Surgical and systemic therapies for addressing occult disease in advanced epithelial ovarian cancer

The incidence of peritoneal recurrence in advanced epithelial ovarian cancer (EOC) is high and could be attributed to the high prevalence of occult disease the persists despite complete cytoreductive surgery (CRS) and systemic chemotherapy. Several therapeutic approaches have been used to address such occult disease. Hyperthermic intraperitoneal chemotherapy (HIPEC) acts on microscopic disease as well as free intraperitoneal cancer cells shed during surgery, thus, reducing the risk of recurrence. Maintenance therapies like Poly ADP-Ribosyl Polymerase (PARP) inhibitors and the anti-angiogenic agent bevacizumab are used as maintenance therapies to delay recurrence. The most definitive way to eradicate such occult disease completely is resection of the peritoneum. The high preponderance of occult disease in the parietal peritoneum and some regions of the visceral peritoneum has led some surgeons to investigate the role of a total parietal peritonectomy (TPP) performed along with wide resection of the visceral peritoneum as a strategy for addressing occult disease. The mechanism of action differs from that of HIPEC and systemic therapies. It is possible that the benefit of each of these therapies is additive. EOC is a heterogeneous disease with a number of clinicopathological and molecular factors influencing the prognosis. There are likely to be different subgroups of patients that benefit from each of these 4 therapies or a combination of these. In this manuscript, we review the rationale and current evidence for the use of each of these therapies and discuss the potential role of a TPP in light of other therapies.

Advanced ovarian cancer; Cytoreductive surgery; Total parietal peritonectomy; HIPEC; PARP inhibitors; Antia-ngiogenic therapy

[1] Lee JY, Kim S, Kim YT, Lim MC, Lee B, Jung KW, et al. Changes in ovarian cancer survival during the 20 years before the era of targeted therapy. BMC Cancer. 2018; 18: 601.

[2] Bhatt A, Glehen O. The role of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer: A Review. Indian Journal of Surgical Oncology. 2016; 7: 188–197.

[3] Shoji T, Sato C, Tomabechi H, Takatori E, Kaido Y, Nagasawa T, et al. Expectations and Challenges of First-Line Maintenance Therapy for Advanced Ovarian Cancer. Medicina. 2021; 57: 501.

[4] González-Moreno S, González-Bayón LA, Ortega-Pérez G. Hyperthermic intraperitoneal chemotherapy: Rationale and technique. World Journal of Gastrointestinal Oncology. 2010; 2: 68–75.

[5] van Driel WJ, Koole SN, Sikorska K, Schagen van Leeuwen JH, Schreuder HWR, Hermans RHM, et al. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. The New England Journal of Medicine. 2018; 378: 230–240.

[6] Walsh CS. Latest clinical evidence of maintenance therapy in ovarian cancer. Current Opinion in Obstetrics and Gynecology. 2020; 32: 15–21.

[7] Bhatt A, Kammar P, Mehta S, Sinukumar S. ASO Author Reflections: Total Parietal Peritonectomy during Interval Cytoreductive Surgery for Advanced Ovarian Cancer—Proof-of-Principle and Analysis of Morbidity. Annals of Surgical Oncol-ogy. 2020; 27: 861–862.

[8] Murphy EM, Sexton R, Moran BJ. Early results of surgery in 123 patients with pseudomyxoma peritonei from a perforated appendiceal neoplasm. Diseases of the Colon and Rectum. 2007; 50: 37–42.

[9] Kostić Z, Cuk V, Bokun R, Ignjatović D, Usaj-Knezević S, Ignjatović M. Detection of free cancer cells in peritoneal cavity in patients surgically treated for gastric adenocarcinoma. Vojnosanitetski Pregled. 2006; 63: 349–356. (In Serbian)

[10] Lemoine L, Sugarbaker P, Van der Speeten K. Pathophysiology of colorectal peritoneal carcinomatosis: Role of the peritoneum. World Journal of Gastroenterology. 2016; 22: 7692–7707.

[11] Shimotsuma M, Shields JW, Simpson-Morgan MW, Sakuyama A, Shirasu M, Hagiwara A, et al. Morpho-physiological function and role of omental milky spots as omentum-associated lymphoid tissue (OALT) in the peritoneal cavity. Lymphology. 1993; 26: 90–101.

