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Journal of Clinical Oncology, Vol 25, No 20 (July 10), 2007: pp. 2865-2866 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.9544
Progress in the Management of Gynecologic Cancer1 Beth Israel Deaconess Medical Center, Boston, MA
2 Franklin Square Hospital Center, Baltimore, MD This issue of the Journal of Clinical Oncology is dedicated to recent advances in the management of gynecologic cancers, with special reference to epithelial ovarian cancer. Improvement in the survival of patients with ovarian cancer has been slow but steady over the past three decades. Although the combination of intravenous (IV) taxane and platinum chemotherapy has improved survival in newly diagnosed patients with advanced disease, most are still not cured.1 More recently, three randomized trials have demonstrated that intraperitoneal (IP) administration of cisplatin confers an additional survival advantage compared with systemic chemotherapy in newly diagnosed patients with optimally debulked, stage III epithelial ovarian cancer.2 One of these studies used a regimen of IV paclitaxel on day 1, IP cisplatin on day 2, and IP paclitaxel on day 8, yielding a 16-month prolongation of median overall survival compared with the control arm of IV paclitaxel and cisplatin therapy.3 However, a substantial number of patients (58%) could not complete this regimen due to toxicities including catheter infection and blockage, febrile neutropenia, and neuropathy. The article by Rao et al4 discusses IP therapy in detail and reviews strategies to reduce the toxicity and further improve the efficacy of this approach. In this regard, the use of IP carboplatin instead of cisplatin, the use of lower doses of IP cisplatin, and the inclusion of bevacizumab into first-line IP therapy are approaches that are currently being investigated.5 Although IP therapy has now been embraced by many physicians as a reasonable strategy in the management of selected patients with newly diagnosed epithelial ovarian cancer, we must be careful not to extrapolate to populations in which efficacy has not been demonstrated. Such patients include those with stage IV disease, those with suboptimally debulked stage III tumors, those with high-risk early-stage disease, or those with recurrent disease. Furthermore, some patients with optimally debulked, stage III disease might be poor candidates for IP therapy due to comorbid conditions such as pre-existing neuropathy, renal disease, or extensive bowel adhesions. The treatment of patients with newly diagnosed ovarian cancer involves both surgical debulking and chemotherapy administration. Our gynecologic oncology colleagues have contributed a great deal to the initial treatment of patients with this disease, as discussed in the review by Fader et al.6 Achieving an optimal cytoreduction, currently defined as having no residual lesions larger than 1 cm in diameter, is associated with improved survival.7 Whether the ability to debulk simply selects for patients who are more responsive to postoperative chemotherapy, or whether debulking itself is therapeutically useful, is a question that will most likely never be answered. Fader et al discusses the important role of surgery in this disease and also reviews the proper place for secondary cytoreductive procedures in the management of recurrence. It is likely that further improvements in the outcome of patients with advanced ovarian cancer will not be based solely on traditional cytotoxic chemotherapy approaches. The recent demonstration that triple-drug combinations are no better than the paclitaxel and carboplatin doublet is a case in point.8 In recognition of this fact, we present three articles in this issue discussing immunologic approaches9 and novel strategies designed to target the angiogenesis pathway.10,11 These authors discuss exciting developments in their respective areas, including randomized trials such as Gynecologic Oncology Group (GOG) 218, which is designed to explore the role of bevacizumab in the first-line and maintenance setting. Single-agent bevacizumab has also been shown to induce responses in patients with recurrent ovarian cancer, although enthusiasm for this approach has been tempered by the recent demonstration of an 11% incidence of bowel perforation with this agent.12 It has been suggested that the number of prior cytotoxic regimens and the presence of bowel obstruction might predispose to this complication, although our ability to identify high-risk patients requires further investigation. In addition to antiangiogenic drugs, inhibitors of novel targets such as poly-ADP ribose polymerase hold a great deal of promise in patients with relapsed disease who harbor either BRCA-1 or BRCA-2 germline mutations.13 Not all ovarian cancers are associated with a poor prognosis. Within the epithelial category, early-stage disease is often curable with surgery alone, or with surgery followed by adjuvant chemotherapy. Trope et al14 discuss the management of early-stage disease and the selection of appropriate patients for adjuvant chemotherapy. Prevention of malignant transformation is the most definitive strategy for managing epithelial ovarian cancer, and Kauff et al15 review the role of risk reduction salpingo-oophorectomy in patients with BRCA-1 or BRCA-2 germline mutations. Borderline ovarian tumors are an interesting category of epithelial ovarian tumors that do not invade, are typically early stage and chemotherapy resistant, and generally have a good prognosis. These neoplasms are reviewed by Cadron et al, 16 and a case is made for more conservative surgery in selected young women who wish to preserve fertility. It is important to note that a subset of borderline tumors can behave aggressively, with a higher chance of relapse and transformation into low grade invasive serous carcinoma.17 Such borderline tumors are often characterized by the presence of micropapillary features and invasive implants at the time of original diagnosis. Other ovarian tumors that are derived from germ cell or stromal origin are reviewed by Gershenson18 and Colombo,19 respectively. Such nonepithelial ovarian tumors are often highly curable and platinum sensitive. This is especially the case for ovarian