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Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase
Gynecologic Oncology 140 (2016) 457–462
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Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase Jacek P. Grabowski a,h,⁎, Philipp Harter a, •, Florian Heitz a, Eric Pujade-Lauraine b, Alexander Reuss c, Gunnar Kristensen d, Isabelle Ray-Coquard e, Julia Heitz f, Alexander Traut a, Jacobus Pfisterer g, Andreas du Bois a a
Department of Gynecology and Gynecological Oncology, Kliniken Essen Mitte, Henricistrasse 92, 45136 Essen, Germany Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Oncology Department, Universite Paris Descartes, AP-HP, Hopitaux Universitaires Paris Centre, Site Hotel Dieu, Paris, France c Koordinierungszentrum fuer Klinische Studien, Philipps-Universitaet Marburg, Karl-von-Frisch-Str. 4, 35043 Marburg, Germany d Nordic Society of Gynaecological Oncology Group (NSGO), Department of Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, PB4953 Nydalen, 0424 Oslo, Norway e Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Université de Lyon-Centre Léon Bérard, Department of Medical Oncology and EA SIS, 4128 Lyon, France f Department of Gynecology and Obstetrics, Klinikum Duisburg, Zu den Rehwiesen 9-11, 47055 Duisburg, Germany g Gynecologic Oncology Center, Kiel, Herzog-Friedrich-Str. 21, 24103 Kiel, Germany h Department of Gynecology, European Competence Center for Ovarian Cancer, Charite-University Medicine of Berlin, Augustenberger Platz 1, 13353 Berlin, Germany b
H I G H L I G H T S • Primary low-grade serous ovarian cancer (LGSOC) is not as responsive to platinum-taxane-based chemotherapy as high-grade serous advanced ovarian cancer (HGSOC) • Surgical debulking showed a similar impact on outcome in primary LGSOC and HGSOC however LGSOC were associated with better prognosis • LGSOC is less responsive to platinum-taxane-based chemotherapy Surgical debulking showed a similar impact on outcome in LGSOC and HGSOC
a r t i c l e
i n f o
Article history: Received 28 October 2015 Received in revised form 18 January 2016 Accepted 21 January 2016 Available online 22 January 2016 Keywords: Low-grade serous ovarian cancer High-grade serous ovarian cancer Platinum chemotherapy Objective response
a b s t r a c t Objective. Since almost two decades standard 1st-line chemotherapy for advanced ovarian cancer (AOC) has been a platinum/taxane combination. More recently, this general strategy has been challenged because different types of AOC may not benefit homogenously. Low-grade serous ovarian cancer (LGSOC) is one of the candidates in whom efficacy of standard chemotherapy should be revised. Methods. This study is an exploratory case control study of the AGO-metadatabase of 4 randomized phase III trials with first-line platinum combination chemotherapy without any targeted therapy. Patients with advanced FIGO IIIB\\IV low-grade serous ovarian cancer were included and compared with control cases having high-grade serous AOC. Results. Out of 5114 patients in this AGO database 145 (2.8%) had LGSOC and of those thirty-nine (24.1%) had suboptimal debulking with post-operative residual tumor N1 cm, thus being eligible for response evaluation. An objective response was observed in only 10 patients and this 23.1% response rate (RR) was significantly lower compared to 90.1% RR in the control cohort of high-grade serous ovarian cancer (HGSOC) (p b 0.001). Both, LGSOC and HGSOC patients who underwent complete cytoreduction had significantly better progression free survival (PFS) and overall survival (OS) in comparison to those with residuals after primary surgery, accordingly (p b 0.001). Conclusions. Our observation indicates that low-grade serous cancer is not as responsive to platinum-taxane-based chemotherapy as high-grade serous AOC. In contrast, surgical debulking showed a similar impact on outcome in both types of AOC thus indicating different roles for both standard treatment modalities. Systemic treatment of low grade serous AOC urgently warrants further investigations. © 2016 Elsevier Inc. All rights reserved.
1. Introduction ⁎ Corresponding author at: Department of Gynecology and Gynecological Oncology, Kliniken-Essen-Mitte, Henricistr. 92, 45136 Essen, Germany. E-mail address: [email protected] (J.P. Grabowski).
http://dx.doi.org/10.1016/j.ygyno.2016.01.022 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Malpica et al. introduced in 2004 a two-tier grading system in epithelial ovarian cancers dividing tumors in low- and high-grade
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according to the degree of nuclear atypia [1]. Low-grade category characterizes the presence of mild to moderate nuclear atypia. They show up to 12 mitoses per 10 high power fields (HPFs), whereas the high-grade more than 12 mitoses per 10 HPFs. According to Malpica et al. the mean age of patients with low-grade serous ovarian cancer (LGSOC) was significantly lower in comparison to those with high-grade serous ovarian cancer (HGSOC) [1]. In parallel, Shih and Kurman introduced the concept of two pathways leading to either HGSOC or LGSOC [2]. This model indicates that both types are not only differentially graded neoplasm of the same type, but rather two distinct tumor types with different underlying pathogenesis, molecular events, clinical and epidemiological features. Related to this theory BRAF and KRAS mutations were detected in LGSOC, whereas p53 mutational status is characteristic for HGSOC. In this scenario, LGSOC arises in a stepwise fashion from benign cystadenoma through atypical hyperplasia/borderline tumor, which eventually progresses to an invasive LGSOC [2–8]. Stage and surgical outcome (i.e. complete resection without any macroscopic post-operative tumor residuals) as surrogates of initial tumor load and post-operative tumor load have been described as most important prognostic factors in advanced ovarian cancer (AOC) [9]. Another significant