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PubMed1996

Patient compliance with prolonged oral altretamine treatment in relapsed ovarian cancer.

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.

Administration, Oral↗
PubMed1991

A comparison of hexamethylmelamine (altretamine), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) vs. cyclophosphamide, doxorubicin, and cisplatin (CAP) in advanced ovarian cancer.

We retrospectively compared the results of treatment with hexamethylmelamine (HMM), cyclophosphamide, doxorubicin, and cisplatin (H-CAP) to treatment results using cyclophosphamide, doxorubicin, and cisplatin (CAP) in patients with advanced ovarian cancer. The treatments were identical in dosage and schedule with the exception of the addition of HMM to one regimen. Fifty-five patients treated with H-CAP between August 1977 and March 1980 were compared with a subsequent group of 22 patients who received CAP between October 1984 and October 1987. Following 6 months of therapy, patients were restaged either with second-look laparotomy or with clinical restaging. Fifty-three of 55 patients (96%) and 14/21 (67%) patients had objective responses to H-CAP and CAP respectively (p = 0.001). The pathologic complete response rate as determined by second-look laparotomy was higher in the patients who received H-CAP (35% vs. 19%). The median survival of patients receiving H-CAP is 47 months compared to 21 months for the CAP patients. In limited residual disease patients (maximum tumor diameter less than or equal to 3 cm), the median survival also favored the H-CAP treatment (101 months vs. 21 months, p = 0.002). The median time to progression was greater in patients receiving H-CAP vs. those receiving CAP (67 months vs. 16 months, p = 0.045). Treatment-related toxicity was similar for the two regimens. These findings suggest that the addition of HMM to CAP chemotherapy prolongs the median survival for patients with limited residual disease advanced ovarian cancer.

Altretamine↗
PubMed1999

The effect of reimbursement policies on the management of Medicare patients with refractory ovarian cancer.

Ovarian cancer patients who are covered by Medicare are faced with therapeutic decisions that require consideration of out-of-pocket costs for oral anticancer agents and complete reimbursement for more expensive intravenous and often more toxic medications. The response rates for oral agents such as altretamine or etoposide are similar to those for intravenous paclitaxel or topotecan (14% to 26%), but the economic considerations differ markedly. Under current legislation, Medicare will completely cover the costs for the two intravenous outpatient chemotherapy regimens, but does not provide any financial support for oral regimens that do not have associated injectable formulations. This is a matter of concern for patients, as 89% prefer oral therapies. We compared the out-of-pocket costs and costs to the Medicare system of oral and intravenous agents used for refractory ovarian cancer, using published phase II and phase III data. The total cost of treatment was $18,635 for topotecan, $15,767 for paclitaxel, $7,721 for etoposide, and $4,477 for altretamine. Conversely, out-of-pocket costs for Medicare patients without Medigap coverage were highest for altretamine, at the full cost of $4,477, whereas Medicare covered all but $83 for topotecan, $37 for paclitaxel, and $66 for etoposide. Current Medicare reimbursement policies may affect patient options for cancer care. These policies are changing and should continue to change as Medicare adopts more managed care strategies.

Antineoplastic Agents↗
PubMed1993

Importance of multiagent chemotherapy regimens in ovarian carcinoma: dose intensity analysis.

