Surgery and chemotherapy for recurrent epithelial ovarian cancer Department of Obstetrics and Gynecology, Qilu Hospital, Shandong University (250012) Song Kun Kong Beihua Abstract: There is no standard treatment plan for patients with recurrent ovarian cancer, for which surgery and/or chemotherapy are mainly used. After rigorous patient selection, satisfactory re-tumor cytoreductive surgery can improve patient survival; and with the availability of more effective novel chemotherapeutic agents, chemotherapy alone can also achieve higher survival rates. When considering which treatment option to adopt, it should be noted that the aim of treatment for recurrent ovarian cancer is palliative rather than curative, with emphasis on issues such as toxic and side effects and quality of life. Song Kun, Department of Gynecology, Qilu Hospital, Shandong University, China Keywords: recurrent ovarian cancer, chemotherapy, re-tumor cytoreductive surgery, ovarian cancer ranks first in the death rate of female reproductive system tumors. Due to the lack of specific symptoms in early stage ovarian cancer, 70% of patients are already in advanced stage when they are diagnosed. After standard treatment, 70% of patients will eventually recur or present with persistent disease, and the recurrence rate is still as high as 30-50% even in patients with negative second-investigation surgery. The Gynecologic Oncology Group (GOG) defines Recurrent Ovarian Cancer (ROC) as a recurrent lesion that has been treated with initial platinum-based chemotherapy and has achieved clinical remission and has been discontinued for more than 6 months. Generally, ROC is classified into the following four categories: (i) chemotherapy-sensitive: a definite response to first-line platinum-based chemotherapy and has achieved clinical remission, with recurrence of lesions more than 6 months after discontinuation of chemotherapy; (ii) chemoresistant: a response to first-line chemotherapy, but confirmed recurrence within 6 months after the end of chemotherapy; (iii) recalcitrant: effective to first-line chemotherapy, but the patient still has residual tumor lesions; (iv) refractory: no minimal effective response to Refractory type: patients who do not have minimal effective response to chemotherapy, including those with stable or progressive disease during first-line chemotherapy, and such patients have the lowest efficiency for second-line chemotherapy. For ovarian cancer patients, once recurrence occurs, the aim of treatment changes from cure to palliative treatment. ROC is almost difficult to be cured, but through proper selection of treatment plan, palliative treatment can be achieved to prolong patients’ survival time and improve their quality of life. The treatment of ROC should take into account the patient’s wishes, treatment effect, treatment cost and quality of life to select the appropriate treatment plan. Due to the lack of data from prospective randomized controlled clinical trials (RCTs) with large samples to prove which protocols or agents have positive efficacy and can prolong patient survival, there is no standard treatment protocol for ROC so far. Surgery and chemotherapy are the most widely used in clinical practice as traditional treatments and still dominate in the treatment of ROC. Chemotherapy ovarian cancer is one of the more sensitive tumors to chemotherapy among solid tumors, and 80% of patients are effective to standard first-line chemotherapy regimens. However, the vast majority of advanced ovarian cancers eventually recur and may develop drug resistance. For patients with ROC, most require second-line chemotherapy, and the choice of chemotherapy regimen depends largely on the nature of the recurrence. In the development of second-line chemotherapy regimens, patients with drug-resistant, recalcitrant and refractory types are often considered as a group and encouraged to undergo clinical trials with new drugs or to receive chemotherapy with non-platinum agents; for patients with sensitive ovarian cancer, platinum-based or platinum+paclitaxel-based chemotherapy regimens are recommended. In addition to clinical efficacy, the selection of chemotherapy regimens should also focus on the expected toxic effects, quality of life, patient compliance and treatment costs. In addition to platinum and paclitaxel, many second-line chemotherapeutic agents have been shown to be effective in patients with platinum and/or paclitaxel resistance, including topotecan, oral pegylated glycosides (VP16), liposomal adriamycin, gemcitabine, doxorubicin, oxaliplatin, and vincristine. I. Carboplatin (carboplatin) or/and paclitaxel (paclitaxel) Carboplatin is a second-generation platinum derivative with