factor positively associated with superior outcome is quality of treatment both surgically and with respect to systemic treatment [10]. Currently, chemotherapy consisting of platinum-taxane combination with or without bevacizumab is prescribed to almost all histological types of AOC. However, analyses of another trial metadatabase could show that outcome differs substantially according to different histological types. Especially mucinous and clear cell histology were associated with inferior outcome compared to serous AOC [11]. More recently, the “one-size-fits-all-concept” has also been challenged for LGSOC, a small subgroup of AOC [12–14]. The aims of this study were twofold: (1) to evaluate the efficacy of standard first-line chemotherapy with platinum-paclitaxel in previously untreated low-grade serous advanced ovarian cancer and compare this to high-grade serous AOC, and, (2) to evaluate if both serous subtypes differ with respect to the prognostic responsiveness to surgical debulking. 2. Methods This study was an exploratory analysis of the metadatabase of the AGO-OVAR 3 [15], AGO-OVAR 5 [16], AGO-OVAR 7 [17], and AGOOVAR 9 [18] phase III trials. All four trials had been fully published and included patients with epithelial ovarian cancer stages FIGO IIIB\\IV who had received upfront surgery followed by 6 courses platinumpaclitaxel. AGO-OVAR 3 introduced carboplatin-paclitaxel comparing it to cisplatin-paclitaxel and AGO-OVAR 5, 7 and 9 evaluated triple drug regimens adding epirubicin, or topotecan, or gemcitabine to carboplatin-paclitaxel. None of the 4 trials did show any significant difference with respect to progression-free (PFS), and overall survival (OS). Only AGO-OVAR 9 showed a higher objective response rate in patients treated within the experimental arm. The AGO-OVAR 5, 7 and 9
trials were multinational intergroup trials with AGO-Study Group Germany and GINECO France and NSGO Scandinavia joined this axis for AGO-OVAR 9 [16–18]. Patients with serous ovarian cancer in advanced disease stage FIGO IIIB\\IV were included in our study. For the chemotherapy-sensitivity analysis, women who underwent incomplete initial surgery with macroscopic residuals N1 cm in diameter after primary surgery (to allow response assessment) were investigated. Tumor measurements using radiologic imaging were performed before chemotherapy start (baseline) and at least after the last cycle in patients with measurable or assessable disease. The tumor assessment methods (i.e., ultrasound, Xray, computed tomography, or magnetic resonance imaging) that were employed for baseline measurement were also used for each repetitive evaluation. Tumor response was classified according to the definitions of the World Health Organization (WHO) in AGO-OVAR 3, 5 and 7 and Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) in AGOOVAR 9 [19,20]. The pathological findings were determined by a standardized central review in AGO-OVAR 3 study. The other trials were performed in the same centers, however without central pathology review. For further analysis of surgical parameters all patients with serous histology were identified and divided according to residual tumor after primary surgery into three subgroups: residuals N 10 mm, residuals 1–10 mm and complete cytoreduction (no macroscopic residual disease). The response to chemotherapy was investigated only in the first subgroup of patients with large post-operative tumor residuals, while the impact of primary surgery outcome was evaluated in all mentioned subgroups. Furthermore, we compared LGSOC with high-grade (previously grade 2 and 3) serous ovarian cancer patients using the following criteria for matching: (1) FIGO stage, (2) residual tumor size after primary surgery (residuals 1–10 mm and N1 cm), (3) serous histopathology, (4) age (±3 years), (5) Eastern Cooperative Oncology Group (ECOG) performance status, (6) specific trial, and (7) number of chemotherapy cycles received. Control HGSOC patients cohort who underwent cytoreduction with residuals 1–10 mm and N1 cm were randomly selected in a 2:1 ratio from the metadatabase. The number of LGSOC patients who underwent complete cytoreduction was significantly higher in comparison to those LGSOC with residual tumor, therefore a 1:1 selection ratio was applied to match control HGSOC group. Overall survival (OS) was calculated from randomization until death from any cause or censored on the date of the last follow-up. Progression-free survival (PFS) was defined as the time from randomization to disease progression or death from any cause; patients who were still alive without progressive disease at the time of analysis were censored on the date of their last follow-up. Kaplan-Meier estimates were calculated with Graph Pad Prism 4.02 (La Jolla, California). All other statistical analyses were performed using SPSS 18.0 (Chicago, Illinois). The comparison of two or more groups of discrete variables was performed with Fisher's exact test or the χ2 test, and metric variables were tested with appropriate non-parametric methods (Kruskal-Wallis test). The Kaplan-Meier method including a
Table 1 Characteristics of patients with LGSOC and HGSOC after primary cytoreduction. Variable
n Age (median, range) FIGO IIIB IIIC IV ECOG 0 1 2
Low-grade
High-grade
TR = 0
TR = 1–10 mm
TR N 10 mm
TR = 0
TR = 1–10 mm
TR N 10 mm
75 48 (20–76)
31 51 (20–70)
39 58 (27–74)
76 49 (22–77)
62 51 (26–73)
80 58 (26–73)
18 (24.0%) 50 (66.7%) 7 (9.3%)
10 (32.3%) 20 (64.5%) 1 (3.2%)
– 27 (69.2%) 12 (30.8%)
18 (23.7%) 51 (67.2%) 7 (9.2%)
20 (32.3%) 40 (64.5%) 2 (3.2%)
– 60 (75%) 20 (25%)
42 (56%) 30 (40%) 3 (4%)
14 (45.2%) 15 (48.4%) 2 (6.5%)
14 (35.9%) 22 (56.4%) 3 (7.7%)
43 (56.6%) 30 (39.5%) 3 (3.9%)
28 (45.2%) 30 (48.4%) 4 (6.5%)
40 (50%) 34 (42.5%) 6 (7.5%)
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Fig. 1. Overall survival (OS) and progression free survival (PFS) in patients with LGSOC according to residual disease after primary cytoreduction; R - residual disease.
