J Korean Med Sci.  2009 Aug;24(4):679-683. 10.3346/jkms.2009.24.4.679.

Hexamethylmelamine as Consolidation Treatment for Patients with Advanced Epithelial Ovarian Cancer in Complete Response after First-Line Chemotherapy

• Kwon YS
• Nam JH
• Kim DY
• Suh DS
• Kim JH
• Kim YM
• Kim YT

• KMID: 1779203
• DOI: http://doi.org/10.3346/jkms.2009.24.4.679

Abstract

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.

Keyword

Altretamine; Consolidation Therapy; Advanced Epithelial Ovarian Cancer

MeSH Terms

Altretamine/*therapeutic use
Antineoplastic Agents, Alkylating/*therapeutic use
Antineoplastic Combined Chemotherapy Protocols/therapeutic use
Disease-Free Survival
Female
Humans
Middle Aged
Neoplasm Staging
Neoplasms, Glandular and Epithelial/*drug therapy/mortality
Ovarian Neoplasms/*drug therapy/mortality
Retrospective Studies

Figure

• 

  Fig. 1 Progression-free survival of HMM-treated and -untreated patients.

• 

  Fig. 2 Progression-free survival of patients with optimal debulked disease (residual tumor <1 cm), treated or untreated with HMM.

• 

  Fig. 3 Progression-free survival of patients with suboptimal debulked disease (residual tumor ≥1 cm), treated or untreated with HMM.

Reference

1. Ozols RF, Bundy BN, Greer BE, Fowler JM, Clarke-Pearson D, Burger RA, Mannel RS, DeGeest K, Hartenbach EM, Baergen R. Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol. 2003. 21:3194–3200.

2. Markman M, Liu PY, Wilczynski S, Monk B, Copeland LJ, Alvarez RD, Jiang C, Alberts D. Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: a Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol. 2003. 21:2460–2465.

3. McMeekin DS, Tillmanns T, Chaudry T, Gold M, Johnson G, Walker J, Mannel R. Timing isn't everything: an analysis of when to start salvage chemotherapy in ovarian cancer. Gynecol Oncol. 2004. 95:157–164.

4. Ozols RF. In : Perry MC, editor. Current controversies in ovarian cancer: maintenance chemotherapy and neoadjuvant chemotherapy as standard care. 2004 Educational Book. 2004. Spring. 40th Annual Meeting; June 5-8 2004; New Orleans, LA. Alexandria, VA: American Society of Clinical Oncology;268–275.

5. Eisenhauer EA, Vermorken JB, van Glabbeke M. Predictors of response to subsequent chemotherapy in platinum pretreated ovarian cancer: a multivariate analysis of 704 patients. Ann Oncol. 1997. 8:963–968.

6. Markman M, Bookman MA. Second-line treatment of ovarian cancer. Oncologist. 2000. 5:26–35.

7. Vergote I, Himmelmann A, Frankendal B, Scheistroen M, Vlachos K, Trope C. Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer. Gynecol Oncol. 1992. 47:282–286.

8. Rustin GJ, Nelstrop AE, Crawford M, Ledermann J, Lambert HE, Coleman R, Johnson J, Evans H, Brown S, Oster W. Phase II trial of oral altretamine for relapsed ovarian carcinoma: evaluation of defining response by serum CA125. J Clin Oncol. 1997. 15:172–176.

9. 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. 66:20–26.

10. Markman M, Blessing JA, Moore D, Ball H, Lentz SS. Altretamine (hexamethylmelamine) in platinum-resistant and platinum-refractory ovarian cancer: a Gynecologic Oncology Group phase II trial. Gynecol Oncol. 1998. 69:226–229.

11. Malik IA. Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer. Jpn J Clin Oncol. 2001. 31:69–73.

12. Alberts DS, Jiang C, Liu PY, Wilczynski S, Markman M, Rothenberg ML. Long-term follow-up of a phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer in the Southwest Oncology Group. Int J Gynecol Cancer. 2004. 14:224–228.

13. Mano MS, Awada A, Minisini A, Atalay G, Lago LD, Cardoso F, Piccart M. Remaining controversies in the upfront management of advanced ovarian cancer. Int J Gynecol Cancer. 2004. 14:707–720.

14. Gadducci A, Sartori E, Maggino T, Zola P, Landoni F, Fanucchi A, Palai N, Alessi C, Ferrero Am, Cosio S, Cristofani R. Analysis of failures after negative second-look in patients with advanced ovarian cancer: an Italian multicenter study. Gynecol Oncol. 1998. 68:150–155.

15. Thigpen JT. In : Perry MC, editor. Current controversies in ovarian cancer: maintenance chemotherapy as standard care. 2004 educational book. 2004. Spring. 40th Annual Meeting; June 5-8 2004; New Orleans, LA. Alexandria VA: American Society of Clinical Oncology;281–284.

16. Rothenberg ML, Liu PY, Wilczynski S, Hannigan EV, Weiner SA, Weiss GR, Hunter VJ, Chapman JA, Tiersten A, Kohler PC, Alberts DS. Phase II trial of oral altretamine for consolidation of clinical complete remission in women with stage III epithelial ovarian cancer: a Southwest Oncology Group trial (SWOG-9326). Gynecol Oncol. 2001. 82:317–322.

17. De Placido S, Scambia G, Di Vagno G, Naglieri E, Lombardi AV, Biamonte R, Marinaccio M, Carteni G, Manzione L, Febbraro A, De Matteis A, Gasparini G, Valerio MR, Danese S, Perrone F, Lauria R, De Laurentiis M, Greggi S, Gallo C, Pignata S. Topotecan compared with no therapy after response to surgery and carboplatin/paclitaxel in patients with ovarian cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) randomized study. J Clin Oncol. 2004. 22:2635–2642.

18. Conte PF, Gadducci A, Cianci C. Second-line treatment and consolidation therapies in advanced ovarian cancer. Int J Gynecol Cancer. 2001. 11:Suppl 1. 52–56.

19. Ames MM. Hexamethylmelamine: pharmacology and mechanisms of action. Cancer Treat Rev. 1991. 18:Suppl A. 3–14.

20. Lee CR, Faulds D. Altretamine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cancer chemotherapy. Drugs. 1995. 49:932–953.

21. Bast RC Jr, Xu FJ, Yu YH, Barnhill S, Zhang Z, Mills GB. CA 125: the past and the future. Int J Biol Markers. 1998. 13:179–187.

22. Makar AP, Kristensen GB, Kaern J, Bormer OP, Abeler VM, Trope CG. Prognostic value of pre- and postoperative serum CA 125 levels in ovarian cancer: new aspects and multivariate analysis. Obstet Gynecol. 1992. 79:1002–1010.

23. Markman M, Federico M, Liu PY, Hannigan E, Alberts D. Significance of early changes in the serum CA-125 antigen level on overall survival in advanced ovarian cancer. Gynecol Oncol. 2006. 103:195–198.

24. Podratz KC, Malkasian GD Jr, Wieand HS, Cha SS, Lee RA, Stanhope CR, Williams TJ. Recurrent disease after negative second-look laparotomy in stages III and IV ovarian carcinoma. Gynecol Oncol. 1988. 29:274–282.

25. Chiara S, Lionetto R, Campora E, Oliva C, Merlini L, Bruzzi P, Rosso R, Conte PF. The Gruppo Oncologico Nord Ovest. Long-term prognosis following macroscopic complete response at second-look laparotomy in advanced ovarian cancer patients treated with platinum-based chemotherapy. Eur J Cancer. 1995. 31A:296–301.