Japanese Journal of Clinical Oncology 31:69-73 (2001)
© 2001 Foundation for Promotion of Cancer Research
Altretamine is an Effective Palliative Therapy of Patients with Recurrent Epithelial Ovarian Cancer
Department of Medical Oncology, National Cancer Institute, Karachi, Pakistan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Background: Management of patients with recurrent epithelial ovarian cancer is difficult. Although several agents are active, responses are short-lived and observed in only a small number of patients. Side effects of these drugs are substantial. There is a need for more effective and less toxic therapies. Altretamine is a well tolerated oral agent with minimal toxicity. There are only a few trials evaluating its efficacy as a single agent in recurrent epithelial ovarian cancer.
Methods: We prospectively studied patients with recurrent epithelial ovarian cancer who were able to take oral medication and had adequate bone marrow, liver and renal functions. All had been previously treated with at least one platinum-based chemotherapy regimen and had either relapsed or failed to achieve an adequate response.
Results: Seventeen patients were studied. The commonest histological subtype was serous adenocarcinoma. Seven patients had platinum refractory disease. The mean duration of therapy was 6.1 months. Six patients (35%) achieved complete or partial remission, time to progression was 6.0 months and mean overall survival was 15.1 months. Toxicity was primarily nausea, vomiting and asthenia and was easily manageable.
Conclusion: Altretamine is an acceptable and apparently less toxic alternative to other cytotoxic drugs used for palliation of patients with recurrent epithelial ovarian cancer.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Management of patients with recurrent epithelial ovarian cancer who fail first-line platinum-based combination chemotherapy is problematic (1). Although many chemotherapeutic agents have been investigated and several have demonstrated activity, responses generally range from 8 to 35% (2–8). The results are particularly poor in those who fail to respond to cisplatin-based therapy or relapse within 6 months of treatment (9). Even amongst those who respond, the duration of response is short and almost all patients eventually die of their disease. There is a need for newer therapeutic options to improve the outcome of these patients. Since treatment at this point is mostly palliative, there is also a need for less toxic alternatives. Most of the parenteral cytotoxic drugs used for recurrent epithelial ovarian cancer have substantial side effects which further reduce the ultimate therapeutic benefit and lower patients’ acceptance of treatment.
Altretamine (Hexalen, US Biosciences, PA, USA and Hexastat, Rhône Poulenc Rorer, France) is a sym-triazine derivative that is structurally related to alkylating agents. Its exact mechanism of action is poorly understood. It has been used as part of first-line combination chemotherapy of patients with advanced epithelial ovarian cancer as well as palliation of those with recurrent disease as a single agent or in combination with other drugs (10–28). Response rates as high as 32% have been reported in patients with relapsed ovarian cancer; however, it is rarely effective in those with platinum-resistant disease (26,28). One major advantage of altretamine is that its oral use reduces the need for hospitalization. It also minimizes physical and psychological discomfort associated with the parenteral therapies. Furthermore, side effects are few and primarily related to the gastrointestinal tract.
In developing countries, altretamine is a particularly attractive agent for palliation of patients with relapsed ovarian cancer. Its oral use reduces problems associated with already compromised intravenous access, enhancing patients’ acceptability. This is particularly relevant, since intravenous access devices are not always a viable option in developing countries. Cost is also an important issue since most of the patients have to pay for the drugs. Altretamine is a cheaper alternative to other salvage therapies such as taxol and topotecan. The side effects profile is extremely favorable and there is less need for laboratory monitoring and use of growth factors. Its use, however, is limited to those able to take oral medication.