log-rank test was used to show survival differences. Univariate Cox regression was performed to calculate hazard ratios for PFS and OS. All p-values were two-sided. 3. Results The metadatabase of the four mentioned trials included 5114 patients with AOC. Out of those, 145 pts had low-grade serous ovarian cancer (LGSOC; 2.8%) and 2424 had high-grade serous ovarian cancer (HGSOC; 47.4%). Among the LGSOC cohort we identified 39 patients with tumor residuals N1 cm after upfront cytoreduction (26.9% of all LGSOC). In addition, we identified 31 (21.4%) patients with tumor residuals 1–10 mm and 75 (51.7%) with complete tumor resection after primary cytoreduction (Table 1). The impact of surgery was analyzed in the whole group of 145 patients with LGSOC. Significant differences in OS and PFS between subgroups with complete cytoreduction, with residuals between 1– 10 mm, and with residuals N1 cm in diameter were observed. The 5year OS in the group of low-grade serous ovarian cancer patients with tumor residuals N 1 cm was 32% (median 35 months, range 31– 39 months), whereas in women who received a complete cytoreduction it was 85% (median 97 months, range 60–124 months) (p b 0.001) (Fig. 1). Significant differences in PFS between patients in regard to residual disease were observed as well (Fig. 1). In addition, nearly complete resection with residuals up to 1 cm also showed a significant benefit in this cohort with 61% 5-years overall survival. The comparison between complete cytoreduction and resection to residuals up to 1 cm revealed a risk reduction of 55.3% (HR 0.447, 95% CI 0.297–0.673 p b 0.001). Risk reduction of debulking to b1 cm residual tumor in comparison to residuals larger than 1 cm yielded a HR of 0.514 (95% CI 0.258–1.022). Finally, the comparison of complete resection with incomplete resection and residuals N1 cm showed a HR of 0.144 (95% CI 0.071–0.289). The corresponding hazard ratios for the HGSOC matched control group are shown in Table 2. Overall, surgical debulking showed a similar impact on prognosis in LGSOC and HGSOC. Subsequently, we compared survival rates between LGSOC and HGSOC according to surgical outcome. We did not find any significant differences between low- and high-grade serous ovarian cancer patients who underwent surgery with residuals larger than 1 cm with respect to 5-year PFS and OS, 10.9% vs. 5.6% (p = 0.955) and 32% vs. 28% (p = 0.813). However, we observed significant differences in PFS and OS in cases with complete- and 1–10 mm cytoreduction. LGSOC patients who received complete cytoreduction presented with a 63% 5years PFS rate (median 92 months, range 43–140 months). In comparison, HGSOC patients with complete resection showed only a
30% 5-years progression free survival rate (median 35 months, range 22–48 months; p b 0.001). Accordingly, LGSOC showed a superior outcome for OS with 5-years of 85% (median 97 months) compared to 61% (median 72 months) in HGSOC (p = 0.001). In patients who underwent cytoreduction to residuals 1–10 mm we observed only a significant difference in PFS with median 32 months in LGSOC versus median 15 months in HGSOC (p = 0.04; Figs. 2 and 3). In cases with residual disease equal or larger than 1 cm PFS and OS did not show any significant differences. These observations indicate a significant impact of surgical upfront debulking independent from histo-type, LGSOC or HGSOC (Table 2). Nevertheless, the impact of different tumor biology penetrates in patients with complete resection resulting in different PFS and OS. In patients with incomplete resection outcome is worse in both histo-types. In addition differences between both entities vanish with increasing residual tumor indicating the interaction of residual tumor and tumor histo-type. Bulky residual tumor is such a strong negative prognostic factor that it even disguised the impact of histo-type in our cohort. The cohort of LGSOC patients with residuals over 1 cm after primary surgery was investigated in order to compare the responsiveness to chemotherapy. The median age in this group was 58 years (range 27– 74). 27 (69.2%) women had FIGO stage IIIC and 12 pts (30.8%) FIGO IV stage disease. The majority of patients (92.3%) were in good performance status (ECOG 0–1). In 9 (23.1%) patients complete and partial response was reported. Thirty patients (76.9%) did not show any response to chemotherapy. Among those, 27 (69.2%) had stable disease (SD) as their best response and 3 (7.7%) had progressive disease (PD) during first-line treatment. The match-pair analysis included 80 patients with high-grade serous ovarian cancer. Significantly higher response rate among the patients with high-grade tumors was observed: sixtyseven (83.8%) patients had complete response (CR) and 5 (6.3%) partial response (PR) (p b 0.001) (Table 3). This observation indicated a different impact of both modalities surgery and chemotherapy on different histo-types. HGSOC is sensitive to Table 2 Surgical outcome and overall survival (OS) in LGSOC and HGSOC patients. Grade
Residual disease
p-Value
HR
LGSOC
TR N 1 cm TR = 0 TR = 1–10 mm TR N 1 cm TR = 0 TR = 1–10 mm
b0.001 b0.001 0.058 b0.001 b0.001 0.312
1 (ref) 0.144 0.514 1 (ref) 0.405 0.809
HGSOC
95% CI for HR LCL
UCL
0.071 0.258
0.289 1.022
0.259 0.537
0.633 1.220
CI = confidence interval; LCL = lower confidence limit; UCL = upper confidence limit.
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Fig. 2. Overall survival (OS) in patients with LGSOC and HGSOC according to residual disease after primary cytoreduction; TR - residual disease.
both successful surgery and chemotherapy while LGOSC is mainly sensitive to surgery but to a much less extent to traditional chemotherapy.
4. Discussion Low-grade serous ovarian cancer represents a minority within the group of invasive serous tumors of the genital tract [21]. In our study, LGSOC constituted 2.8% of 5114 patients with invasive advanced epithelial ovarian cancer and 3.9% out of 3693 patients with serous subtype included in the AGO-OVAR 3, 5, 7, 9 trials [15–18]. Most of the patients
received debulking to small or microscopic disease leaving “only” 39 women with residual tumors large enough to assess response in the primary therapy setting. Nevertheless, this analysis is among the largest series of patients with LGSOC investigated so far. In addition, we could compare for the first time PFS and OS according to the outcome of primary surgery between LGSOC and HGSOC. Moreover, we could demonstrate the beneficial impact of complete cytoreduction, that could be demonstrated in both histo-types. The cytoreduction to residual disease under 1 cm showed a PFS improvement in LGSOC patients. This correlation was not observed in regard to OS. Nevertheless, due to a relatively small numbers of patients in subgroups with residual disease, a further
Fig. 3. Progression free survival (PFS) in patients with LGSOC and HGSOC according to residual disease after primary cytoreduction; TR - residual disease.
