Neoadjuvant Chemotherapy for Advanced Ovarian Cancer: New Perspectives and Challenges

Table of Contents

• Introduction: Understanding Ovarian Cancer
• Why Consider Neoadjuvant Chemotherapy?
• Key Clinical Trial Results
• Surgical Considerations and Outcomes
• Quality of Life and Complications
• New Treatment Approaches
• When NACT Doesn't Work
• Recommendations for Patients
• Study Limitations
• Future Research Directions
• Source Information

Introduction: Understanding Ovarian Cancer

Ovarian cancer remains the deadliest gynecological cancer in developed countries, despite being less common than cervical or endometrial cancers. This comprehensive review focuses on advanced epithelial ovarian cancer, which includes cancers originating in the ovaries, fallopian tubes, or peritoneum (the lining of the abdominal cavity).

Approximately 90% of ovarian cancers are epithelial in origin, with most having serous histology. The alarming reality is that over 75% of patients are diagnosed at advanced stages (IIIC or IV), leading to poor outcomes. Survival is directly related to the stage at diagnosis, making effective treatment strategies critically important.

The standard treatment has been primary debulking surgery (PDS) followed by platinum-based chemotherapy. The goal of surgery is to remove all visible tumor tissue, as achieving optimal debulking with residual disease less than 1 cm is associated with significantly improved overall survival. However, major abdominal surgery presents substantial challenges for many patients.

Why Consider Neoadjuvant Chemotherapy?

Neoadjuvant chemotherapy (NACT) involves giving chemotherapy before surgery rather than after it. This approach has been implemented mostly for treating advanced disease when immediate major surgery might be too risky or unlikely to successfully remove all visible tumor.

The theoretical benefits of NACT include shrinking tumors before surgery, potentially making complete removal more achievable. It may also help identify patients whose cancers respond well to chemotherapy versus those that don't, providing valuable treatment information. Additionally, by reducing tumor size, NACT might enable less extensive surgery with fewer complications.

Research suggests NACT increases immune infiltration and programmed death ligand-1 (PDL-1) expression, induces local immune activation, and can potentially enhance the immunogenicity of immune-excluded high-grade serous ovarian tumors. These immunological effects represent promising areas for future treatment combinations.

Key Clinical Trial Results

Several major clinical trials have compared NACT followed by interval debulking surgery (IDS) versus primary debulking surgery (PDS) followed by chemotherapy:

EORTC 55971 Trial (632 patients): This landmark study found no difference in survival between the two approaches. Median overall survival was 29 months in the PDS group versus 30 months in the NACT group. Progression-free survival was identical at 12 months for both groups. The study confirmed that the extent of residual disease after surgery is the most important prognostic factor, regardless of when surgery occurs.

CHORUS Trial (550 patients): This study specifically enrolled older patients (median age 65 years) with poorer performance status. It showed median overall survival of 23.7 months in the IDS group versus 25.8 months in the NACT group, demonstrating non-inferiority of the NACT approach. Importantly, NACT followed by IDS led to significantly fewer postoperative complications of Grade 3 and 4 severity.

Pooled Analysis of EORTC and CHORUS (1,220 patients): This comprehensive analysis provided crucial guidance for treatment selection. It showed that PDS remains the gold standard for women with FIGO stage IIIB or lower disease. However, NACT should be the standard approach for most patients with stage IV ovarian cancer. For stage IIIC patients, decisions should be individualized based on specific disease characteristics.

JCOG0602 Trial (301 patients): This Japanese study demonstrated that NACT was associated with lower surgical invasiveness, leading to fewer postoperative adverse events and blood transfusions. Median overall survival was 49.0 months in the PDS group versus 44.3 months in the NACT group, while progression-free survival was 15.1 versus 16.4 months respectively.

SCORPION Trial (171 patients): This Italian study showed significantly higher rates of complete resection achieved after NACT (67.0% versus 47.6% with PDS). The toxicity profile also differed substantially, with significantly fewer postoperative complications in the NACT arm (9.5% versus 46.4%). There was no difference in median progression-free survival (15 vs 14 months) or overall survival (41 vs 43 months).

Surgical Considerations and Outcomes

The ability to achieve complete tumor removal (no visible residual disease) remains the single most important factor determining survival outcomes, regardless of whether surgery comes before or after chemotherapy. Studies consistently show that patients with no gross residual disease after surgery have significantly better outcomes.

Specialized surgical expertise is crucial for optimal outcomes. Surgery for ovarian cancer should be performed by specialist gynecological oncologists in high-volume centers. The diverse outcomes observed between different countries and institutions in clinical trials highlight the impact of surgical quality on patient results.

The number of NACT cycles before surgery appears important, though optimal timing isn't yet standardized. Some studies suggest that more than four cycles of NACT may have negative effects on patient outcomes, though evidence remains mixed. Two ongoing phase III trials (GOGER-01 and CHRONO) are specifically investigating whether 3 or 6 cycles of NACT produce better results.

Quality of Life and Complications

Quality of life considerations represent a significant advantage for the NACT approach. The SCORPION trial found statistical improvements in six different quality of life scales for patients receiving NACT compared to those undergoing primary surgery. This suggests that delaying major surgery until after chemotherapy may help patients maintain better daily functioning and well-being during treatment.

