Non-cancer-related deaths in patients with resectable locally advanced esophageal squamous cell carcinoma: A supplementary analysis of JCOG1109.
Authors: Imazeki Hiroshi , Kato Ken , Ito Yoshinori , Daiko Hiroyuki , Chin Keisho , Koyanagi Kazuo , Ogata Takashi , Hara Hiroki , Fujita Takeo , Abe Tetsuya , Endo Fumitaka , Tsunoda Shigeru , Takeno Atsushi , Nagatani Yoshiaki , Matsushita Hisayuki , Sato Hiroshi , Matsuda Satoru , Kawabata Kota , Machida Ryunosuke , Takeuchi Hiroya 
Published: January 2025

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Background:
Neoadjuvant docetaxel, cisplatin, and 5-FU (DCF) has become the standard treatment for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) in Japan, based on the result of JCOG1109. In this study, more non-cancer-related deaths were observed in the cisplatin, and 5-FU (CF) plus radiotherapy (CF-RT) arm compared to the CF and DCF arm. However, the details of these non-cancer-related deaths remain unclear. We aimed to evaluate the influence of neoadjuvant therapies on non-cancer-related deaths using the data from JCOG1109.
Methods:
We analyzed patients' characteristics, classification, time of onset, risk factors associated with onset, and cumulative incidences in patients with non-cancer-related deaths. Cumulative incidences of non-cancer-related deaths in each arm were estimated, considering cancer-related deaths as a competing risk. Risk factors were explored using multivariable Fine-Gray model with Firth penalization.
Results:
Among 601 enrolled patients, 164 in the CF arm, 169 in the DCF arm, and 173 in the CF-RT arm were completed the surgery. Of those, non-cancer-related deaths were observed in 19 (12%), 12 (7%), and 32 (18%) patients, respectively. Patient characteristics of non-cancer-related deaths in the CF/DCF/CF-RT arm were as follows: male, 89/92/88%; median age, 69/69/69 years old; ECOG PS 0, 89/100/97%; lower thoracic esophagus, 21/25/19%; previous history of ischemic disease of heart, 5/0/0%; brain, 0/0/0%; other malignancies, 5/8/0%; comorbidity of hypertension, 26/25/47%; COPD, 0/8/3%; thoracoscopic approach, 37/42/38%. The median follow-up time was 5.7 years (range, 0.3-10.4 years). The causes of non-cancer-related deaths in the CF/DCF/CF-RT arm were pulmonary, 4 (21%)/1 (8%)/10 (31%); cardiovascular, 1 (6%)/0/2 (6%); infectious, 2 (11%)/1 (8%)/3 (9%); other malignancy, 2 (11%)/3 (25%)/5 (16%); treatment-related, 0/1 (8%)/1 (3%), and the median time from surgery to onset of non-cancer-related death was 3.3/3.8/4.3 years, respectively. Cumulative incidences of non-cancer-related deaths after 3, 6, 9 years in the CF/DCF/CF-RT arm were 4.9/3.0/7.0%, 10.7/6.1/15.6%, 12.4/8.8/26.1%, respectively. In multivariable analyses, ≥ 65 years old (hazard ratio [HR]: 3.243, 95% confidential interval [CI]: 1.797–5.852, vs. < 65 years old), ECOG PS 0 (HR: 3.579, 95% CI: 1.148–11.162, vs. PS 1), and serum CRP ≥ 1.0 mg/dl (HR: 2.238, 95% CI: 1.003–4.995, vs. <1.0 mg/dl) were significantly associated with the onset of non-cancer-related deaths. Whereas the CF-RT arm was not significantly associated (HR: 1.600, 95% CI: 0.885–2.892, P = 0.12, vs. CF).
Conclusions:
The incidence of non-cancer-related deaths was relatively higher in the CF-RT arm, and pulmonary-related complications tended to be a particularly common cause of death.