Safety and outcome of definitive chemoradiotherapy in elderly patients with oesophageal cancer

Little is known about chemoradiotherapy (CRT) in elderly patients with a locally advanced oesophageal cancer (OC). The aim of our study was to evaluate the tolerance and the outcome of elderly patients older than 70 years treated with CRT for a non-metastatic OC. Chemoradiotherapy was based on radiotherapy combined with a cisplatin-based chemotherapy. Clinical complete response (CCR) to CRT was evaluated on upper digestive endoscopy and computed tomography scan 6–8 weeks after CRT completion. One hundred and nine consecutive patients were included. A CCR was observed in 63 patients (57.8%) and 2-year survival was 35.5%. Adverse events ⩾grade 3 were observed in 26 (23.8%) patients. Chemotherapy dose reduction, chemotherapy delays more than 1 week, and treatment discontinuation were observed in 33 (30.3%), 45 (41.3%), and 17 patients (15.6%), respectively. Comorbidity index according to Charlson score was significantly associated with treatment tolerance. In multivariate analysis, a CCR to CRT (P<0.01), a dose of radiotherapy ⩾80% (P=0.02), and a Charlson score ⩽2 (P=0.046) were identified as independent prognostic factors of overall survival. These results suggest that CRT could be considered as an effective treatment without major toxicity in elderly patients with OC.

Management of elderly patients with cancer is a therapeutic challenge. It is well established that cancer occurs primarily in elderly patients, with approximately two-thirds of cancer-related death in the elderly over 60 years and 25% in patients older than 80 years. Oesophageal cancer (OC) is the eighth most common cancer and the sixth cause of cancer mortality worldwide (Parkin, 2001). In France, approximately 54% of OC occurs in patients older than 65 years, with 23% over 75 years (Remontet et al, 2003).
The most relevant treatment modalities in elderly patients with OC remain a subject of debate. Although survival improvement has been observed during the past decade, prognosis of OC has remained significantly influenced by age (Bouvier et al, 2005;Cranea et al, 2007). A recent population-based study including patients with locoregional OC showed a difference in treatment and survival according to age, comorbidity, race, and geographical region (Steyerberg et al, 2007). It has also been reported that elderly patients were less likely to undergo surgery and chemotherapy, which was however partially explained by their comorbidity (Steyerberg et al, 2007;Ruol et al, 2007a). Currently, definitive chemoradiotherapy (CRT) based on the 5-fluorouracilcisplatin (5FU -CDDP) regimen has been considered in curative intent in locally advanced or inoperable non-metastatic OC (Kleinberg and Forastiere, 2007;National Cancer Institute recommendations, 2008;Stahl and Oliveira, 2008).
Little is known about the efficacy of CRT in elderly patients with a locally advanced OC. Indeed, data on tolerance and outcome in these patients remain lacking. In the two recent randomised trials that investigated the efficacy of CRT, the mean ages of included patients were 59.1 and 57 years, respectively (Bedenne et al, 2007;Stahl et al, 2005). Moreover, patients up to 70 years were not eligible in the Stahl et al (2005) trial. More recently, in a limited number of 25 patients older than 65 years, Anderson et al (2007) reported that definitive chemoradiation using two cycles of 5FU plus mitomycin-C associated with 50.4 Gy radiation could be considered as an active regimen with moderate toxicity.
The aim of our study was to evaluate the safety and the efficacy of CRT in elderly patients older than 70 years treated for a nonmetastatic OC. endoscopic dilation) were collected. Degree of dysphagia was evaluated using the Atkinson (1977) score.
All patients had a histologically proven OC without visceral metastasis at the time of diagnosis and were treated with definitive CRT (Herskovic et al, 1992;Stahl et al, 2005;Bedenne et al, 2007). Patients who had a cancer of the lower and the upper oesophagus associated with an involvement of the coeliac or the sus-clavicular lymph node areas (M1a stage), respectively, were also selected.
We used the Charlson score, which is widely used in comorbidity index, for the analysis of patient's comorbidities. The Charlson score consists of 19 different disease comorbidity categories (coronary artery disease, congestive heart failure, chronic pulmonary disease, peptic ulcer disease, peripheral vascular disease, liver disease, cerebrovascular disease, connective tissue disease, diabetes, dementia, renal disease, prior tumour, and AIDS), each allocated a weight of 1 -6 based on the adjusted relative risk of 1-year mortality and summed to provide a total score.