anticancer effects similar to those of cisplatin, but with less nephrotoxicity. The length of the treatment interval (TFI) is generally considered to be a predictive indicator of the sensitivity of ROC patients to platinum-containing regimens. It has been reported that patients with TFI <12 months, 13-24 months, and >24 months ROC have an efficiency rate to platinum of 26%, 33%, and 77%, respectively. For patients with longer TFI (chemotherapy-sensitive), carboplatin is usually used as the drug of choice for second-line chemotherapy. Recently Bolis et al [1] designed an RCT to compare the efficacy of single-agent carboplatin and carboplatin + epoetin combination chemotherapy in chemotherapy-sensitive ROC patients. The complete efficiency (CR) and partial efficiency (PR) of chemotherapy in the former and the latter were 36% and 18% and 31.8% and 26%, respectively, with no significant difference in the percentage of patients with CR, PR, stable disease and disease progression in the two groups (p=0.16). The incidence of toxic reactions, especially hematologic toxicity, was higher in the combination chemotherapy group than in the single-agent carboplatin group, which led to the conclusion that the use of combination chemotherapy was not necessary. Paclitaxel is a new antitumor drug with a complex diterpenoid chemical structure. Some studies have demonstrated that paclitaxel has an efficiency of 20% to 37% as a second-line chemotherapeutic agent for ROC patients. Single-dose paclitaxel for ROC can be divided into weekly therapy (40-100 mg/m2 1h/week) and three-week therapy (135-200 mg/m2 3h/3 weeks), both of which have similar efficacy, but weekly therapy has significantly less toxic side effects. zanotti et al [3] analyzed 34 ROC patients who achieved complete effectiveness after first-line chemotherapy (carboplatin + paclitaxel) and received paclitaxel 135 to 175 mg/m2 3h/3 weeks, with an efficiency rate of 44% and a median progression-free interval (PFI) of 8.6 months, and another 41% of patients with stable disease and a median PFI of 7.4 months, with repeat dosing and mild cumulative toxic effects that were tolerated by patients. However, Cantu et al [4] designed a randomized controlled trial comparing the efficacy of single-agent paclitaxel with a platinum-containing chemotherapy regimen (CAP) for chemotherapy-sensitive ROC, and showed that both single-agent paclitaxel and CAP regimens were effective for ROC, but the former was statistically less effective (45%) than the latter (55%). Therefore, more large randomized controlled studies are still needed to further determine the therapeutic value of single-agent paclitaxel for ROC. study GOG158 has identified carboplatin + paclitaxel as the standard first-line chemotherapy regimen for ovarian cancer patients, and its therapeutic value for ROC remains controversial. Some scholars believe that its second-line chemotherapy for chemotherapy-sensitive ROC patients should refer to first-line chemotherapy and suggest carboplatin+paclitaxel as the preferred second-line chemotherapy regimen with higher chemotherapy efficiency and longer survival. The results of retrospective case studies by many scholars support this conclusion. At the 39th annual meeting of the American Society of Clinical Oncology (ASCO) just this year, Ledermann [5] presented the preliminary results of a large RCT in Europe. In patients with sensitive ROC, paclitaxel + platinum combination chemotherapy showed a significant improvement in overall efficiency and patient survival time compared to single-agent platinum. The combination chemotherapy group showed a 10% improvement in 1-year progression-free survival (50% vs 40% 95% CI 4%-15% HR=0.76 p=0.0004 ) and a 7% improvement in 2-year overall survival (57% vs 50% HR =0.82 p=0.02) compared to the single-agent chemotherapy group. Although toxic effects (mainly neurotoxicity and hair loss) were more severe in the combination chemotherapy group than in the single-agent group, there was no significant difference in quality of life between the two groups. This is the first strong international evidence that combination chemotherapy is more effective than single-agent platinum-based chemotherapy in the treatment of sensitive ROC patients. Another randomized controlled trial comparing the efficacy of carboplatin + gemcitabine with single-agent carboplatin in ROC is currently underway in Europe, taking into account not only treatment efficacy and toxic effects, but also quality issues. The results of this trial, when published, will provide stronger evidence to guide chemotherapy in patients with sensitive ROC, and the previous recommendation of single-agent carboplatin for ROC will probably be