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© 2003 American Society for Clinical Oncology Progress in the Management of Gynecologic Cancer: Consensus Summary StatementFrom the Department of Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center, Department of Pathology, Harvard Medical School, Division of Women’s and Perinatal Pathology, Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital, Boston; InforMEDical Communications Inc, Carlisle, MA; Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, and Institute for Drug Development Cancer Therapy and Research Center, San Antonio, TX; Department of Obstetrics and Gynecology, David Geffen School of Medicine at the University of California, Los Angeles, CA; Division of Medical Science, Fox Chase Cancer Center, Philadelphia, PA; Department of Obstetrics-Gynecology, University of Kentucky Medical Center, Lexington, KY; Department of Radiation Oncology, University of Washington Medical Center, Seattle, WA; Hematology/Medical Oncology, The Cleveland Clinic Foundation and MetroHealth Medical Center, Cleveland, OH; Franklin Square Hospital Center, Baltimore, MD; Department of Medical Oncology, Mount Vernon Cancer Centre, Northwood, Middlesex, United Kingdom; and Department of Medical Oncology, Beatson Oncology Centre, Western Infirmary, Strathclyde, Glasgow, Scotland. The conference and proceedings publication were made possible by unrestricted educational grants from Aventis Pharmaceuticals and Ortho Biotech Products, L.P. CME Sponsorship was provided by InforMEDical Communications, Inc. Address reprint requests to InforMEDical Communications Inc, 83 Acton St, Carlisle, MA 01741; email: informedical{at}aol.com.
PROGRESS IN the Management of Gynecologic Cancer, chaired by Stephen A. Cannistra, MD, was held October 25 to 26, 2002, in Cambridge, Massachusetts. The conference brought together many of the leading clinical investigators in the field of gynecologic cancer from North America and Europe, who met to contribute new information and perspectives in the field of gynecologic cancer. The proceedings of the conference will be of interest to oncologists and other medical professionals who wish to expand their knowledge of gynecologic cancer. The goals of the conference were to review several issues in the management of epithelial ovarian cancer and cervical cancer, including integration of new agents such as docetaxel into first-line treatment, role of maintenance therapy with paclitaxel after achieving a complete response in ovarian cancer, status of intraperitoneal therapy, management of patients with potentially platinum-sensitive relapse, potential screening tools for early detection of ovarian cancer, and strategies for improving combined-modality therapy of advanced cervix cancer. The final session of the conference was devoted to discussing the conclusions of the two-day meeting, which are briefly summarized below. More detail regarding each of these topics is presented by individual conference participants in the peer-reviewed manuscripts presented in this supplement.
Taxane and Platinum-Based Chemotherapy. Both the Gynecologic Oncology Group (GOG) study GOG-1111 and the European intergroup study OV102 demonstrated an improvement in disease-free and overall survival with the inclusion of paclitaxel in first-line, platinum-based therapy of patients with advanced ovarian cancer. Since that time, researchers have examined both which platinum analog has a better therapeutic index and the optimum dose and duration of infusion of paclitaxel. In that regard, GOG-1583 compared short-infusion (3-hour) paclitaxel (175 mg/m2) and carboplatin (area under the curve [AUC] of 7.5) with long-infusion (24-hour) paclitaxel (135 mg/m2) and cisplatin (75 mg/m2). The results of this study demonstrate that the carboplatin-paclitaxel combination is not inferior to cisplatin-paclitaxel in terms of survival but is associated with a more favorable toxicity profile. Nonetheless, the optimal dose of carboplatin in combination with paclitaxel is controversial, and it is not clear that a carboplatin AUC of 7.5 confers added benefit compared with lower AUCs. Interestingly, the results of ICON-3,4 which compared initial therapy with a nonpaclitaxel regimen of either single-agent carboplatin (AUC 5) or a three-drug regimen (cyclophosphamide, doxorubicin, and cisplatin) with carboplatin (AUC 5) and paclitaxel (175 mg/m2) for 3 hours, showed no significant difference in outcome between the paclitaxel-treated and non–paclitaxel-treated groups. In this trial, patients who did not receive initial therapy with paclitaxel were generally able to receive paclitaxel at time of disease progression, indicating that sequential therapy with two active agents may have similar long-term clinical outcomes compared with initial combined therapy. Until the results of ICON-3 are better understood, it is reasonable to consider taxane and platinum-based combination chemotherapy as the preferred first-line option for patients with newly diagnosed advanced disease.
