Survival of the grade 1 cohort was then compared with that of the higher-grade serous carcinoma study cohort. Table 4 demonstrates that when stratified by extent of residual disease, those with grade 1 and no gross residual disease after surgery experienced the longest median progression-free survival at 33.2 months, followed by those with high-grade disease and no gross residual disease with a median progression-free survival of 26.8 months. In contrast, those with grade 1 and higher-grade serous carcinoma with any residual measurable disease after surgery experienced almost identical and shorter progression-free survival outcomes (14.11 months and 14.39 months, respectively; P<.001). Similarly, those with grade 1 and no gross residual disease after surgery experienced the longest median overall survival at 96.89 months, followed by those with high-grade disease and no gross residual disease with a median overall survival of 77.07 months, whereas those with low-grade and high-grade serous carcinoma with any residual measurable disease after surgery experienced much shorter median overall survival rates (42.02 months and 37.68 months, respectively; P<.001). Kaplan–Meier survival curves for those with low-grade and high-grade serous carcinoma are shown in Figure 2A and B. Finally, after controlling for other variables, when comparing the risks of progression and death for women with low-grade compared with high-grade serous carcinoma, those with low-grade tumors and measurable residual disease after primary cytoreductive surgery had adjusted HRs for disease progression (HR 2.28, P<.001) and death (HR 2.12, P=.002) similar to their high-grade counterparts with measurable disease.
Approximately 75% of women with newly diagnosed invasive epithelial ovarian cancer present with stage III or IV disease. Studies demonstrate that survival rates improve accordingly when the primary cytoreductive surgical paradigm is aggressive and incorporates radical techniques aimed at achieving microscopic residual disease.25 For purposes of uniformity, the GOG has defined optimal cytoreduction as residual implants smaller than 1 cm in diameter, although increasing evidence suggests that those women who undergo a primary cytoreductive procedure for microscopic or “no gross” residual experience the best survival outcomes.25 Despite this, it remains controversial whether the better outcome is attributable to the technical proficiency of the surgeon or the intrinsic biology of the cancer that may allow for easier removal of the tumors. Notably, in the current ancillary analysis of GOG-182, although the women in the low-grade serous ovarian carcinoma cohort were younger at diagnosis, had a lower initial serum CA 125, and had a lower likelihood of tumors that produced ascites than the high-grade serous cohort (P<.001 for all), the frequency of achieving no gross residual disease at primary cytoreductive surgery was essentially similar between the low-grade and high-grade groups (∼25%). This speaks to factors other than tumor grade and biology that may contribute to the ability to achieve optimal resection.
Although there is considerable data from phase III epithelial ovarian carcinoma trials regarding the optimal treatment of those with high-grade serous carcinoma,20 less is known about the best treatment strategies for those with grade 1 (low-grade serous) disease. In the current clinicopathologic analysis of GOG-182, only residual disease status after primary surgery was significantly associated with survival. When stratified by extent of residual tumor, patients with microscopic residual had a significantly longer median overall survival compared with those with any disease residual. Further, the HRs for progression and death for patients with residual of 0.1–1.0 cm and residual disease more than 1.0 cm were virtually identical, suggesting that patients with any residual disease did not have a durable recurrence-free interval or a robust response to adjuvant chemotherapy.
In fact, the Kaplan-Meier survival curves for the low-grade (grade 1) serous cohort in the current study illustrated a much stronger effect of residual disease than observed with the larger previously published GOG-182 study cohort.20 In other words, the survival differences in those who underwent surgery for no gross residual compared with those who were left with macroscopic disease were more striking in the low-grade cohort than in the high-grade serous cohort (Fig. 2A and B). Although it is known that high-grade serous ovarian carcinoma is moderately sensitive to platinum-based and taxane-based chemotherapy,20 the same does not appear to be true of low-grade serous carcinoma, which has a relatively low mitotic index and is considerably more chemoresistant. Consequently, it could be hypothesized that chemotherapy is relatively inactive in low-grade serous carcinoma; therefore, the potential benefit associated with maximal cytoreductive surgery may be more pronounced in this cohort than in those with high-grade disease. Our data suggest that it is of critical importance to consider an aggressive primary surgical cytoreductive effort in women with primary ovarian carcinoma, irrespective of disease grade.
There is clear biologic and pathologic evidence indicating that low-grade compared with high-grade serous tumors develop through different pathways.24,26–29 Whereas the high-grade tumors exhibit a prevalence of p53 mutations and grow rapidly, the low-grade tumors are notable for mutations in the RAS-RAF-MAPK pathways and for their indolent course. These clinicopathologic factors may account for the fact that conventional cytotoxic chemotherapy agents, including the platinum and taxane drugs, have not exhibited exceptional activity against low-grade serous carcinoma tumors.19,28 The preponderance of RAS-RAF-MAPK signaling in low-grade serous carcinoma represents an appealing therapeutic target for patients. A recent, open-label, phase II GOG study of selumetinib, a MEK 1 and MEK 2 inhibitor, was quite tolerable and demonstrated excellent activity in recurrent low-grade serous carcinoma.29 The emergence of specific targeted therapies with beneficial effects in this cohort of patients further highlights the importance of identifying those with low-grade disease by the two-tiered criteria.
An ancillary analysis of GOG protocol 158 demonstrated that patients with grade 1 serous carcinoma (a reproducible surrogate of low-grade serous ovarian carcinoma) had significantly improved survival outcomes compared with those with grade 2–3 disease.4 However, GOG-158 included only 21 women with low-grade disease, all of whom had undergone an optimal cytoreductive surgery. In contrast, the current GOG-182 ancillary study contains a substantially larger subset of patients with stage III–IV, low-grade serous carcinoma who underwent both optimal and suboptimal cytoreduction. When including “all-comers” with advanced-stage, low-grade disease, our study suggests that the survival outcomes may not be as robust as previously believed, especially when residual disease remains after primary cytoreductive surgery.
Study weaknesses include the ad hoc analysis with its intrinsic limitations and the fact that study participants received a heterogeneous array of adjuvant therapies. Study strengths include that data were prospectively collected from a phase III GOG study, tumor specimens had undergone central pathology review by gynecologic pathologists, and the large sample size of women with low-grade serous carcinoma.
Our analysis suggests that women with advanced-stage, low-grade (grade 1) serous carcinoma have a high risk of recurrence and cancer-related death. In those who are left with any gross residual disease after primary cytoreductive surgery, the risk for death is almost identical to that of women with high-grade serous carcinoma. Cytoreductive surgery with the goal of microscopic residual disease appears to improve progression-free and overall survival. Given that low-grade serous ovarian carcinoma is not exceptionally chemosensitive, it is particularly compelling to consider an attempt at maximal primary cytoreductive surgery in this population and to continue to investigate potentially active cytotoxic and targeted agents for the treatment of this disease.
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