Consolidation therapy-can it be integrated into the overall treatment plan of ovarian cancer
Song Kun, Department of Gynecology, Qilu Hospital, Shandong University, China Kong Beihua
Abstract: In recent years, the treatment efficiency of progressive epithelial ovarian cancer has improved significantly, but its long-term survival rate is still unsatisfactory. It is a new attempt to provide consolidation therapy for patients who have achieved complete clinical remission after standard treatment in order to prevent, delay recurrence and improve prognosis. The optimal treatment plan for consolidation therapy has not yet been determined, nor has its status and role in the overall treatment of ovarian cancer been established. In this paper, we analyze the literature related to consolidation therapy and conclude that until sufficient evidence is available, consolidation therapy should not be routinely applied in clinical practice and should only be used in clinical trials. Song Kun, Department of Gynecology, Qilu Hospital, Shandong University
Keywords: epithelial ovarian cancer, consolidation therapy
Substantial progress has been made in the treatment of progressive epithelial ovarian cancer within the past 20 years. This is mainly attributed to improved surgical techniques, which have led to more patients achieving satisfactory surgical outcomes (residual foci ≤1 cm), and the advent of improved and more effective platinum-based first-line chemotherapy regimens. The 5-year tumor survival rate has increased from 30% to 50% in patients with ovarian cancer of longer duration, but the long-term survival rate remains low at 20-25% in patients with progressive disease (1). This result is unsatisfactory and therefore new treatment strategies have been explored to improve their prognosis. These include prolonged induction chemotherapy, high-dose chemotherapy, the use of new drugs, and biologic therapy. However, three randomized controlled trials comparing the efficacy of 5 to 6 cycles with 8, 10, and 12 cycles of first-line chemotherapy did not demonstrate that longer cycles of chemotherapy improved patient survival, and the standard first-line chemotherapy should still be 6 courses (2). None of the newer chemotherapeutic agents, except gemcitabine, has been shown to be more effective than standard first-line chemotherapy with carboplatin + paclitaxel. The combination of gemcitabine with carboplatin and paclitaxel as first-line chemotherapy has an efficiency of up to 100% and is a promising drug (3, 4). Biological therapy for ovarian cancer is only in the developmental stage, and various biological agents are used in clinical trials for recurrent ovarian cancer (ROC) patients, similar to many new chemotherapeutic agents (5). In addition, the ability of consolidation therapy to improve patient prognosis has attracted much interest. After initial tumor cytoreductive surgery, the standard first-line chemotherapy regimen of platinum + paclitaxel has an overall efficacy of 75%, with 50% of patients achieving clinical complete remission cCR. However, only 25-30% of cCR patients are free of residual lesions confirmed by second-look laparotomy SLL (5), i.e., pathologic complete remission pCR; even in pCR patients, the recurrence rate is as high as 50% (6). Therefore, in patients with cCR after standard treatment (tumor cytoreductive surgery and postoperative platinum + paclitaxel combination chemotherapy), it seems necessary to administer further treatment, rather than just follow-up, i.e. consolidation, to maintain the efficacy and prevent recurrence before disease recurrence. Some scholars have proposed the concept of maintenance chemotherapy, which refers to the continuation of long-term intermittent treatment after achieving cCR with induced chemotherapy, and is essentially the same as consolidation therapy. To date, no optimal consolidation regimen has been established and there is no certainty that it will improve the prognosis of patients. The main forms of consolidation therapy are chemotherapy, radiotherapy and other forms such as biological therapy, which are discussed as follows.
I. Consolidation chemotherapy
Chemotherapy is a traditional adjuvant treatment for malignant tumors, and platinum + paclitaxel is a part of the standard treatment for patients with progressive ovarian cancer, and it has been studied most often as consolidation therapy.
1.Intraperitoneal chemotherapy
Intraperitoneal chemotherapy is a logical treatment for ovarian cancer recurrent foci, which are mostly confined to the pelvic cavity, abdominal cavity or both. The pharmacokinetic advantage of intraperitoneal chemotherapy is that it has the highest ratio of intraperitoneal drug levels to plasma drug levels, thus exposing tumor cells to high local drug concentrations and overcoming drug resistance caused by standard systemic dosing. Intraperitoneal drugs can enter the systemic circulation through the lymphatic system as well as by active diffusion, thus making intraperitoneal infusion chemotherapy effective in treating local as well as systemic lesions (7). In addition to being used as first-line chemotherapy and salvage therapy for persistent ovarian cancer, it has been used as consolidation therapy for patients with cCR.