Tumour staging
The tumour staging was based on the 1983 AJCC staging system according to published recommendations (Coia et al, 2000). Tumour evaluation was based on oesophagoscopy, barium oesophagography, chest and abdominal computed tomography (CT scan) (Bosset et al, 1997), and oesophageal ultrasonography (Tio et al, 1990) when it was feasible. Tumour baseline characteristics (TNM stage, location, length, diameter, and histologic type) were collected. The tumour length was defined by oesophagoscopy±barium oesophagography and tumour diameter by endoscopic ultrasound and/or CT scan.

Treatment and CRT regimen
Patients received a CRT regimen based on the CDDP and 5FU chemotherapy combination described by Herskovic et al (1992) or on the CDDP/irinotecan chemotherapy combination described by Michel et al (2006). The Herskovic CRT regimen was based on four CDDP/5FU chemotherapy courses, which were delivered concomitantly with 50 -55 Gy radiotherapy (weeks 1 -5). Starting dose regimens were 1000 mg m À2 at days 1 -5 for 5FU and 75 mg m À2 at day 1 for CDDP. The CRT regimen based on the CDDP/irinotecan chemotherapy combination has been recently reported in a phase II multicentric trial and consisted of eight chemotherapy courses delivered concomitantly with 50 -55 Gy radiotherapy (courses five to eight). Starting dose regimens were 60 mg m À2 for irinotecan and 30 mg m À2 for CDDP at each cycle. Radiotherapy was delivered 5 days per week at 1.8 or 2 Gy day À1 in both CRT regimens. The target volume of radiotherapy was the macroscopic tumour and enlarged lymph nodes, if any, surrounded by 5-cm proximal and distal margins and a 2-cm radial margin. The target was extended to the inferior cervical area in cases of tumours located above the carina. The specified dose was delivered at the intersection of the central axis of the beams, according to international guidelines.
Twenty-five patients have an initial dose reduction due to their age or comorbidities. Among these patients, the chemotherapy start dose was generally 50 or 75% of complete dose.
At day 1 of each chemotherapy course, toxicities related to the treatment were evaluated using the National Cancer Institute Common Toxicity Criteria (NCI-CTC, version 2.0). We also noted a delay of chemotherapy and CRT stop for toxicity. Percentage of planned radiotherapy and chemotherapy dose was calculated.

Response to CRT and follow-up
Patients were considered to have a clinical complete response (CCR) to CRT when no residual tumour was identified on upper digestive endoscopy and when no metastatic disease occurrence was observed on CT scan. This evaluation was performed 6 -8 weeks after CRT completion. The follow-up was performed on a clinical basis, with upper digestive endoscopy with biopsy and chest and abdominal CT scans every 3 months. Local recurrence was defined by positive biopsy at upper digestive endoscopy. Salvage surgery in patients without CCR or with local recurrence and absence of metastases were also collected. Follow-up data were updated in December 2007. Among patients alive at 6 months, median follow-up was 20.5 months (6 -127 months).

Statistical analysis
Overall survival was calculated from the date of CRT initiation until the date of death or the date of last follow-up. Survival curve was established using Kaplan -Meier method. Disease-free survival was estimated from the date of the first day of CRT initiation to the time of documented failure (local recurrence or metastasis occurrence) or the date of the last follow-up for those remaining with CCR. Specific survival excluded patients who died of other causes than cancer or treatment. Predictive factors of CCR to CRT were determined by a univariate analysis and further evaluated in multivariate logistic regression analysis. Predictive factors of survival were studied by a univariate analysis and further evaluated in multivariate Cox regression analysis to estimate the hazard ratio (HR) with 95% confidence interval (CI). Nine predefined baseline variables for the univariate analysis were sex, age, WHO performance status o2, initial weight loss o10%, albumine X30 g l À1 , Charlson score p2, dose of cisplatin X80%, dose of radiotherapy X80%, and CCR to CRT. Any variables reaching P ¼ 0.05 were introduced in multivariate analysis. We also performed an analysis with stratification for age X75 years vs o75 years and patients with or without comorditidies (Charlson index p2 vs 42). All statistical analyses were performed with a two-side significance value of 0.05. Statistical analysis was performed using the Statview software (Statview for Windows, SAS Institut Inc., version 5.0).

