Primary surgery is the cornestone of treatment of LGSOC [2
]. Patients with disease apparently confined to the gonad(s) should undergo bilateral salpingo-oophorectomy, total hysterectomy and comprehensive peritoneal and retroperitoneal staging, although fertility-sparing surgery including unilateral salpingo-oophorectomy, surgical staging and endometrial biopsy could be taken into consideration in young women with stage IA-IC1
disease who strongly desire to preserve their childbearing potential. Patients with advanced disease should undergo primary debulking surgery (PDS) with the aim of removing all macroscopically detectable disease.
However, there is a small percentage of patients who may not be candidates for PDS due to the extent of disease. Neoadjuvant chemotherapy followed by interval debulking surgery (IDS) should be reserved to these patients, who usually experience a poorer prognosis
A subset analysis of GOG 182 trial, comparing carboplatin [CBCDA] + paclitaxel [PTX] alone versus combination with triplet or sequential doublet regimens, assessed 189 patients with FIGO stage III-IV LGSOC [43
]. The women, who had no gross residual disease (RD) after PDS, experienced better progression-free survival (PFS) (median, 33.2 months) and OS (median, 96.9 months) compared with those with RD 0.1–1 cm (14.7 months and 44.5 months, respectively) and those with RD >1 cm (14.1 months and 42.0 months, respectively) (PFS, p
< 0.001; OS, p
In a retrospective Italian investigation, PDS was performed in 68 of 72 patients (94.4%) with FIGO stage IIIb-IV LGSOC and achieved RD = 0 in 44 patients (64.7%), RD ≤ 1 cm in 49 (72.1%), and RD > 1 cm in 19 (27.9%) [48
]. IDS was then carried out in 15 of the 19 women with RD > 1 cm after PDS and in 4 patients who did not attempt PDS. Overall, 12 of the 19 (63.1%) patients who underwent IDS had macroscopic RD after operation. Multivariate analysis showed that non-optimal cytoreduction was an independent poor prognostic factor for the risk of recurrence (hazard ratio [HR] = 2.79; 95% confidence interval [CI] = 1.16–6.70; p
= 0.021) and the performance of IDS instead of PDS was an independent poor prognostic variable for the risk of death (HR = 2.95; 95% CI = 1.12–7.74; p
Neoadjuvant platinum ± taxane-based chemotherapy obtained a complete radiological response in one (4.2%) and stable disease in 21 (87.5%) of the 24 patients with LGSOC [49
]. Nineteen patients underwent IDS, which was optimal in 12 cases (63.2%), suboptimal in 6 (31.6%) and unknown in one case (5.2%). For the entire cohort, median PFS was 21.4 months and median OS was 56.1 months.
Secondary cytoreductive surgery (SCS) may have a role in the management of recurrent LGSOC [50
A retrospective study of Johns Hopkins Medical Institutions assessed 26 patients with ovarian micropapillary serous carcinoma, of which 21 underwent SCS and 15 (71.4%) achieved an optimal cytoreduction to RD ≤ 1cm [50
]. Patients undergoing optimal SCS had longer median survival after recurrence (61.2 months) compared with either patients undergoing suboptimal SCS (25.5 months, p
< 0.02) or not surgically-treated patients (29.9 months, p
< 0.01), and the difference retained statistical significance on multivariate analysis (p
A retrospective investigation of MD Anderson Cancer Center evaluated 41 patients who underwent SCS for recurrent LGSOC after a median time of 33.2 months from PDS [51
]. Median survival after SCS was longer for the nine patients with no macroscopic RD than for the 32 patients with gross RD (93.6 months versus 45.8 months, p
= 0.04). Women who were initially treated with SCS at the time of recurrence showed a trend towards a longer median survival than those who underwent chemotherapy followed by SCS (83.3 versus 33.2 months, p
3.2. Chemotherapy and Endocrine Therapy
LGSOC is an indolent neoplasia less responsive to chemotherapy both in first-line and in the recurrent setting compared with HGSOC [5
]. An in vitro study showed that LGSOC was quite resistant to PTX, CBDCA, cyclophosphamide, gemcitabine and cisplatin and less likely to be resistant to etoposide, doxorubicin and topotecan [53
The metadata base of four AGO-OVAR phase III trials, including patients with FIGO stage IIIb-IV ovarian carcinoma who underwent PDS followed by platinum /PTX- based regimens, identified 145 patients with LGSOC, of which 39 (24.1%) had RD > 1 cm and were evaluable for response to chemotherapy [46
]. An objective response was obtained in 10 patients (23.1%) and this response rate was significantly lower compared to 90.1% response rate in the 80 matched control women with HGSOC with RD > 1 cm (p
Twelve patients with measurable recurrent LGSOC received platinum-based salvage chemotherapy, with the most common regimen being a platinum agent combined with PTX [50
]. Two patients achieved a complete response and one patient achieved a partial response, for an overall response rate of 25.0%, and three patients (25.0%) had stable disease. The analysis of the departmental databases of MD Anderson Cancer Center reported one complete response and three partial responses following 108 different chemotherapy regimens to 58 patients with recurrent LGSOC, for on overall response rate of 3.7%, ranging from 2.1% for platinum-resistant to 4.9% for platinum-sensitive patients [51
]. The stable disease rate was 60.2% and the median time to progression was 29.0 weeks.
