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DISCUSSION

In this study, we presented a large cohort of elderly esophageal cancer patients treated with CCRT using PTX plus CDDP with curative intent. Our results showed that the median OS and PFS time were 26.9 and 18.2 months, with the 2-year OS rate of 76.0% and 38.6% for stage I–II and III–IV, respectively. These survival results seemed comparable with RTOG 0113 trial20 and a series of contemporary randomized studies of patients from all age groups undergoing definitive chemoradiation.12,21–23 In RTOG 0113, 35 patients were enrolled for the treatment of induction chemotherapy followed by chemoradiotherapy with PTX and CDDP for localized esophageal cancer, and their results showed that the median survival time was 14.9 months and 1- and 2-year OS rates were 69% and 37%, respectively. In another Phase II prospective clinical trial which investigated the efficacy and the safety of a 3-week schedule of PTX plus CDDP combined with concurrent radiotherapy for esophageal squamous cell cancer,12 the results showed that the overall median survival time was 28.5 months, the PFS was 14.7 months, and 1- and 2-year survival rates were 75% and 54%, respectively. Both these trials enrolled relatively nonelder patients (median age was 66 and 58 years, respectively). In our report, all patients were aged 70 years or older, and patients aged ≥75 years accounted for more than a half of the overall population. Although two patients with T1stage were enrolled in our analysis, almost 70% of our cohort were in stages III–IV, which was also comparable with Tang et al’s12 report mentioned earlier (72.3% for stage III–IV). In 2015, Servagi-Vernat et al also conducted a Phase II clinical trial to evaluate the efficacy of CCRT comprising a single platinum-based agent combined with radiotherapy in patients ≥75 years of age with esophageal cancer, and their results showed that the 3-year OS rate and 2-year disease-free survival rate were 22.2% and 38%, respectively. They concluded that elderly patients should not be excluded from CCRT and that the elderly might be able to tolerate the treatment with acceptable acute toxicities. They also suggested that the therapeutic ratio or locoregional control might be improved by increasing the radiotherapy dose or by testing new radiosensitizer agents.24

In general, the toxicities of the combined therapy were tolerable in our study. The main grade ≥3 toxicity was leukopenia, in 15 (18.3%) and ten (12.2%) patients with grade 3 and 4 leukopenia, respectively. Most of these elderly patients were treated by using G-CSF, which was monitored weekly during the treatment course for acute toxicity. Compared with the TP arm of RTOG 0113 trial in which the radiation dose was 50.4 Gy/28 Fx,20 the grade 3 and 4 adverse reactions of blood/bone marrow occurred in 40% (14/35) and 28.6% (10/35) of the cases, respectively; and the treatment-related death was 6%. Traditionally, elderly patients were considered to have less reserve of body function when compared with young patients, and our results indicated that with proper application of G-CSF, elderly patients could also undergo definitive treatment course without having a severe hematologic toxicity. The rate of severe esophagitis in our study was high compared with the results of Tang et al.12 Twenty-eight (34.1%) patients in our study got esophagitis, including five (6.1%) and two (2.4%) patients with grade 3 and 4, respectively; while in their report, only two patients suffered from grade 3 esophagitis and none had grade 4 esophageal dysfunction. Possible factors causing the high rate in our study are as follows: 1) a different radiation delivery schedule was used in their trial, 21% patients were given with a combination of conventional fractionation of 1.8 Gy/Fx and late-course accelerated hyperfractionated (LCAF) in a second course; 2) 72% patients in our analysis had ≥5 cm tumor, and tumor length has been confirmed as a significant prognostic factor for esophagitis in chest irradiation;25,26 3) total radiation dose in this study was 60 Gy as planned, and 86.6% elderly patients completed the radiation course. In 2007, we also did a Phase II clinical trial in our cancer center to investigate the toxicity of TP regime with 60 Gy/30 Fx radiotherapy for nonelderly esophageal cancer patients and showed comparable toxicities with this cohort. Nowadays, CCRT with 50.4 Gy is the standard treatment regimen for locally advanced esophageal cancer based on the results of RTOG 9405;8 this trial was designed to investigate whether high-dose irradiation in the setting of CCRT could achieve better survival results and local/regional control than 50.4 Gy CCRT. The results showed that higher radiation dose did not increase survival or local/regional control, and a higher treatment-related mortality rate was observed in the high-dose arm. But, interpretations about the results of RTOG 9405 trial were different; although, more treatment-related deaths in the 9405 trial occurred in the high-dose arm than in the 50.4 Gy arm (11 vs 2), seven of these eleven treatment-related deaths occurred before the dose of 50.4 Gy for unclear reasons. Therefore, more deaths were not as a result of high-dose radiation therapy, and our results also showed that only one patient suffered from treatment-related death (esophageal fistula). In the present study, we also confirmed that clinical stage was a strong prognostic factor in elderly patients, as shown in Table 5. A clinical response rate of CR had an approximately statistical significance with PFS; these findings were consistent with the results conducted by Tougeron et al.16 Their analysis revealed that factors of clinical CR, radiation dose, and Charlson score were independent prognostic factors with survival.

In conclusion, elderly patients (70 years or older) could benefit from definitive CCRT containing PTX, but attention should be paid to the relatively high incidence of toxicities. Further prospective studies in large cohorts of elderly esophageal cancer patients are highly warranted to confirm the findings in our report.

Acknowledgment

There was no funding support for this study. We thank Ruifei Xie for his help with translation and proofreading.

Disclosure

Tao Song and Xuebang Zhang are listed as co first authors. The authors report no conflicts of interest in this work.


Tao Song,1,* Xuebang Zhang,2,* Min Fang,1 Shixiu Wu1

1Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Radiation Oncology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China

*These authors contributed equally to this work  


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Source: OncoTargets and Therapy
Originally published October 22, 2015.