Efficacy and Safety of Bevacizumab-Containing Neoadjuvant Chemotherapy Followed by Interval Debulking Surgery in Advanced Epithelial Ovarian, Fallopian Tube, and Primary Peritoneal Carcinomas: A Comparative Study

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy globally and remains a major public health concern due to late-stage presentation and high recurrence rates [1]. According to global cancer statistics, the majority of patients are diagnosed at advanced stages (FIGO stage IIIC–IV), contributing to poor overall survival outcomes [2]. High-grade serous carcinoma constitutes the predominant histological subtype and is characterized by aggressive biological behavior and early peritoneal dissemination [3]. Primary debulking surgery (PDS) followed by platinum-based chemotherapy has historically been considered the standard treatment approach for advanced disease [4]. Numerous studies have demonstrated that the extent of residual disease following cytoreductive surgery is one of the strongest prognostic factors for survival, with complete gross resection (R0) conferring the most favorable outcomes [5]. However, optimal primary cytoreduction is not feasible in a significant proportion of patients due to extensive tumor burden or poor performance status. The EORTC 55971 trial demonstrated that neoadjuvant chemotherapy (NACT) followed by interval debulking surgery (IDS) was non-inferior to primary surgery in terms of overall survival [6]. Similarly, the CHORUS trial confirmed comparable survival outcomes with reduced perioperative morbidity in the NACT group [7]. These findings established NACT followed by IDS as a validated alternative in selected patients with advanced ovarian cancer. Angiogenesis plays a critical role in ovarian cancer progression, ascites formation, and metastatic spread. Vascular endothelial growth factor (VEGF) over expression has been correlated with tumor aggressiveness and poor prognosis [8]. Targeting VEGF has therefore emerged as a rational therapeutic strategy. Bevacizumab is a recombinant humanized monoclonal antibody directed against VEGF-A. In the frontline setting, the GOG-0218 trial demonstrated improved progression-free survival (PFS) with the addition of bevacizumab to carboplatin and paclitaxel [9]. Likewise, the ICON7 trial reported improved PFS and suggested an overall survival benefit in high-risk subgroups [10]. Despite evidence supporting bevacizumab in first-line therapy, limited data exist regarding its incorporation into neoadjuvant chemotherapy, particularly in Indian populations.

Therefore, this study aimed to evaluate the efficacy and safety of bevacizumab-containing NACT followed by IDS in advanced epithelial ovarian, fallopian tube, and primary peritoneal cancers

This comparative non-randomized clinical trial was conducted over 18 months (May 2023 to November 2024) at the Department of Medical Oncology, Jawaharlal Nehru Cancer Hospital and Research Center, Bhopal. The study included newly diagnosed patients with FIGO stage IIIC and IV epithelial ovarian, fallopian tube, and primary peritoneal cancers. Sample size was calculated based on the ANTHALYA trial methodology using the chi-square test formula to detect differences between treatment groups.

INCLUSION CRITERIA

·        Female of more than 18 year of age.

·        Histologically confirmed and documented high-risk FIGO stage IIIC/IV epithelial ovarian carcinoma, Fallopian tube carcinoma, or primary peritoneal carcinoma.

·        Not eligible for primary complete debulking surgery.

·        Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2 5. Life expectancy greater than or equal to (>/=) 3 months.

·        Eligible for Carboplatin and Paclitaxel chemotherapy in accordance with local standards.

EXCLUSION CRITERIA

·        Non-epithelial ovarian cancer, ovarian tumor with low malignant potential, Mucinous and Clear cell ovarian cancer, or Carcinosarcoma.

·        Previous systemic therapy for ovarian cancer.

·        Inadequate bone marrow, liver, or renal function

·        History of myocardial infarction, unstable angina, stroke, or transient ischemic attack within 6 months, congestive heart failure.

·        History of other clinically active malignancy within 5 years of enrollment.

TREATMENT PROTOCOL

In the Neoadjuvant period, patients were given:

Group 1:

·        Area under the curve 5 mg/mL/min of Carboplatin and 175 mg/m² of Paclitaxel intravenously on Day 1.

·        Four cycles of Paclitaxel and Carboplatin were given 3 weekly.

Group 2:

·        Three cycles of Paclitaxel plus Carboplatin + Bevacizumab 3 weekly followed by 4th cycle of Paclitaxel plus Carboplatin only.

·        Bevacizumab dose was 15 mg/kg intravenously every 3 weeks (q3w) on Day 1 of each cycle.

Ethical approval for the study was obtained from the Institutional Ethics Committee prior to initiation of the study.

Statistical Analysis: All statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) software, version 24.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation and compared using the independent t-test for between-group analysis, while paired t-test was applied for within-group comparisons before and after chemotherapy. Categorical variables were presented as frequencies and percentages and analyzed using the chi-square test or Fisher’s exact test where appropriate. A p-value of <0.05 was considered statistically significant.

Table 1: Histopathological Distribution of Patients (n=98)

Serous adenocarcinoma was the predominant histological subtype, accounting for 85% of cases. Other types like Mucinous (8%), Papillary (5%), and Clear Cell Carcinoma (2%) were present.