Patient and tumour characteristics
One hundred and nine patients over 70 years were analysed. Clinical baseline characteristics are detailed in Table 1. Mean age was 74.4±3.7, ranging from 70 to 88 years. There were 38 patients (34.9%) aged more than 75 years. Majority of patients (79.8%) had a good WHO performance index (0 or 1). Majority of patients had a severe dysphagia X2 (70.6%) and 33.0% had an initial weight lost X10%.
A CCR to CRT was observed in 63 patients (57.8%), and 26 (23.8%) of them had no recurrence at follow-up (median follow-up was 20.5 months and eight patients were lost to follow-up). Median overall survival in patients with CCR was 27.2 ± 5.1 months as compared with 6.0±2.5 months in non-responders (Po0.01) ( Figure 2). Among responders to CRT, 21 patients (33.3%) had a local recurrence, with a median time of 13.4 ± 2.2 months. Two patients with local recurrence underwent surgery but the majority of patients were treated by oesophageal stent (n ¼ 9), chemotherapy (n ¼ 4), or the best supportive care (n ¼ 6). In non-responder patients to CRT, a salvage surgery was performed in five patients. One patient died after surgery and three had local or metastasis recurrence. Patients without CCR to CRT and surgical contraindications were treated by oesophageal stent (n ¼ 7), chemotherapy (n ¼ 3), or the best supportive care.
Predictive factors of overall survival in univariate analysis were a CCR to CRT (Po0.01), a WHO performance status o2 (Po0.01), an initial weight loss o10% (P ¼ 0.03), a dose of cisplatin X80% (P ¼ 0.03), a dose of radiotherapy X80% (Po0.01), and a Charlson score p2 (P ¼ 0.02). T stage and age o or 475 years were not predictive factors of overall survival in univariate analysis (T stage, P ¼ 0.85 and age o or 475 years,

Factors that influence treatment tolerance
Age X75 years was associated with worse creatinine clearance (Po0.01) and more chemotherapy dose reduction at treatment onset due to age (Po0.01), but this had no influence on total CRT dose, adverse events, CCR to RCT, or overall survival. Patient with a dose reduction at treatment onset was older but age did not influence chemotherapy dose. This result was probably explained by the fact that the patient with a dose reduction up front has a secondary increase of chemotherapy dose if the tolerance was good (nine patients). Charlson score p2 vs 42 did not influence adverse events, chemotherapy delay, CRT dose, or CCR to CRT, but only overall survival. Nevertheless, patients with Charlson score X1 experienced more adverse events grade X2 (76.5 vs 51.2%; P ¼ 0.01) and chemotherapy delay (66.7 vs 39.5%; P ¼ 0.02).

