Esophageal cancer (EC) is the 4th most common cause of cancer deaths in China (1). The RTOG85-01 trial established the efficacy of definitive concurrent chemoradiotherapy (dCRT), which can significantly improve survival compared with radiotherapy (RT) alone (2). All patients in the RT alone arm died of cancer by 3 years. Since then, dCRT has become the standard treatment for inoperable locally advanced EC patients, and RT alone should only be reserved for palliation or for patients who are medically unable to receive chemotherapy. However, there is indeed a group of EC patients who rejected or were intolerant to intravenous chemotherapy due to old age or serious comorbidities. The management of these patients is a therapeutic challenge. Searching an alternative effective chemotherapy agent with moderate treatment related toxicities seems to be a promising strategy for these patients.

S-1 is an oral chemotherapy agent of fluoropyrimidine, consisting of tegafur, gimeracil, and oteracil potassium, and has been proven to be noninferior in efficacy to infusional fluorouracil in gastric cancer (3). In addition, the S-1-based regimen showed a good safety profile with lower incidence of grade 3/4 neutropenia (OR = 0.33) than the 5-fluorouracil based regimen in advanced gastric cancer (4). Moderate toxicities and promising response rates were also observed in EC patients treated with concurrent chemoradiotherapy with an S-1 based regimen (5, 6). Therefore, S-1 combined with definitive RT may be an optimal option for locally advanced EC patients who rejected or were intolerant to intravenous chemotherapy due to old age or serious comorbidities.

In this phase 2 clinical trial (ESO-Shanghai 7), we aimed to verify the safety and efficacy of definitive RT combined with S-1 alone in locally advanced esophageal squamous cell carcinoma (ESCC) patients who rejected or were intolerant to intravenous chemotherapy due to old age or serious comorbidities. We hypothesized that S-1 combined with radiotherapy had low toxicity and improves local control in these ESCC patients.

From March 2013 to October 2015, a total of 105 patients with ESCC were enrolled in the Fudan University Shanghai Cancer Center (Figure 1). The baseline and tumor characteristics of the enrolled patients are listed in Table 1. The median age was 77 years (IQR 72–80). Seven (6.7%) patients who were initially staged as stage IVa were upstaged to IVb due to the incorrect staging for supraclavicular lymph node metastasis after staging review. Two patients were initially staged as stage IIa were downstage to I due to reevaluation by endoscopic ultrasound. The median tumor lengths of the patients enrolled were 5.3 cm (IQR 3.8–6.5). Details of serious comorbidities of patients enrolled are listed in Table A.1.

Sixty-eight (64.8%) patients completed the full treatment, namely, 93 (88.6%) patients completed the full radiotherapy prescribed and 70 (66.7%) patients completed the full-prescribed dose of S-1. The details of the treatment compliance are shown in Table A.2. Treatment delay and cessation were mainly due to treatment-induced toxicities. One hundred one (96.2%a patients received at least 50 Gy radiotherapy.

At the data cutoff date (October 31, 2020), the median follow-up of the surviving patients was 73.1 months (IQR 65.5–81.4 months). Two patients were lost to follow-up. Twenty-three (21.9%) patients were alive without local disease progression. The 1, 3, and 5-year local control rates were 77.8, 61.1, and 58.1%, respectively (Figure 2A). Twenty-three (21.9%) were alive without metastasis. The patterns of treatment failure are shown in Table 2. Eighty-one (77.1%) patients suffered deaths at the time of analysis, namely, 59 patients who died of tumor progression and 22 patients who died of other causes. The median survival was 26.1 months. The 1, 3, and 5-year OS rates were 77.9, 42.3, and 24.8%, respectively (Figure 2B). Moreover, the differences in terms of OS between the patients aged >75 years and patients aged ≤75 years, and between the patients with serious comorbidities and patients without serious comorbidities were not significant (Figure A.1).

Since all patients received at least one dose of S-1, the safety population was equal to the intention-to-treat population. All ≥grade 2 side effects and grade 1 side effects that occurred in more than 10% of the patients reported during treatment are shown in Table 3. Seventy (66.7%) patients had ≥grade 2 acute side effects from the treatment, most of which were related to leukopenia and radiation-induced esophagitis. Twenty-six (24.8%) patients had grade 3 or above adverse events, namely, anemia, leukopenia, thrombocytopenia, anorexia, hiccups, fatigue, radiation-induced pneumonitis, and esophagitis. Two patients (1.9%) died of late esophageal hemorrhage, and one patient (1.0%) died of late radiation-induced pneumonitis.

Definitive concurrent chemoradiotherapy is the standard treatment for inoperable esophageal cancer patients. The RTOG 85-01 trial showed that EC patients treated with cisplatin plus fluorouracil concurrent with radiotherapy had significantly better overall survival than those treated with radiotherapy alone (2). Likewise, our previous ESO-Shanghai 1 trial, enrolling ESCC patients aged 18–75 without serious medical comorbidities, showed a promising 3-year OS in both dCRT with cisplatin plus fluorouracil (51.8%) and dCRT with paclitaxel plus fluorouracil (55.4%) (8). However, the optimal evidence-based management for the EC patients who rejected or were intolerant to intravenous chemotherapy due to old age or serious comorbidities is currently lacking. The long-term results of this prospective phase 2 trial showed a promising local control and a low incidence of side effects of dCRT with S-1 alone when treating this group of ESCC patients. The 3-year local control rate in this trial was comparable with that of the ESO-Shanghai 1 trial (61% vs. 62.2%) and the incidence of ≥grade 3 acute AEs was much lower (24.8% vs. 50.2%) (8).