Hormonal therapy may provide clinical benefit in women with LGSOC [11
]. Escobar et al. [11
] found ER+/PR+ in 21.8%, ER + /PR- in 17.4%, ER- /PR+ in 13.0% and ER- /PR- in 47.8% of 27 LGSOCs and assumed that only the subset of tumors with double steroid receptor expression could benefit from endocrine treatment.
Gershenson et al. [55
] examined 203 patients with FIGO stage II-IV LGSOC who underwent PDS and platinum-based chemotherapy, followed by hormone therapy in 70 cases and observation alone in 133 cases. Hormone therapy consisted of letrozole in 38 cases (54.3%), anastrozole in 2 (2.9%), tamoxifen in 20 (28.6%), leuprolide acetate as single agent or in combination in 9 (12.9%), and medroxyprogesterone acetate in one (1.4%) case. Patients who had maintenance endocrine therapy had better PFS (median, 64.9 versus 26.4 months, p
< 0.001) than those who had not, whereas OS was similar in the two groups (115.7 versus 102.7 months, p
A retrospective study of Johns Hopkins School of Medicine, Cleveland Clinic and Memorial Sloan Kettering Cancer Center assessed 27 patients with FIGO stage II–IV LGSOC who underwent either PDS (n
= 26) or neoadjuvant CBDCA/PTX-based chemotherapy plus IDS (n
= 1) followed by endocrine therapy, consisting of letrozole (55.5% of cases), anastrozole (37.1%) or tamoxifen (7.4%), for a median time of 18 months [13
]. Six (22.2%) patients relapsed after a median time of 21.5 months, 3-year PFS was 79.0% and 3-year OS was 92.6%. It is noteworthy that none of the three patients who had tumor tissue collected for molecular analysis at recurrence showed ESR1 mutations which have been associated with resistance to aromatase inhibitors in ER+ metastatic breast cancer [57
A randomized phase III trial is currently comparing CBDCA/PTX for six cycles followed by maintenance letrozole versus letrozole monotherapy after PDS in women with stage II-IV LGSOC (NRG-GY-019).
The M.D. Anderson Cancer Center analyzed 64 patients who received 89 different hormone regimens for recurrent LGSOC [54
]. There were six complete responses and two partial responses, for an overall response rate of 9.0% in the entire cohort, 2.7% in platinum-resistant patients and 13.5% in platinum-sensitive patients. The objective responses were achieved in six of the 33 cases (18.2%) treated with letrozole, one of the 21 (4.8%) treated with anastrozole, one of the 17 (5.9%) treated with tamoxifen, none of the 14 treated with leuprolide alone or combined with other agents, and none of the four treated with fulvestrant, megestrol acetate or raloxifene. Median to progression was 7.4 months in the entire cohort, 8.9 months in patients with ER+/PR+ disease and 6.2 months in those with ER+ /PR- disease.
Anastrozole obtained a partial response in 5 (13.9%), 3-month clinical benefit (partial response + stable disease) in 23 (63.9%) and a 6-month clinical benefit in 21 (60.8%) of the 36 post-menopausal women with ER+ and/or PR+ recurrent/metastatic LGSOCs and SBOTs [56
]. The median PFS was 11.1 months.
An ongoing basket phase II study is assessing the oral progesterone antagonist onapristone ER(Apristor) in patients with PR+ recurrent LGSOC, ovarian granulosa cell tumor or endometrioid endometrial carcinoma (NCT03909152).