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National Comprehensive Cancer Network ®

NCCN Guidelines treatment
recommendations

LGSOC is a distinct rare subtype associated with more indolent disease, younger patients vs HGSOC, and typical diagnosis at advanced stages.3,4 As a distinct entity, LGSOC requires a different approach for treatment and management.5

LGSOC has a poor response rate to chemotherapy compared with HGSOC (0% to 15% in recurrent setting vs 90%)6,7

NCCN-recommended treatment for
LGSOC stages IA-IC13

Cytoreductive surgery is the primary treatment for all epithelial ovarian cancers2

Adjuvant treatment options

Stage IA-IB2

Observe2

(Consider surgical setting and resection of residual disease if not done previously)

Stage IC2
  • Observe (cat. 2B) 
  • Systemic chemotherapy
    • Followed by observation, maintenance letrozole (2B), or other hormonal therapy (2B)
  • Hormonal therapy (cat. 2B)2

Preferred Regimens

  • Paclitaxel/carboplatin q3weeks ± maintenance letrozole or other hormonal therapy (2B)
  • Hormone therapy (aromatase inhibitors: anastrozole, letrozole, exemestane) (2B)2

Other Recommended Regimens

  • Carboplatin/liposomal doxorubicin ± maintenance letrozole or other hormonal therapy (2B)2
  • Docetaxel/carboplatin ± maintenance letrozole or other hormonal therapy (2B)2
  • Hormone therapy (leuprolide acetate, tamoxifen, fulvestrant) (2B)2

Useful in Certain Circumstances

  • Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab (2B)2

Note: All recommendations are category 2A unless otherwise indicated.

NCCN-Recommended Treatment
for LGSOC Stages II-IV

Cytoreductive surgery is the primary treatment for all epithelial ovarian cancers2

Adjuvant treatment options

Stage II-IV2
  • Systemic chemotherapy
    • Followed by maintenance letrozole (2B), or other hormonal therapy (2B)
  • Hormonal therapy (cat 2B)

Preferred Regimens

  • Paclitaxel/carboplatin q3weeks ± maintenance letrozole or other hormonal therapy (2B)
  • Paclitaxel/carboplatin/bevacizumab + maintenance bevacizumab2
  • Hormone therapy (aromatase inhibitors: anastrozole, letrozole, exomestane) (2B)

Other Recommended Regimens

  • Paclitaxel weekly/carboplatin weekly2
  • Docetaxel/carboplatin ± maintenance letrozole or other hormone therapy (2B)
  • Carboplatin/liposomal doxorubicin ± maintenance letrozole or other hormonal therapy (2B)
  • Paclitaxel weekly/carboplatin q3weeks2
  • Docetaxel/carboplatin/bevacizumab + maintenance bevacizumab2
  • Hormone therapy (leuprolide acetate, tamoxifen, fulvestrant) (2B)2

Useful in Certain Circumstances

  • Docetaxel/oxaliplatin/bevacizumab + maintenance bevacizumab (2B)2

Note: All recommendations are category 2A unless otherwise indicated.

Monitoring and follow-up for recurrence2

  • Visits every 2-4 months for 2 years, 3-6 months for 3 years, annually after 5 years 
  • Physical exam, including pelvic exam as clinically indicated 
  • Tumor molecular testing, if not previously done 
  • Refer for genetic risk evaluation, if not previously done 
  • Chest/abdominal/pelvic CT, MRI, PET/CT, or PET (skull base to mid-thigh) as clinically indicated 
  • CBC and chemistry profile as indicated 
  • CA-125 or other tumor markers if initially elevated 
  • Long-term wellness care 

Managing recurrent disease

Treatment options for recurrent disease in LGSOC are limited and include secondary cytoreduction, clinical trials, chemotherapy, endocrine therapy, or RAF- and MEK-targeted therapies.8-10 Recent expert consensus is that there is no defined standard-of-care treatment for recurrent LGSOC.1 Though there are no FDA-approved treatments specifically for LGSOC,11 NCCN does recommend the following:

NCCN recurrence therapy recommendations
Recurrence therapy options1,2
  • Secondary cytoreductive surgery
  • Clinical trial
  • Trametinib
  • Binimetinib (category 2B)
  • Dabrafenib + trametinib (for BRAF V600E positive tumors)
  • Hormonal therapy
    • Use an aromatase inhibitor (letrozole, anastrozole, exemestane) if not previously used  
    • Use fulvestrant, tamoxifen, or leuprolide acetate if an aromatase inhibitor was already given
  • Chemotherapy if not previously used
  • Other systemic therapy (bevacizumab)
  • Observation

No standard sequencing of drugs for recurrent disease, individual patient factors will play a role in decision-making

Note: All recommendations are category 2A unless otherwise indicated.