In addition to paclitaxel, docetaxel is another taxane with significant activity in the treatment of patients with epithelial ovarian cancer. During the 1990s, four trials of single-agent docetaxel (100 mg/m2) were performed in platinum-pretreated, taxane-naive ovarian cancer patients.5–8 A meta-analysis9 of patients from all four trials revealed an overall response rate of 30% (95% confidence interval, 24% to 36%). Adverse effects included hypersensitivity, diarrhea, and fluid retention. However, the most commonly reported, clinically important toxic effect in these trials was myelosuppression. In all studies, significant neurologic toxic effects were rarely reported. Preliminary results from the Scottish Randomized Trial in Ovarian Cancer (SCOTROC) have recently been presented.10,11 SCOTROC compared paclitaxel (175 mg/m2 for 3 hours) or docetaxel (75 mg/m2 for 1 hour) in combination with carboplatin (dosed to achieve an AUC of 5), given for six cycles every 21 days following initial surgery. To date, no difference in response rate, median progression-free interval, or overall survival has been observed between the two arms. However, there was more neurotoxicity in the paclitaxel and carboplatin combination and more myelosuppression in the docetaxel-carboplatin combination. There was a marked difference in the incidence of clinically important neurotoxicity, with the results strongly in favor of the docetaxel and carboplatin combination. Using patient quality-of-life scales, other positive benefits of docetaxel were demonstrated in parameters such as myalgias, fatigue, and alopecia. These data indicate that the docetaxel and carboplatin combination offers another option for first-line treatment of patients with epithelial ovarian cancer, especially in those patients with pre-existing neuropathy. Whether a docetaxel dose of 75 mg/m2 in combination with carboplatin is necessary or whether lower doses may result in less myelosuppression with equal efficacy is unknown.
In 1996, the results of a study conducted by the Southwest Oncology Group (SWOG) and the GOG were published, comparing intraperitoneal cisplatin plus intravenous cyclophosphamide to intravenous cisplatin plus intravenous cyclophosphamide as initial treatment of small-volume residual advanced ovarian cancer.12 Although this study demonstrated a statistically significant improvement in overall patient survival associated with intraperitoneal therapy, the relevance of these data was unclear as the study was designed before incorporation of taxanes. Therefore, two subsequent trials13,14 were performed comparing intraperitoneal with intravenous cisplatin, with all patients also receiving paclitaxel. In the trial by Markman et al,13 patients randomly assigned to receive intraperitoneal chemotherapy experienced a statistically significant improvement in both progression-free survival (28 v 22 months, P = .01) and overall survival (63 v 52 months, P = .05). However, this survival advantage was only of borderline statistical significance when analyzed by a one-tailed t test, and the intraperitoneal regimen used in this study was associated with significant toxicity. The preliminary results of a more recent trial by Armstrong et al14 indicated that the intraperitoneal approach was associated with greater toxicity but also with an improvement in progression-free survival when compared with systemic drug delivery. Although promising, these data need to mature before the effects of intraperitoneal therapy on overall survival and quality of life can be assessed. Until that time, intravenous taxane and platinum-based therapy is a reasonable off-protocol choice for most patients with advanced disease.