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Table 3 The response rate in patients with LGSOC and HGSOC after incomplete primary cytoreduction with residual disease (TR) N1 cm. Variable
LGSOC HGSOC
Number of cycles
6 (3−10) 6 (3–10)
Response
No response
CR
PR
SD
PD
6 (15.4%) 67 (83.8%)
3 (7.7%) 5 (6.3%)
27 (69.2%) 6 (7.5%)
3 (7.7%) 2 (2.5%)
study on a larger cohort might reveal new information in regard to survival differences. However, even successful surgery could not completely compensate the tumor biology and LGSOC patients without residual disease after the surgery had a better outcome than its high-grade counterpart. The impact of tumor biology vanished with increasing post-operative tumor burden and completely disappeared in patients with large residuals N1 cm. In the latter cohort we did not find any significant differences in PFS and OS. Similar observation of the impact of surgical debulking in serous and mucinous ovarian cancer when biological prognostic factors showed penetrance only in patients with very low tumor burden was reported [9]. Possible explanation could be an interaction between post-operative tumor volume and other biological factors as grading or histo-type and more underlying biological factors, whereas tumor volume itself may contain several factors as tumor heterogeneity, resistant clones, and/or less vascularized area potentially contributing to a negative outcome. On the other hand, higher responsiveness to chemotherapy of high-grade tumors may compensate the slower growth pattern of low-grade tumors. Furthermore, different treatment pattern after progression may contribute to different outcome. In this respect, the improvement of PFS and OS after complete macroscopic cytoreduction in recurrent LGSOC has been reported [22]. In our cohort, the treatment between both cohorts could not explain different outcome. In contrast to the surgery, which effect in both histo-types was proven, the platinum-taxane chemotherapy efficacy seems to be higher in HGSOC in comparison to LGSOC. A response rate of b25% in primary therapy indicates the urgent need for a better treatment regimen in LGSOC. Our data fits well with other recent analyses showing limited effectiveness of chemotherapy in LGSOC [12–14,23,24]. Schmeler et al. showed a 4% complete response and 88% stable disease rate among 25 patients who underwent platin-based neoadjuvant chemotherapy. Response to chemotherapy in recurrent low-grade serous ovarian cancer was reported by Bristow et al. showing an overall response rate of 25% while six patients (50%) experienced disease progression [12]. Gershenson et al. showed in recurrent disease an overall response rate of 3.7% according to Response Evaluation Criteria in Solid Tumors (RECIST) [13]. No significant difference in response rate between platinum-sensitive and platinum-resistant patients was reported in LGSOC group [14]. These observations showed 23.1% response rate in previously untreated patients, which is even lower than in our findings. We analyzed patients recruited into the prospective randomized trials only, what might explain this slightly higher response rate as a result of a selection bias. Response rates may be better documented in prospective clinical trials than in retrospective hospital series. In addition, study cohorts represent a subgroup of selected patients commonly bearing a preferable risk profile than a normal population and therefore resulting in a better outcome [25]. The retrospective approach is of course a limitation of our analysis. However, the available exploratory data of prospective trials provides us with the most accurate information at the moment. The cooperative global prospective trials within the established trial networks (GCIG and ENGOT) may overcome this hurdle in the future. Another limitation is the lack of central pathologic review in the underlying studies, which might result in diagnosis inaccuracy in some patients. Thus our data reflect clinical reality where central pathology review was not established at that time. However, recent data on this aspect indicate the need for central review pathology at least in clinical trials focusing on specific histo-types [26,27]. The steps towards
Relative risk (CI 95%)
Odds-ratio (CI 95%)
p-Value
7.3 (3.9–13.8) 0.24 (0.13–0.44)
30.8 (10.9–97.5) 1 (reference)
b0.001
personalized medicine will improve the importance of standardized pathology and molecular biology tools in order to accurately characterize tumors and patients. First attempts to evaluate more effective treatment methods in LGSOC have already been reported. Gershenson et al. reported a 9% response rate to different hormonal therapies in recurrent low-grade serous ovarian cancer [24]. Another approach aimed the high frequency of KRAS and BRAF mutations in LGSOC [28,29]. This pathway including its downstream effectors (i.e. MEK–MAPK) seems to be an attractive therapeutic option [30–33]. Farley et al. showed 15% complete response rate and 65% stable disease rate after treatment with MEK-1/2 inhibitor in patients with recurrent low-grade serous ovarian cancer [34]. So far no correlation between response and the BRAF, KRAS and NRAS mutational status was observed. Further studies are ongoing in this area and hopefully help to develop better therapies for LGSOC. In summary, HGSOC and LGSOC differ mainly with respect to its chemosensitivity, but also to its growth pattern and outcome despite complete surgery. The primary cytoreduction with complete tumor resection could be identified as an effective therapy in LGSOC. In contrast, the currently recommended platinum-taxane-chemotherapy showed limited activity in approximately 1 in 4 LGSOC patients only. Despite the limitations of the platinum-taxane regimen and no superior alternative at the moment, the available data do not justify to withhold chemotherapy. International multicenter studies on alternative therapies (e.g. MEK inhibitors, hormonal therapy) are urgently needed.
Conflict of interest statement The authors declare that there are no conflicts of interest.
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[23] D.M. Gershenson, C.C. Sun, K.H. Lu, R.L. Coleman, A.K. Sood, A. Malpica, et al., Clinical behavior of stage II–IV low-grade serous carcinoma of the ovary, Obstet. Gynecol. 108 (2006) 361–368. [24] D.M. Gershenson, C.C. Sun, R.B. Iyer, A.L. Malpica, J.J. Kavanagh, D.C. Bodurka, et al., Hormonal therapy for recurrent low-grade serous carcinoma of the ovary or peritoneum, Gynecol. Oncol. 125 (2012) 661–666. [25] P. Harter, A. du Bois, C. Schade-Brittinger, A. Burges, K. Wollschlaeger, M. Gropp, et al., Non-enrolment of ovarian cancer patients in clinical trials: reasons and background, Ann. Oncol. 16 (2005) 1801–1805. [26] S. Kommoss, J. Pfisterer, A. Reuss, J. Diebold, S. Hauptmann, C. Schmidt, et al., Specialized pathology review in patients with ovarian cancer: results from a prospective study, Int. J. Gynecol. Cancer 23 (2013) 1376–1382. [27] S. Kommoss, J. Pfisterer, A. du Bois, D. Schmidt, F. Kommoss, Specialized histopathological second opinion of advanced ovarian cancer. Experiences with collectives from prospective randomized phase III studies, Pathologe 35 (2014) 355–360. [28] G. Singer, R. Oldt III, Y. Cohen, B.G. Wang, D. Sidransky, R.J. Kurman, et al., Mutations in BRAF and KRAS characterize the development of low-grade ovarian serous carcinoma, J. Natl. Cancer Inst. 95 (2003) 484–486. [29] G. Singer, I.M. Shih, A. Truskinovsky, H. Umudum, R.J. Kurman, Mutational analysis of K-ras segregates ovarian serous carcinomas into two types: invasive MPSC (low-grade tumor) and conventional serous carcinoma (high-grade tumor), Int. J. Gynecol. Pathol. 22 (2003) 37–41. [30] C.Y. Hsu, R. Bristow, M.S. Cha, B.G. Wang, C.L. Ho, R.J. Kurman, et al., Characterization of active mitogen-activated protein kinase in ovarian serous carcinomas, Clin. Cancer Res. 10 (2004) 6432–6436. [31] G. Pohl, C.L. Ho, R.J. Kurman, R. Bristow, T.L. Wang, I.M. Shih, Inactivation of the mitogen-activated protein kinase pathway as a potential target-based therapy in ovarian serous tumors with KRAS or BRAF mutations, Cancer Res. 65 (2005) 1994–2000. [32] N. Nakayama, K. Nakayama, S. Yeasmin, M. Ishibashi, A. Katagiri, K. Iida, et al., KRAS or BRAF mutation status is a useful predictor of sensitivity to MEK inhibition in ovarian cancer, Br. J. Cancer 99 (2008) 2020–2028. [33] I. Romero, C.C. Sun, K.K. Wong, R.C. Bast, D.M. Gershenson, Low-grade serous carcinoma: new concepts and emerging therapies, Gynecol. Oncol. 130 (2013) 660–666. [34] J. Farley, W.E. Brady, L.H.A. Vathipadiekal, R. Coleman, M.A. Morgan, et al., Selumetinib in women with recurrent low-grade serous carcinoma of the ovary or peritoneum: an open-label, single-arm, phase 2 study, Lancet Oncol. 14 (2013) 134–140.