Biomarker-directed therapy options2
  • Tumors carrying NTRK fusions 
    • Entrectinib 
    • Larotrectinib 
  • Mismatch repair deficient or microsatellite instability high
    • Dostarlimab-gxly
    • Pembrolizumab 
  • Tumor mutational burden high 
    • Pembrolizumab 
  • RET gene fusion positive tumors
    • Sepercatinib
  • BRAF V600E
    • Dabrafenib + trametinib 
  • FRa-expressing tumors 
    • Mirvetuzimab soravtansine-gynx/bevacizumab
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LGSOCs are less sensitive to chemotherapy than HGSOC12 and is at high risk for recurrence.13
Current treatment
Challenges and unmet need
Chemotherapy and systemic therapy
Chemotherapy and systemic therapy

In LGSOC, lower sensitivity to chemotherapy compared to HGSOC (0% to 15% in the recurrent setting vs 90%) represents an ongoing treatment challenge.6,7

In addition, hormonal treatment of primary adjuvant and recurrent disease of LGSOC is not well studied.14 Nor is it well defined in the NCCN and European Society for Medical Oncology (ESMO)-ESGO guidelines, the currently accepted standard of care for primary systemic treatment of LGSOC.1

While evidence indicates that LGSOC responds to hormonal therapy, efficacy data are retrospective.1 

High risk of recurrence in Stage II-IV disease:
Over 80% of people with LGSOC will have a relapse13
Burden of treatment: Quality of life challenges

LGSOC is characterized by a younger age at diagnosis, indolent progression, relative chemo-resistance, and long-term survival.3-5-12 As a result, patients with LGSOC may be living with disease, and side effects of treatment, for many years.1,5

Treatment-associated toxicities may negatively affect patients’ quality of life. An expert panel on LGSOC highlighted the importance of reducing treatment burden by proactively managing treatment-related side effects.1

Burden-of-treatment

MEK-only inhibitor (MEKi)-specific toxicities

It is important to monitor patients for MEKi-related toxicities and address side effects as they arise.1,15 Discontinuation rates for some treatments, such as trametinib and binimetinib, are over 30%.6,7

MEK-only inhibitor1-specific toxicities may include:

  • Cutaneous skin reactions, diarrhea, peripheral edema, cardiac toxicity, ocular toxicity, and interstitial lung disease1,6

Aromatase inhibitor (AI)-specific toxicities

HCPs should follow current guidelines and prior reviews regarding managing AI toxicities, including musculoskeletal symptoms and osteoporosis.1

  • Patients who are receiving AIs should be counseled regarding musculoskeletal side effects16
    • These may be managed through exercise; acupuncture; application of heat or cold; use of a nonsteroidal anti-inflammatory drug (NSAID) or other analgesics, a diuretic, duloxetine, or omega-3 fatty acids; conversion to an alternative AI; and an AI holiday1,17-21 
  • Patients should be monitored for bone mineral density and for appropriate patients, treatment should be initiated22
There are no FDA-approved drugs or treatments
specifically for LGSOC11
Clinical trials and in treatment options in

Low-grade serous ovarian cancer

Prospective clinical trials are pivotal in the search for better ways to manage and treat LGSOC.23

