Challenges to the Paclitaxel/Carboplatin Algorithm in Ovarian Cancer Treatment

After years of maintaining the status quo in ovarian cancer treatment, a number of recent advances have challenged the paradigm based on intravenous (IV) taxane and platinum as the therapy of choice for advanced ovarian cancer. These new data are summarized concisely by Liu and Matulonis in this issue.[1]

Interestingly, a review of recent history reveals that a major milestone in ovarian cancer chemotherapy is reached about every 10 years. The publication of Gynecologic Oncology Group (GOG) protocol 47 in 1986 provided randomized evidence of a 4-month improvement in overall survival with the addition of cisplatin to the previous standard of doxorubicin and cyclophosphamide.[2] In 1996, GOG 111 was published, documenting a 14-month improvement in overall survival with the addition of paclitaxel to cisplatin.[3] GOG 172 was published in 2006, becoming the third in a series of GOG trials to demonstrate a survival advantage with the use of combined IV and intraperitoneal (IP) chemotherapy.[4] Despite a 17-month improvement in overall survival that triggered an NCI alert commenting on the results, combined IV/IP therapy has yet to be broadly accepted as a new standard of care.[5] Widespread acceptance of the GOG 172 regimen has been limited by the relative complexity of the treatment (especially when compared to IV paclitaxel/carboplatin); the increased potential for toxicity; the requirement for IP port placement and maintenance; and the relative lack of experience in community centers with IP chemotherapy administration. Perhaps the most challenging part about incorporating IV/IP treatment into routine management of ovarian cancer is the idea that a route of administration-rather than a particular drug, such as cisplatin in the 1980s and then paclitaxel in the 1990s-appears to be the advance.

Concurrent with the evolution of the IP chemotherapy story has been the development of targeted or biologic therapy, particularly the antiangiogenic agent bevacizumab. Results from a phase II trial in women with recurrent ovarian cancer were published in 2007 and revealed a response rate of 21%, made more remarkable by a 51.6% stable disease rate.[6] This level of activity in recurrent disease led to a randomized phase III trial in the frontline setting, GOG 218, which tested the inclusion of bevacizumab both with IV paclitaxel/carboplatin and as a maintenance strategy. Preliminary results from GOG 218 were presented at ASCO 2010, showing a significant improvement in progression-free survival in the arm where patients received bevacizumab maintenance after their initial six cycles of chemotherapy plus bevacizumab, but not in the arm where patients received bevacizumab only during their initial chemotherapy.[7] The improvement was somewhat disappointing at 3.8 months, however, making it a difficult question of whether, despite the added toxicity and expense, bevacizumab merits inclusion in frontline regimens. The overall survival data from GOG 218, when mature, as well as the results from the ongoing ICON study with a comparable design, will help inform that question. In the meantime, oncologists caring for women with ovarian cancer have been left with the decision of whether to prioritize IV/IP therapy or bevacizumab in treatment plans.

Liu and Matulonis point to the GOG's attempt to incorporate both of these treatment advances in the current phase III trial, GOG 252. An additional confounder has been introduced by recent Japanese results, which showed a benefit from weekly IV paclitaxel compared to the traditional IV dose given every 3 weeks.[8] GOG 252 incorporates bevacizumab into IV/IP therapy, while also trying to address the toxicity issue by comparing a modified GOG 172 regimen to an IP carboplatin regimen. It also addresses the dose-density issue by utilizing weekly paclitaxel in the IV arm.

Besides the renewed hope for meaningful improvement in outcomes with advanced ovarian cancer that these trials have provided, we are witnessing another development that has the potential to advance ovarian cancer care on an even more fundamental level. The pathogenesis of ovarian cancer has been exhaustively investigated but never fully elucidated. The identification of the BRCA1 and BRCA2 genes in the early 1990s, however, has allowed a population at high risk for the development of ovarian cancer to be clearly defined. These women, in turn, have been able to undergo risk-reducing bilateral salpingo-oophorectomy to manage their risk. Studies of the specimens collected at the time of prophylactic surgeries have identified an unexpectedly high rate of tubal cancers.[9] Further study of serous cancers thought to be ovarian in origin has shown the unexpectedly frequent presence of fallopian tube dysplasia (termed tubal intraepithelial neoplasia or TIC).[10] Although larger-scale confirmation of these studies is needed, the high-risk population has provided a potential insight into the development of sporadic ovarian cancer. As we move to a more mechanistic understanding of cancer therapy and its targets, these insights into the BRCA pathway may well provide the next big advance in ovarian cancer care through manipulation with agents such as PARP inhibitors. For a disease that saw only halting advances for too long, ovarian cancer is now on the verge of being better understood and more effectively treated than ever before.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References:

1. Liu J, Matulonis UA: New advances in ovarian cancer. ONCOLOGY 24: 691-698, 2010.

2. Omura G, Blessing JA, Ehrlich CE, et al: A randomized trial of cyclophosphamide and doxorubicin with or without cisplatin in advanced ovarian carcinoma. Cancer 57:1725-1730, 1986.

3. 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.

4. Armstrong DK, Bundy B, Wenzel L, et al: Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 354:34-43, 2006.

5. NCI Clinical Alert. Available online at www.nlm.nih.gov/databases/alerts/ovarian_ip_chemo.html

6. Burger RA, Sill MW, Monk BJ, et al: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: A Gynecologic Oncology Group Study. J Clin Oncol 25:5165-5171, 2007.

7. Burger RA, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab in the primary treatment of advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer: A Gynecologic Oncology Group study. Late-breaking abstract 1, ASCO 2010.

8. Katsumata N, Yasuda M, Takahashi F, et al: Dose-dense paclitaxel once a week in combination with carboplatin every 3 weeks for advanced ovarian cancer: A phase 3, open-label, randomised controlled trial. Lancet 374:1331-1338, 2009.

9. Carcangiu ML, Peissel B, Pasini B, et al: Incidental carcinomas in prophylactic specimens in BRCA1 and BRCA2 germ-line mutation carriers, with emphasis on fallopian tube lesions. Am J Surg Pathol 30:1222-1230, 2006.

10. Kindelberger DW, Lee Y, Miron A, et al: Intraepithelial carcinoma of the fimbria and pelvic serous carcinoma: Evidence for a causal relationship. Am J Surg Pathol 31:161-169, 2007.