Barakat (8) et al. recently retrospectively analyzed 89 SLL-confirmed pCR patients receiving postoperative platinum-based intraperitoneal infusion chemotherapy with a median survival time of up to 8.7 years, but the absence of a control and the fact that patients took multiple therapies after disease progression did not thereby prove that intraperitoneal infusion consolidation chemotherapy prolongs patient survival. In one of his earlier phase II clinical trials, he compared 36 patients with II-IV ovarian cancer who received cisplatin + VP16 intraperitoneal infusion chemotherapy after SLL-confirmed pCR with 46 patients who were included in the criteria-matched group during the same period (SLL-negative followed by observation only). At a median follow-up of 36 months in both groups, 61% of patients in the treatment group had no evidence of recurrence compared with 54% in the control group; disease-free survival DFS was significantly different between the two groups (p=0.03); multifactorial analysis showed that the only factor associated with improved prognosis was treatment strategy (9). This led Barakat to conclude that intraperitoneal infusion consolidation chemotherapy is feasible and has some clinical efficacy, and Menczer’s findings were similar. Of the 37 patients with cCR, 25 received cisplatin intraperitoneal infusion consolidation chemotherapy and 12 were followed up for observation. The likelihood of survival was significantly higher in the treatment group than in the control group (74.9% vs 35.6%, p=0.03) from the time the diagnosis was established to 45 months of follow-up (10). In another of their reports, 31 patients with cCR treated with cisplatin intraperitoneal infusion chemotherapy had a 5-year overall survival OS of 60.4%, a median survival time of 69 months, and a progression-free interval PFI of 35 months (11). In addition to platinum, mitoxantrone hydrochloride has been used as an intraperitoneal infusion chemotherapeutic agent.Dufour (12) reported that 50 patients with SLL confirmed pCR were treated with intraperitoneal infusion consolidation chemotherapy with a median follow-up of 2 years and a 5-year expected survival rate of 59.8% (95% CI 48.3-71.3%) and a 5-year expected disease-free survival rate of 47.3% (95% CI 47.3%). Tarraza (13) reported 56 patients with SLL-negative ovarian cancer receiving consolidation chemotherapy by intraperitoneal infusion, 41 of whom were treated with cisplatin and the remaining 15 with mitoxantrone hydrochloride due to cisplatin toxicity, with a median follow-up time of 24 months and The median follow-up time was 24 and 30 months for the two groups, respectively, and the recurrence rates were 24% and 26%, with no significant differences. The median recurrence-free interval for all patients was 18 months.
The above studies suggest that consolidation chemotherapy by intraperitoneal infusion is feasible for patients with progressive ovarian cancer after achieving cCR with standard treatment, and can improve the efficiency of chemotherapy and prognosis to a certain extent. However, the above studies are retrospective case studies, and their long-term efficacy has yet to be verified by large-scale randomized controlled trials RCTs.
2.high-dose chemotherapy (HDC)
Drug resistance in ovarian cancer cells is partly caused by insufficient doses of chemotherapy drugs. In order to overcome the drug resistance of ovarian cancer and improve the effect of chemotherapy, people began to study the feasibility of high-dose chemotherapy for ovarian cancer. In recent years, the development of hematopoietic system support therapy has largely facilitated the use of mega-dose chemotherapy in the treated malignancies. The use of colony-stimulating factor (CSF) and peripheral blood stem cell transplantation (PBSCT) has significantly reduced the morbidity and mortality rates of high-dose chemotherapy compared to conventional autologous bone marrow transplantation (ABMT), thus making high-dose chemotherapy more feasible as consolidation therapy. There is a dose-effect relationship between ovarian cancer and chemotherapeutic agents, especially alkylating agents. As early as 1982, Dufour began experimenting with high-dose Marfalan + ABMT as consolidation therapy for ovarian cancer patients, with 2/6 patients surviving disease free for more than 3 years (14). The median follow-up time was 63 months, with a 5-year disease-free survival rate of 32% and a 5-year overall survival rate of 46%, which showed that high-dose chemotherapy + HSCS was more effective than conventional treatment in terms of long-term outcomes. However, since this study was a retrospective analysis, the results are not fully reliable. Recently, Cure et al (16) designed a phase III RCT comparing the efficacy of high-dose carboplatin + cyclophosphamide + PBSCT with conventional dose chemotherapy regimens. Preliminary results showed that HDC consolidation chemotherapy significantly improved DFS compared to conventional chemotherapy in highly selected patients (chemosensitive, those with small residual SLL lesions.) However, previous studies in Europe have shown that HDC + HSCS has similar outcomes to standard-dose chemotherapy patients (17). Therefore, there is no conclusive evidence that HDC improves patient prognosis. Also, because of the advanced technology and expensive equipment of HDC + PBSCT, it cannot replace conventional treatment and should be limited to clinical trials.