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Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno
Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase Jacek P. Grabowski a,h,⁎, Philipp Harter a, •, Florian Heitz a, Eric Pujade-Lauraine b, Alexander Reuss c, Gunnar Kristensen d, Isabelle Ray-Coquard e, Julia Heitz f, Alexander Traut a, Jacobus Pfisterer g, Andreas du Bois a a
Department of Gynecology and Gynecological Oncology, Kliniken Essen Mitte, Henricistrasse 92, 45136 Essen, Germany Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Oncology Department, Universite Paris Descartes, AP-HP, Hopitaux Universitaires Paris Centre, Site Hotel Dieu, Paris, France c Koordinierungszentrum fuer Klinische Studien, Philipps-Universitaet Marburg, Karl-von-Frisch-Str. 4, 35043 Marburg, Germany d Nordic Society of Gynaecological Oncology Group (NSGO), Department of Gynecologic Oncology, Norwegian Radium Hospital, Oslo University Hospital, PB4953 Nydalen, 0424 Oslo, Norway e Group d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens (GINECO), Université de Lyon-Centre Léon Bérard, Department of Medical Oncology and EA SIS, 4128 Lyon, France f Department of Gynecology and Obstetrics, Klinikum Duisburg, Zu den Rehwiesen 9-11, 47055 Duisburg, Germany g Gynecologic Oncology Center, Kiel, Herzog-Friedrich-Str. 21, 24103 Kiel, Germany h Department of Gynecology, European Competence Center for Ovarian Cancer, Charite-University Medicine of Berlin, Augustenberger Platz 1, 13353 Berlin, Germany b
H I G H L I G H T S • Primary low-grade serous ovarian cancer (LGSOC) is not as responsive to platinum-taxane-based chemotherapy as high-grade serous advanced ovarian cancer (HGSOC) • Surgical debulking showed a similar impact on outcome in primary LGSOC and HGSOC however LGSOC were associated with better prognosis • LGSOC is less responsive to platinum-taxane-based chemotherapy Surgical debulking showed a similar impact on outcome in LGSOC and HGSOC
a r t i c l e
i n f o
Article history: Received 28 October 2015 Received in revised form 18 January 2016 Accepted 21 January 2016 Available online 22 January 2016 Keywords: Low-grade serous ovarian cancer High-grade serous ovarian cancer Platinum chemotherapy Objective response
a b s t r a c t Objective. Since almost two decades standard 1st-line chemotherapy for advanced ovarian cancer (AOC) has been a platinum/taxane combination. More recently, this general strategy has been challenged because different types of AOC may not benefit homogenously. Low-grade serous ovarian cancer (LGSOC) is one of the candidates in whom efficacy of standard chemotherapy should be revised. Methods. This study is an exploratory case control study of the AGO-metadatabase of 4 randomized phase III trials with first-line platinum combination chemotherapy without any targeted therapy. Patients with advanced FIGO IIIB\\IV low-grade serous ovarian cancer were included and compared with control cases having high-grade serous AOC. Results. Out of 5114 patients in this AGO database 145 (2.8%) had LGSOC and of those thirty-nine (24.1%) had suboptimal debulking with post-operative residual tumor N1 cm, thus being eligible for response evaluation. An objective response was observed in only 10 patients and this 23.1% response rate (RR) was significantly lower compared to 90.1% RR in the control cohort of high-grade serous ovarian cancer (HGSOC) (p b 0.001). Both, LGSOC and HGSOC patients who underwent complete cytoreduction had significantly better progression free survival (PFS) and overall survival (OS) in comparison to those with residuals after primary surgery, accordingly (p b 0.001). Conclusions. Our observation indicates that low-grade serous cancer is not as responsive to platinum-taxane-based chemotherapy as high-grade serous AOC. In contrast, surgical debulking showed a similar impact on outcome in both types of AOC thus indicating different roles for both standard treatment modalities. Systemic treatment of low grade serous AOC urgently warrants further investigations. © 2016 Elsevier Inc. All rights reserved.
1. Introduction ⁎ Corresponding author at: Department of Gynecology and Gynecological Oncology, Kliniken-Essen-Mitte, Henricistr. 92, 45136 Essen, Germany. E-mail address: [email protected] (J.P. Grabowski).
http://dx.doi.org/10.1016/j.ygyno.2016.01.022 0090-8258/© 2016 Elsevier Inc. All rights reserved.