[12] Yonemura Y, Kawamura T, Bandou E, Tsukiyama G, Endou Y, Miura M. The Natural History of Free Cancer Cells in the Peritoneal Cavity. In Gonzalez-Moreno S (ed.) Advances in peritoneal surface oncology (pp. 11–23). Springer: Berlin. 2007.

[13] Kusamura S, Baratti D, Zaffaroni N, Villa R, Laterza B, Balestra MR, et al. Pathophysiology and biology of peritoneal carcinomatosis. World Journal of Gastrointestinal Oncology. 2010; 2: 12–18.

[14] Bhatt A, Yonemura Y, Benzerdjeb N, Mehta S, Mishra S, Parikh L, et al. Pathological assessment of cytoreductive surgery specimens and its unexplored prognostic potential-a prospective multi-centric study. European Journal of Surgical Oncology. 2019; 45: 2398–2404.

[15] Tan DS, Agarwal R, Kaye SB. Mechanisms of transcoelomic metastasis in ovarian cancer. The Lancet Oncology. 2006; 7: 925–934.

[16] Sehouli J, Senyuva F, Fotopoulou C, Neumann U, Denkert C, Werner L, et al. Intra-abdominal tumor dissemination pattern and surgical outcome in 214 patients with primary ovarian cancer. Journal of Surgical Oncology. 2009; 99: 424–427.

[17] Minig L, Patrono MG, Gallego RA, de Bernabé JV, Diaz-Padilla I.Ovarian Cancer: A Clinical and Translational Update. In Ivan Díaz-Padilla (ed.) Surgical treatment of ovarian cancer (pp. 161). InTech: Croatia. 2013.

[18] Azaïs H, Vignion-Dewalle AS, Carrier M, Augustin J, Da Maïa E, Penel A, et al. Microscopic Peritoneal Residual Disease after Complete Macroscopic Cytoreductive Surgery for Advanced High Grade Serous Ovarian Cancer. Journal of Clinical Medicine. 2020; 10: 41.

[19] Hynninen J, Lavonius M, Oksa S, Grénman S, Carpén O, Auranen A. Is perioperative visual estimation of intra-abdominal tumor spread reliable in ovarian cancer surgery after neoadjuvant chemotherapy? Gynecologic Oncology. 2013; 128: 229–232.

[20] Bhatt A, Kammar P, Sinukumar S, Parikh L, Jumale N, Shaikh S, et al. Total parietal peritonectomy can be performed with acceptable morbidity in patients with advanced ovarian cancer following neoadjuvant chemotherapy: results from a prospective multi-centric study. Annals of Surgical Oncology. 2021; 28: 1118–1129.

[21] Lim MC, Song YJ, Seo SS, Yoo CW, Kang S, Park SY. Residual cancer stem cells after interval cytoreductive surgery following neoadjuvant chemotherapy could result in poor treatment outcomes for ovarian cancer. Onkologie. 2010; 33: 324–330.

[22] Luo Y, Lee M, Kim HS, Chung HH, Song YS. Effect of neoadjuvant chemotherapy on platinum resistance in stage IIIC and IV epithelial ovarian cancer. Medicine. 2016; 95: e4797.

[23] Bhatt A, Yonemura Y, Mehta S, Benzerdjeb N, Kammar P, Parikh L, et al. Target region resection in patients undergoing cytoreductive surgery for peritoneal metastases-is it necessary in absence of visible disease? European Journal of Surgical Oncology. 2020; 46: 582–589.

[24] Vergote I, Trope CG, Amant F, Kristensen GB, Ehlen T, Johnson N, et al. Neoadjuvant Chemotherapy or Primary Surgery in Stage IIIC or IV Ovarian Cancer. New England Journal of Medicine. 2010; 363: 943–953.

[25] Kehoe S, Hook J, Nankivell M, Jayson GC, Kitchener H, Lopes T, et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. The Lancet. 2015; 386: 249–257.

[26] Fagotti A, Ferrandina MG, Vizzielli G, Pasciuto T, Fanfani F, Gallotta V, et al. Randomized trial of primary debulking surgery versus neoadjuvant chemotherapy for advanced epithelial ovarian cancer (SCORPION-NCT01461850). International Journal of Gynecologic Cancer. 2020; 30: 1657–1664.