In Pakistan, ovarian cancer is the commonest cancer of gynaecological origin (29). Clinicopathological features and response to therapy do not differ markedly from other patient populations (unpublished data). We present here our experience with the management of 17 patients with epithelial ovarian cancer who received altretamine as second-line or subsequent therapy in a developing country.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Eligibility Criteria
Patients entered in this study were required to have histological proof of epithelial ovarian cancer. They should have failed first-line therapy with a platinum-based combination. Patients were required to have either progressive bidimentionally measurable disease or assessable disease with clear evidence of rising serum CA-125 levels as per Rustin et al. (30). Other eligibility criteria included: age >18 years, Eastern Cooperative Oncology Group performance status of <2, estimated life expectancy >3 months, adequate bone marrow function (WBC count >3500/cm3, neutrophil count >1500/cm3 and platelet count >100 000/cm3), normal liver function tests (bilirubin <2.0 mg/dl, transaminases and alkaline phosphatase <2 times upper limit of normal except in those with liver or bone metastasis where alkaline phosphatase could be <5 times upper limit of normal) and normal renal function tests (creatinine level <1.5 mg/dl or creatinine clearance >60 ml/min). Patients must have been off previous anticancer therapy for at least 4 weeks and should not have had major surgery in the same time period. Patients with cerebral metastases, clinically significant laboratory abnormalities, uncontrolled infection, concurrent severe medical problems unrelated to malignancy which would expose the patient to extreme risks, patients receiving another investigational drug within 30 days prior to study or receiving concurrent hormonal therapy, immunotherapy or radiation therapy (except for palliation of bone metastasis), history of allergic reactions to chemically related compounds and those pregnant or lactating were excluded from the study. Platinum resistance was defined as progression of disease while receiving platinum therapy or progression or relapse within 6 months of last treatment.
This study was conducted at the National Cancer Institute, Karachi, Pakistan from August 1, 1995 until December 30, 1998. Written informed consent was obtained from each patient before study entry. The study was conducted in accordance with Good Clinical Practices and the Declaration of Helsinki as amended in Hong Kong (1989). The Institutional Human Subjects Committee approved the protocol. No pharmaceutical company or governmental agency supported the study. Information was collected prospectively by the data managers assisted by junior physicians.
Pretreatment Evaluation and Treatment Plan
Pretreatment evaluation included complete history, physical examination, evaluation of performance status, urinalysis, chest X-ray, diagnostic studies required for disease assessment such as ultrasound abdomen and pelvis or CT scan and serum CA-125 levels. The treatment plan involved altretamine 200 mg/m2 per day orally in three divided doses for 21 consecutive days. Treatment cycles were repeated every 28 days provided the patient had recovered from any drug-related toxicity associated with the previous course. After initial experience with five patients, subsequently they were started on 100 mg/m2 during the first cycle increasing to full dosage by the end of the first week. Toxicity grades were reviewed after each course of therapy. Patients were continued on therapy until complete remission (and two cycles beyond) was achieved, disease progression was observed or unacceptable toxicity occurred. Patients were withdrawn from the study if there was >2 weeks delay in treatment because of toxicity. During treatment, complete blood counts were obtained at mid-cycle and before the start of the next cycle. Blood chemistries including renal and hepatic profiles were repeated as required. CA-125 levels and indicator lesions were assessed after every two cycles of therapy.
Toxicity and Response Evaluation
All toxicities were assessed according to National Cancer Institute toxicity criteria (31). Hematological and non-hematological toxicities were evaluated prior to the next cycle of therapy. Responses were determined according to WHO criteria (32). Complete remission (CR) required total disappearance of all measurable disease as determined by two measurements not less than 4 weeks apart and normalization of serum CA-125 level. Partial remission (PR) was defined as >50% decrease in the sum of two perpendicular diameters of all measurable lesions at least 4 weeks apart and with no new lesion or progression of any lesion. Progressive disease (PD) required documentation of >25% increase in a single measurable lesion, reappearance of measurable disease, clear worsening of assessable disease or the development of a new metastatic lesion. Stable disease (SD) was defined as tumor measurement not fulfilling the criteria for response or progression and lasting at least 8 weeks. The duration of response was measured from the time of initial documented response to the first signs of disease progression. Time to progression was measured from the time of first study drug administration to documented progressive disease. Survival was measured from the time of initial drug administration to the most recent evaluation or death.