germ cell tumors, where most patients are young and can be effectively treated with fertility-sparing surgery followed by postoperative chemotherapy when appropriate. Advances have occurred in other aspects of gynecologic oncology, including treatment of patients with cervical cancer and high-risk uterine cancer. The status of combined modality platinum and radiation therapy for patients with locally advanced cervix cancer is reviewed in detail by Monk et al.20 Advances in the management of metastatic cervix cancer have been more modest but include demonstration of a survival benefit in some patients through the use of combination topotecan and cisplatin.21 This and other chemotherapy options for the management of metastatic cervical cancer are comprehensively reviewed in Long's article.22 Perhaps the most exciting development is the prevention of this disease through vaccination against HPV serotypes 16 and 18, which are responsible for 70% of invasive cervix cancers. A review of the effectiveness of this approach and indications for vaccination is provided by Chan et al.23 Given the prevalence of invasive cervix cancer throughout the world, especially in developing countries, the availability of an effective prevention strategy is an important advance. It is astonishing that such an advance is associated with controversy, although hopefully this situation will change as society becomes more enlightened about the value of preventing a disease that can result in much pain, suffering, and death. Finally, Fleming24 provides an overview of the role of chemotherapy in the management of high-risk uterine cancers, including histologies such as papillary serous and mixed mullerian tumors (carcinosarcoma). This timely review discusses the value of platinum-based chemotherapy for high-risk patients with stages IIIC and intra-abdominal stage IVB uterine cancer, as recently demonstrated in a randomized trial performed by the GOG.25 However, as noted by Fleming, the role of adjuvant chemotherapy in the management of earlier stages of uterine cancer requires further investigation. This is an exciting time to be involved in gynecologic oncology. We designed this special issue to address the most important new developments in this field, and we hope that the readership will find it useful in the care of their patients with gynecologic cancers. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Manuscript writing: Stephen A. Cannistra Final approval of manuscript: William P. McGuire REFERENCES
1. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 334:1-6, 1996 2. Cannistra SA: Intraperitoneal chemotherapy comes of age. N Engl J Med 354:77-79, 2006 3. Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34-43, 2006 4. Rao G, Crispens M, Rothenberg ML: Intraperitoneal chemotherapy for ovarian cancer: Overview and perspective. J Clin Oncol 25:2867-2872, 2007 5. Konner JA, Fallon K, Pezzuli S, et al: A phase II study of intravenous (IV) and intraperitoneal (IP) paclitaxel (Tax), IP cisplatin (Cis), and IV bevacizumab (Bev) as first-line chemotherapy for optimal stage II or III ovarian, primary peritoneal, and fallopian tube cancer. J Clin Oncol 25:279s, 2007 (abstr 5523) 6. Fader AN, Rose PG: Role of surgery in ovarian carcinoma. J Clin Oncol 25: 2873-2883, 2007 7. Bristow RE, Tomacruz RS, Armstrong DK, et al: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis. J Clin Oncol 20:1248-1259, 2002 8. Bookman MA: GOG 182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. J Clin Oncol 24:256s, 2006 (abstr 5002) 9. Sabbatini P, Odunsi K: Immunologic approaches to ovarian cancer treatment. J Clin Oncol 25:2884-2893, 2007 10. Martin L, Schilder R: Novel approaches in advancing the treatment of epithelial ovarian cancer: the role of angiogenesis inhibition. J Clin Oncol 25: 2894-2901, 2007 11. Burger RA: Experience with bevacizumab in the management of epithelial ovarian cancer. J Clin Oncol 25:2902-2908, 2007 12. Cannistra SA, Matulonis U, Penson RT, et al: Bevacizumab in patients with advanced platinum-resistant ovarian cancer. J Clin Oncol 24:257s, 2006 (abstr 5006) 13. Yap TA, Boss DS, Fong PC, et al: First in human phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of KU-0059436 (Ku), a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in cancer patients (p), including BRCA1/2 mutation carriers. J Clin Oncol 25:145s, 2007 (abstr 3529) 14. Tropé C, Kaern J: Adjuvant chemotherapy for early-stage ovarian cancer: Review of the literature. J Clin Oncol 25:2909-2920, 2007 15. Kauff ND, Barakat RR: Risk-reducing salpingo-oophorectomy in patients with germline mutations in BRCA1 or BRCA2. J Clin Oncol 25:2921-2927, 2007 16. Cadron I, Leunen K, Van Gorp T, et al: Management of borderline ovarian neoplasms. J Clin Oncol 25:2928-2937, 2007 17. Deavers MT, Gershenson DM, Tortolero-Luna G, et al: Micropapillary and cribriform patterns in ovarian serous tumors of low malignant potential: A study of 99 advanced stage cases. Am J Surg Pathol 26:1129-1141, 2002[CrossRef][Medline] 18. Gershenson DM: Management of ovarian germ cell tumors. J Clin Oncol 25:2938-2943, 2007 19. Colombo N, Parma G, Zanagnolo V, et al: Management of ovarian stromal cell tumors. J Clin Oncol 25:2944-2951, 2007 20. Monk BJ, Tewari KS, Koh W-J: Mulitmodality therapy for locally advanced cervical carcinoma: state of the art and future directions. J Clin Oncol 25: 2952-2965, 2007 21. Long III HJ, Bundy BN, Grendys EC Jr, et al: Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: A Gynecologic Oncology Group Study. J Clin Oncol 23:4626-4633, 2005 22. Long III HJ: Management of metastatic cervical cancer: Review of the literature. J Clin Oncol 25:2966-2974, 2007 23. Chan JK, Berek JS: Impact of the human papilloma vaccine on cervical cancer. J Clin Oncol 25:2975-2982, 2007 24. Fleming GG: Systemic chemotherapy for uterine carcinoma: Metastatic and adjuvant. J Clin Oncol 25:2983-2990, 2007 25. Randall ME, Filiaci VL, Muss H, et al: Randomized phase III trial of whole-abdominal irradiation versus doxorubicin and cisplatin chemotherapy in advanced endometrial carcinoma: A Gynecologic Oncology Group study. J Clin Oncol 24:36-44, 2006
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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