[27] Chi DS, Musa F, Dao F, Zivanovic O, Sonoda Y, Leitao MM, et al. An analysis of patients with bulky advanced stage ovarian, tubal, and peritoneal carcinoma treated with primary debulking surgery (PDS) during an identical time period as the randomized EORTC-NCIC trial of PDS vs neoadjuvant chemotherapy (NACT). Gynecologic Oncology. 2012; 124: 10–14.

[28] Rauh-Hain JA, Rodriguez N, Growdon WB, Goodman AK, Boruta DM 2nd, Horowitz NS, et al. Primary debulking surgery versus neoadjuvant chemotherapy in stage IV ovarian cancer. Annals of Surgical Oncology. 2012; 19: 959–965.

[29] Bhatt A, Sinukumar S, Mehta S, Damodaran D, Zaveri S, Kammar P, et al. Patterns of pathological response to neoadjuvant chemotherapy and its clinical implications in patients undergoing interval cytoreductive surgery for advanced serous epithelial ovarian cancer- a study by the Indian Network for Development of Peritoneal Surface Oncology (INDEPSO). European Journal of Surgical Oncology. 2019; 45: 666–671.

[30] Bhatt A, Bakrin N, Kammar P, Mehta S, Sinukumar S, Parikh L, et al. Distribution of residual disease in the peritoneum following neoadjuvant chemotherapy in advanced epithelial ovarian cancer and its potential therapeutic implications. European Journal of Surgical Oncology. 2021; 47: 181–187.

[31] Amate P, Huchon C, Dessapt AL, Bensaid C, Medioni J, Le Frère Belda MA, et al. Ovarian cancer: sites of recurrence. International Journal of Gynecological Cancer. 2013; 23: 1590–1596.

[32] Tanner EJ, Black DR, Zivanovic O, Kehoe SM, Dao F, Konner JA, et al. Patterns of first recurrence following adjuvant intraperitoneal chemotherapy for stage IIIC ovarian cancer. Gynecologic Oncology. 2012; 124: 59–62.

[33] Ceresoli M, Verrengia A, Montori G, Busci L, Coccolini F, Ansaloni L, et al. Effect of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy on relapse pattern in primary epithelial ovarian cancer: a propensity score based casecontrol study. Journal of Gynecologic Oncology. 2018; 29: e53.

[34] Sinukumar S, Damodaran D, Ray M, Mehta S, Paul L, Bhatt A. Pattern of recurrence after interval cytoreductive surgery and HIPEC following neoadjuvant chemotherapy in primary advanced stage IIIC/IVA epithelial ovarian cancer. European Journal of Surgical Oncology. 2021; 47: 1427–1433.

[35] Gadducci A, Cosio S. Surveillance of patients after initial treatment of ovarian cancer. Critical Reviews in Oncology/Hematology. 2009; 71: 43–52.

[36] Vaidya AP, Curtin JP. The follow-up of ovarian cancer. Seminars in Oncology. 2003; 30: 401–412.

[37] Bhatt A, Bakrin N, Gertych W, Kammar P, Parikh L, Sheth S, et al. Extent and distribution of peritoneal disease in patients undergoing cytoreductive surgery for first platinum sensitive recurrence in ovarian cancer and its potential therapeutic implications. European Journal of Surgical Oncology. 2020; 46: 2276–2282.

[38] Chi DS, McCaughty K, Diaz JP, Huh J, Schwabenbauer S, Hummer AJ, et al. Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma. Cancer. 2006; 106: 1933–1939.

[39] Ferrandina G, Legge F, Salutari V, Paglia A, Testa A, Scambia G. Impact of pattern of recurrence on clinical outcome of ovarian cancer patients: clinical considerations. European Journal of Cancer. 2006; 42: 2296–2302.

[40] Meigs JV. Tumors of the female pelvic organs. MacMillan: London. 1934.

[41] Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: A Gynecologic Oncology Group study. Gynecologic Oncology. 1992; 47: 159–166.

