Clinical research progress of abdominal chemotherapy for ovarian cancer Qilu Hospital, Shandong University Song Kun Kong Beihua (Shandong, Jinan 250012) The standard first-line treatment for advanced ovarian cancer is tumor cytoreductive surgery + platinum-based combination chemotherapy. Tumor cytoreductive surgery, as the cornerstone of first-line treatment, has not developed significantly in decades. As an important adjuvant treatment for patients with advanced ovarian cancer, the first-line chemotherapy regimen has undergone three important historical stages of development with the introduction of new chemotherapeutic agents: cisplatin + cyclophosphamide (PC), cisplatin + paclitaxel (PT), and the current standard chemotherapy regimen of carboplatin + paclitaxel (CT). Many other new chemotherapeutic agents such as topotecan, liposomal adriamycin, and oxaliplatin are currently in clinical trials, and triple-drug combinations and sequential dosing regimens have been attempted. Regardless of the changes in chemotherapy regimens, the mainstay of first-line chemotherapy is intravenous administration, and although intraperitoneal chemotherapy has its theoretical basis, its application is mostly limited to consolidation chemotherapy or second-line chemotherapy. However, in recent years, three large randomized controlled clinical trials (RCTs) have concluded that intraperitoneal infusion of chemotherapeutic agents as first-line chemotherapy for ovarian cancer can significantly improve patient prognosis compared with intravenous administration, and some scholars even believe that first-line chemotherapy has entered the era of intraperitoneal chemotherapy. It is still controversial internationally whether celiac chemotherapy should replace intravenous chemotherapy as first-line chemotherapy for advanced ovarian cancer, and this paper discusses this issue. Song Kun, Department of Gynecology, Qilu Hospital, Shandong University, China Advanced ovarian cancer is mostly confined to diffuse growth in the pelvic and abdominal cavities, so intraperitoneal administration seems to be theoretically the ideal mode of drug delivery. After intraperitoneal administration, cytotoxic drugs can enter the tumor body directly through the dysplastic vascular system of tumor tissue, thus increasing the drug concentration in tumor tissue; intraperitoneal administration of drugs stays in the local area for a longer time, and tumor tissue can be exposed to cytotoxic drugs for a longer time; intraperitoneal drugs are mainly absorbed through portal vein, and the liver first-pass effect can reduce the systemic toxicity of chemotherapeutic drugs. It is worth noting that the penetration of chemotherapeutic drugs to tumor tissues is limited, and some studies have shown that only 1-2 mm of superficial tumor tissues can be exposed to high concentration of drugs, therefore, intraperitoneal chemotherapy is suitable for patients with small residual lesions in the abdominal cavity, i.e., patients who achieve satisfactory results of tumor cytoreduction; meanwhile, intraperitoneal chemotherapy requires uniform drug dispersion in the abdominal tissues, so it is not suitable for patients with abdominal adhesions. It is not suitable for patients with abdominal adhesions, but it is difficult to determine whether abdominal adhesions have occurred after surgery; for extraperitoneal lymph node metastases, abdominal chemotherapy does not seem to play its advantage. There are many drugs that can be used for intraperitoneal chemotherapy, including mafalan, 5-Fu, mitogen, adriamycin, topotecan, etc. The most promising applications are cisplatin, paclitaxel and carboplatin, among which cisplatin has the most clinical applications and more relevant information. Some studies have shown that the tumor surface drug concentration of cisplatin administered intraperitoneally is 10-20 times higher than that of intravenous administration, and the drug concentration in peripheral blood is significantly lower than that of intravenous administration; to achieve the same intra-tumor platinum concentration, the dose of carboplatin is 10 times higher than that of cisplatin, and the therapeutic efficiency is better than that of carboplatin. However, carboplatin is also an ideal drug for intraperitoneal chemotherapy because it is more than 50% effective as second-line chemotherapy and its peripheral neurotoxicity is weak. Paclitaxel is relatively less used in the abdominal cavity, which is characterized by less systemic absorption, high peritoneal/peripheral blood concentration ratio of 1000, longer retention in the abdominal cavity, and deeper penetration. These are the theoretical advantages of intraperitoneal chemotherapy, and in view of this, there are few studies related to the use of intraperitoneal perfusion in ovarian cancer chemotherapy over the years, but they are mostly small sample studies or retrospective analyses, and they are mostly used as second-line chemotherapy or consolidation chemotherapy options. There have been 5 small RCTs on peritoneal chemotherapy as a first-line chemotherapy regimen, and their results concluded that peritoneal chemotherapy did not improve outcomes compared with intravenous chemotherapy. However, recently published evidence from three large phase III RCTs provides evidence that cisplatin administered intraperitoneally offers greater advantages as first-line chemotherapy. The Southwest Oncology Group (SWOG) SWOG8501/GOG104 study randomized 546 patients with primary ovarian cancer to receive CTX (600 mg/m2) with cisplatin administered intraperitoneally (100 mg/m2) or intravenously (100 mg/m2), and all patients underwent satisfactory initial tumor cytoreduction with 6 cycles of chemotherapy. The results showed that the median survival time (OS) was 8 months longer in the intraperitoneal group compared to the intravenous group (49 vs 41 months), and the complete remission rate (cCR) was significantly higher in the former group than in the control group (47% vs 31%) as confirmed by the second-investigation procedure. This is