Impact of Age and Comorbidity on Choice and Outcome of Two Different Treatment Options for Patients with Potentially Curable Esophageal Cancer

Data from all patients with a primary esophageal cancer (CI 5.1–5.9), diagnosed between 2004 and 2014 in the South East of the Netherlands, were obtained from the population-based nationwide Netherlands Cancer Registry (NCR). Data from this region was used, because data on comorbidities was not routinely registered by the NCR in other parts of the Netherlands during the study period. Trained data managers of the NCR routinely extract information on diagnosis, tumor stage, comorbidity, and treatment from the medical hospital records, using a strict registration and coding manual. Tumors were clinically staged according to the UICC/AJCC TNM classification that was valid at the time of diagnosis.

Patients with potentially curable EC (cT1N+/cT2-3, TX, any cN, cM0) and treated with dCRT or nCRT plus surgery were eligible for this study (Fig. 1). Patients were classified as cTX when the tumor could not be sufficiently subcategorized, for example due to an obstructing tumor that could not be passed during endoscopic ultrasonography. Patients were considered potentially curable if they had clinically no distant metastasis (cM0 according to TNM-7 and cM1a, i.e., positive coeliac nodes, according to TNM-6), and no tumor invasion into surrounding organs (no cT4 according to TNM-6 and no cT4a or cT4b according to TNM-7). Although patients with a cT4a tumor could theoretically be treated with curative intent, all cT4 tumors were excluded, because they were only distinguished after 2010 by TNM-7. For the analysis, patients with a cM1a tumor according to TNM-6 were categorized as having cN+ according to TNM-7. As of 2010, coding regulations to register a cM0 or cM1 status into the NCR were less strict than before 2010. As a consequence, since 2010, relatively more patients were registered with no (cM0) rather than unknown clinical distant metastases into the NCR. To account for this, we decided to include all patients with cMX. Patients with cervical esophageal cancer (CI 5.0) and those with a cT1N0 tumor were excluded, because surgery was not standard care in these patients. Patients who underwent palliative or other treatment were excluded from the analysis (Fig. 1).

In this study, neoadjuvant CRT with curative intent consisted of 5 cycles of carboplatin (area under the curve 2 mg/ml/min)/paclitaxel 50 mg/m² and 41.4 Gy/1.8 Gy or occasionally 50.4 Gy/1.8 Gy radiotherapy followed by potentially curative surgery, based on the CROSS regimen.1,18 Definitive or primary CRT usually included concurrent chemotherapy (cisplatin/5-FU or carboplatin/paclitaxel) and radiotherapy > 50.4 Gy/1.8–2 Gy as first treatment in patients who were unable to undergo surgical resection.19,20 In the analysis, patients with primary intended nCRT of 41.4–50.4 Gy/1.8 Gy in whom additional surgical resection was denied because of deteriorated medical condition and potentially high risk for severe morbidity and mortality.

In the NCR, comorbidities were registered according to a slightly modified version of the Charlson comorbidity index.21 The Charlson comorbidity index is most widely used for recording comorbidity and was validated in various studies. Comorbidity was defined as life-shortening diseases that were present at the time of cancer diagnosis.22‐24

The following groups of comorbidities were included in our analyses: pulmonary disease (COPD, emphysema, chronic bronchitis), cardiovascular disease (angina pectoris, myocardial infarction, cardiomyopathy, myocarditis, vascular disease, TIA, CVA), hypertension, diabetes mellitus, and previous invasive malignancies. Patients with no serious comorbidity in the medical file were registered as having no comorbidity. Patients were excluded if comorbidity status was not registered.

Statistics Netherlands developed an indicator of Socio-Economic Status Score (SES), using individual fiscal data based on the economic value of the home and household income. This SES indicator is provided at an aggregated level for each postal code (covering an average of 17 households). SES was categorized as low (deciles 1–3), medium (deciles 4–7), or high (deciles 8–10). A separate category was made for postal codes of care-providing institutions, because assigning SES for those living in nursing home or other care providing institutions is difficult.

The results of this population-based study support the use of nCRT plus surgery in operable patients with EAC, which was associated with a better overall survival regardless of age, number and type of pretreatment comorbidities. The administration of dCRT was preferable in patients with ESCC with at least two comorbidities or age ≥ 75 years, because there were no differences in overall survival than with nCRT plus surgery in these patients. This was seen particularly among those with cardiovascular diseases or previous malignancies as their overall survival after dCRT was comparable to the overall survival for patients after nCRT plus surgery.

