Special Feature: Moving the Bar in Primary Advanced Ovarian Cancer Therapy
Special Feature
Moving the Bar in Primary Advanced Ovarian Cancer Therapy
By Robert L. Coleman, MD, Professor, University of Texas; M.D. Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is a consultant to GlaxoSmithKline, Eli Lilly Co., Abbott Laboratories, Sanofi-Aventis, and Pfizer; and serves on the speakers bureaus for GlaxoSmithKline, Eli Lilly Co., and OrthoBiotech.
Discontent is the first step in the progress of man … ." —Oscar Wilde
It is not a great mystery that primary ovarian cancer, when presenting with metastatic intra-abdominal and/or extra-abdominal disease, represents a formidable therapeutic challenge, as these women are usually highly symptomatic, frequently of poor nutrition, and in need of aggressive dual modality therapy: surgery and chemotherapy. Advances in their care have indeed been made over the last four decades, including better and more complete surgical cytoreduction, introduction of platinum, and, more recently, paclitaxel chemotherapy, comprehensive nursing, widespread intensive care unit support, formalized thrombosis prophylaxis, and establishment of a specialty (gynecologic oncology) devoted to comprehensive and long-term management. In fact, median survival for this disease, as documented in the SEER registry, nearly doubled from 1973 to 1997.1
Unfortunately, despite these major advances in care and increased awareness, trivial gains in disease-specific mortality have been registered, with even the most optimistic 10-year survival estimates still less than 40%. The principle reason for this sobering realization is the static proportion of patients diagnosed with advanced-stage disease, which remains about 75% of the ovarian cancer cohort. It is unlikely that large gains in mortality rates will be achieved from therapeutic alterations alone. Indeed, our greatest promise lies in an effective screening/early detection strategy that induces a "stage migration" of the incident population. However, until this strategy is identified, validated, and implemented, our focus continues on the latter — developing more effective treatment options.
In 1996, a seminal paper published in the New England Journal of Medicine introduced paclitaxel to the gynecologic oncology community.2 This large phase III clinical trial of women with advanced-stage ovarian cancer left with > 1 cm residual disease following primary cytoreduction, compared cisplatin and cyclophosphamide to an experimental doublet, cisplatin and paclitaxel. The primary endpoints were overall and progression-free survival (OS and PFS, respectively). Remarkably, the substitution of paclitaxel for cyclophosphamide increased the median PFS by 6 months (median, 13-18 month) and OS by 14 months (median, 24-38 months), both of which were highly significant. Overnight, and without corroborating evidence, the treatment standard for ovarian cancer patients changed, despite the regimen being studied in only the suboptimal population: Using a 24-hour inpatient infusion protocol of paclitaxel, and incorporating cisplatin on day 2, was broadly adopted as the treatment of choice in any clinical scenario where potential platinum sensitivity was inferred. In addition, the paclitaxel infusion was shortened and carboplatin was quickly substituted for cisplatin, making the regimen one that could be administered in the outpatient setting and with less toxicity. Several years would pass before the safety and efficacy data would support this culture.3
Since this time, several attempts have been made to hit the next "home run." This has included the substitution of the novel and non-cross-resistant taxane, docetaxel, in a large international trial against paclitaxel and carboplatin.4 No progression-free or overall survival advantage was observed in the 1077-patient superiority SCOTROC trial; however, better definition of the attendant toxicities of the two regimens was recorded.
Several cooperative groups also have tried to introduce a third agent to the paclitaxel/carboplatin backbone in phase III studies, including the recently reported 4312-patient GOG 182, which also addressed the question of sequential platinum doublets.5 The two arms of this study with paclitaxel/carboplatin triplets added gemcitabine and pegylated liposomal doxorubicin, respectively. The doublets, administered for 4 cycles before 4 additional cycles of paclitaxel/carboplatin, introduced compounds with preclinical documentation of platinum synergy, namely, topotecan and gemcitabine. Despite the promise rooted in these hypotheses and the spectacular accrual, no benefit in either survival parameter was observed over paclitaxel/carboplatin.
These data became known on the cusp of the report of GOG 172 — the third of three phase III clinical studies addressing intraperitoneal (IP) chemotherapy in women with low-volume (optimal) post-surgical tumor residuum (see Table).6-8 Each of these studies was positive for OS, and the latter two were also positive for PFS. While representing just a subset of the global experience with IP, they were the largest and most rigorously conducted and contribute substantially to the recent meta-analysis touting this strategy's merit.9 However, widespread adoption has been limited by lack of a consistent experimental group (different in each of the trials), lack of a consistent control standard (GOG 104 used cisplatin and cyclophosphamide, GOG 114 and GOG 172 used cisplatin/paclitaxel), lack of a carboplatin/paclitaxel control arm (GOG 114 and GOG 172), heightened and unacceptable toxicities in the experimental arm (GOG 114 and GOG 172), and unpopular infusion schedule (GOG 172), among other concerns. Further, each of these studies lack investigation with newer biologics, particularly those targeting vascular endothelial growth factor (VEGF), which have shown substantial promise in the recurrent setting.10-12 Indeed, two phase III studies addressing the role of bevacizumab, a monoclonal antibody to VEGF, in the primary and maintenance setting (GOG 218 and ICON7), have recently completed accrual and results will not be reported for several months. Unfortunately, all the effort seemingly has amounted to little more than a "sacrifice bunt."