Statistical Methods
The Epi Info statistical package (Center for Disease Control, Atlanta, GA) was used for analysis.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Seventeen patients were studied; all were evaluable. Demographic features of the patients are provided in Table 1. The majority had serous cyst adenocarcinoma. In two patients, proper histological sub-typing and grading could not be done because the diagnosis was based upon fine needle aspiration biopsy or cytological analysis of the ascitic fluid. At the time of initial diagnosis, 15 patients had bulky post-operative residual disease. The commonest first-line chemotherapy regimen utilized had been carboplatin and cyclophosphamide. Most of the patients had received at least two chemotherapy regimens and had responded to the first-line therapy. The most common evaluable disease site was the pelvis (seven patients). Five had rising CA-125 levels and ascites as the only clinical and radiological evidence of disease. Three patients had liver metastases. Seven patients were considered to have platinum refractory disease. Table 2 provides information regarding response to therapy, duration of response and toxicity. Six patients responded to therapy. Only one patient with platinum-refractory disease responded (as defined in the eligibility section). Duration of response was 8.2 ± 5.6 months. Time to progression was 6.0 ± 4.3 months and overall survival was 15.1 ± 9.8 months. Treatment was extremely well tolerated. Duration of each treatment cycle was planned as 4 weeks (with altretamine administered daily for the first 3 weeks). This was possible in 95% of the cycles. More commonly, (15% of cycles) the drug could not be taken on all days due to nausea, vomiting or asthenia. No significant hematological toxicity was observed. Common side effects included nausea, vomiting and asthenia. Metoclopramide 10–20 mg orally before meals was used for GI symptoms on a PRN basis. In patients with more severe symptoms, oral serotonin antagonists such as ondansetron were utilized. Patients with severe asthenia with concomitant anemia received a trial of recombinant erythropoietin. No patient was withdrawn from the study due to severe gastrointestinal side effects.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The use of altretamine as a single agent or in combination with other drugs has been previously evaluated in patients with ovarian cancer (10–29). As a single agent in patients receiving primary therapy with altretamine, a response rate of 41% was observed (10). Very high response rates have been reported with altretamine as part of first-line combination chemotherapy (12–17). These compare favorably with other combination chemotherapy regimens. As a single agent in recurrent cases, response rates vary between 10 and 46%, depending upon the patient population studied (23–29). Altretamine, however, appears to be ineffective when administered intravenously (33). It is also not beneficial for those with platinum-resistant disease (28). Long-term disease control has also been achieved in some cases (26). Our results are similar to the published reports. We, however, did have one responder amongst those with cisplatin-refractory disease.
The most appropriate dose and scheduling of altretamine remain unknown. We used 200 mg/m2 for 21 days every 4 weeks. This is different than the more commonly used method of 260 mg/m2 for 14 days in a 4 weeks cycle. Our schedule actually is slightly more dose intense (4200 versus 3640 mg/m2 per cycle). The response observed with this schedule is very encouraging and these results were achieved with minimal toxicity. No significant bone marrow suppression was observed except for the need of transfusion in two cases. Nausea and vomiting were easily manageable, although three patients required chronic use of anti-emetics. Usually nausea and vomiting were worst in the first cycle. Once we started using a lower starting dose and increasing it to full doses over a week, gastric tolerance further improved.
There are several options for patients who relapse after first-line combination chemotherapy of epithelial ovarian cancer. In patients with platinum-sensitive disease, probably the best option is to repeat the use of platinum alone or in combination with other drugs. In patients who have not received paclitaxel as part of the initial regimen, its use is associated with a favorable response in about a quarter of patients (4–6). More recently, topotecan and doxil have been approved for use in patients with relapsed epithelial ovarian cancer (7,8,34). The response rates to these agents vary between 15 and 25%. Side effects, however, including alopecia, myelosuppression, peripheral neuropathy, hand–foot syndrome, etc., are substantial, frequent and very disturbing to the patients. The influence of these agents on the quality of life of a patient with relapsed ovarian cancer has not been extensively evaluated. Furthermore, these agents require parenteral administration in the physician’s office or hospital, a very unattractive proposition for patients with relapsed cancer requiring palliation alone. Oral agents certainly would be preferable. Etoposide is an active oral agent in relapsed ovarian cancer. It can, however, cause severe myelosuppression and GI toxicity (3). Although no direct comparisons have been made, altretamine appears to have a more favorable toxicity profile while maintaining a similar degree of efficacy. However, one major drawback is restriction of its use to those able to take oral drugs. Ovarian cancer patients frequently have gastrointestinal problems related to tumor deposits or ascitis. We have been able to use this agent successfully in some of these patients by initially relieving their symptoms with repeated paracentesis.
In conclusion, we observed a very favorable response rate with the use of oral altretamine in patients with relapsed epithelial ovarian cancer. Toxicity was minimal and treatment was extremely well tolerated. This regimen offers an excellent therapeutic option to those able to tolerate oral medications.