rejected. Topotecan is a water-soluble semi-synthetic camptothecin analogue that is a DNA topoisomerase I inhibitor. After platinum and paclitaxel, Topotecan has been identified as a second-line chemotherapeutic agent for ovarian cancer after the most extensive clinical trials. For ROC, the phase III clinical trial found no significant difference in efficacy between topotecan and paclitaxel. In addition, early treatment with topotecan is effective for those who are resistant to first-line platinum-based chemotherapy, prolonging the interval between platinum-free treatments and allowing for satisfactory results with subsequent platinum-based treatment. The clinical efficacy of topotecan is related to the treatment regimen. The more established method of administration is the 5-d regimen: topotecan 1.5 mg/m2・d*5d/21d. McGuire et al [6] reported that a study by GOG showed that this regimen was 33% effective in treating chemotherapy-sensitive ROC patients with a median effective duration of 11.2 months. However, topotecan can produce more severe myelosuppression in ROC patients who have received first-line chemotherapy.Bookman et al [7] reported the results of an earlier phase II clinical trial in which a 5d regimen for ROC patients was 12.4% effective in resistant patients and 19.2% effective in sensitive patients, with a high incidence of grade IV neutropenia of 82% and grade IV thrombocytopenia of 30%. Fortunately, this myelosuppression is not cumulative and usually occurs during the first course of therapy and can be controlled by reducing the dose and/or using hematopoietic growth factors to complete multiple cycles of therapy. To improve efficacy and reduce the incidence of toxic side effects, GOG has conducted clinical trials to evaluate the efficacy of alternative dosing regimens. However, topotecan 24-hour continuous titration is only 7% effective in sensitive patients and 4% effective in resistant patients, and the incidence of toxicities is similar to that of the 5d regimen; the topotecan 3d regimen is only 7% effective in refractory patients, and trials are underway to treat sensitive patients [8]. At this year’s ASCO meeting, Morris et al [9] reported preliminary results of a phase IV clinical trial of topotecan weekly therapy (4.0 mg/m2・30 min/week) with an efficiency rate of 32%, median PFI of 29 weeks in effective patients, and mild toxic effects. Other scholars have reported low-dose therapy, long-term therapy, and oral topotecan dosing regimens with some efficacy, but most of the studies were retrospective analyses and the results were not highly credible. In addition, clinical studies on combination chemotherapy regimens of topotecan have been started, and GOG is currently conducting clinical trial studies on the combination regimens of oral topotecan and oral VP16 sequential administration, topotecan + gemcitabine for ROC. Docetaxel is a new generation of paclitaxel antitumor drug with a mechanism of action similar to that of paclitaxel. It has a tendency to replace paclitaxel in the treatment of ovarian cancer because: (1) preclinical experimental models prove that it is superior to paclitaxel; (2) it has similar efficacy to paclitaxel in platinum-resistant patients and still has therapeutic effects in paclitaxel-resistant patients; (3) it has significant efficacy in breast cancer (indirect evidence); (4) the regimen is easy to administer, with 1h/3 weeks dosing; (5) the toxicity, especially neurotoxicity, is less than that of paclitaxel. In view of these characteristics, studies on doxorubicin have been very active in recent years. In a Japanese study, a single dose of doxorubicin treated ovarian cancer patients who had been treated with platinum-based chemotherapy had an overall efficiency of 28%, with 33% and 25% for sensitive and refractory patients, respectively; the main toxic reaction was myelosuppression, with grade III and IV neutropenia occurring in 86% of patients [10]. Recently, Rose [11] et al. reported a multicenter phase II clinical trial of GOG in which a single dose of doxorubicin was used to treat platinum- and paclitaxel-resistant ROC patients with an overall efficacy of 22.4% (CR 5.2%,PR 17.2%) and a median effective duration of 2.5 months, but with severe myelosuppression, 75% incidence of grade IV neutropenia, and 36% of patients requiring dose reduction. Considering the high incidence of toxic side effects of doxorubicin, further studies should be conducted to determine the optimal treatment dose and regimen. Gemcitabine/Gemzar Gemcitabine is an antimetabolite with additive or synergistic effects with other antitumor drugs and remains effective against tumor cells resistant to other drugs, including platinum. Single-agent