In the Netherlands, nCRT in combination with surgery is the standard potentially curative treatment for locally advanced esophageal cancer. This treatment potentially downstages the tumor and increases the radical resectability (R0) rate, which in turn reduces locoregional recurrences with improved long-term survival.1 Moreover, the regimen of the CROSS trial also showed control of distant disease beyond the first 24 months after nCRT, supporting a direct systemic effect.25

Of great importance for a prolonged survival is a pathological complete response following nCRT, which occurred in 49% of the patients with ESSC included in the CROSS trial and in 23% of those with EAC.1

In our study, 78% of the elderly patients were treated with dCRT and survival in elderly patients with ESCC was equal for both treatment modalities. Elderly patients are generally regarded as less suitable for surgery because of advanced age (≥ 75 years), comorbidity severity or decreased performance status. Moreover, dCRT seems a well-tolerated alternative for patients with EC who are not fit enough to undergo surgery.1,7,11,12,17,22,23,26,27 Nevertheless, selecting the appropriate treatment for elderly patients requires the presence a consulted geriatric physician in the multidisciplinary board.28

A relatively good outcome was reported after dCRT in selected groups of patients.12,29‐32 Two studies have found a comparable OS after dCRT compared with surgery alone for patients with resectable ESCC.11,12 However, in these studies, survival differences were not investigated according to number and type of comorbidities. We found no significant difference in OS following dCRT or nCRT plus surgery in patients with ESCC having at least two comorbidities. This suggests that patients derive the same benefits from both treatment methods, although the type of comorbidity may have an impact on the outcome.

In patients with EAC, the standard approach of nCRT followed by surgery indeed resulted in a better survival, which also was found in the group with diabetes mellitus, hypertension, or cardiovascular disease. Tougeron et al. reported a more frequent use of dCRT in advanced staged EAC, in elderly patients and those with comorbidities of Charlson score ≥ 2.13 Despite selection bias may be present, survival after surgery was better compared with survival after dCRT (median overall survival 36.2 vs. 16.5 months; P = 0.02). Another study has found a significant improvement in median survival for patients with locally advanced EAC treated with nCRT followed by surgery compared with dCRT.14

These differences in treatment response between patients with EAC and ESCC may be associated with tumor aggressiveness and different carcinogenesis.13 Moreover, tumor site (distal vs. proximal) and pulmonary based differences with larger fields of radiotherapy in lower esophageal tumors also may play a role in outcome differences between EAC and ESCC following dCRT.33

With current radiation techniques, including intensity-modulated radiotherapy (IMRT), direct simulation based on 3D or 4D planning CT, respiratory gated radiotherapy, and intensity-modulated proton therapy the radiation dose can be accurately delivered with less damage to normal tissues.15,33‐36 Moreover, in diminishing toxicity of chemotherapy regimens, the combination of carboplatin/paclitaxel has shown to be a good alternative or even the standard approach in dCRT, especially in patients with cardiovascular and pulmonary comorbidities.37

Our study has some limitations. First, the intent of curative treatment with chemoradiotherapy (primary dCRT or nCRT) was uncertain in this retrospective study. As patients with M1 disease were excluded, it was assumed that chemoradiotherapy was given with curative intent in all included patients. However, a small subset of patients were not fit enough or unable to undergo the planned surgery after nCRT and were treated with CRT alone or allocated to the dCRT group. This may lead to a less homogeneous group of patients treated with dCRT. Moreover, of the excluded EC patients who had surgery alone (Fig. 1), surgery could had been still a treatment options for some patients not suitable for chemoradiotherapy. As reported, a considerable number of these patients were not eligible for surgery due high age (> 75 years) and serious multiple comorbidities, the OS was worse after surgery alone in a previous analysis of potentially curable EC patients (n = 1,184) during 1995–2013.2,3,19 The 3-year OS in patients with EAC after surgery alone was worse but comparable among those with ≥ 2 comorbidities after dCRT (HR 1.07; 95% CI 0.72–1.60). The 3-year OS among ESCC patients after dCRT was comparable with those after surgery alone, despite the number of comorbidities, and even more favourable in those with pulmonary disease (HR 0.81; 95% CI 0.32–0.71).38 Second, limited information was given about the radiotherapy techniques and schedules of the given chemoradiotherapy. Since 2004, however, there was an increased preference for carboplatin/paclitaxel with less severe toxicity (6%) compared with cisplatin/5-FU (15%) as standard regimen in dCRT, especially in patients with cardiovascular comorbidity.37 Third, the impact of type of some comorbidities could not be assessed accurately due to a small number of patients. Moreover, information about the performance status was not registered for the study period. Furthermore, the accuracy of the diagnostic and staging methods used is unknown, while endoscopic ultrasonography was not always possible in patients with EC leading to unknown reported clinical T-stage in 15% of patients. Although out of the scope of this study, salvage surgery in solitary localized recurrences or persistent disease after CRT could be a curative option in selective cases. However, these procedures were not registered accurately at that time, because intensive follow-up was not commonly performed, and these procedures were then only performed occasionally in special centers.19

The strength of this population-based study is that the results are based on patients diagnosed in ten hospitals providing an overview of everyday clinical practice, rather than single-institution results in which patients are possibly more carefully selected.

In conclusion, neoadjuvant chemoradiotherapy plus surgery should basically be advised in operable patients with potentially curable esophageal adenocarcinoma regardless of age, number, and the type of comorbidities. Definitive CRT may be preferred in patients with esophageal squamous cell carcinoma having at least two comorbidities or being older than 75 years. For a better selection of patients, who may benefit from dCRT, prospective studies are needed.