  • Grisham RN, Slomovitz BM, Andrews N, et al. Low-grade serous ovarian cancer: expert consensus report on the state of the science. Published online August 17, 2023. Int J Gynecol Cancer. 2023;3(9):1331-1344. doi:10.1136/ijgc-2023-00461
  • NCCN Guidelines Recommendations. Clinical Practice Guidelines in Oncology: Ovarian Cancer. Version 2.2023.
  • Plaxe SC. Epidemiology of low-grade serous ovarian cancer. Am J Obstet Gynecol. 2008;198(4):459.e1-8; discussion 459.e8-9.doi:10.1016/j.ajog.2008.01.035
  • Malpica A, Deavers MT, Lu K, et al. Grading ovarian serous carcinoma using a two-tier system. Am J Surg Pathol. 2004;28(4):496-504. doi:10.1097/00000478-200404000-00009
  • Gockley A, Melamed A, Bregar AJ, et al. Outcomes of women with high-grade and low-grade advanced-stage serous epithelial ovarian cancer. Obstet Gynecol. 2017;129:439-447. doi:10.1097/AOG.0000000000001867
  • Gershenson DM. Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial. Lancet. 2022;399(10324):541-553. doi:10.1016/S0140-6736(21)02175-9
  • Monk JB. MILO/ENGOT-ov11: Binimetinib versus physician’s choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum. J Clin Oncol. 2020;38(32):3753-3762. doi:10.1200/JCO.20.01164
  • Crane EK, Sun CC, Ramirez PT, et al. The role of secondary cytoreduction in low-grade serous ovarian cancer or peritoneal cancer. Gynecol Oncol. 2015;136(1):25-29. doi:10.1016/j.ygyno.2014.11.005
  • Manning-Geist B, Gordhandas S, Liu YL, et al. MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma. Clin Cancer Res. 2022;28:4456-4465. doi:10.1158/1078-0432.CCR-21-4183
  • Armstrong DK, Alvarez RD, Backes FJ, et al. NCCN Guidelines® Insights: Ovarian Cancer, Version 3.2022. J Natl Compr Canc Netw. 2022;20(9):972-980. doi:10.6004/jnccn.2022.0047
  • Banerjee SN, Ring KL, Nieuwenhuysen EV, et al. Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) 6 defactinib in recurrent low-grade serous ovarian cancer (LGSOC). J Clin Oncol. 41. No 16_suppl (June 1, 2023) 5515.
  • Grabowski JP, Harter P, Heitz F, et al. Operability and chemotherapy responsiveness in advanced low-grade serous ovarian cancer. An analysis of the AGO Study Group metadatabase. Gynecol Oncol. 2016;140:457-462. doi:10.1016/j.ygyno.2016.01.0222
  • Babaier A, Mal H, Alselwi W, Ghatage P. Low-grade serous carcinoma of the ovary: the current status. Diagnostics (Basel). 2022;12(2):458. doi:10.3390/diagnostics12020458
  • Gershenson DM, Bodurka DC, Coleman RL, et al. Hormonal maintenance therapy for women with low-grade serous cancer of the ovary or peritoneum. J Clin Oncol. 2017;1;35(10):1103-1111. doi:10.1200/JCO.2016.71.0632
  • Welsh SJ, Corrie PG. Management of BRAF and MEK inhibitor toxicities in patients with metastatic melanoma. Ther Adv Med Oncol. 2015;7:122-136. doi:10.1177/1758834014566428
  • Hyder T, Marino CC, Ahmad S, et al. Aromatase inhibitor-associated musculoskeletal syndrome: understanding mechanisms and management. Front Endocrinol (Lausanne). 2021;12:713700. doi:10.3389/fendo.2021.713700
  • Gupta A, Henry NL, Loprinzi CL. Management of aromatase inhibitor-induced musculoskeletal symptoms. JCO Oncol Pract. 2020;16:733-739. doi:10.1200/OP.20.00113
  • Crew KD, Capodice JL, Greenlee H, et al. Randomized, blinded, sham-controlled trial of acupuncture for the management of aromatase inhibitor-associated joint symptoms in women with early-stage breast cancer. J Clin Oncol. 2010;1;28(7):1154-1160. doi:10.1200/JCO.2009.23.4708
  • Irwin ML, Cartmet B, Gross CP, et al. Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol. 2015;33(10):1104-1111. doi:10.1200/JCO.2014.57.1547
  • Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain. 2007;129(1-2):210-223. doi:10.1016/j.pain.2007.01.020
  • Henry NL, Unger JM, Till C, et al. Association between body mass index and response to duloxetine for aromatase inhibitor-associated musculoskeletal symptoms in SWOG S1202. Cancer. 2019;125(12):2123-2129. doi:10.1002/cncr.32024
  • Hadji P, Aapro MS, Body JJ, et al. Management of aromatase inhibitor-associated bone loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017;7:1-12. doi:10.1016/j.jbo.2017.03.001
  • Grisham RN, Manning‐Geist BL, Chui MH. The highs and lows of serous ovarian cancer. Cancer. 2023;1-8. doi:10.1002/cncr.34903