Developmental chemotherapy in the setting of ovarian cancer includes platinum derivatives, taxanes, nontaxane antimicrotubular agents, nucleoside analogues, antifolates, and inhibitors of topoisomerase and other enzymes involved in DNA synthesis and repair. Because of the central role of platinum compounds, there has also been particular interest in nonplatinum agents that may accentuate the platinum response. Such agents include paclitaxel, topotecan, gemcitabine, and liposomal doxorubicin. A major focus of GOG has been the design and execution of definitive phase 3 trials to evaluate the use of such agents in front-line therapy. For example, in a phase 1 trial, GOG explored a triplet regimen of carboplatin (AUC 5, day 1), paclitaxel (135 mg/m2, day 1), and gemcitabine (800 to 1,000 mg/m2, days 1 and 8) in patients with advanced epithelial ovarian cancer (GOG-9801).15 Although the triplet regimen was found to be highly active and associated with substantial hematologic toxicity, the potential benefit of incorporating gemcitabine required phase 3 evaluation. Similar phase 1 studies have also been performed to assess the feasibility of combining other drugs, such as topotecan or liposomal doxorubicin, into first-line therapy. This background work has culminated in the development of GOG-0182-ICON5, which is a randomized trial comparing four experimental arms with a reference arm of paclitaxel and carboplatin. The four experimental arms of GOG-0182-ICON5 include topotecan, gemcitabine, or liposomal doxorubicin, and the study is also designed to investigate the relative merits of sequential doublet or triplet combinations. This trial was opened to patient enrollment in January 2001, with current accrual exceeding 1,100 patients per year, and is expected to require 3 to 4 years to complete accrual. Although larger, multiarmed phase 3 trials appear feasible with international collaboration, other strategies will need to be considered to optimally evaluate an increasing number of new cytotoxic agents, including dual randomization, bifactorial designs, streamlined tools for data management and regulatory review, core laboratory facilities, and appropriate sponsorship to enhance study accrual. In addition, strong phase 1 and 2 therapeutics trials will continue to be necessary to identify and evaluate promising new agents for future phase 3 trials.
Biologic and immunologic therapy of ovarian cancer has been conducted using cytokines, monoclonal antibodies, vaccines, and gene therapy. Results of phase 1 and 2 trials of intracavitary cytokine therapies, including interferon-alfa, interferon-gamma, and interleukin 2, have demonstrated intraperitoneal lymphoid cell stimulation and antitumor responses. Phase 2 and 3 trials of monoclonal antibodies directed toward antigens such as MUC-1 and CA-125 are ongoing, and preliminary results have shown that these agents are well tolerated. It is not yet known, however, whether this strategy will result in a survival advantage. Finally, gene therapy trials using adenoviral vectors containing a wild-type or modified p53 have shown that intraperitoneal treatment with such agents is generally well tolerated, although as yet no definite survival advantage has been proven. Agents that inhibit signal transduction are also under active study in this disease. Currently under evaluation or development are therapeutic agents that target erbB2, various farnesyl-transferases, Raf1, mitogen-activated ERK kinase inhibitors, and the mammalian target of rapamycin. Given the novel mechanism of action of these agents, it may be necessary to use nontraditional end points (such as biologic surrogates of in vivo activity) in the preliminary evaluation of these agents in the clinic.
Currently, transvaginal sonography (TVS) and serum tumor marker determinations are being explored as techniques for early detection of ovarian cancer. Both techniques are promising but have limitations. A study from the University of Kentucky16 looked at 14,469 women who were enrolled in the University of Kentucky Ovarian Cancer Screening Program; 180 of these women with persistent ovarian masses underwent surgery to remove the lesion. Seventeen women were found to have ovarian cancer, 11 of whom had epithelial ovarian cancer. Five of these epithelial cancers were stage I, three were stage II, and three were stage III. Four patients had false-negative findings on TVS. These patients developed interval ovarian cancer within 12 months of a normal scan result. Two of these patients had stage II disease and two patients had stage III disease. This study found that ovarian cancer screening with TVS had a sensitivity of 81% and survival rates of 93% at 2 years and 84% at 5 years. In a study from Hirosaki University,17 51,550 women underwent TVS for ovarian cancer screening; 324 of these women subsequently underwent surgery for abnormal test results. Ovarian cancer was found in 22 women, 77% of whom had stage I disease. The authors concluded that TVS screening was a viable method for the early detection of ovarian cancer. However, the positive predictive value for TVS was 9.4% in the Kentucky trial and 6.8% in the Hirosaki trial, requiring more than 10 laparotomies for each case of ovarian cancer detected. These studies indicate that ultrasonography can detect ovarian cancer, but the technique is limited by expense and low specificity. More work is needed to determine the ultimate value of TVS as a screening tool for ovarian cancer detection. Among the serum markers, CA-125 has been studied most extensively as a possible screening tool. At present, CA-125 is used routinely in clinical practice to determine whether patients are responding to therapy. In healthy women, isolated values of CA-125 lack adequate sensitivity and specificity to serve as an adequate screening test, but the concept of performing serial CA-125 measurement to detect a rising trend may offer a powerful new way to use this marker for screening purposes.18,19 At present, routine screening with CA-125 and TVS does not have proven value for women at standard risk for developing epithelial ovarian cancer, although two large phase 3 studies are evaluating these approaches. These tests are used in women at higher risk, such as those who carry a BRCA-1 or BRCA-2 germ-line mutation, but the value is uncertain.
