Introduction
Esophageal cancer is one of the most malignant forms of gastrointestinal cancer. The efficacy of chemoradiotherapy and chemotherapy has been demonstrated, and so they are widely used to treat esophageal cancer. Reports have also documented the efficacy of preoperative chemotherapy, which has become the standard form of treatment in Japan. Currently, the standard treatment for stage II and III esophageal cancer is preoperative chemotherapy (cisplatin + 5-fluorouracil [5-FU]: CF regimen) + radical surgery. According to a previous report [
1], the 5-year survival rate for cT1-2 cancer is favorable at 79% following preoperative treatment with the CF regimen. In contrast, the 5-year survival rate for cT3 is poor at 49%, with results showing poorer efficacy of the CF regimen in more advanced cases. A more potent form of preoperative treatment is therefore desirable. For this reason, there has been a growing number of reports on the DCF regimen (docetaxel + CF) as this is the more potent form of treatment in recent years [
2‐
4], and the high success rate has attracted attention. On this background, we are currently in the late stages of JCOG1109, a phase 3 comparative clinical trial [
5] to clarify the superiority of the preoperative DCF regimen and preoperative CF chemoradiotherapy compared to the standard preoperative CF regimen. The DCF regimen, which is more potent than the conventional CF regimen, is associated with high rates of febrile neutropenia, which is viewed as problematic. Although the efficacy of pegfilgrastim for preventing febrile neutropenia has been established in other fields such as hematological diseases, it has not yet been in patients undergoing the DCF regimen as a form of treatment for esophageal cancer. For this reason, in this study, we investigated the risk factors for febrile neutropenia in addition to performing an analysis of pegfilgrastim-treated cases at our hospital and investigated the effectiveness of the DCF regimen.
Discussion
In this study, we attempted to identify the factors predictive of febrile neutropenia in patients with esophageal cancer treated using initial DCF therapy. Study 1 shows that the non-use of pegfilgrastim was an independent factor predictive of febrile neutropenia in multivariate analysis. Although several background risk factors were suspected among the risk factors for febrile neutropenia in univariate analysis, only the absence of pegfilgrastim administration remained as an independent risk factor for febrile neutropenia through multivariate analysis. Although the FN group was significantly younger (p = 0.032) in univariate analysis, this can be explained by the fact that we performed DCF therapy for young patients at first, but came to perform DCF therapy for the elderly patients after the use of pegfilgrastim was started. In study 2, the pegfilgrastim group had a significantly lower incidence of both neutropenia and febrile neutropenia than the control group. Including these, the pegfilgrastim group had a significantly lower incidence of entire CTCAE grade ≥ 3 events. As a consequence, the pegfilgrastim group had less incidence of dose reduction in the following DCF therapy. Therefore, the use of pegfilgrastim can be an option for chemotherapy to achieve the goal of successful completion of scheduled chemotherapy with DCF regimen.
The results of long-term follow-up during the MRC-OE2 clinical trial, which allocated patients with resectable esophageal cancer into a neoadjuvant CF group and a surgery only group, showed that the hazard ratio for overall survival was 0.84 (
p = 0.03) in a neoadjuvant CF group, which was significantly more favorable [
8,
9]. Currently, based on the results of the Japan Clinical Oncology Group (JCOG) 9907 clinical trial [
1], the standard treatment for stage II and III esophageal cancer is preoperative chemotherapy (cisplatin + 5-FU: CF regimen) + radical surgery. Furthermore, a meta-analysis compared studies of neoadjuvant chemotherapy to surgery alone reported that the hazard ratio for overall survival was 0.87 (
p = 0.005) when all the preoperative chemotherapy groups were compared to the surgery alone group, suggesting the efficacy of preoperative chemotherapy [
10]. Meanwhile, neoadjuvant chemoradiotherapy has been widely performed in Western countries; however, the survival of neoadjuvant chemotherapy followed by surgery in Japanese study appears not inferior to the western results of neoadjuvant CRT. The JCOG 9907 clinical trial subgroup analysis results [
1] showed that the 5-year survival rate for cT1-2 cancer is favorable at 79% when treated with the CF regimen preoperatively. By contrast, the 5-year survival rate for cT3 is poor at 49%, with results showing poorer efficacy of the regimen in more advanced cases. A more potent form of preoperative treatment is therefore desirable. There have been increasing numbers of reports of using the DCF regimen (docetaxel + CF regimen) in practice as this more potent form of treatment in recent years [
2‐
4], and the high success rate has attracted much attention. Against this background, we are currently in the advanced stages of a phase 3 comparative clinical trial JCOG1109 [
5] to verify the superiority of the preoperative DCF regimen and preoperative CF chemoradiotherapy compared to the preoperative CF regimen, which is the standard form of treatment. The DCF regimen, which is more potent than the conventional CF regimen, causes high rates of febrile neutropenia, which is viewed as problematic. Febrile neutropenia is an adverse reaction to anticancer drug treatment that may have serious outcomes, and primary prophylaxis with pegfilgrastim is recommended when using regimens with a high rate of febrile neutropenia onset of ≥ 20%. Going forward, based on the results of the JCOG 1109 clinical trial [
5], the DCF regimen may become a standard form of treatment, so it is needed before this occurs to rapidly establish an effective modality of prophylaxis for febrile neutropenia. For this reason, we performed an analysis of pegfilgrastim-treated cases at our hospital and investigated its effectiveness in the DCF regimen.
In September 2014, conventional G-CSF was pegylated to prolong its serum half-life, yielding pegfilgrastim; a single administration at a dose of 3.6 mg during each cycle is sufficient to prevent febrile neutropenia. Although the efficacy of pegfilgrastim for preventing febrile neutropenia has been demonstrated in other fields, such as hematological diseases, there are few reports assessing it in patients undergoing the DCF regimen as a form of treatment for esophageal cancer [
2‐
4]. In this study, the administration of pegfilgrastim in practice resulted in a significantly lower incidence of adverse drug reactions ranked as CTCAE grade ≥ 3, and significantly fewer patients had neutropenia (
p < 0.001) and febrile neutropenia (
p = 0.001) in particular. No changes were observed in terms of other adverse events, such as hyponatremia, anorexia, and nausea. And also, we were able to decrease the rate of reduced/ interruption of next cycle DCF therapy due to adverse effects by using the pegfilgrastim from 30.5 to 6.1%, significantly (
p = 0.006). There were no patients who administered additional classical G-CSF in the pegfilgrastim group; meanwhile, these occurred in 31 out of 59 subjects (52.5%).
In this study, of 92 patients, 77 patients underwent esophagectomy after neoadjuvant DCF therapy. Other 15 patients did not undergo esophagectomy and received only chemotherapy included DCF therapy. We usually perform esophagectomy about 3 to 4 weeks after the last cycle of DCF therapy. Of all patients, 67 patients (72.8%) underwent 3-field esophagectomy in this study. And also, there were no significant differences in surgical complications between two groups with or without severe neutropenia/ febrile neutropenia (p = 0.722) (data were not shown).
The major limitations of our study are the single-center, retrospective design and the small number of patients investigated. However, the current data are based on a prospectively collated database for consecutive patients over a relatively short period. An external validation study involving a sufficient number of patients would be needed to confirm our observations; a multicenter study with a larger number of cases is also warranted.
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