Due to physiological limitations and tolerance to the toxicity of aggressive treatment, elderly patients with ESCC are usually given palliative care to prevent deterioration of the general condition of patients. However, cumulative studies have proven that elderly patients with EC achieve long-term survival from curative treatment, such as radical esophagectomy or definitive RT or CRT [11-13]. Alberto et al reported that short- and long-term outcomes after esophagectomy for EC in patients older than 70 years are comparable with those of their younger counterparts . Xu et al reported that, compared to young patients with similar prognostic status, the elderly population exhibits similar long-term survival following definitive CRT . In the current study, which enrolled patients aged over 70 who were treated with RT or CRT, the 5-year OS rate of the whole cohort was similar to that of our previous studies, which enrolled patients aged under 70 (with an OS rate of 27.2% at 5 years) . The results confirmed that old age should not be a contraindication for curative treatment in patients with EC.
Although advanced age is not a contraindication for aggressive treatment, data on whether CRT is superior to RT alone for patients with unresectable or medically inoperable ESCC are scarce, and the efficacy of definitive CRT has not been established . Zhao et al reported that CRT with platinum and 5-FU is well-tolerated and more effective than RT alone for elderly patients older than 75 years with locally advanced ESCC . In the current study, the survival rates between the CRT and RT-alone groups were not significantly different, whether in pre- or post-PSM. The impact of treatment complications on survival is often a common explanation for this discrepancy. However, the treatment-related mortality rate between RT-alone and CRT was not found to be significantly different in the current study. Therefore, for elderly patients with ESCC, combined treatment of RT with a contemporary regimen of chemotherapy should be conducted cautiously .
Other potential reasons for the inconsistency are the inadequate intensity of chemotherapy and unified chemotherapy regimens in the current study. However, to date, the appropriate doses and schedules of chemotherapy for these patients are yet to be determined . Several studies had proven that dual-agent therapy achieved superior survival than single-agent CRT for elderly patients with ESCC [20, 21]. Zhao et al demonstrated that CRT with a single agent in elderly patients had a similar survival benefit compared to CRT with a dual agent, accompanied by less toxicity . Similar to Zhao et al, in the current study, the survival of patients treated with CRT with various CC regimens or CC cycles did not alter significantly. The aforementioned results indicate that the efficacy of CC in patients treated with RT is debatable, and novel drug treatment options with lower toxicity and higher efficacy must be developed for elderly patients with ESCC [23, 24].
Despite the controversies, some studies have argued that CRT should be considered for a certain subgroup rather than for all elderly ESCC patients. Zhang et al reported a single-center retrospective study demonstrating that, compared with RT-alone, only elderly ESCC patients aged 65-72, and not patients older than 72 years, benefited from CRT in terms of survival . To identify which subgroup of patients may benefit from CRT, exploratory subgroup analyses basing on the potential factors influencing prognosis were performed in the present study. The results demonstrated that, compared with RT alone, CRT did not confer a survival benefit to elderly patients in the various subgroups, except cT4, cN0 or diabetic patients.
The T category of the current AJCC staging system is based on anatomical information related to primary tumor invasion of the esophageal wall. Although CRT was considered an optimal treatment for unresectable EC, its feasibility and effectiveness for T4 tumors, which are defined by invasion of the adjacent structures and are not indicated for surgery, is still unclear, and a high incidence of esophageal perforation has been reported after standard CRT for T4 tumors . Previous studies have reported the use of a low-dose concurrent chemotherapy regimen to obtain the maximal radiosensitizing effect, which may improve patient survival without the rapid depopulation of massive T4 tumors and perforation caused by full-dose chemotherapy [26-28]. The current study, similar to Nishimura et al , demonstrated that CRT compared to RT alone achieved superior survival in cT4 patients. The results suggested that, even in elderly patients, patients with more advanced disease should be administered more aggressive treatments to improve their survival.
Lymph node metastasis (LNM) is a poor prognosis factor in patients with ESCC and an indicator that more intensive treatment may be required [29, 30]. Numerous studies in non-elderly patients have found that for patients with LNM, CRT can achieve a greater survival benefit than RT-alone . However, the efficacy of CC in elderly ESCC patients with LNM treated with RT had not been confirmed. The current study took the lead in discussing this topic. Unfortunately, contrary to the non-elderly patients, the current study found that whether in the entire cohort or in the PSM patients, compared with RT-alone, CRT benefited survival only in N0 patients, and not in N1 patients who were hypothesized to benefit from CC. The inaccurate division of the cN stage into N0 and N1 may have explained the results of the current study. The accurate determination of cN stage based on a CT scan image is crucial for the re-evaluation of the role of CRT in elderly patients with ESCC with LNM.
SLNM is still considered a distant metastatic disease even in the newest 8th edition of the AJCC TNM staging system , and palliative treatment is recommended by the NCCN guidelines. Recently, several studies have argued that SLNM does not constitute an important independent prognostic factor for patients treated with CRT [33, 34]. Our previous data demonstrate that the OS of patients with SLNM(+) is superior to those with cN3 SLNM(-), and is similar to those with cN1 SLNM(-) or cN2 SLNM(-), but inferior to cN0 SLNM(-), confirming that SLNM should be treated with curative intent as a regional, rather than a distant, disease in patients with ESCC when treated with CRT . However, in the current study, CRT failed to demonstrate a survival advantage in patients with SLNM compared to RT-alone whether in pre- or post-PSM patients. The enrolled sample of SLNM patients was too small in the current study, which may have been the reason for the lack of statistical differences.
Chronic comorbidities are thought to affect cancer patient outcomes [36-38] and impact treatment decisions. He et al reported that certain comorbidities (hypothyroidism/levothyroxine) affect EC-specific survival in EC patients treated with CRT . Barone et al reported that patients diagnosed with cancer who have preexisting diabetes are at increased risk for long-term, all-cause mortality compared with those without diabetes . It is generally recognized that elderly patients are more frequently affected by different chronic comorbidities. However, the influence of chronic comorbidities on the survival of patients with ESCC treated with RT or CRT had not been reported. Similar to Barone et al , in the current study, among the four common chronic comorbidities, diabetes was the only one identified to be an negative factor affecting patient prognosis, whether in the entire cohort or the PSM patients. Further subgroup analysis found that compared to RT-alone, CRT improved patient survival significantly in diabetic patients, but not in non-diabetic patients. Certainly, despite the survival benefits, the greater risk posed by more aggressive treatment in elderly patients with chronic comorbidities must be kept in mind in clinical practice .