RCT: Comparing Perioperative Chemotherapy Alone to Perioperative Chemotherapy Plus Preoperative Chemoradiotherapy in Resectable Gastric Cancer

Background:

In the management of resectable gastric cancer, perioperative chemotherapy—chemotherapy administered both before (neoadjuvant) and after (adjuvant) surgery—is the standard of care in many Western countries. This approach is based on trials like MAGIC and FLOT4-AIO, which demonstrated improved survival with perioperative chemotherapy compared to surgery alone.

Preoperative chemoradiotherapy (the combination of chemotherapy and radiotherapy before surgery) has shown benefits in other gastrointestinal cancers, such as esophageal cancer, by downstaging tumors and potentially improving surgical outcomes. However, its efficacy in gastric cancer, especially when added to perioperative chemotherapy, has not been well-established.

Objective:

To determine whether adding preoperative chemoradiotherapy to standard perioperative chemotherapy improves overall survival compared to perioperative chemotherapy alone in patients with resectable gastric and gastroesophageal junction adenocarcinoma.

Methods:

• Study Design: International, phase 3, randomized controlled trial (TOPGEAR).
• Participants: 574 patients with resectable adenocarcinoma of the stomach or gastroesophageal junction (Siewert type II or III), clinical stage T3 or T4, and considered suitable for curative surgery.
• Interventions:

  1. Perioperative Chemotherapy Group (Control Group):

  • Definition of Perioperative Chemotherapy: Chemotherapy administered both before (preoperative/neoadjuvant) and after (postoperative/adjuvant) surgery.
  • Chemotherapy Regimens:
    • Before 2017: Patients received three cycles before surgery and three cycles after surgery of either:
      • ECF: Epirubicin, Cisplatin, and continuous-infusion Fluorouracil.
      • ECX: Epirubicin, Cisplatin, and Capecitabine (an oral prodrug of fluorouracil).
    • After 2017 Amendment: Patients received four cycles before surgery and four cycles after surgery of:
      • FLOT: Fluorouracil, Leucovorin, Oxaliplatin, and Docetaxel.

  2. Perioperative Chemotherapy Plus Preoperative Chemoradiotherapy Group (Experimental Group):

  • Modifications to Chemotherapy:
    • Received one less cycle of preoperative chemotherapy compared to the control group to accommodate the addition of radiotherapy.
    • Postoperative chemotherapy was the same as in the control group.
  • Preoperative Chemoradiotherapy:
    • Chemoradiotherapy Definition: Concurrent administration of chemotherapy and radiotherapy before surgery.
    • Radiotherapy Regimen:
      • Total dose of 45 Gy, delivered in 25 fractions over 5 weeks (1.8 Gy per fraction, 5 days per week).
      • Target Area: Entire stomach, any perigastric tumor extension, and regional lymph nodes.
    • Concurrent Chemotherapy During Radiotherapy:
      • Continuous infusion of Fluorouracil (200 mg/m² per day) 7 days a week during radiotherapy.
      • Alternatively, Capecitabine (825 mg/m² twice daily on days 1–5 of each radiotherapy week) could be used.
• Surgical Procedure:
  • Surgery was performed 4–6 weeks after completion of preoperative therapy.
  • Recommended surgery included total gastrectomy, subtotal distal gastrectomy, or esophagogastrectomy with D2 lymphadenectomy (removal of additional lymph node stations beyond the immediate perigastric nodes).

Endpoints:

• Primary Endpoint: Overall survival (time from randomization to death from any cause).
• Secondary Endpoints: Progression-free survival, pathological complete response rate (no residual tumor in the resected specimen), treatment-related toxic effects, and quality of life.

Results:

• Pathological Findings:
  • Pathological Complete Response Rate:
    • Higher in the experimental group (preoperative chemoradiotherapy) at 17% compared to 8% in the control group.
  • Tumor Downstaging:
    • More patients in the experimental group had their tumors downstaged to a lower T category and had fewer involved lymph nodes.
• Survival Outcomes:
  • Overall Survival:
    • Median Overall Survival:
      • Experimental Group: 46 months.
      • Control Group: 49 months.
    • Hazard Ratio for Death: 1.05 (95% CI, 0.83–1.31), indicating no significant difference between the groups.
  • Progression-Free Survival:
    • Median progression-free survival was similar between the groups (31 months vs. 32 months).
• Treatment Adherence:
  • Preoperative Therapy Completion:
    • High completion rates in both groups for preoperative chemotherapy.
    • Slightly lower in the experimental group due to the addition of radiotherapy.
  • Postoperative Chemotherapy Completion:
    • Lower completion rates overall, with fewer patients in the experimental group completing postoperative chemotherapy (48% vs. 59%).
• Adverse Events:
  • Similar rates of grade 3 or higher toxic effects in both groups.
  • No significant differences in surgical complications or postoperative mortality.

Conclusion:

Adding preoperative chemoradiotherapy to standard perioperative chemotherapy did not improve overall survival or progression-free survival in patients with resectable gastric and gastroesophageal junction adenocarcinoma, despite achieving higher pathological complete response rates and increased tumor downstaging. These findings suggest that the routine addition of preoperative chemoradiotherapy to perioperative chemotherapy does not confer additional survival benefits and should not change the current standard of care.

Clinical Implications:

• Standard Treatment Remains Perioperative Chemotherapy:
  • Perioperative chemotherapy alone continues to be the standard approach for resectable gastric cancer.
  • Regimens like FLOT are preferred due to their demonstrated efficacy.
• Role of Radiotherapy:
  • Routine use of preoperative radiotherapy in addition to chemotherapy is not supported by this trial’s findings.
  • Radiotherapy may still have a role in specific clinical scenarios, but not as a standard addition to perioperative chemotherapy.
• Future Directions:
  • Further research may focus on identifying subgroups of patients who might benefit from chemoradiotherapy.
  • Biomarker-driven approaches and personalized treatment strategies could optimize outcomes.

Reference: Leong, T., et al. (2024). Preoperative Chemoradiotherapy for Resectable Gastric Cancer. The New England Journal of Medicine.  DOI: http://doi.org/10.1056/NEJMoa2405195