BACKGROUND: In the previous meta-analysis of dose intensity (dosage) of chemotherapy in advanced ovarian cancer, we analyzed data on cyclophosphamide, altretamine (hexamethylmelamine), doxorubicin, and cisplatin. Only cisplatin showed statistically significant association of complete and partial clinical response with dose intensity. PURPOSE: This analysis updates the previous results and further characterizes response to cisplatin alone or in multiagent regimens. METHODS: We analyzed data from 18 regimens containing platinum (cisplatin or carboplatin) that were used in nine new randomized trials, in addition to data from the 60 groups of patients in our previous study in which responses were reported. Relative dose intensity was calculated as a fraction of the dosage of a drug in the standard regimen of cyclophosphamide, altretamine, doxorubicin, and platinum (CHAP). We performed single and multiple regression analyses to determine the relationship between disease outcome and relative dose intensity for cyclophosphamide, platinum, and doxorubicin alone or in combination. RESULTS: The association between outcome and dose intensity for platinum alone or in multiagent regimens was statistically significant. This association was of borderline significance for cyclophosphamide alone but was not significant for this drug in multiagent regimens. There were insufficient data to test the relationship for doxorubicin as a single agent, but in multiagent regimens, the relationship was borderline (P = .05). Multiagent regimens containing platinum produced greater response rates than platinum alone for any fixed, planned relative dose intensity for platinum. CONCLUSIONS: Our results support other published findings that use of cyclophosphamide and doxorubicin increases the efficacy of single-agent platinum. Relative dose intensity values for cyclophosphamide used alone were larger than those used in multiagent regimens, which might explain why the relationship between relative dose intensity and outcome for cyclophosphamide was not significant for use in multiagent regimens. Similarly, none of the multiagent regimens incorporated doxorubicin at a relative dose intensity for which the drug is found to be effective as a single agent. IMPLICATIONS: Prospective clinical trials are required to test the effect of higher relative dose intensity for doxorubicin and cyclophosphamide added to platinum in advanced ovarian cancer. An important element in the design of prospective trials will be to test for the relative importance of dose intensity versus total dose. This testing is best achieved in a three-arm study design such as that reported in adjuvant treatment of stage II breast cancer conducted by the Cancer and Leukemia Group B.

Altretamine↗
PubMed1999

Cost analysis of second-line therapies for platinum-refractory ovarian cancer: reimbursement dilemmas for Medicare patients.

Currently used options for salvage therapy for epithelial ovarian cancer include intravenously administered paclitaxel or topotecan and orally administered altretamine or etoposide. The response rates for these agents are similar (14-26%), whereas the type and incidence of adverse events differ. Under current legislation, Medicare will reimburse intravenous outpatient chemotherapy regimens only or oral regimens with a marketed intravenous formulation, despite that 89% of cancer patients prefer oral therapies. To compare the out-of-pocket costs and costs to the Medicare system, a cost minimization analysis of treatment with these agents was conducted using published phase II and phase III data. The total cost of treatment was $15,767 for paclitaxel, $18,635 for topotecan, $4477 for altretamine, and $5016 for etoposide. The out-of-pocket costs to the patient were $83, $37, $4477, and $6, respectively. Although a physician's first consideration in choosing a therapy is efficacy and toxicity, current Medicare reimbursement policies restrict patient options for cancer care. Because Medicare adopts managed care and health maintenance organizations into the management of patient care, cost effectiveness will likely become an important consideration in the treatment of cancer.

Aged↗
PubMed1999

Treatment of refractory and recurrent ovarian cancer.

Patients with recurrent ovarian cancer can be divided into two groups: those who have recurrence more than 6 months after primary therapy with paclitaxel/platinum (ie, platinum-sensitive) and those with tumor progression or recurrence within 6 months of primary therapy (ie, platinum-resistant). In patients with platinum-sensitive tumors and good performance status, re-treatment with paclitaxel/platinum combination therapy is usually the most appropriate choice. For patients with minimum residual disease, the greatest promise for long-term disease-free survival is associated with intensive intraperitoneal therapy with combinations of cisplatin and intravenous/intraperitoneal paclitaxel. Alternatively, patients with platinum-sensitive disease can receive intravenous carboplatin or paclitaxel. Patients with platinum-resistant ovarian cancer can benefit from single-agent therapy with altretamine, topotecan, oral etoposide, ifosfamide, liposomal doxorubicin, or other standard or investigational regimens. (Of these drugs, only altretamine and topotecan are approved by the US Food and Drug Administration for persistent or recurrent ovarian cancer.) Since the response rates achieved with these drugs are similar, patient convenience, side effects, and cost may play a significant role in drug selection.

Algorithms↗
PubMed1995

In vivo antitumor activity of hexamethylmelamine against human breast, stomach and colon carcinoma xenografts.