Malpica et al. introduced in 2004 a two-tier grading system in epithelial ovarian cancers dividing tumors in low- and high-grade
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according to the degree of nuclear atypia [1]. Low-grade category characterizes the presence of mild to moderate nuclear atypia. They show up to 12 mitoses per 10 high power fields (HPFs), whereas the high-grade more than 12 mitoses per 10 HPFs. According to Malpica et al. the mean age of patients with low-grade serous ovarian cancer (LGSOC) was significantly lower in comparison to those with high-grade serous ovarian cancer (HGSOC) [1]. In parallel, Shih and Kurman introduced the concept of two pathways leading to either HGSOC or LGSOC [2]. This model indicates that both types are not only differentially graded neoplasm of the same type, but rather two distinct tumor types with different underlying pathogenesis, molecular events, clinical and epidemiological features. Related to this theory BRAF and KRAS mutations were detected in LGSOC, whereas p53 mutational status is characteristic for HGSOC. In this scenario, LGSOC arises in a stepwise fashion from benign cystadenoma through atypical hyperplasia/borderline tumor, which eventually progresses to an invasive LGSOC [2–8]. Stage and surgical outcome (i.e. complete resection without any macroscopic post-operative tumor residuals) as surrogates of initial tumor load and post-operative tumor load have been described as most important prognostic factors in advanced ovarian cancer (AOC) [9]. Another significant factor positively associated with superior outcome is quality of treatment both surgically and with respect to systemic treatment [10]. Currently, chemotherapy consisting of platinum-taxane combination with or without bevacizumab is prescribed to almost all histological types of AOC. However, analyses of another trial metadatabase could show that outcome differs substantially according to different histological types. Especially mucinous and clear cell histology were associated with inferior outcome compared to serous AOC [11]. More recently, the “one-size-fits-all-concept” has also been challenged for LGSOC, a small subgroup of AOC [12–14]. The aims of this study were twofold: (1) to evaluate the efficacy of standard first-line chemotherapy with platinum-paclitaxel in previously untreated low-grade serous advanced ovarian cancer and compare this to high-grade serous AOC, and, (2) to evaluate if both serous subtypes differ with respect to the prognostic responsiveness to surgical debulking. 2. Methods This study was an exploratory analysis of the metadatabase of the AGO-OVAR 3 [15], AGO-OVAR 5 [16], AGO-OVAR 7 [17], and AGOOVAR 9 [18] phase III trials. All four trials had been fully published and included patients with epithelial ovarian cancer stages FIGO IIIB\\IV who had received upfront surgery followed by 6 courses platinumpaclitaxel. AGO-OVAR 3 introduced carboplatin-paclitaxel comparing it to cisplatin-paclitaxel and AGO-OVAR 5, 7 and 9 evaluated triple drug regimens adding epirubicin, or topotecan, or gemcitabine to carboplatin-paclitaxel. None of the 4 trials did show any significant difference with respect to progression-free (PFS), and overall survival (OS). Only AGO-OVAR 9 showed a higher objective response rate in patients treated within the experimental arm. The AGO-OVAR 5, 7 and 9
trials were multinational intergroup trials with AGO-Study Group Germany and GINECO France and NSGO Scandinavia joined this axis for AGO-OVAR 9 [16–18]. Patients with serous ovarian cancer in advanced disease stage FIGO IIIB\\IV were included in our study. For the chemotherapy-sensitivity analysis, women who underwent incomplete initial surgery with macroscopic residuals N1 cm in diameter after primary surgery (to allow response assessment) were investigated. Tumor measurements using radiologic imaging were performed before chemotherapy start (baseline) and at least after the last cycle in patients with measurable or assessable disease. The tumor assessment methods (i.e., ultrasound, Xray, computed tomography, or magnetic resonance imaging) that were employed for baseline measurement were also used for each repetitive evaluation. Tumor response was classified according to the definitions of the World Health Organization (WHO) in AGO-OVAR 3, 5 and 7 and Response Evaluation Criteria in Solid Tumors 1.0 (RECIST) in AGOOVAR 9 [19,20]. The pathological findings were determined by a standardized central review in AGO-OVAR 3 study. The other trials were performed in the same centers, however without central pathology review. For further analysis of surgical parameters all patients with serous histology were identified and divided according to residual tumor after primary surgery into three subgroups: residuals N 10 mm, residuals 1–10 mm and complete cytoreduction (no macroscopic residual disease). The response to chemotherapy was investigated only in the first subgroup of patients with large post-operative tumor residuals, while the impact of primary surgery outcome was evaluated in all mentioned subgroups. Furthermore, we compared LGSOC with high-grade (previously grade 2 and 3) serous ovarian cancer patients using the following criteria for matching: (1) FIGO stage, (2) residual tumor size after primary surgery (residuals 1–10 mm and N1 cm), (3) serous histopathology, (4) age (±3 years), (5) Eastern Cooperative Oncology Group (ECOG) performance status, (6) specific trial, and (7) number of chemotherapy cycles received. Control HGSOC patients cohort who underwent cytoreduction with residuals 1–10 mm and N1 cm were randomly selected in a 2:1 ratio from the metadatabase. The number of LGSOC patients who underwent complete cytoreduction was significantly higher in comparison to those LGSOC with residual tumor, therefore a 1:1 selection ratio was applied to match control HGSOC group. Overall survival (OS) was calculated from randomization until death from any cause or censored on the date of the last follow-up. Progression-free survival (PFS) was defined as the time from randomization to disease progression or death from any cause; patients who were still alive without progressive disease at the time of analysis were censored on the date of their last follow-up. Kaplan-Meier estimates were calculated with Graph Pad Prism 4.02 (La Jolla, California). All other statistical analyses were performed using SPSS 18.0 (Chicago, Illinois). The comparison of two or more groups of discrete variables was performed with Fisher's exact test or the χ2 test, and metric variables were tested with appropriate non-parametric methods (Kruskal-Wallis test). The Kaplan-Meier method including a
Table 1 Characteristics of patients with LGSOC and HGSOC after primary cytoreduction. Variable
n Age (median, range) FIGO IIIB IIIC IV ECOG 0 1 2
Low-grade
High-grade
TR = 0
TR = 1–10 mm
TR N 10 mm
TR = 0
TR = 1–10 mm
TR N 10 mm
75 48 (20–76)
31 51 (20–70)
39 58 (27–74)
76 49 (22–77)
62 51 (26–73)
80 58 (26–73)
18 (24.0%) 50 (66.7%) 7 (9.3%)
10 (32.3%) 20 (64.5%) 1 (3.2%)
– 27 (69.2%) 12 (30.8%)
18 (23.7%) 51 (67.2%) 7 (9.2%)
20 (32.3%) 40 (64.5%) 2 (3.2%)
– 60 (75%) 20 (25%)
42 (56%) 30 (40%) 3 (4%)
14 (45.2%) 15 (48.4%) 2 (6.5%)
14 (35.9%) 22 (56.4%) 3 (7.7%)
43 (56.6%) 30 (39.5%) 3 (3.9%)
28 (45.2%) 30 (48.4%) 4 (6.5%)
40 (50%) 34 (42.5%) 6 (7.5%)
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Fig. 1. Overall survival (OS) and progression free survival (PFS) in patients with LGSOC according to residual disease after primary cytoreduction; R - residual disease.