With global aging, it is very important to understand the treatment of geriatric cancer patients. However, most of clinical trials excluded elderly patients because of the high risk of treatment-related morbidity and mortality, limited life expectancy, and functional status. The treatment effects of this age group were underrepresentation with paucity of data (9, 10). Chemotherapy concurrently combined with radiotherapy is often considered to be too toxic for most elderly EC patients. Jingu et al. showed concurrent chemotherapy with radiotherapy for esophageal cancer in patients aged 80 years or older did not have a significant OS benefit but led to significantly more severe late toxicities than RT alone (11). Likewise, Xu et al. compared patients ≥80 years with esophageal cancer treated with conventional dCRT with 2 younger patient cohorts (65–79 years and <65 years) treated with dCRT by propensity score matching and showed that the elderly cohort exhibited statistically significant evidence of an increased rate of severe radiation pneumonitis (12). Several studies have suggested that dCRT improves overall survival in elderly patients only in locally advanced stage compared with RT alone (13, 14). Since elderly patients have unique issues, namely, life expectancy, comorbidities, and the risk of treatment-induced morbidity, chemoradiotherapy requires careful consideration and should be carefully selected in elderly EC patients (10).

Single agent or doublet agents, such as docetaxel, nedaplatin/5-fluorouracil, and cisplatin/capecitabine, have been combined with radiotherapy for treating with elderly EC patients in several studies and have achieved promising survival results (15–18). However, for elderly EC patients, compared with double-agent-based dCRT, single-agent-based dCRT was considered to have a lower incidence of treatment side effects and comparable OS (19, 20). The long-term results of a retrospective analysis of elderly ESCC patients treated with S-1 concurrent with radiotherapy showed satisfactory survival outcomes and tolerable toxicities (21). Furthermore, several prospective trials also showed mild toxicity and satisfactory efficacy in elderly ESCC patients treated with S-1 concurrent with radiotherapy (22–24). In our prospective trial, S-1 concurrent with definitive radiotherapy was well tolerated in either elderly patients or patients with serious comorbidities. The incidence of ≥grade 3 toxicities in each side effect was less than 10%, which was comparable to previous studies with single S1 and much lower than that with doublet agents in dCRT in elderly ESCC patients (21–25). The median survival time in present trial was favorable (26.1 months) and comparable to previous similar studies (22.6–25.7 months) (21–24).

A phase 2 trial using a single agent of platinum concurrent with radiotherapy of 50 Gy in 30 elderly EC patients and showed mediocre mid-term efficacy with a 3-year OS of only 22.2%, and nine patients died from local failure. They suggested that the therapeutic ratio or locoregional control might be improved by increasing the radiotherapy dose or by testing new radiosensitizer agents (26). In this phase 2 trial, we used a radiotherapy dosage of 61.2 Gy according to the treatment guidelines of radiotherapy for Chinese esophageal carcinoma and achieved a promising 3-year local control rate (61.1%) and OS (1, 3, and 5-year OS of 77.9, 42.3, and 24.8%, respectively) (27). Our results were comparable to the long-term results of a retrospective study treating elderly ESCC patients with S-1 concurrent with radiation doses of 54.0–60.0 Gy (21). The 1, 3, and 5-year OS in that study were 70.6, 41.8, and 25.9% respectively.

It is known that comorbidities have an independent prognostic effect on cancer patients (28). However, few studies have focused on comorbidities in the treatment decision of EC patients. Patients with serious comorbidities, such as chronic diseases of the cardiovascular, pulmonary, and hepatic systems, are usually excluded from clinical trials. In this phase 2 trial, the enrollment included this group of ESCC patients, and promising local control and good tolerance of S-1 concurrent with definitive RT with low treatment toxicities were observed. However, we did observe that a high percentage of patients (13.3%) died of nononcologic causes, which is undoubtedly related to the aging and serious comorbidities pretreatment.

Our study had several limitations. First, we did not set the control group of radiotherapy alone, and a randomized controlled study would be ideal for the comparison. A randomized phase 3 trial comparing simultaneous integrated boost radiotherapy with or without S-1 is ongoing (29). Another limitation is that we did not assess the quality of life of patients enrolled, which may offer more comprehensive knowledge of the safety results of S-1 concurrent with radiotherapy when treating ESCC patients who were elderly or had serious comorbidities.

In summary, the long-term results of this phase 2 trial demonstrated that S-1 concurrent with radiotherapy was well tolerated in ESCC patients who rejected or were intolerant to intravenous chemotherapy due to old age or serious comorbidities. The promising 3-year local control rate suggests that this approach was effective and merits randomized phase 3 trial evaluation.

Parts of this manuscript were previously presented in 2016 ASTRO meeting and 2019 ASTRO meeting, respectively.

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethical Committee of Fudan University Shanghai Cancer Center. The patients/participants provided their written informed consent to participate in this study.

This trial was supported by the National Natural Science Foundation of China (grant 81703160).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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