The results of several landmark clinical trials have led to the practice of administering radiotherapy concurrently with platinum-based chemotherapy in the treatment of most patients with locally advanced cervical cancer.20 Nevertheless, questions remain regarding optimal scheduling, dosing, and choice of agents for radiosensitization. Future studies examining the following issues are needed: the effect of concurrent chemotherapy and prophylactic para-aortic radiation in treating patients with locally advanced cervical cancer, the value of intensity-modulated radiation therapy, the role of image-guided brachytherapy in cervical cancer treatment, and the role of radioprotectors in reducing or ameliorating treatment-related tissue injury. In addition to the use of cisplatin, several newer agents deserve further investigation as potential radiosensitizers, including paclitaxel, gemcitabine, and topotecan. In addition to advances in the treatment of locally advanced disease, progress is also being made in cervical cancer screening. The advent of human papillomavirus testing has provided significant advances in this field, but the test may currently be too expensive for widespread use throughout the world. Future research is necessary to identify more host-derived cellular makers that would serve as surrogates for high-risk human papillomavirus infection, to distinguish markers for determining which abnormal Papanicolaou smear results merit immediate attention, and to better understand the types of cells infected and their role in the evolution of cervical neoplasia. The recent discoveries in vaccines may ultimately shape the above efforts as the balance of the equation is shifted toward prevention of human papillomavirus infection and its consequences.21
Appropriate first-line chemotherapy for advanced epithelial ovarian cancer includes paclitaxel and carboplatin or docetaxel and carboplatin. The toxicity profiles of these regimens differ, with paclitaxel and carboplatin being associated with less myelosuppression but more neuropathy than the docetaxel and carboplatin regimen. On the basis of data from ICON-3, it may even be appropriate to use single-agent carboplatin in selected patients, introducing the taxane component of treatment as a second step in management, although this is a controversial move. Most patients with advanced ovarian cancer will unfortunately experience relapse. Patients who relapse after a long treatment-free interval (eg, > 6 months) are often considered to be potentially platinum sensitive and may respond again to platinum-based second-line treatment. As yet, there are no data to support the use of nonplatinum versus platinum-based second-line regimens in patients with platinum-sensitive relapse, and there are no published data to indicate that combinations are superior to single agents for most patients in this setting. In this regard, GOG-202 may eventually provide insight into these issues, as it involves a randomization to either topotecan or carboplatin, with a cross-over design in patients with potentially platinum-sensitive relapse. Until these data are available, physicians should choose second-line agents on the basis of toxicity considerations and likelihood of response, as the goal of treatment for most patients in the relapsed setting is palliation. Several biologic and immunologic therapy agents, particularly those that inhibit signal transduction, also appear to have potential in ovarian cancer treatment. Currently under evaluation or development are agents that target erbB2, various farnesyltransferases, Raf1, mitogen-activated ERK kinase inhibitors, and the mammalian target of rapamycin. In the field of cervical cancer, several newer agents, including paclitaxel, gemcitabine, and topotecan, may also play a role as radiosensitizers, although more work is needed in this area. In ovarian cancer screening, both TVS and CA-125 have been studied extensively for their role in the early detection of this disease. More recently, the concept of using serial CA-125 values to detect a rising trend represents an interesting approach to improving the value of this test for screening purposes. At present, there is no screening modality that has proven value in early detection of ovarian cancer in women with standard risk, and the value of these modalities for screening women at high risk is uncertain. Active investigation with large phase 3 screening trials will help to resolve the value of these approaches. For cervix cancer, the ability to detect human papillomavirus DNA represents an important advance in the ability to diagnose premalignant lesions.