DISCUSSION
This study suggested that definitive CRT in elderly patients with an OC was an effective treatment without a major increase in adverse events. Moreover, our results showed that CRT in elderly patients produced a similar response rate and overall survival as usually reported in younger patients treated with the same regimen. These findings suggest that a treatment based on a CRT regimen may be discussed in elderly patients. Improvements in general health care   Chemoradiotherapy in elderly patients D Tougeron et al and increased life expectancy have resulted in more elderly patients with an OC. At 75 years of age, life expectancy was more than 10 years (Arias, 2006). Therefore, if there are no major comorbidities, elderly patients with OC should benefit from curative treatment. Definitive CRT is considered as a feasible non-surgical treatment for patients with a locally advanced OC with approximately 50 -65% CCR rate, 17 -26 months of median overall survival, and 30 -40% 2-year survival rate (Minsky et al, 1999;Ohtsu et al, 1999;Coia et al, 2000;Seitz et al, 2000;Stahl et al, 2005;Michel et al, 2006;Di Fiore et al, 2006a;Bedenne et al, 2007). Interestingly, our results in elderly patients were relatively close to those reported in these series, with a CCR to CRT of 57.8% and a 2-year overall survival rate of 35.5%. However, overall median survival in our study (15.2 months) was slightly lower as compared with that reported in previous randomised trials. These results were strictly similar to those published by our group on series including non-selected patients with an oesophageal carcinoma treated with the same CRT regimens (Michel et al, 2006;Di fiore et al, 2006a, b;Tougeron et al, 2008). Indeed, the mean age of patients ranged from 39 to 88 years in these series and we found that the complete response to CRT was 50 -80% and the overall survival was 16 -20 months as in this study in elderly patients. Although age and comorbidity were associated with higher difficulties encountered during treatment, no significant association was found between these factors and survival in our study. Moreover, the difference in median overall survival could be partially explained by a selection bias in these prospective trials, whereas our study possibly reflected the outcome of non-selected patients. In a recent study, predictive factors of prognosis in locally advanced OC from the randomised FFCD 9102 trial in the multivariate analysis were age more than 65 years, inability to ingest solid food, and the presence of more than three neoplastic coeliac lymph nodes on endoscopic ultrasonography (Burtin et al, 2008). Anderson et al (2007) reported significant results from a single institution experience of chemoradiation in 25 elderly patients older than 65 years with OC. On the basis of a median follow-up of 32 months, the CCR rate was 68% and the 2-year survival rate was Patients with CCR to CRT Patients without CCR to CRT Figure 2 Overall survival in responders and non-responders to CRT. The median overall survival was 27.2 ± 5.1 months in responder patients as compared with 6.0 ± 2.5 months in non-responder patients (Po0.01).
CCR ¼ clinical complete response; CRT ¼ chemoradiotherapy.   in this study. The overall survival was very good probably because there was a careful selection of patients using Charlson score and data were only available on 25 patients with a very significant CI for survival rate. Different findings were found in the Takeuchi et al (2007) study in which results of CRT based on 5FU/CCDP and 60 Gy of radiation were compared between 33 elderly patients vs 145 non-elderly. In fact, a significant worse survival and higher CRT discontinuation and toxicity were reported in elderly. These contradictory results strongly support that more data on larger population, as in our study, are required to accurately estimate the safety and efficacy of the CRT approach in an elderly population. Local recurrence and metastasis occurrence in our study were in accordance with randomised trials (Minsky et al, 1999;Seitz et al, 2000;Bedenne et al, 2007). Salvage oesophagectomy has been reported in a small group of elderly patients who did not respond to CRT. Five patients underwent surgery in our series and only one in the study of Anderson et al (2007). Death due to post-operative complications occurred in one patient in our study and also in one patient in the Anderson et al (2007) study. Although a significant improvement has been obtained in post-operative resuscitation, oesophagectomy for OC remains associated with significant morbidity and mortality rates. In this context, surgical approach in patients older than 70 years with OC is still debated because of potentially higher postoperative complication rates (Poon et al, 1998;Law et al, 2004;Moskovitz et al, 2006). On the basis of a population of 421 patients with intrathoracic squamous cell carcinoma treated with surgical resection, Law et al (2004) found that age was significantly associated with pulmonary complications and hospital mortality. In a single institution study on 751 patients including 31 patients older than 80 years, Moskovitz et al (2006) reported that postoperative death and hospital length of stay were significantly worse in elderly patients, independently of comorbidity. In contrast, Ruol et al (2007b, c) recently showed similar short-and long-term postoperative outcomes in elderly patients as compared with younger patients. This difference could be due to difference in surgical and resuscitation experience between centres. Median survival after oesophagectomy remains poor in elderly patients, ranging from 6 to 27 months, with major post-operative mortality ranging from 4.7 to 7.2% (Thomas et al, 1996;Poon et al, 1998;Sabel et al, 2002;Internullo et al, 2008).
In our study, the planned treatment was achieved in only 38.5% of patients, and 53.2% of them required dose adjustment. However, grade 4 toxicity was observed only in three patients (2.7%), with two treatment-related deaths (1.8%). In the Anderson et al (2007) study, 88% of patients completed the planned CRT, grade 4 toxicity occurred in 16%, and no treatment-related deaths were observed. Moreover, severe adverse events (grade 3 or 4) were observed in 23.8% of patients in this study and 31% of patients randomised in the definitive CRT arm of FFCD 9102 study. Chemoradiotherapy tolerance in 'selected' elderly patients with an OC was acceptable as compared with younger patients, but a dose reduction was frequently necessary due to adverse events. Age X75 years had no influence on adverse events. These results underlined that age criteria alone is not sufficient for guidance of therapy and that better characterisation of patients with Charslon score, for example, may be helpful for decision making. 5-Fluorouracil tolerance was the same in the elderly and younger patients (Popescu et al, 1999). Moreover, a recent study on patients with an advanced oesophagogastric adenocarcinoma suggested that cisplatin-based chemotherapy toxicities did not increase with age (Trumper et al, 2006). In patients with other cancers (rectum, lung, or head and neck cancers) treated with concomitant CRT, the same results were observed. In these elderly patients treated with CRT for other tumours, no major toxicity was observed with similar survival rates than in younger patients (Airoldi et al, 2004;Pasetto et al, 2006;Semrau et al, 2007).
The main reported predictive factors of response to CRT and overall survival were WHO performance status, nutritional status, treatment dose, and TNM stage (Coia et al, 2000;Polee et al, 2003;Rohatgi et al, 2005;Di Fiore et al, 2006a). No major difference was found, in our multivariate analysis, in predictive factors of CCR to CRT and survival in elderly patients. Although age and Charlson score were associated with nutritional impairment and a greater chemotherapy dose reduction, our analysis also underlined that the success rate of CRT in OC was not dependant on age.
In conclusion, our results showed that definitive CRT could be considered as an effective treatment with no significant toxicity in elderly patients with OC.