We have evaluated the antitumor activity of Altretamine (hexamethylmelamine, HMM) on human carcinoma xenografts serially transplanted in nude mice. Five human breast carcinoma xenografts, MX-1, T-61, MCF-7, R-27 and Br-10, were inoculated subcutaneously into female nude mice. Two human stomach carcinoma xenografts, SC-1-NU and St-4, and three human colon carcinoma xenografts, Co-3, Co-4 and Co-6, were inoculated subcutaneously into male nude mice. One pellet of 17 beta-estradiol (0.1 mg/mouse) was inoculated subcutaneously in the mice transplanted with MCF-7 when the tumors were inoculated. HMM was administered per os daily for 4 weeks. MX-1 and T-61 tumors regressed completely after treatment with HMM at a dose of 75 mg/kg (the maximum tolerated dose: MTD) for MX-1 and 25 mg/kg for T-61. Br-10 was sensitive, whereas MCF-7 and R-27 were resistant to HMM at its MTD. HMM exerted the most potent antitumor effect against T-61. Against MX-1, it exerted an antitumor effect equivalent to that of cisplatin or cyclophosphamide. In addition, this agent was effective against all stomach and colon carcinoma xenografts, in particular St-4 (T/C% = 10.7: the mean tumor weight of treated group/the mean tumor weight of control group) and Co-3 (T/C% = 31.5%) which are insensitive to presently available agents. HMM seems worthy of further clinical investigation as a candidate agent to treat breast, stomach, colon and other carcinomas.

Altretamine↗
PubMed1990

A randomized comparison of standard chemotherapy versus alternating chemotherapy and maintenance versus no maintenance therapy for extensive-stage small-cell lung cancer: a phase III study of the Eastern Cooperative Oncology Group.

The present randomized, prospective study was designed to assess whether alternating induction cyclophosphamide, doxorubicin, vincristine-altretamine (hexamethylmelamine), etoposide, and methotrexate (CAV-HEM) chemotherapy is better than standard chemotherapy (CAV) in improving response, survival, and remission time in 577 evaluable patients having extensive-disease small-cell lung cancer (SCLC). In addition, the study was designed to assess the impact of maintenance chemotherapy following a complete response (CR) on the time to progression and survival. The response rates (CR plus partial response [PR]) for CAV-HEM and CAV were 64% and 61%, respectively, but 23% of the patients on CAV-HEM achieved a CR compared with 16% for CAV alone (P = .03). Among complete responders, the continuation of therapy significantly increased the remission time for patients on CAV, while maintenance therapy for patients on CAV-HEM had no significant impact on remission time. However, the increased remission had little effect on survival. Patients on CAV maintenance therapy survived marginally longer than those patients on no maintenance therapy, whereas patients who received CAV-HEM and no maintenance therapy survived longer than those on maintenance therapy. CAV-HEM was associated with significantly higher severity of complications (ie, mainly myelosuppression) than CAV (P = .01). Maintenance chemotherapy was associated with significantly more complications than no maintenance therapy. Patients on CAV-HEM lived significantly longer than those on CAV alone (45.9 weeks v 42.7 weeks; P = .002). Ten percent of patients treated on CAV-HEM survived at least 2 years, compared with 4% on CAV alone. In our study involving patients with extensive-disease SCLC, the alternating induction chemotherapy significantly increased the CR rates and had a small impact on long-term survival compared with the results achieved with standard induction chemotherapy. Moreover, when the alternating induction chemotherapy was used, long-term maintenance chemotherapy was not needed.

Aged↗
PubMed2006

Pretreatment CA-125 and risk of relapse in advanced ovarian cancer.

PURPOSE: A previous report suggested the nadir serum CA-125 level within the group of patients with ovarian cancer who achieved normalization of CA-125 accurately defined the risk of relapse. Using similar CA-125 subgroups, we sought to determine if the baseline CA-125 level before initiation of maintenance chemotherapy in women achieving a clinically-defined complete response to primary chemotherapy would be of prognostic value. PATIENTS AND METHODS: Patients included in this retrospective analysis had been treated on one of two previously reported trials of maintenance chemotherapy (three v 12-monthly cycles of paclitaxel; oral altretamine), with a baseline CA-125 level of < or = 35 u/mL. Progression-free survival (PFS) from study entry was analyzed by the Cox regression model. RESULTS: The distribution of premaintenance baseline CA-125 levels for the 384 patients was 58%, 34%, and 8% for values of (A) < or = 10 u/mL, (B) 11 to 20 u/mL, and (C) 21 to 35 u/mL, respectively. The baseline CA-125 was highly statistically significant, either as a categoric variable (P < .001) or as a continuous variable (P < .0001). Median PFS was 24 months, 17 months, and 7 months for groups (A), (B), and (C), respectively. There was no evidence the CA-125 effect differed by trial or treatment in an interaction analysis (P = .70). CONCLUSION: The baseline CA-125 level before initiation of maintenance chemotherapy strongly predicts the risk of subsequent relapse. Patients with premaintenance baseline CA-125 values < or = 10 u/mL have a superior PFS compared with higher levels in the normal CA-125 range.