[42] Bristow RE, Tomacruz RS, Armstrong DK, Trimble EL, Montz FJ. Survival Effect of Maximal Cytoreductive Surgery for Advanced Ovarian Carcinoma during the Platinum Era: A Meta-Analysis. Journal of Clinical Oncology. 2002; 20: 1248–1259.

[43] Chi DS, Eisenhauer EL, Zivanovic O, Sonoda Y, Abu-Rustum NR, Levine DA, et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecologic Oncology. 2009; 114: 26–31.

[44] Aletti GD, Dowdy SC, Podratz KC, Cliby WA. Surgical treatment of diaphragm disease correlates with improved survival in optimally debulked advanced stage ovarian cancer. Gynecologic Oncology. 2006; 100: 283–287.

[45] Eisenhauer EL, Abu-Rustum NR, Sonoda Y, Levine DA, Poynor EA, Aghajanian C, et al. The addition of extensive upper abdominal surgery to achieve optimal cytoreduction improves survival in patients with stages IIIC-IV epithelial ovarian cancer. Gynecologic Oncology. 2006; 103: 1083–1090.

[46] Colombo PE, Mourregot A, Fabbro M, Gutowski M, Saint-Aubert B, Quenet F, et al. Aggressive surgical strategies in ad-vanced ovarian cancer: a monocentric study of 203 stage IIIC and IV patients. European Journal of Surgical Oncology. 2009; 35: 135–143.

[47] Wallace S, Kumar A, Mc Gree M, Weaver A, Mariani A, Langstraat C, et al. Efforts at maximal cytoreduction improve survival in ovarian cancer patients, even when complete gross resection is not feasible. Gynecologic Oncology. 2017; 145: 21–26.

[48] Chang SJ, Bristow RE. Evolution of surgical treatment paradigms for advanced-stage ovarian cancer: redefining ‘optimal’ residual disease. Gynecologic Oncology. 2012; 125: 483–492.

[49] Lee JY, Kim S, Kim YT, Lim MC, Lee B, Jung K, et al. Changes in ovarian cancer survival during the 20 years before the era of targeted therapy. BMC Cancer. 2018; 18: 601.

[50] Pentheroudakis G, Pavlidis N. Serous papillary peritoneal carcinoma: Unknown primary tumour, ovarian cancer counterpart or a distinct entity? a systematic review. Critical Reviews in Oncology/Hematology. 2010; 75: 27–42.

[51] NCCN guidelines. 2021. Available at: https://www.nccn.org/p rofessionals/physician\_gls/pdf/ovarian.pdf (Accessed: 12 January 2021).

[52] Bakrin N, Gladieff L. Malignant epithelial ovarian cancer: Role of intra-peritoneal chemotherapy and hyperthermic intra peritoneal chemotherapy(HIPEC): Article drafted from the French Guidelines in oncology entitled “Initial management of patients with epithelial ovarian cancer” developed by FRANCOGYN, CNGOF, SFOG, GINECO-ARCAGY under the aegis of CNGOF and endorsed by INCa. Gynecologie Obstetrique Fertilite et Senologie. 2019; 47: 214–221. (In French)

[53] Colombo N, Sessa C, du Bois A, Ledermann J, McCluggage WG, McNeish I, et al. ESMO–ESGO consensus conference recommendations on ovarian cancer: pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Annals of Oncology. 2019; 30: 672–705.

[54] Sugarbaker PH. Peritonectomy procedures. Annals of Surgery. 1995; 221: 29–42.

[55] Sabel MS, Diehl KM, Chang AE. Principles of Surgical Therapy in Oncology. In Chang AE, et al. (eds.) Oncology. Springer: New York. 2006.

[56] van ’t Sant I, Engbersen MP, Bhairosing PA, Lambregts DMJ, Beets-Tan RGH, van Driel WJ, et al. Diagnostic performance of imaging for the detection of peritoneal metastases: a meta-analysis. European Radiology. 2020; 30: 3101–3112.

[57] Goswami G, Kammar P, Mangal R, Shaikh S, Patel MD, Bhatt A. Accuracy of CT Scan in Predicting the Surgical PCI in Patients Undergoing Cytoreductive Surgery with/without HIPEC—a Prospective Single Institution Study. Indian Journal of Surgical Oncology. 2019; 10: 296–302.