And then came the provocative Japanese Gynecologic Oncology Group (JGOG) phase III study comparing standard every-3-weeks paclitaxel/carboplatin to weekly paclitaxel and every-3-weeks carboplatin, reported in September in the journal Lancet.13 These investigators capitalized on a observation initially reported more than a decade ago: Paclitaxel, administered weekly (at one-third the bolus dose), could induce a similar response rate, time to progression, and overall survival to paclitaxel administered once every 3 weeks, but with less toxicity.14 Further, the weekly strategy had been shown in several phase II reports to produce responses in women felt to be taxane-insensitive or taxane-resistant.15,16 This fractionated approach is frequently referred to as "dose-dense" therapy.
In the JGOG study, the only variable distinguishing the treatment groups was the dose-dense strategy, which was also "dose-intense" as the weekly dose was 80 mg/m2 compared to 180 mg/m2 every 3 weeks (or 60 mg/m2/week) in the control group. The trial was looking for a 5-month gain in median PFS for the experimental group (16 months to 21 months), which was based on the observations of GOG 182. The trial accrued 631 patients who were evaluable for the primary endpoint of PFS. More than 80% of the treatment population was stage III-IV and approximately 45% were optimally cytoreduced following primary surgery. With a median follow-up of 42 months, PFS in the weekly paclitaxel arm is substantially longer than the control arm (median, 28.0 vs 17.2 months; hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.58-0.88; P = 0.0015) and, although OS is immature, the 3-year OS is also significantly longer (72.1% vs 65.1%; HR, 0.75; 95% CI, 0.57-0.98; P = 0.03).
It is important to note that the performance of the control group in this study was as anticipated and designed. In the primary setting, PFS usually serves as a good surrogate for OS, so as the data set matures we anticipate these initial assessments will be corroborated. The median number of cycles infused in both arms was 6, but there were more dose reductions, delays, and discontinuations with the dose-dense arm. The primary reason for these interventions was hematological toxicity. Nevertheless, except anemia, high-grade (grade 3/4) toxicity was generally uncommon and balanced between the two arms. In all, the simple strategic infusion design appears to levy substantial impact on survival parameters, and to a degree not previously observed in ovarian clinical investigation. While concerns about toxicity, under-represented serous histology cohorts, low rates of optimal cytoreduction, and lack of benefit in the clear cell histology subgroup have been raised, these were addressed in the multivariate model and don't substantially detract from this trial's exciting observations.
The strongest arguments that might be raised to curtail general adoption of this strategy into standard clinical practice would be the logistical difficulty of administering paclitaxel without any break from the weekly schedule, the question of whether a lower dose could produce the same effect, and the potential contribution of bevacizumab. Fortunately, the latter will be addressed in two planned GOG trials (GOG 252 and 262), which will randomize women with optimal and suboptimal disease, respectively, to an arm consisting of dose-dense paclitaxel with bevacizumab.
Progress in the management of women with ovarian cancer is proceeding along several fronts simultaneously, with arguably the most promising being those shooting for prevention and early detection. In addition, the world of new therapeutics targeting molecular processes of growth, proliferation, and survival is upon us and will no doubt be incorporated into our future armamentarium. However, it is remarkable that the legacy practice of dose-dense infusion appears to be one further step on this path.
References
- Barnholtz-Sloan JS, et al. Ovarian cancer: Changes in patterns at diagnosis and relative survival over the last three decades. Am J Obstet Gynecol 2003;189:1120-1127.
- McGuire WP, et al. Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and stage IV ovarian cancer. N Engl J Med 1996;334:1-6.
- Ozols RF, et al. 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.
- Vasey PA, et al. Phase III randomized trial of docetaxel-carboplatin versus paclitaxel-carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004;96:1682-1691.
- Bookman MA, et al. Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: A Phase III Trial of the Gynecologic Cancer Intergroup. J Clin Oncol 2009;27:1419-1425.
- Alberts DS, et al. Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer. N Engl J Med 1996;335:1950-1955.
- Markman M, 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 2001;19:1001-1007.
- Armstrong DK, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med 2006;354:34-43.
- Jaaback K, Johnson N. Intraperitoneal chemotherapy for the initial management of primary epithelial ovarian cancer. Cochrane Database Syst Rev 2006;(1):CD005340.
- Cannistra SA, et al. Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 2007;25:5180-5186.
- Burger RA, 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 2007;25:5165-5171.
- Garcia AA, et al. Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: A trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 2008;26:76-82.
- Katsumata N, 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 2009 Sept 18; Epub ahead of print.
- Rosenberg P, et al. Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum. Acta Oncol 2002;41:418-424.
- Markman M, et al. Phase II trial of weekly paclitaxel (80 mg/m2) in platinum and paclitaxel-resistant ovarian and primary peritoneal cancers: A Gynecologic Oncology Group study. Gynecol Oncol 2006;101:436-440.
- Markman M, et al. Phase II trial of weekly single-agent paclitaxel in platinum/paclitaxel-refractory ovarian cancer. J Clin Oncol 2002;20:2365-2369.
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