Aged↗
PubMedDate not supplied

Paclitaxel, carboplatin, and hexamethyl-melamine (taxchex) as first-line therapy for ovarian cancer.

BACKGROUND: The addition of hexamethylmelamine to therapy with cisplatin, cyclophosphamide, and doxorubicin significantly enhanced outcomes of patients with advanced ovarian cancer. Hexamethylmelamine, also known as altretamine, has potent antineoplastic activity when used as a single agent in patients who have failed to respond to both platinum-based and paclitaxel therapy. We have conducted a pilot study to evaluate the efficacy and safety of adding this drug to the popular ovarian cancer regimen of paclitaxel plus carboplatin. METHODS: Patients with advanced ovarian, fallopian tube, or primary peritoneal cancer (International Federation of Gynecology and Obstetrics stages IIA, IIIC, and IV) were prospectively enrolled to receive six cycles, repeated every 4 weeks, of paclitaxel (150 mg/m2 i.v., day 1), carboplatin (AUC 5.0 i.v., day 1), and hexamethylmelamine (150 mg/m2 p.o., days 2-15). Colony stimulating factors were prohibited. Response and toxicity were monitored by use of Eastern Cooperative Oncology Group criteria. RESULTS: Twenty patients were enrolled, 18 with ovarian cancer, one with fallopian tube cancer, and one with peritoneal cancer; 17 of these patients were evaluable for response and toxicity. At a median follow-up of 6.5 months, 13 of the patients had a complete response (76%), and four had progressive disease. Three of those with a complete response had a recurrence within 1 year of completing treatment. Toxicity was acceptable, with myelosuppression the most severe adverse effect; one patient had grade 3 anemia, one patient had grade 4 thrombocytopenia, and 12 patients had grade 4 neutropenia. Quality of life showed improvement over the course of therapy, particularly in the physical well-being subscale. CONCLUSION: The addition of hexamethylmelamine to paclitaxel and carboplatin is a well-tolerated multidrug combination for women with advanced ovarian cancer that deserves further testing in a phase III study.

Adult↗
PubMed1999

Salvage therapy for ovarian cancer.

The majority of patients with ovarian cancer will relapse after initial chemotherapy and will be candidates for salvage treatment. Currently, five agents show clear activity in patients with platinum- and paclitaxel-resistant disease: topotecan, oral etoposide, liposomal doxorubicin, gemcitabine, and, possibly, docetaxel. In addition, other agents have activity in platinum-resistant patients: vinorelbine, tamoxifen, ifosfamide, altretamine, 5-fluorouracil with leucovorin, and, possibly, irinotecan. Furthermore, selected patients may benefit from other therapeutic approaches such as surgery or radiation therapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2002

Part II: chemotherapy for epithelial ovarian cancer-treatment of recurrent disease.

For women with advanced ovarian cancer, rates of response to first-line chemotherapy are high but most patients have relapses and become candidates for further chemotherapy. Chemotherapy for recurrence can palliate symptoms, and there is some evidence that it can also improve survival in this clinical situation. Patients who relapse quickly after first-line therapy should not be given the same drugs as were used initially. However, for patients who have longer intervals from treatment to relapse, the rates of response to a rechallenge with platinum are clinically significant. Several cytotoxic drugs have shown activity in patients whose disease has relapsed after therapy with platinum and a taxane; these drugs include topotecan, etoposide, pegylated liposomal doxorubicin, epirubicin, gemcitabine, altretamine, oxali platin, and vinorelbine. Recurrent ovarian cancer is also an important setting in which to test investigational agents with promising activity, such as new platinum compounds, new taxanes, and other cytotoxic agents, as well as non-cytotoxic compounds with novel mechanisms of action.

Female↗