log-rank test was used to show survival differences. Univariate Cox regression was performed to calculate hazard ratios for PFS and OS. All p-values were two-sided. 3. Results The metadatabase of the four mentioned trials included 5114 patients with AOC. Out of those, 145 pts had low-grade serous ovarian cancer (LGSOC; 2.8%) and 2424 had high-grade serous ovarian cancer (HGSOC; 47.4%). Among the LGSOC cohort we identified 39 patients with tumor residuals N1 cm after upfront cytoreduction (26.9% of all LGSOC). In addition, we identified 31 (21.4%) patients with tumor residuals 1–10 mm and 75 (51.7%) with complete tumor resection after primary cytoreduction (Table 1). The impact of surgery was analyzed in the whole group of 145 patients with LGSOC. Significant differences in OS and PFS between subgroups with complete cytoreduction, with residuals between 1– 10 mm, and with residuals N1 cm in diameter were observed. The 5year OS in the group of low-grade serous ovarian cancer patients with tumor residuals N 1 cm was 32% (median 35 months, range 31– 39 months), whereas in women who received a complete cytoreduction it was 85% (median 97 months, range 60–124 months) (p b 0.001) (Fig. 1). Significant differences in PFS between patients in regard to residual disease were observed as well (Fig. 1). In addition, nearly complete resection with residuals up to 1 cm also showed a significant benefit in this cohort with 61% 5-years overall survival. The comparison between complete cytoreduction and resection to residuals up to 1 cm revealed a risk reduction of 55.3% (HR 0.447, 95% CI 0.297–0.673 p b 0.001). Risk reduction of debulking to b1 cm residual tumor in comparison to residuals larger than 1 cm yielded a HR of 0.514 (95% CI 0.258–1.022). Finally, the comparison of complete resection with incomplete resection and residuals N1 cm showed a HR of 0.144 (95% CI 0.071–0.289). The corresponding hazard ratios for the HGSOC matched control group are shown in Table 2. Overall, surgical debulking showed a similar impact on prognosis in LGSOC and HGSOC. Subsequently, we compared survival rates between LGSOC and HGSOC according to surgical outcome. We did not find any significant differences between low- and high-grade serous ovarian cancer patients who underwent surgery with residuals larger than 1 cm with respect to 5-year PFS and OS, 10.9% vs. 5.6% (p = 0.955) and 32% vs. 28% (p = 0.813). However, we observed significant differences in PFS and OS in cases with complete- and 1–10 mm cytoreduction. LGSOC patients who received complete cytoreduction presented with a 63% 5years PFS rate (median 92 months, range 43–140 months). In comparison, HGSOC patients with complete resection showed only a
30% 5-years progression free survival rate (median 35 months, range 22–48 months; p b 0.001). Accordingly, LGSOC showed a superior outcome for OS with 5-years of 85% (median 97 months) compared to 61% (median 72 months) in HGSOC (p = 0.001). In patients who underwent cytoreduction to residuals 1–10 mm we observed only a significant difference in PFS with median 32 months in LGSOC versus median 15 months in HGSOC (p = 0.04; Figs. 2 and 3). In cases with residual disease equal or larger than 1 cm PFS and OS did not show any significant differences. These observations indicate a significant impact of surgical upfront debulking independent from histo-type, LGSOC or HGSOC (Table 2). Nevertheless, the impact of different tumor biology penetrates in patients with complete resection resulting in different PFS and OS. In patients with incomplete resection outcome is worse in both histo-types. In addition differences between both entities vanish with increasing residual tumor indicating the interaction of residual tumor and tumor histo-type. Bulky residual tumor is such a strong negative prognostic factor that it even disguised the impact of histo-type in our cohort. The cohort of LGSOC patients with residuals over 1 cm after primary surgery was investigated in order to compare the responsiveness to chemotherapy. The median age in this group was 58 years (range 27– 74). 27 (69.2%) women had FIGO stage IIIC and 12 pts (30.8%) FIGO IV stage disease. The majority of patients (92.3%) were in good performance status (ECOG 0–1). In 9 (23.1%) patients complete and partial response was reported. Thirty patients (76.9%) did not show any response to chemotherapy. Among those, 27 (69.2%) had stable disease (SD) as their best response and 3 (7.7%) had progressive disease (PD) during first-line treatment. The match-pair analysis included 80 patients with high-grade serous ovarian cancer. Significantly higher response rate among the patients with high-grade tumors was observed: sixtyseven (83.8%) patients had complete response (CR) and 5 (6.3%) partial response (PR) (p b 0.001) (Table 3). This observation indicated a different impact of both modalities surgery and chemotherapy on different histo-types. HGSOC is sensitive to Table 2 Surgical outcome and overall survival (OS) in LGSOC and HGSOC patients. Grade
Residual disease
p-Value
HR
LGSOC
TR N 1 cm TR = 0 TR = 1–10 mm TR N 1 cm TR = 0 TR = 1–10 mm
b0.001 b0.001 0.058 b0.001 b0.001 0.312
1 (ref) 0.144 0.514 1 (ref) 0.405 0.809
HGSOC
95% CI for HR LCL
UCL
0.071 0.258
0.289 1.022
0.259 0.537
0.633 1.220
CI = confidence interval; LCL = lower confidence limit; UCL = upper confidence limit.
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Fig. 2. Overall survival (OS) in patients with LGSOC and HGSOC according to residual disease after primary cytoreduction; TR - residual disease.
both successful surgery and chemotherapy while LGOSC is mainly sensitive to surgery but to a much less extent to traditional chemotherapy.
