gynecology and obstetrics
Ovarian, Fallopian Tube, and Peritoneal Cancer
Treatment of Ovarian Cancer
Usually hysterectomy and bilateral salpingo-oophorectomy Cytoreductive surgery Usually postoperative chemotherapy, often withcarboplatinandpaclitaxel (See alsoNational Comprehensive Cancer Network (NCCN): NCCN Clinical Practice Guidelines in Oncology: Ovarian Cancer.) Treatment of ovarian, fallopian tube, and peritoneal cancer is based on stage, grade, and histology: For stage IA or IB ovarian tumors (confined to the ovary) and/or grade 1 endometrioid tumors, prognosis is excellent (survival 90%) after surgery alone. For patients with stage IC, II, grade 3, or clear cell histology, adjuvant chemotherapy treatment (eg, withcarboplatinandpaclitaxel) is recommended. For stage III or IV, primary surgical cytoreduction followed by systemic chemotherapy is the standard treatment. Neoadjuvant chemotherapy followed by cytoreductive surgery is the preferred option for patients who are not candidates for surgical resection (due to location and volume of the cancer or because of comorbidities). Hysterectomy and bilateral salpingo-oophorectomy are usually indicated, but fertility preservation by conserving the unaffected ovary and uterus may be considered for stage I nonepithelial or low-grade unilateral epithelial ovarian cancers in young patients. Potential indications for neoadjuvant chemotherapy include one or more of the following: Multiple liver metastases Lymphadenopathy in the porta hepatis Suprarenal para-aortic lymph nodes Diffuse mesenteric disease Evidence of pleural or parenchymal lung disease In a large randomized trial, neoadjuvant chemotherapy followed by surgery had less perioperative morbidity than primary surgery followed by chemotherapy and similar long-term survival rates ( Treatment references ). The surgical procedure for ovarian, fallopian tube, and peritoneal cancers includes staging and cytoreduction (all visibly involved tissue is surgically removed if possible). Cytoreduction is associated with increased survival time; the volume of residual disease remaining after cytoreduction correlates inversely with survival time. Cytoreductive surgery for ovarian cancer usually includes Supracolic omentectomy, sometimes with rectosigmoid resection (usually with primary reanastomosis) Radical peritoneal stripping Resection of diaphragmatic peritoneum or splenectomy Cytoreduction may be Complete: Cytoreduction to no grossly visible disease Optimal: Cytoreduction with residual disease that is ≤ 1 cm in maximum tumor diameter, as defined by the Gynecologic Oncology Group Suboptimal: Cytoreduction with any visible tumor nodules > 1 cm remaining Because cytoreduction is associated with increased survival, being able to predict when cytoreduction to no gross residual disease can be done is important, but doing so is difficult; there are no uniform criteria. Optimal cytoreduction is less likely if patients have the following: Poor performance status Age > 60 years American Society of Anesthesiologists physical status 3 or 4 Medical comorbidities Poor nutritional status Extra-abdominal disease Large tumor bulk Involvement of large bowel Metastases to retroperitoneal lymph nodes above the renal vessels and > 1 cm in largest dimension Parenchymal liver involvement A preoperative CA 125 > 500 U/mL The Fagotti score, based on seven laparoscopic findings, can help predict the likelihood of optimal cytoreduction in patients with advanced ovarian cancer. This scoring system assigns a value of 0 or 2 depending on whether disease is present in certain locations. If patients score ≥ 10, optimal cytoreduction is very unlikely. If they score < 10, they are considered candidates for cytoreductive surgery ( Treatment references ). Diagnostic laparoscopy before laparotomy can spare patients an unnecessary laparotomy, which would result in suboptimal cytoreduction. Laparoscopy enables clinicians to do a tissue biopsy, make a definitive diagnosis, and analyze the biopsy sample. Thus, patients who are not candidates for cytoreduction can begin chemotherapy treatment earlier. Laparoscopic findings indicating that optimal cytoreduction is