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. Piccart MJ, Bertelsen K, James K, et al: Randomized intergroup trial of cisplatin-paclitaxel versus cisplatin-cyclophosphamide in women with advanced epithelial ovarian cancer: Three-year results. J Natl Cancer Inst 92:699, 2000 3. Ozols RF, Bundy BN, Fowler J, et al: Randomized phase III study of cisplatin/paclitaxel versus carboplatin/paclitaxel in optimal stage III epithelial ovarian cancer: A Gynecologic Oncology Group trial. Proc Am Soc Clin Oncol 18:A1373, 1999 4. The ICON Group: Paclitaxel plus carboplatin versus standard chemotherapy with either single-agent carboplatin or cyclophosphamide, doxorubicin, and cisplatin in women with ovarian cancer: ICON3 randomised trial. Lancet 360:505–515, 2002[CrossRef][Medline]
5. Francis P, Schneider J, Hann K, et al: Phase II trial of docetaxel in patients with platinum-refractory advanced ovarian cancer. J Clin Oncol 12:2301–2308, 1994 6. Kavanagh JJ, Kudelka AP, Gonzalez de Leon C, et al: Phase II study of docetaxel in patients with epithelial ovarian carcinoma refractory to platinum. Clin Cancer Res 2:837–842, 1996[Abstract]
7. Piccart MJ, Gore M, Ten Bokkel Huinink W, et al: Docetaxel: An active new drug for treatment of advanced epithelial ovarian cancer. J Natl Cancer Inst 87:676–681, 1995 8. Aapro MS, Pujade-Laruaine E, Lhomme C, et al: EORTC Clinical Screening Group: Phase II study of Taxotere in ovarian cancer. Proc Am Soc Clin Oncol 12:A809, 1993 9. Kaye SB, Piccart M, Aapro M, et al: Phase II trials of docetaxel (Taxotere) in advanced ovarian cancer: An updated overview. Eur J Cancer 33:2167–2170, 1997 10. Vasey PA: Preliminary results of the SCOTROC trial: A phase III comparison of paclitaxel-carboplatin and docetaxel-carboplatin as first-line chemotherapy for stage IC-IV epithelial ovarian cancer. Proc Am Soc Clin Oncol 20:2001 (abstr 804) 11. Vasey PA: Survival and longer-term toxicity results of the SCOTROC study: Docetaxel-carboplatin versus paclitaxel-carboplatin in epithelial ovarian cancer. Proc Am Soc Clin Oncol 21:2002 (abstr 804)
12. Alberts DS, Liu PY, Hannigan EV, et al: Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 335:1950–1955, 1996
13. Markman M, Bundy BN, Alberts DS, et al: Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: An intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol 19:1001–1007, 2001 14. Armstrong DK, Bundy BN, Baergen R, et al: Randomized phase III study of intravenous paclitaxel and cisplatin versus intravenous paclitaxel, intraperitoneal cisplatin and intraperitoneal paclitaxel in optimal stage II epithelial ovarian cancer: A Gynecologic Oncology Group trial (GOG 172). Proc Am Soc Clin Oncol 21:201a, 2002 (abstr 803) 15. Look KY, Bookman MA, Brady M, et al: Update of the phase I feasibility trial of carboplatin, paclitaxel, and gemcitabine in patients with previously untreated epithelial ovarian or primary peritoneal cancer (EOC/PPC): A Gynecologic Oncology Group (GOG) study. Proc Soc Gynecol Oncol 32:A154, 2000 (abstr 201) 16. van Nagell J, DePriest PD, Reedy MB, et al: The efficacy of transvaginal sonographic screening in asymptomatic women at risk for ovarian cancer. Gynecol Oncol 77:350–356, 2000[CrossRef][Medline] 17. Sato S, Yokoyama Y, Sakamoto T, et al: Usefulness of mass screening for ovarian carcinoma using transvaginal ultrasonography. Cancer 89:582–588, 2000[CrossRef][Medline] 18. Skates SJ, Xu F-J, Yu Y-H, et al: Toward an optimal algorithm for ovarian cancer screening with longitudinal tumor markers. Cancer 76:2004–2010, 1995[CrossRef][Medline] 19. Rosenthal AN, Jacobs IJ: The role of CA 125 in screening for ovarian cancer. Int J Biol Markers 13:216–220, 1998[Medline]
20. Thomas GM: Improved treatment for cervical cancer: Concurrent chemotherapy and radiotherapy. N Engl J Med 340:1198–1200, 1999
21. Koutsky LA, Ault KA, Wheeler CM, et al: A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 347:1645–1651, 2002
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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INTRODUCTION
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