Table 2: Comparison of Surgery Performed Between Treatment Groups

A high proportion of patients underwent surgery—92% in the Bevacizumab group and 85% in the control group. The difference was not significant (p = 0.67), indicating that both groups had similar surgical management.

Table 3: Comparison of serum CA-125 levels before and after neoadjuvant chemotherapy

Baseline CA-125 levels were higher in the Bevacizumab group (2169.1 U/ml) compared to the control group (1025.4 U/ml), though not statistically significant. After chemotherapy, both groups showed significant reductions (Bevacizumab: 97.2 U/ml, control: 171.1 U/ml), with a larger mean drop in the Bevacizumab group. Paired tests confirmed statistically significant within-group reductions (p < 0.05), highlighting effective tumor marker response in both regimens.             

Table 4: Comparison of the two treatment groups based on response as per RECIST 1.1 criteria

This table evaluates treatment response per RECIST 1.1 criteria. Partial response was significantly higher in the Bevacizumab group (89% vs. 71%), and objective response was statistically superior (p < 0.05). Stable disease was less common in the Bevacizumab group. Clinical benefit rates (partial + complete + stable disease) were comparable (94% vs. 90%), suggesting a better overall response with Bevacizumab inclusion, especially in tumor shrinkage.

Table 5: Comparison of the two treatment groups based on resection status

Among patients who underwent surgery, R0 resection (no residual tumor) was achieved in 94% of the Bevacizumab group and 88% of the control group. R1 resection (microscopic residual tumor) was slightly more common in the control group. However, this difference was not statistically significant (p = 0.38).

Table 6: Comparison of the two treatment groups based on side effects

Side effects were significantly more common in the Bevacizumab group (39% vs. 15%, p < 0.01). Cardiovascular toxicities like hypertension and DVT, as well as GI complications such as hematemesis and perforation, were observed only in the Bevacizumab group. Peripheral neuropathy was observed more frequently in the control group. Hematological side effects were equal in both groups.

Figure 1: Comparison of Objective Response Rate between treatment groups (p < 0.05).

Figure 2: Comparison of Chemotherapy Response Grades between groups (p = 0.09).

The present study demonstrated that the addition of bevacizumab to neoadjuvant carboplatin and paclitaxel significantly improved objective response rate compared to chemotherapy alone. These findings are biologically plausible, as VEGF inhibition reduces tumor vascular permeability and angiogenesis, thereby enhancing chemotherapy delivery and tumor shrinkage [11]. In frontline therapy trials, bevacizumab has consistently shown improved progression-free survival. Long-term follow-up of the GOG-0218 study confirmed sustained PFS benefit in patients receiving bevacizumab during chemotherapy and maintenance phases [12]. Similarly, final analyses of the ICON7 trial demonstrated that high-risk patients derived the greatest survival advantage from bevacizumab-containing regimens [13]. Although those trials were not specifically designed for neoadjuvant settings, the improved tumor response observed in our study aligns with these findings. The neoadjuvant role of bevacizumab was directly evaluated in the ANTHALYA trial, which reported higher complete resection (R0) rates without significantly increasing perioperative complications [14]. In our study, R0 resection was achieved in 94% of patients in the bevacizumab group compared to 88% in the control group, demonstrating a favorable trend. Similar improvements in surgical outcomes have been reported in observational analyses evaluating bevacizumab-containing NACT [15]. The greater decline in CA-125 levels in the bevacizumab arm suggests enhanced tumor cytoreduction. Several studies have demonstrated that early normalization or significant decline in CA-125 during NACT correlates with improved surgical outcomes and survival [16]. Our findings reinforce the predictive value of CA-125 as a surrogate marker of treatment response. Regarding safety, the bevacizumab group experienced a higher incidence of hypertension and thromboembolic events. This toxicity profile is consistent with previously reported data. Meta-analyses of bevacizumab in ovarian cancer have shown increased risks of hypertension and vascular events compared to chemotherapy alone [17]. Gastrointestinal perforation, although rare, remains a recognized but serious complication associated with VEGF inhibition [18]. Importantly, hematologic toxicities were comparable between groups, suggesting that bevacizumab does not significantly exacerbate chemotherapy-induced myelosuppression.

Although long-term endpoints such as progression-free survival and overall survival were not evaluated due to limited follow-up, prior studies indicate that the greatest benefit of bevacizumab is observed in high-risk and stage IV patients [19]. Given that our cohort predominantly consisted of advanced-stage cases unsuitable for primary surgery, the observed improvement in tumor response is clinically meaningful. The non-randomized design and single-center setting may introduce selection bias. However, this study provides valuable real-world evidence supporting the incorporation of bevacizumab into neoadjuvant regimens in carefully selected patients. Overall, bevacizumab-containing NACT appears to enhance tumor shrinkage and may improve surgical cytoreduction rates, albeit with increased but manageable toxicity

Bevacizumab-containing neoadjuvant chemotherapy significantly improves radiological and biochemical response in advanced epithelial ovarian cancer, with a trend toward improved surgical cytoreduction. However, the increased incidence of treatment-related toxicity necessitates careful patient selection and close monitoring. Larger randomized multicentric trials are warranted to validate these findings.

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