3.Systemic drug use
Altretamine (Hexalen) has anti-ovarian cancer activity, and its specific mechanism is unclear, but it may be related to interference with cellular DNA and RNA synthesis. Clinical trials have confirmed its efficacy as first-line chemotherapy and salvage therapy (18-20), and Albert et al. (21) tried it as a consolidation drug and achieved some efficacy with acceptable toxicity. They used hexamethonium to consolidate 112 patients with stage III ovarian cancer and achieved a 2-year survival rate of 75% (95% CI 66-84%) in 97 evaluable patients; for those with satisfactory initial surgical results (residual foci ≤1 cm), the 2-year survival rate was as high as 82% (95% CI 72-92%) with acceptable toxic effects. Umesaki, a Japanese scholar, has tried maintenance treatment with intermittent CDDP in patients with progressive ovarian cancer for many years and achieved good results. He reported 15 patients with stage III ovarian cancer without residual lesions or CA125 <8u/ml after surgery and induction chemotherapy were treated with intermittent chemotherapy: CDDP 20mg/m2×5d/3~4m for 5 years. The 5-year survival rate was significantly increased compared with the control group (n=10) (22). However, oral 5-Fu and tegafur maintenance chemotherapy were not efficacious (23).Eltabbakh (24) studied patients with chemosensitive recurrent ovarian cancer treated with CDDP maintenance chemotherapy (8-week interval) after 1 year of salvage chemotherapy to achieve complete remission, and the median DFS in the treatment group (n=16) compared with the control group (n=11) was 35 months and 6 months (p=0.001), a significant difference. However, the overall survival was 119 and 90 months, respectively, with no statistical difference (p = 0.056). Although this study was conducted in patients with recurrent ovarian cancer, the results are also informative. meden et al. reported that 39 ovarian cancer patients who received oral Treosulfan 1250 mg x 5d/5w for at least 3 cycles (median 6 cycles) as maintenance therapy after achieving cCR had a median survival time of 24 months and a median progression-free interval of 8 months (3 to 24 months), and the toxic side effects were well tolerated (25).
Consolidation radiotherapy
As mentioned above, with the development of chemotherapy, especially the emergence of platinum and paclitaxel combination chemotherapy regimens, the clinical efficiency of ovarian cancer patients has been greatly improved. However, the long-term survival rate of ovarian cancer patients is still very low. Therefore, radiotherapy is gradually gaining interest as a part of comprehensive treatment for salvage therapy and consolidation therapy to improve patients’ prognosis.
1.Whole abdominal radiation WAR
Ovarian cancer recurrence is mostly confined to the pelvic and abdominal cavities, so it is logical to irradiate the pelvic and abdominal cavities locally to control the lesions. It has been suggested that whole abdominal consolidation radiotherapy is effective for patients with cCR and no residual foci confirmed by SLL or microscopic residual foci (26, 27). The results showed that DFS and OS were significantly higher in the treatment group than in the control group (2- and 5-year DFS 68% vs. 56%, 49% vs. 26% p=0.013; 2- and 5-year OS 87% vs. 61%,59% vs. 33% p=0.029), with significant differences. Side effects were within acceptable limits. This result initially confirms the role of WAR in the treatment of patients with ovarian cancer. However, some authors have concluded that WAR consolidation with radiotherapy does not improve patient prognosis and that the incidence of toxic side effects is high and severe (29-31). Therefore, the therapeutic value of WAR consolidation radiotherapy after surgery + chemotherapy has not been confirmed and remains controversial.
2.P32 perfusion in the abdominal cavity
Local consolidation therapy for ovarian cancer patients includes WAR, peritoneal perfusion chemotherapy and peritoneal perfusion radionuclide. While the first two have been described previously, the latter is usually treated with P32 infusion, which releases beta radiation and can penetrate 3-5 mm of tissue with a half-life of 14.3 days. It has been used previously for the treatment of early-stage disease and for the control of intra-abdominal micrometastases, and its effectiveness has been confirmed by clinical trials. Spencer (32) analyzed 31 SLL-negative patients, 14 of whom received P32 intraperitoneal perfusion, and the rest did not undergo further treatment. At a mean follow-up of 4 years, the difference was significant with 100% DFS in the former and 4 recurrences in the latter. Rogers (33) reported 69 SLL-negative patients, with the treatment group (n = 51) receiving P32 intraperitoneal perfusion and the control group (n = 18) not treated. The 5-year OS and 5-year DFS in the two groups were 90%, 86% vs 78%, and 67%, respectively, p=0.05. Two other reports with similar results concluded that P32 intraperitoneal perfusion was effective as consolidation therapy, especially in those with SLL-negative or residual microscopic lesions (34, 35). However, it is noteworthy that the above reports are all from the literature around the 1980s and are not RCT trials, and in recent years, with the development of intraperitoneal perfusion chemotherapy, P32 intraperitoneal perfusion has gradually been replaced by it.
In conclusion, the best treatment plan for consolidation therapy of ovarian cancer has not been determined so far. The choice of treatment regimen should be based on clinical trial data, taking into account the patient’s quality of life, treatment side effects, compliance and economic burden. According to evidence-based medical EBM, consolidation therapy is not suitable as routine treatment, but only for clinical trials.
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