[58] Baratti D, Kusamura S, Cabras AD, Deraco M. Cytoreductive Surgery with Selective Versus Complete Parietal Peritonectomy Followed by Hyperthermic Intraperitoneal Chemotherapy in Patients with Diffuse Malignant Peritoneal Mesothelioma: a Controlled Study. Annals of Surgical Oncology. 2012; 19: 1416–1424.

[59] Deraco M, Sinukumar S, Salcedo-Hernández RA, Rajendra VJ, Baratti D, Guaglio M, et al. Clinico-pathological outcomes after total parietal peritonectomy, cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in advanced serous papillary peritoneal carcinoma submitted to neoadjuvant systemic chemotherapy- largest single institute experience. European Journal of Surgical Oncology. 2019; 45: 2103–2108.

[60] Sugarbaker PH. Peritoneum as the first-line of defense in carcinomatosis. Journal of Surgical Oncology. 2007; 95: 93–96.

[61] Sinukumar S, Rajan F, Mehta S, Damodaran D, Zaveri S, Kammar P, et al. A comparison of outcomes following total and selective peritonectomy performed at the time of interval cytore-ductive surgery for advanced serous epithelial ovarian, fallopian tube and primary peritoneal cancer—a study by INDEPSO. European Journal of Surgical Oncology. 2021; 47: 75–81.

[62] Yokosu K, Tanabe H, Nomura S, Ozone H, Saito M, Takano H, et al. Total parietal peritonectomy in primary debulking surgery for advanced ovarian cancer. Gynecologic Oncology Reports. 2021; 37: 100805.

[63] Bhatt A, Kammar P, Sinukumar S, Goswami G, Mishra B, Bhavsar M, et al. Perioperative outcomes in patients treated with total parietal peritonectomy and multivisceral resections with or without HIPEC at different time points in the history of advanced ovarian cancer. European Journal of Gynaecological Oncology. 2021; 42: 711–720.

[64] Aletti GD, Dowdy SC, Podratz KC, Cliby WA. Relationship among surgical complexity, short-term morbidity, and overall survival in primary surgery for advanced ovarian cancer. American Journal of Obstetrics and Gynecology. 2007; 197: 676.e1– 676. e7.

[65] Somashekhar SP, Ashwin KR, Kumar R, Ramya Y, Zaveri SS, Rauthan A. Comparison of Outcomes Following Complete and Selective Parietal Peritonectomy during Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Advanced Epithelial Ovarian Cancer: A Study by Indian Society of Peri-toneal Surface Malignancies (ISPSM). Indian Journal of Gynecologic Oncology. 2018; 16: 71.

[66] Bhatt A, Sinukumar S, Parikh L, Mehta S, Shaikh S, Jumle N, et al. Total parietal peritonectomy performed during interval cytoreductive surgery for advanced epithelial serous ovarian cancer results in a low incidence of platinum resistant recurrence—results of a prospective multicentre study. European Journal of Surgical Oncology. 2021; 47: 2150–2157.

[67] Böhm S, Faruqi A, Said I, Lockley M, Brockbank E, Jeyarajah A, et al. Chemotherapy Response Score: Development and Validation of a System to Quantify Histopathologic Response to Neoadjuvant Chemotherapy in Tubo-Ovarian High-Grade Serous Carcinoma. Journal of Clinical Oncology. 2015; 33: 2457–2463.

[68] Liang WF, Li H, Wu JY, Liu CH, Wu MF, Li J. Identification of Ovarian Cancer Patients Most Likely to Achieve Chemotherapy Response Score 3 Following Neoadjuvant Chemotherapy: Development of a Predictive Nomogram. Frontiers in Oncology. 2020; 10: 560888.

[69] Fischer J, Eglinton TW, Richards SJ, Frizelle FA. Predicting pathological response to chemoradiotherapy for rectal cancer: a systematic review. Expert Review of Anticancer Therapy. 2021; 21: 489–500.

[70] Bhatt A, Benzerdjeb N, Mishra S, Glehen O. Therapeutic Rationale and Data Set for Reporting Cytoreductive Surgery Specimens. In Glehen O, Bhatt A (eds.) Pathology of Peritoneal Metastases. Springer: Singapore. 2020.