4. Discussion Low-grade serous ovarian cancer represents a minority within the group of invasive serous tumors of the genital tract [21]. In our study, LGSOC constituted 2.8% of 5114 patients with invasive advanced epithelial ovarian cancer and 3.9% out of 3693 patients with serous subtype included in the AGO-OVAR 3, 5, 7, 9 trials [15–18]. Most of the patients
received debulking to small or microscopic disease leaving “only” 39 women with residual tumors large enough to assess response in the primary therapy setting. Nevertheless, this analysis is among the largest series of patients with LGSOC investigated so far. In addition, we could compare for the first time PFS and OS according to the outcome of primary surgery between LGSOC and HGSOC. Moreover, we could demonstrate the beneficial impact of complete cytoreduction, that could be demonstrated in both histo-types. The cytoreduction to residual disease under 1 cm showed a PFS improvement in LGSOC patients. This correlation was not observed in regard to OS. Nevertheless, due to a relatively small numbers of patients in subgroups with residual disease, a further
Fig. 3. Progression free survival (PFS) in patients with LGSOC and HGSOC according to residual disease after primary cytoreduction; TR - residual disease.
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Table 3 The response rate in patients with LGSOC and HGSOC after incomplete primary cytoreduction with residual disease (TR) N1 cm. Variable
LGSOC HGSOC
Number of cycles
6 (3−10) 6 (3–10)
Response
No response
CR
PR
SD
PD
6 (15.4%) 67 (83.8%)
3 (7.7%) 5 (6.3%)
27 (69.2%) 6 (7.5%)
3 (7.7%) 2 (2.5%)
study on a larger cohort might reveal new information in regard to survival differences. However, even successful surgery could not completely compensate the tumor biology and LGSOC patients without residual disease after the surgery had a better outcome than its high-grade counterpart. The impact of tumor biology vanished with increasing post-operative tumor burden and completely disappeared in patients with large residuals N1 cm. In the latter cohort we did not find any significant differences in PFS and OS. Similar observation of the impact of surgical debulking in serous and mucinous ovarian cancer when biological prognostic factors showed penetrance only in patients with very low tumor burden was reported [9]. Possible explanation could be an interaction between post-operative tumor volume and other biological factors as grading or histo-type and more underlying biological factors, whereas tumor volume itself may contain several factors as tumor heterogeneity, resistant clones, and/or less vascularized area potentially contributing to a negative outcome. On the other hand, higher responsiveness to chemotherapy of high-grade tumors may compensate the slower growth pattern of low-grade tumors. Furthermore, different treatment pattern after progression may contribute to different outcome. In this respect, the improvement of PFS and OS after complete macroscopic cytoreduction in recurrent LGSOC has been reported [22]. In our cohort, the treatment between both cohorts could not explain different outcome. In contrast to the surgery, which effect in both histo-types was proven, the platinum-taxane chemotherapy efficacy seems to be higher in HGSOC in comparison to LGSOC. A response rate of b25% in primary therapy indicates the urgent need for a better treatment regimen in LGSOC. Our data fits well with other recent analyses showing limited effectiveness of chemotherapy in LGSOC [12–14,23,24]. Schmeler et al. showed a 4% complete response and 88% stable disease rate among 25 patients who underwent platin-based neoadjuvant chemotherapy. Response to chemotherapy in recurrent low-grade serous ovarian cancer was reported by Bristow et al. showing an overall response rate of 25% while six patients (50%) experienced disease progression [12]. Gershenson et al. showed in recurrent disease an overall response rate of 3.7% according to Response Evaluation Criteria in Solid Tumors (RECIST) [13]. No significant difference in response rate between platinum-sensitive and platinum-resistant patients was reported in LGSOC group [14]. These observations showed 23.1% response rate in previously untreated patients, which is even lower than in our findings. We analyzed patients recruited into the prospective randomized trials only, what might explain this slightly higher response rate as a result of a selection bias. Response rates may be better documented in prospective clinical trials than in retrospective hospital series. In addition, study cohorts represent a subgroup of selected patients commonly bearing a preferable risk profile than a normal population and therefore resulting in a better outcome [25]. The retrospective approach is of course a limitation of our analysis. However, the available exploratory data of prospective trials provides us with the most accurate information at the moment. The cooperative global prospective trials within the established trial networks (GCIG and ENGOT) may overcome this hurdle in the future. Another limitation is the lack of central pathologic review in the underlying studies, which might result in diagnosis inaccuracy in some patients. Thus our data reflect clinical reality where central pathology review was not established at that time. However, recent data on this aspect indicate the need for central review pathology at least in clinical trials focusing on specific histo-types [26,27]. The steps towards
Relative risk (CI 95%)
Odds-ratio (CI 95%)
p-Value
7.3 (3.9–13.8) 0.24 (0.13–0.44)
30.8 (10.9–97.5) 1 (reference)
b0.001
personalized medicine will improve the importance of standardized pathology and molecular biology tools in order to accurately characterize tumors and patients. First attempts to evaluate more effective treatment methods in LGSOC have already been reported. Gershenson et al. reported a 9% response rate to different hormonal therapies in recurrent low-grade serous ovarian cancer [24]. Another approach aimed the high frequency of KRAS and BRAF mutations in LGSOC [28,29]. This pathway including its downstream effectors (i.e. MEK–MAPK) seems to be an attractive therapeutic option [30–33]. Farley et al. showed 15% complete response rate and 65% stable disease rate after treatment with MEK-1/2 inhibitor in patients with recurrent low-grade serous ovarian cancer [34]. So far no correlation between response and the BRAF, KRAS and NRAS mutational status was observed. Further studies are ongoing in this area and hopefully help to develop better therapies for LGSOC. In summary, HGSOC and LGSOC differ mainly with respect to its chemosensitivity, but also to its growth pattern and outcome despite complete surgery. The primary cytoreduction with complete tumor resection could be identified as an effective therapy in LGSOC. In contrast, the currently recommended platinum-taxane-chemotherapy showed limited activity in approximately 1 in 4 LGSOC patients only. Despite the limitations of the platinum-taxane regimen and no superior alternative at the moment, the available data do not justify to withhold chemotherapy. International multicenter studies on alternative therapies (e.g. MEK inhibitors, hormonal therapy) are urgently needed.
Conflict of interest statement The authors declare that there are no conflicts of interest.
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