Postoperative complication rates consistently favor the NACT approach across multiple studies:

• EORTC 55971: Postoperative death 2.5% in PDS vs 0.7% in NACT-IDS; hemorrhage 7.4% vs 4.1%; infection 8.1% vs 1.7%
• CHORUS: Grade 3 or 4 adverse events 24% in PDS vs 14% in NACT-IDS; peri-operative death 6% vs <1%
• JCOG0602: Grade 3 or 4 adverse events after surgery 15% in PDS vs 4.6% in NACT-IDS
• SCORPION: Major complications 46.4% in PDS vs 9.5% in NACT-IDS

A meta-analysis of seventeen studies comprising 3,759 patients confirmed that NACT was associated with significantly lower perioperative morbidity and 30-day postoperative mortality compared to PDS.

New Treatment Approaches

Researchers are exploring several innovative approaches to enhance NACT effectiveness:

Hyperthermic Intraperitoneal Chemotherapy (HIPEC): This approach involves delivering heated chemotherapy directly into the abdominal cavity during surgery. The OVHIPEC trial showed promising results, with patients receiving HIPEC during interval debulking surgery achieving median overall survival of 45.7 months compared to 33.9 months for surgery alone. However, questions about patient selection and center expertise mean these results should be interpreted cautiously.

Combination with Targeted Therapies: Research is ongoing into combining NACT with bevacizumab (a drug that inhibits blood vessel formation), PARP inhibitors (which target DNA repair pathways in cancer cells), or immunotherapy. These combinations remain to be fully evaluated but represent promising future directions.

Biomarker Development: A critical need exists for biomarkers that can help individualize treatment. The ACA-125 to CEA ratio (higher than 25) has been shown useful for ruling out primary gastrointestinal tumors with metastases to the peritoneum or ovaries, which is important before selecting NACT.

When NACT Doesn't Work

Despite generally high response rates, some patients with advanced ovarian cancer progress during or after NACT. This represents a significant clinical challenge with several potential mechanisms:

1. Difficulty detecting residual cancer cells during interval debulking surgery
2. Enhancement of cancer stem cells that are more resistant to treatment
3. Induction of gene mutations that promote platinum resistance

For patients who do not respond to NACT, interval debulking surgery is not a viable option. These patients, who have a particularly unfavorable prognosis, are typically treated as platinum-resistant and require alternative treatment strategies.

Recommendations for Patients

Based on current evidence, NACT followed by interval debulking surgery is recommended for specific patient groups:

• FIGO Stage IV ovarian cancer patients - This should be the standard approach for most patients with stage IV disease
• FIGO Stage IIIC patients when optimal debulking cannot be achieved with upfront surgery
• Patients with significant comorbidities that make immediate major surgery too risky
• Older patients and those with poorer performance status who may tolerate the staged approach better

Primary debulking surgery remains the preferred approach for patients with earlier stage disease (FIGO stage IIIB or lower) and those who are good surgical candidates with disease that appears completely resectable.

Study Limitations

The existing studies comparing NACT and primary surgery have several important limitations that affect how we interpret their results. Many trials included patients from different centers treated by surgeons with diverse experience levels, leading to variability in surgical outcomes. Some studies had low complete cytoreduction rates in the primary surgery arm, which might bias results against upfront surgery.

The most significant limitation across multiple trials is the substantial heterogeneity between included studies, making direct comparisons challenging. Additionally, some trials had low accrual rates at selected centers, potentially affecting the generalizability of their findings.

Many studies did not require diagnostic surgery before treatment randomization, meaning some patients might have had different cancer types. The EORTC and CHORUS trials addressed this by using the ACA-125 to CEA ratio to help identify gastrointestinal cancers masquerading as ovarian cancer.

Future Research Directions

Several ongoing trials will provide additional insights into NACT for ovarian cancer:

TRUST Trial: An international randomized controlled multicenter trial investigating overall survival after primary cytoreductive surgery versus NACT and subsequent interval debulking. This study includes strict quality assurance criteria for participating centers and completed patient recruitment in 2019, with results expected in 2024 after 5 years of follow-up.

SGOG SUNNY (SOC-2) Trial: A randomized phase III clinical trial in Asian countries specifically designed to overcome limitations of previous studies by ensuring high surgical quality standards and including only specialized ovarian cancer centers.

GOGER-01 and CHRONO Trials: These ongoing phase III randomized trials are specifically investigating whether 3 or 6 cycles of NACT produce better outcomes, addressing an important unanswered question about optimal treatment duration.

Future research should also focus on developing better biomarkers to predict which patients will benefit most from NACT versus primary surgery, and which might benefit from innovative combinations with targeted therapies or immunotherapy.

Source Information

Original Article Title: Neoadjuvant treatment in ovarian cancer: New perspectives, new challenges

Authors: Adamantia Nikolaidi, Elena Fountzilas, Florentia Fostira, Amanda Psyrri, Helen Gogas, Christos Papadimitriou

Publication: Frontiers in Oncology, 26 July 2022

DOI: 10.3389/fonc.2022.820128

This patient-friendly article is based on peer-reviewed research and aims to make complex medical information accessible while preserving all scientific findings and data from the original publication.