# Real-World Effectiveness of Cisplatin, 5-Fluorouracil, and Pembrolizumab Combination Therapy for Unresectable or Recurrent Esophageal Cancer

## TL;DR

This study shows that reducing the dose of chemotherapy in combination with pembrolizumab for esophageal cancer does not harm effectiveness and reduces side effects.

## Contribution

The study demonstrates that dose reduction of chemotherapy in combination with pembrolizumab is safe and effective in real-world clinical settings.

## Key findings

- Dose reduction did not compromise treatment effectiveness with overall response and disease control rates of 55.6% and 81.5%.
- Grade ≥ 3 adverse events occurred in 16.7% of patients, with fewer events in the dose-reduction group.
- Median overall survival was 18.6 months and progression-free survival was 6.5 months, with no significant differences based on dose reduction.

## Abstract

Esophageal cancer is one of the most aggressive cancers worldwide, and many patients are diagnosed at an advanced stage where surgery is not possible. A combination of cisplatin, 5-fluorouracil, and pembrolizumab has recently become a standard first-line treatment for unresectable or recurrent esophageal cancer, but many patients in real-world practice are elderly or have impaired renal function, which makes full-dose chemotherapy difficult to tolerate. In this study, we evaluated the outcomes of patients treated with this combination therapy at our institution, with particular attention to those who started treatment with reduced doses. We found that dose reduction did not compromise the effectiveness of treatment and was associated with fewer severe side effects, allowing patients to continue therapy for longer periods. These findings suggest that careful dose adjustment may help provide safe and effective treatment options for vulnerable patients in clinical practice.

Background: Immune checkpoint inhibitors (ICIs) such as pembrolizumab (Pem) have demonstrated clinical benefits in esophageal cancer. Cisplatin, 5-fluorouracil, and Pem combination (CF plus Pem) has emerged as a promising first-line regimen. However, dose reduction of cytotoxic agents is necessary in real-world practice in patients with advanced age and/or renal dysfunction. This study aimed to evaluate the real-world effectiveness and safety of CF plus Pem therapy and assess survival outcomes based on the initial dose intensity. Methods: We retrospectively analyzed patients with unresectable or recurrent esophageal cancer who received CF plus Pem between February 2022 and February 2025. Clinical data, including patient characteristics, treatment details, tumor response, adverse events, and survival outcomes, were collected and analyzed. Results: We included 54 patients (median age, 72.5 years; 74.1% male). The initial CF dose was reduced in 55.6% of the patients. The overall response and disease control rates were 55.6% and 81.5%, respectively. The median overall survival (OS) and progression-free survival (PFS) were 18.6 and 6.5 months, respectively, with no significant differences observed among groups based on dose reduction, age, or change in treatment interval. Grade ≥ 3 adverse events occurred in 16.7% of patients, with fewer events and higher treatment continuity in the dose-reduction group. Conclusions: Thus, CF plus Pem therapy is effective and tolerable in real-world settings. Initial dose reduction does not compromise survival and supports individualized dosing strategies for esophageal cancer treatment.