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FOOTNOTES |
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+ For reprints and all correspondence: Imtiaz A. Malik, University of Cincinnati – Barrett Cancer Center, 234 Goodman Street, Cincinnati, OH 45267–0501, USA. E-mail: malikia@ucmail.uc.edu
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REFERENCES |
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1 Young RC, Perez CA, Hoskins WJ. Cancer of the ovary. In: DeVita VT Jr, Hellman SA, editors. Cancer: Principles and Practice of Oncology, 4th ed. Philadelphia, PA: Lippincott 1993;1126–263.
2 Baker TR, Piver MS, Hempling RE. The addition of etoposide and ifosfamide to cisplatin as second-line therapy in ovarian carcinoma. Eur J Gynecol Oncol 1993;14:18–22.[Medline]
3 Hoskins P, Swenerton KD. Oral etoposide is active against platinum-resistant epithelial ovarian cancer. J Clin Oncol 1994;12:60–3.[Abstract]
4 Einzig AI, Wiernik PH, Sasloff J, Runowicz CD, Goldberg GL. Phase II study and long term follow-up of patients treated with Taxol for advanced ovarian cancer adenocarcinoma. J Clin Oncol 1992;10:1748–53.
5 Thigpen JT, Blessing JA, Ball H, Hummel SJ, Barrett RJ. Phase II trial in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecological Oncology Group study. J Clin Oncol 1994;12:1748–53.
6 Eisehauer EA, ten Bokkel Huinink WW, Swenerton KD, Gianni L, Myles J, van der Burg ME, et al. European–Canadian randomized trail of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994;12:2654–66.
7 Swisher EM, Mutch DG, Rader JS, Elbendary A, Herzog TJ. Topotecan in platinum- and paclitaxel-resistant ovarian cancer. Gynecol Oncol 1997;66:480–6.[Web of Science][Medline]
8 ten Bokkel Huinink W, Gore M, Carmicheal J, Gordon A, Malfetano J, Hudson I, et al. Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 1997;15:2183–93.
9 Markman M, Hoskins W. Responses to salvage chemotherapy in ovarian cancer: a critical need for precise definitions of the treated population. J Clin Oncol 1992;10:513–4.
10 Wharton JT. Hexamethylmelamine (altretamine) activity as a single agent in previously untreated advanced ovarian cancer. Cancer Treat Rev 1991;18(suppl A):15–21.
11 Young RC. Hexamethylmelamine (altretamine): early National Cancer Institute trials. Cancer Treat Rev 1991;18(suppl A):31–5.
12 Sessa C, Colombo N, Bolis G, Marsoni S, Mangioni C. Randomized comparison of hexamethylmelamine, adriamycin;cyclophosphamide (HAC) vs. cisplatin, adriamycin, cyclophosphamide (PAC) in advanced ovarian cancer: long-term results. Cancer Treat Rev 1991;18(suppl A):37–46.
13 Greco FA, Johnson D, Hainsworth JD. A comparison of hexamethylmelamine (altretamine), cyclophosphamide, doxorubicin and cisplatin (H-CAP) vs. cyclophosphamide vs. cyclophosphamide, doxorubicin and cisplatin (CAP) in advanced ovarian cancer. Cancer Treat Rev 1991;18(suppl A):47–55.
14 Neijt JP, van Lindert ACM, Vendrik CPJ, Roozendaal KJ, Stuyvenberg A, Pinedo HM. Treatment of advanced ovarian carcinoma with a combination of hexamethylmelamine, cyclophosphamide, methotrexate and 5-fluorouracil (Hexa-CAF) in patients with and without previous treatment. Cancer Treat Rep 1980;64:323–6.[Web of Science][Medline]
15 Bruckner HW, Cohen C, Mandeli J, Chesser MR, Kabakow B, Wallach R, et al. Hexamethylmelamine for the treatment of ovarian cancer – the Mount Sinai experience. Cancer Treat Rev 1991;18(suppl A):57–65.
16 Kristensen GB, Baekelandt M, Vergote IB, Trope C. A phase II study of carboplatin and hexamethylmelamine as induction chemotherapy in advanced epithelial ovarian carcinoma. Eur J Cancer 1995;31A:1778–80.