unlikely include Omental cake Extensive peritoneal or diaphragmatic carcinomatosis Mesenteric retraction Bowel and stomach infiltration Spleen and/or liver superficial metastasis In most patients with newly diagnosed ovarian cancer, the disease has spread widely throughout the peritoneum; thus, treatment involves one of the following (see table): Staging and cytoreduction, followed by 6 cycles of IV chemotherapy 3 cycles of neoadjuvant chemotherapy, followed by surgery and 3 more chemotherapy cycles Standard chemotherapy is 6 courses ofpaclitaxelandcarboplatin. Other agents may be used depending on patient and tumor characteristics. For certain patients at higher risk of recurrence (eg, those who have pleural effusions or ascites and do not have aBRCAmutation), addingbevacizumabto chemotherapy and continuing it as maintenance therapy is an option. therapy for 15 months is the standard of care, based on a multicenter randomized open-label phase III trial that found no difference in progression-free survival or overall survival in patients treated for 15 versus 30 months ( Treatment references ). PARP (polyadenosine diphosphate-ribose polymerase) enzymes are essential to the repair of single-strand breaks in DNA. Inhibition of PARP enzymes leads to persistent single-strand breaks, which cause double-strand breaks to accumulate during DNA replication and ultimately lead to tumor cell death. mutation ( Treatment references , ( Treatment references ), and the PRIMA/ENGOT-Ov26 study evaluated mutation ( Treatment references ). The VELIA trial included patients with previously untreated stage III or IV high-grade serous ovarian carcinoma. This three-arm trial compared standard chemotherapy alone versus standard chemotherapy plus veliparib versus standard chemotherapy plus veliparib followed by maintenance therapy with veliparib ( Treatment references ). Progression-free survival was longest with veliparib chemotherapy plus veliparib maintenance therapy. Intraperitoneal chemotherapy using a catheter has been suggested as an alternative to IV chemotherapy. Intraperitoneal chemotherapy delivers the agents directly to the peritoneal surface and thus eliminates residual microscopic disease. In advanced-stage ovarian cancer, combination treatment with IV and intraperitoneal chemotherapy appears to prolong overall survival after primary cytoreductive surgery ( Treatment references ). This approach is not without complications; catheter-related complications can limit its use ( Direct delivery of chemotherapy to the abdominal cavity under hyperthermic conditions (HIPEC) intraoperatively after cytoreduction has been used in patients with colon cancer and is under study for ovarian cancer. The potential benefit of HIPEC is increased sensitivity to chemotherapy by impairing DNA repair, it induces apoptosis and activates heat-shock proteins. Even if chemotherapy results in a complete clinical response (ie, normal physical examination, normal serum CA 125, negative CT scan of the abdomen and pelvis), approximately 50% of patients with stage III or IV cancer have residual tumor. Of patients with persistent elevation of CA 125, 90 to 95% have residual tumor. Recurrence of ovarian cancer can be detected serologically with tumor markers (eg, CA 125) and/or by radiologic signs of progression. Treatment of recurrence depends on the time between the completion of platinum-based treatment and detection of recurrence (platinum-free interval [PFI]): A PFI of ≥ 6 months suggests platinum-sensitive disease. A PFI of < 6 months suggests platinum-resistant disease. ( Treatment references ). Targeted therapy with biologic agents is under study. —is used for maintenance therapy ( Treatment references , in these patients ( Treatment references ). Randomized trials of secondary cytoreductive surgery in patients with platinum-sensitive ovarian cancer have had variable results. Several trials compared surgical cytoreduction followed by chemotherapy versus chemotherapy alone, In one trial (GOG-0213), overall survival time did not increase, but in other trials, there were significant increases in overall survival time (in DESKTOP III, 53.7 versus 46.0 months) or progression-free survival time (in SOC-1, 17.4 versus 11.9 months [ Treatment references , 1.Vergote I, Tropé CG, Amant F, et al; Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer.N Engl J Med2010;363 (10):943–953, 2010. doi:10.1056/ NEJMoa0908806 2.Petrillo M, Vizzielli G, Fanfani F, et al: Definition of a dynamic laparoscopic model for the prediction of incomplete cytoreduction in advanced epithelial ovarian cancer: Proof of a concept.Gynecol Oncol139 (1):5–9, 2015. doi:10.1016/j.ygyno.2015.07.095 Epub 2015 Jul 18. 