the first RCT in history to confirm the superiority of intraperitoneal chemotherapy over intravenous chemotherapy, and the study also found a reduced cisplatin intraperitoneal infusion side effect compared to the intravenous group. Shortly after platinum + paclitaxel was established as the standard first-line chemotherapy regimen, the Gynecologic Oncology Group (GOG) began organizing the GOG114/SWOG9227 study. Cisplatin (i.v. 75 mg/m2) + paclitaxel (i.v. 135 mg/m2) x 6 cycles in the control group and carboplatin (i.v. AUC=9) x 2 cycles first followed by paclitaxel (i.v. 135 mg/m2) + cisplatin (i.p. 100 mg/m2) in the study group were available for efficacy evaluation in 462 patients, all of whom experienced satisfactory tumor cytoreductive surgery. Results showed a statistically significant increase in median progression-free survival (PFS) in the intraperitoneal group (28 vs. 22 months) and an 11-month increase in OS in the intraperitoneal group (63 vs. 52 months), but no statistical difference. The incidence of toxic side effects was significantly higher in the intraperitoneal group compared with the control group. In view of the inconsistent results of the two RCTs mentioned above and the inconclusive therapeutic value of intraperitoneal chemotherapy, GOG started the GOG172 study comparing cisplatin (i.v. 75 mg/m2, D1) + paclitaxel (i.v. 135 mg/m2, D1) with paclitaxel (i.v. 135 mg/m2, D1) + cisplatin (i.p. 100 mg/m2, D2 The efficacy of the regimen of paclitaxel (i.p. 60 mg/m2, D8) + paclitaxel (i.v. 135 mg/m2, D1) versus cisplatin (i.v. 135 mg/m2, D2) was statistically significant. 415 patients who underwent satisfactory tumor cytoreduction entered the study with a median PFS of 23.8 and 18.3 months and a median OS extension of 16 months (65.6 vs. 49.7 months) in the peritoneal group compared to the intravenous group. This study suggests that laparoscopic chemotherapy improves patient prognosis, but the incidence of serious side effects, including systemic toxicity, neurotoxicity, and complications due to puncture sets, was significantly higher in the laparoscopic group than in the control group, and quality of life (QOL) was significantly lower in the laparoscopic group at 1 year. Overall, three RCTs showed that intraperitoneal administration as first-line chemotherapy improved patient prognosis, and the National Cancer Institute (NCI) accordingly issued a statement that intraperitoneal chemotherapy combined with intravenous chemotherapy as first-line chemotherapy prolonged patient survival compared with intravenous chemotherapy alone in patients with advanced ovarian cancer after satisfactory tumor cytoreductive surgery. The results of the GOG172 study and the NCI statement have led to extensive discussion in the international academic community about the use of celiac chemotherapy. The German AGO concluded that the abdominal chemotherapy regimen used in the GOG172 study was difficult for patients to tolerate and that abdominal chemotherapy could not yet be included as first-line standard chemotherapy for ovarian cancer. The Canadian Society of Gynecologic Oncologists (GOCs) surveyed gynecologic oncologists via an electronic questionnaire and found that most had concerns about the management of systemic and local toxicity, intubation complications, quality of life, patient compliance, length of hospital stay, and cost of laparoscopic chemotherapy, limiting the use of laparoscopic chemotherapy. In an article published by JCO, physicians from the United Kingdom, Germany, and Belgium analyzed the results of the GOG172 study and concluded that there is no primary evidence to suggest that celiac chemotherapy is safer and more effective than the current standard first-line chemotherapy regimen (CT). The GOG104 study enrolled patients over a long period of time, and the standard first-line chemotherapy regimen was changed from PC to PT at the end of the study, and the PT intravenous regimen improved OS more significantly than the PC intraperitoneal regimen, so the advantages of the PC intraperitoneal regimen were no longer reflected. Similarly, the control intravenous chemotherapy regimen in the GOG172 study was PT, and the standard chemotherapy regimen had already developed into CT before the study was closed, and the CT regimen had low toxic side effects and high quality of life for patients, which made it more convincing to use it as a control group. in the GOG114 and GOG172 studies, the trial and control chemotherapy regimens did not match, and it cannot be excluded that the trial chemotherapy regimen itself had an impact on the study results The effect of the chemotherapy regimen itself on the study results cannot be excluded. In the GOG172 study, only 42% of patients in the intraperitoneal group completed the scheduled 6 cycles of chemotherapy, while the rest (n = 118) completed only 3-4 cycles. The remaining patients (n = 118) completed only 3-4 cycles before being unable to continue with celiac chemotherapy and were switched to intravenous chemotherapy, making it difficult for a regimen that is not tolerated by more than half of the patients to become the standard of care. Complications associated with laparotomy, such as infection, puncture tube blockage, and intestinal tube injury, which are unique to laparoscopic chemotherapy, should also be taken into account, as 36% of the GOG172 study resulted in a change of chemotherapy regimen due to puncture tube-related complications. Thus, the short-term prolongation of PFS and OS comes at the cost of reduced quality of life for patients. Each of these RCTs used different regimens of peritoneal chemotherapy and inconsistent doses. Even if it is determined that peritoneal chemotherapy can be used as first-line standard chemotherapy, how should the specific chemotherapy regimen, drug dose, and number of chemotherapy cycles be determined? These three studies alone do not provide an answer. In view of these issues, more evidence-based evidence is needed for the use of celiac chemotherapy as standard first-line chemotherapy for ovarian cancer.