[71] Kammar P, Bhatt A, Anam J, Waghoo S, Pandey J, Mehta S. Correlation between Pelvic Peritoneal Disease and Nodal Metastasis in Advanced Ovarian Cancer: can Intraoperative Findings Define the need for Systematic Nodal Dissection? Indian Journal of Surgical Oncology. 2019; 10: 84–90.

[72] Harter P, Sehouli J, Lorusso D, Reuss A, Vergote I, Marth C, et al. A Randomized Trial of Lymphadenectomy in Patients with Advanced Ovarian Neoplasms. New England Journal of Medicine. 2019; 380: 822–832.

[73] Bamias A, Bamia C, Zagouri F, Kostouros E, Kakoyianni K, Rodolakis A, et al. Improved survival trends in platinum-resistant patients with advanced ovarian, fallopian or peritoneal cancer treated with first-line paclitaxel/platinum chemotherapy: the impact of novel agents. Oncology. 2013; 84: 158–165.

[74] Moran BJ, Tzivanakis A. The concept of “Obstruction-Free Sur-vival” as an outcome measure in advanced colorectal cancer management. Pleura and Peritoneum. 2018; 3: 20180101.

[75] Paoletti X, Lewsley LA, Daniele G, Cook A, Yanaihara N, Tinker A, et al. Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer. JAMA Network Open. 2020; 3: e1918939.

[76] Flessner MF. The transport barrier in intraperitoneal therapy. American Journal of Physiology - Renal Physiology. 2005; 288: F433–F442.

[77] Flessner MF. Intraperitoneal drug therapy: physical and biological principles. Cancer Treatment and Research Communications. 2007; 134: 131–152.

[78] Yonemura Y. Trans-lymphatic metastasis. In Yonemura Y (ed.) Atlas and principles of peritonectomy for peritoneal surface malignancy. Kyoto: NPO to Support Peritoneal Surface Malignancy (pp. 188–206). NPO: Kyoto, Japan. 2012.

[79] Yonemura Y, Canbay E, Endou Y, Ishibashi H, Mizumoto A. Mechanisms of the formation of peritoneal surface malignancy on omental milky spots from low grade appendiceal mucinous carcinoma. Journal of Clinical Oncology. 2014; 4: 2.

[80] Solass W, Herbette A, Schwarz T, Hetzel A, Sun JS, Dutreix M, et al. Therapeutic approach of human peritoneal carcinomatosis with Dbait in combination capnoperitoneum: proof of concept. Surgical Endoscopy. 2012; 26: 847–852.

[81] Khosrawipour V, Khosrawipour T, Diaz-Carballo D, Forster E, Zieren J, Giger-Pabst U. Exploring the Spatial Drug Distribution Pattern of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC). Annals of Surgical Oncology. 2016; 23: 1220–1224.

[82] Yonemura Y, Sako S, Wakama S, Ishibashi H, Mizumoto A, Takao N, et al. History of Peritoneal Surface Malignancy Treat-ment in Japan. Indian Journal of Surgery. 2019; 10: 3–11.

[83] Sticca RP, Dach BW. Rationale for hyperthermia with intraop-rative intraperitoneal chemotherapy agents. Surgical Oncology Clinics of North America. 2003; 12: 689–701.

[84] Sugarbaker PH. Laboratory and clinical basis for hyperther-mia as a component of intracavitary chemotherapy. International Journal of Hyperthermia. 2007; 23: 431–442.

[85] Chiva LM, Gonzalez-Martin A. A critical appraisal of hyper-thermic intraperitoneal chemotherapy (HIPEC) in the treatment of advanced and recurrent ovarian cancer. Gynecologic Oncology. 2015; 136: 130–135.

[86] Huo YR, Richards A, Liauw W, Morris DL. Hyperthermic intraperitoneal chemotherapy (HIPEC) and cytoreductive surgery (CRS) in ovarian cancer: a systematic review and meta-analysis. European Journal of Surgical Oncology. 2015; 41: 1578–1589.

[87] Zhang G, Zhu Y, Liu C, Chao G, Cui R, Zhang Z. The prognosis impact of hyperthermic intraperitoneal chemotherapy (HIPEC) plus cytoreductive surgery (CRS) in advanced ovarian cancer: the meta-analysis. Journal of Ovarian Research. 2019; 12: 33.