17 Frasci G, Comella G, Comella P, Conforti S, Mastrantonio P, Zullo F, et al. Carboplatin (CBDCA) – hexamethylmelamine (HMM) – oral etoposide (VP-16) first-line treatment of ovarian cancer patients with bulky disease: a phase II study. Gynecol Oncol 1995;58:68–73.[Web of Science][Medline]
18 Johnson BL, Fisher RI, Bender RA, De Vita VT Jr, Chabner BA, Young RC. Hexamethylmelamine in alkylating agent-resistant ovarian carcinoma. Cancer 1978;42:2157–61.[Web of Science][Medline]
19 Omura GA. Hexamethylmelamine in mustard-resistant ovarian adenocarcinoma. Cancer Treat Rep 1981;65:530–1.[Web of Science][Medline]
20 Bonomi PD, Mladineo J, Morrin B, Wilbanks G Jr, Slayton RE. Phase II trial of hexamethylmelamine in ovarian carcinoma resistant to alkylating agents. Cancer Treat Rep 1979;63:137–8.[Web of Science][Medline]
21 Yogl SE, Pagano M, Kaplan BH, Einhorn N, Arseneau J, Moukhtar M, et al. Combination chemotherapy of advanced ovarian cancer with hexamethylmelamine, cis-platinum and doxorubicin after failure of prior therapy. Obstet Gynecol 1980;56:635–40.[Web of Science][Medline]
22 Tempero MA, Kessinger A. Hexamethylmelamine and melphalan as salvage therapy in advanced ovarian carcinoma. J Surg Oncol 1982;21:159–61.[Web of Science][Medline]
23 Moore DH, Fowler WC, Jones CP, Crumpler LS. Hexamethylmelamine chemotherapy for resistant or recurrent epithelial ovarian cancer. Am J Obstet Gynecol 1991;165:573–6.[Web of Science][Medline]
24 Fields AL, Schink JC, Miller DS, Rademaker AW, Lurain JR. Oral hexamethylmelamine: an effective salvage therapy for recurrent ovarian cancer. Int J Gynecol Obstet 1991;Abstract 2048:515.
25 Vergote I, Himmelmann A, Frankendal B, Scheistrøen M, Vlachos K, Tropé, C. Hexamethylmelamine as second-line therapy in platinum-resistant ovarian cancer. Gynecol Oncol 1992;47:282–6.[Web of Science][Medline]
26 Manetta, A, Tewari K, Podczaski ES. Hexamethylmelamine as a single second-line agent in ovarian cancer: follow-up report and review of the literature. Gynecol Oncol 1997;66:20–5.[Web of Science][Medline]
27 Schink J, Harris L, Grosen ER, Balley HH. Altretamine (Hexalen): an effective salvage chemotherapy after paclitaxel (Taxol) in women with recurrent platinum resistant ovarian cancer. Proc Am Soc Clin Oncol 1995;14:275.
28 Markman M, Blessing JA, Moore D, Ball H, Lentz SS. Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecological Oncology Group phase II trial. Gynecol Oncol 1998;69:226–9.[Web of Science][Medline]
29 Malik I, Khan WA, Khan ZK. Pattern of malignant tumors observed in a university hospital: a retrospective analysis. J Pak Med Assoc 1998;48:120–2.[Medline]
30 Rustin GJS, Nelstrop AE, Crawford M, Ledermann J, Lambert HE, Coleman R, et al. Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA-125. J Clin Oncol 1997;15:172–6.
31 National Cancer Institute. Guidelines for Reporting of Adverse Drug Reactions. Bethesda, MD: Division of Cancer Treatment, National Cancer Institute 1988.
32 World Health Organization. Handbook for Reporting Results of Cancer Treatment. WHO Publication No. 48. Geneva: World Health Organization 1979.
33 Hauge MD, Long HJ, Hartmann LC, Edmonson JH, Webb MJ, Su J. Phase II trial of intravenous hexamethylmelamine in patients with advanced ovarian cancer. Invest New Drugs 1992;10:229–301.
34 Muggia FM, Hainsworth JD, Jeffers S, Miller P, Groshen S, Tan M, et al. Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 1997;15:987–93.
Received September 13, 2000; accepted November 13, 2000.
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