gemcitabine is 13% to 19% effective in second-line treatment of ROC, with mild toxic effects, mainly myelosuppression.Du-Bois et al [12] reported that carboplatin + gemcitabine was 62.5% effective in the treatment of chemotherapy-sensitive ROC patients, with median PFI and median survival of 10 months and 18+ months, respectively. The results of a recent phase II clinical trial showed that 21 patients with ROC treated with the combination of topotecan + gemcitabine were available for efficacy evaluation in 11 patients, with three in complete remission and four in partial remission, and a median PFI of 8.8 months (95% CI 6.3 to 13.4 months). Hematologic toxicity was rare, without the need to reduce the drug dose, and non-hematologic toxicity was even less frequent and mild [13]. The combination of gemcitabine with other drugs such as cisplatin, paclitaxel, VP16, and vincristine has shown positive efficacy. More remarkable is the combination of gemcitabine with carboplatin and paclitaxel as first-line chemotherapy, with an efficiency of up to 100%, which is a very promising drug. V. Liposomal Adriamycin (Pegylated Liposomal Doxorubicin) Liposomal Adriamycin is a kind of polyethylene glycol liposome-encapsulated Adriamycin, which has a prolonged circulation time compared with Adriamycin and tends to accumulate in tissues with abnormal microvascular permeability, such as tumor tissues. Toxic reactions are significantly different from those of adriamycin, mainly dominant dose-limiting skin mucosal toxicity, mild bone marrow suppression, and no significant cardiotoxicity.Campos et al[14] showed a single dose of liposomal adriamycin with an overall efficiency of 27% in ROC patients and an efficiency of 29% in resistant patients with mild toxic reactions.GOG has initiated liposomal adriamycin + carboplatin + paclitaxel as Phase I and II studies of first-line chemotherapy for ovarian cancer, while clinical trials of liposomal adriamycin in combination with non-platinum drugs are underway for second-line chemotherapy. VP16 is a cell cycle-specific drug that acts mainly in the G2 phase and can cause cytotoxicity due to DNA breakage in target cells. A meta-analysis found that the efficiency of VP16 in treating ROC patients was 20.4%. A large study by GOG concluded that the overall efficiency was 30.5%: 26.8% in platinum-resistant patients (CR 7.3%) and 34.1% in platinum-sensitive patients (CR 14.6%). The GOG study confirmed the effectiveness of VP16 in both platinum-sensitive and platinum-resistant ROC patients [15]. VII. Oxaliplatin (Oxaliplatin L-OHP) Oxaliplatin is a third-generation platinum derivative with a mechanism of action similar to that of cisplatin and carboplatin, but with greater antitumor activity and the ability to overcome resistance to cisplatin and carboplatin in mismatch repair gene defective tumor cells. Data from a clinical trial showed that a single dose of L-OHP treated ovarian cancer patients who had previously received platinum-based therapy had an overall efficacy of 29%, including 46% in sensitive patients; 17% in resistant patients, with tolerable toxic effects [16]. In addition, there may be synergistic effects of L-OHP with first- and second-generation platinum and other new chemotherapeutic agents.Faivre et al [17] reported that L-OHP + paclitaxel was effective in up to 48% of ovarian cancer patients previously treated with platinum, 33% of resistant patients, and 69% of sensitive patients.L-OHP with agents such as topotecan, gemcitabine, and vincristine The combination of L-OHP with topotecan, gemcitabine and vincristine is currently in phase I and II clinical trials and has shown initial results. The mechanism of action of vinorelbine NVB is similar to other vincristine, but its neurotoxicity is less than that of vincristine. duration of 19 weeks, median survival time of 60 weeks, and toxic reactions were mainly myelosuppression, with some patients requiring dose reduction. Similarly, Sorensen et al [19] reported a 21% overall efficacy, median PFI of 3.1 months, median survival time of 10.1 months, and mild toxicity in patients with resistant ROC treated with a single dose of vincristine. Clinical trials are ongoing regarding the efficacy of combination chemotherapy regimens containing vincristine in patients with ovarian cancer. At this year’s ASCO annual meeting, Oletti et al [20] presented the preliminary results of a phase II clinical trial of liposomal adriamycin + vincristine in second-line treatment of advanced ovarian cancer, with a combination chemotherapy efficacy of 40%, significantly higher than the efficacy of both single-agent chemotherapy, and this regimen was safe and feasible with low toxic effects.