[88] Lei Z, Wang Y, Wang J, Wang K, Tian J, Zhao Y, et al. Evaluation of Cytoreductive Surgery with or without Hyperthermic Intraperitoneal Chemotherapy for Stage III Epithelial Ovarian Cancer. JAMA Network Open. 2020; 3: e2013940.

[89] Lim MC, Chang SJ, Yoo HJ, Nam B, Bristow R, Park S. Randomized trial of hyperthermic intraperitoneal chemotherapy (HIPEC) in women with primary advanced peritoneal, ovarian, and tubal cancer. Journal of Clinical Oncology. 2017; 35: 5520–5520.

[90] Spriggs DR, Zivanovic O. Ovarian Cancer Treatment - are we Getting Warmer? New England Journal of Medicine. 2018; 378: 293–294.

[91] Vergote I, Chiva L, du Bois A. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. The New England Journal of Medicine. 2018; 378: 1362–1363.

[92] Bakrin N, Bereder JM, Decullier E, Classe JM, Msika S, Lorimier G, et al. Peritoneal carcinomatosis treated with cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for advanced ovarian carcinoma: A French multicen-tre retrospective cohort study of 566 patients. European Journal of Surgical Oncology. 2014; 39: 1435–1443.

[93] Di Giorgio A, De Iaco P, De Simone M, Garofalo A, Scambia G, Pinna AD, et al. Cytoreduction (Peritonectomy Procedures) Combined with Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Advanced Ovarian Cancer: Retrospective Italian Multicenter Observational Study of 511 Cases. Annals of Surgical Oncology. 2017; 24: 914–922.

[94] Sugarbaker PH. Avoiding Diverting Ileostomy in Patients Requiring Complete Pelvic Peritonectomy. Annals of Surgical Oncology. 2016; 23: 1481–1485.

[95] Laplace N, Kepenekian V, Friggeri A, Vassal O, Ranchon F, Rioufol C, et al. Sodium thiosulfate protects from renal im-pairement following hyperthermic intraperitoneal chemotherapy (HIPEC) with Cisplatin. International Journal of Hyperthermia. 2020; 37: 897–902.

[96] Markman M, Liu PY, Moon J, Monk BJ, Copeland L, Wilczynski S, et al. Impact on survival of 12 versus 3 monthly cycles of paclitaxel (175 mg/m2) administered to patients with advanced ovarian cancer who attained a complete response to primary platinum-paclitaxel: Follow-up of a Southwest Oncology Group and Gynecologic Oncology Group phase 3 trial. Gynecologic Oncology. 2009; 114: 195–198.

[97] Pfisterer J, Weber B, Reuss A, Kimmig R, du Bois A, Wagner U, et al. Randomized Phase III Trial of Topotecan Following Carboplatin and Paclitaxel in first-line Treatment of Advanced Ovarian Cancer: a Gynecologic Cancer Intergroup Trial of the AGO-OVAR and GINECO. Journal of the National Cancer Institute. 2006; 98: 1036–1045.

[98] De Placido S, Scambia G, Di Vagno G, Naglieri E, Lombardi AV, Biamonte R, et al. Topotecan Compared with no Therapy after Response to Surgery and Carboplatin/Paclitaxel in Patients with Ovarian Cancer: Multicenter Italian Trials in Ovarian Cancer (MITO-1) Randomized Study. Journal of Clinical Oncology. 2004; 22: 2635–2642.

[99] Pecorelli S, Favalli G, Gadducci A, Katsaros D, Panici PB, Carpi A, et al. Phase III Trial of Observation Versus Six Courses of Paclitaxel in Patients with Advanced Epithelial Ovarian Cancer in Complete Response after Six Courses of Paclitaxel/Platinum-Based Chemotherapy: Final Results of the after-6 Protocol 1. Journal of Clinical Oncology. 2009; 27: 4642–4648.

[100] Hoeijmakers JH. Genome maintenance mechanisms for preventing cancer. Nature. 2001; 411: 366–374.

[101] Farmer H, McCabe N, Lord CJ, Tutt ANJ, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005; 434: 917–921.