuscular tumour proved to be responsive to the alkylating agents, nitrosoureas, procarbazine, DTIC and treosulphan, yet insensitive to the antimetabolites and only weakly responsive to adriamycin. Analogues of the antitumour agents hexamethylmelamine and N-methylformamide were tested against this neoplasm. The patterns of activity determined for these analogues against this tumour were identical to those previously reported against other model systems.

Twenty-two patients were treated with concurrent single high-dose and standard fractionated abdominopelvic radiation and chemotherapy (cisplatin or hexamethylmelamine). Those who had prior cisplatin received hexamethylmelamine and radiation (16 patients) while those without prior cisplatin received cisplatin and radiation (6 patients). The primary aim of the study was to assess the tolerance and effectiveness of concurrent radiation and chemotherapy in patients who had failed prior chemotherapy. All patients experienced mild to moderate nausea, vomiting, and diarrhea. Hematologic adverse effects were minimal. Three patients requiring laparotomy for radiation induced small bowel obstruction had confirmed complete responses but 2 died acutely of treatment-related complications without evidence of tumor. In the 15 patients with suboptimal disease (greater than 1 cm residual disease) prior to the study, only 1 had a complete response while 2 of 7 optimal patients (less than or equal to 1 cm residual disease) had a complete response. All 3 complete responders received cisplatin and 2 had 1 cm or less of residual disease prior to the study. In the hexamethylmelamine group 3 of 16 patients had a partial response. Concurrent single high-dose whole abdominopelvic radiation and cisplatin may be effective in patients with minimal disease (less than or equal to 1 cm); however, radiation-associated bowel complications were severe.