Introduction

Previous studies have reported increased risk of second cancer in both esophageal squamous cell cancer (ESCC) and esophageal adenocarcinoma (EAC) survivors during follow-up, and the risk varied across cancer types.

Aims & Methods

Aimed to examine the risk and influential factors of second cancer in ESCC and EAC patients, this population-based study included 7,297 ESCC patients and 11,812 EAC patients who were in 1992-2019 from the Surveillance, Epidemiology, and End Results (SEER) program in the United States. These patients were followed up until diagnosis of second cancer, death, or end of the study (December 31, 2019). We calculated standard incidence ratio (SIR) and 95% confidence interval (CI) of second cancer and performed competing-risk regression to estimate the subdistribution hazard ratios (sHR) comparing categories of patients’ characteristics.

Results

After a total of 49509.38 person-years of follow-up, 431 (5.9%) ESCC patients and 636 (5.9%) EAC patients developed a second cancer. An overall increased risk of second cancer was observed in both ESCC patients (SIR=1.66, 95% CI 1.51-1. 83) and EAC patients (SIR=1.11, 95% CI 1.02-1.20). ESCC patients were at increased risk of second malignancy in oral cavity and pharynx (SIR=12.57, 95% CI 9.87-15.79), stomach (SIR=3.03, 95% CI 1.77-4.85), nose and larynx (SIR=4.79, 95% CI 2.47-8.37), and lung and bronchus (SIR=2.44, 95% CI 1.96-2.99), but decreased risk of prostate cancer (SIR=0.73, 95% CI 0.52-0.99). EAC patients had increased risk of second malignancies in stomach (SIR=4.41, 95% CI 3.23-5.89), lung and bronchus (SIR=1.26, 95% CI 1.02-1.54), and kidney (SIR=1.57, 95% CI 1.05-2.25). The risk of second cancer was higher in female ESCC patients than in males (sHR=1.34, 95% CI 1.11-1.63) and decreased with more advanced tumor stage for in both ESCC patients (sHR=0.62, 95% CI 0.50-0.76 for localized stage; sHR=0.27, 95% CI 0.20-0.36 for distant stage) and EAC patients (sHR=0.47, 95% CI 0.40-0.56 for localized stage; sHR=0.10, 95% CI 0.07-0.13 for distant stage).

Conclusion

Both ESCC and EAC patients are at considerable risk of certain types of second cancer.

References

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Introduction

Optimal management after radical endoscopic resection (R0 ER) of high-risk (HR) T1 esophageal adenocarcinoma (EAC) is still a matter of debate due to conflicting reports on the risk of lymph node metastasis (LNM). In case of submucosal (sm) invasion, a/o poor differentiation, a/o lympho-vascular invasion (LVI), additional treatment is often still recommended. In this prospective international multicenter cohort study (PREFER, NCT03222635), we aim to evaluate the safety of a strict endoscopic follow-up (FU) strategy following R0 ER for T1b and HR-T1a EAC.

Aims & Methods

Patients treated with R0 ER of T1b EAC were included from July 2017 - July 2023, in 19 hospitals in Europe and Australia. Patients were defined as HR-T1b EAC in case of sm invasion ≥ 500um, a/o poor differentiation, a/o LVI. From July 2020 we also included HR-T1a EAC, with HR defined as presence of poor differentiation a/o LVI, as part of an ongoing prospective registry. To allow for appropriate FU we assessed outcomes for patients included up to July 2023, at which time inclusion for the prospective PREFER study was complete.
After R0 ER, patients underwent re-staging with endoscopic ultrasound (EUS) and CT/PET. If there were no signs of metastasis (cN0M0), patients were consented for strict endoscopic FU, with gastroscopy and EUS 3-monthly the first 2 years, 6-monthly during years 3 and 4, and at year 5. CT/PET was repeated after 1 year. Primary outcomes were 5-year disease-specific and overall survival; secondary outcomes were rates of distant metastasis, LNM, and local recurrence ineligible for endoscopic treatment.

Results

Per July 2023, 200 patients (166 male, median age 70 (IQR 63 - 76) years) were included, 157 T1b patients (n = 54 low-risk (LR) T1b and n = 103 HR-T1b) and 43 HR-T1a patients.
For the T1b group, median FU was 21 (IQR 12-38) months. Thus far, 11/157 patients (7%) have successfully completed the 5-year FU without signs of metastatic disease or intra-luminal tumor recurrence ineligible for endoscopic re-treatment. Distant metastases were diagnosed in 3/157 (2%, 95%CI 0 - 4) patients, all without signs of local recurrence or LNM: 1/3 underwent resection of a lung metastasis, with no signs of recurrence after 9 months; 1/3 had liver metastasis and started palliative systemic therapy 4 months ago; 1/3 had liver metastasis, declined further treatment and died. Locoregional LNM were diagnosed in 9/157 (6%, 95% CI 2 - 9). All were detected at a curable stage, but 1/9 declined further treatment and died from EAC; the other patients received appropriate treatment and are disease-free after median 26 (IQR 12 - 27) months post additional treatment. In total, 8/157 patients (5%, 95%CI 2 - 9) developed intra-luminal tumor recurrence ineligible for endoscopic re-treatment, 3/8 declined additional treatment and eventually died from EAC. Furthermore, 10/157 patients (6%) died during FU due to unrelated causes.
In the HR-T1a group, no recurrent disease was diagnosed after a median FU of 16 (IQR 12 - 23) months.

Conclusion

The preliminary findings of this first prospective study on HR-T1 EAC support a strict endoscopic FU strategy in select patients who underwent R0 ER with no signs of metastatic disease (cN0M0) at baseline.