3.Pfisterer J, Joly F, Kristensen G, et al. Optimal Treatment Duration ofBevacizumabas Front-Line Therapy for Advanced Ovarian Cancer: AGO-OVAR 17 BOOST/GINECO OV118/ENGOT Ov-15 Open-Label Randomized Phase III Trial.J Clin Oncol41(4):893-902, 2023. doi:10.1200/JCO.22.01010 4.Coleman RL, Fleming GF, Brady MF, et al: Veliparib with first-line chemotherapy and as maintenance therapy in ovarian cancer.N Engl J Med381 (25):2403–2415, 2019. doi: 10.1056/NEJMoa1909707 Epub 2019 Sep 28. 5.González-Martín A, Pothuri B, Vergote I, et al:Niraparibin patients with newly diagnosed advanced ovarian cancer.N Engl J Med381 (25):2391–2402, 2019. doi: 10.1056/NEJMoa1910962 Epub 2019 Sep 28. 6.Ray-Coquard I, Pautier P, Pignata S, et al:Olaparibplusbevacizumabas first-line maintenance in ovarian cancer.N Engl J Med381 (25):2416–2428, 2019. doi: 10.1056/NEJMoa1911361 7.Moore K, Colombo N, Scambia G, et al: Maintenanceolaparibin patients with newly diagnosed advanced ovarian cancer.N Engl J Med379 (26):2495–2505, 2018. doi: 10.1056/NEJMoa1810858 Epub 2018 Oct 21. 8.Banerjee S, Moore KN, Colombo N, et al: Maintenanceolaparibfor patients with newly diagnosed advanced ovarian cancer and a BRCA mutation (SOLO1/GOG 3004): 5-year follow-up of a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Oncol22 (12):1721–1731, 2021. doi: 10.1016/S1470-2045(21)00531-3 Epub 2021 Oct 26 9.Ray-Coquard I, Pautier P, Pignata S, et al:OlaparibplusBevacizumabas First-Line Maintenance in Ovarian Cancer.N Engl J Med381(25):2416-2428, 2019. doi:10.1056/NEJMoa1911361 10.Armstrong DK, Bundy B, Wenzel L, et al: Intraperitonealcisplatinandpaclitaxelinin ovarian cancer.N Engl J Med354:34–43, 2006. doi: 10.1056/NEJMoa052985 11.Wright AA, Cronin A, Milne DE, et al: Use and effectiveness of intraperitoneal chemotherapy for treatment of ovarian cancer.J Clin Oncol33:2841–2847, 2015. doi: 10.1200/JCO.2015.61.4776 12.Zsiros E, Lynam S, Attwood KM, et al: Efficacy and safety ofpembrolizumabin combination withbevacizumaband oral metronomiccyclophosphamidein the treatment of recurrent ovarian cancer: A phase 2 nonrandomized clinical trial.JAMA Oncol7 (1):78–85, 2021. doi: 10.1001/jamaoncol.2020.5945 13.Ledermann J, Harter P, Gourley C, et al:Olaparibmaintenance therapy in platinum-sensitive relapsed ovarian cancer.N Engl J Med366 (15):1382–1392, 2012. doi: 10.1056/NEJMoa1105535 Epub 2012 Mar 27. 14.Pujade-Lauraine E, Ledermann JA, Selle F, et al:Olaparibtablets as maintenance therapy in patients with platinum-sensitive, relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): A double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol18 (9):1274–1284, 2017. doi: 10.1016/S1470-2045(17)30469-2 Epub 2017 Jul 25. 15.Poveda A, Floquet A, Ledermann JA, et al:Olaparibtablets as maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA1/2 mutation (SOLO2/ENGOT-Ov21): a final analysis of a double-blind, randomised, placebo-controlled, phase 3 trial.Lancet Oncol22(5):620-631, 2021. doi:10.1016/S1470-2045(21)00073-5 16.Coleman RL, Spirtos NM, Enserro D, et al: Secondary surgical cytoreduction for recurrent ovarian cancer.N Engl J Med381 (20):1929–1939, 2019. doi: 10.1056/NEJMoa1902626 17.Harter P, Sehouli J, Vergote I, et al: Randomized trial of cytoreductive surgery for relapsed ovarian cancer.N Engl J Med385 (23):2123–2131, 2021. doi: 10.1056/NEJMoa2103294 18.Shi T, Zhu J, Feng Y, et al: Secondary cytoreduction followed by chemotherapy versus chemotherapy alone in platinum-sensitive relapsed ovarian cancer (SOC-1): A multicentre, open-label, randomised, phase 3 trial.Lancet Oncol 22 (4):439–449, 2021. doi: 10.1016/S1470-2045(21)00006-1 Epub 2021 Mar 8. 