This report focuses on the risk of severe adverse events associated with DCF treatment for esophageal cancer, mainly targeting on squamous cell carcinoma. We conducted this retrospective study to identify the patients receiving DCF therapy who required more support or modification. Several studies have been conducted to investigate the efficiency and safety of platinum-containing triplet chemotherapies for solid tumors. Most of the studies on cisplatin-based triplet regimens for non-small cell lung carcinoma concluded that triplet chemotherapy reduced the tolerability, largely due to an increase in hematological toxicities17,18. Meanwhile, trials of gastroesophageal cancer indicated that triplet procedures, with adequate dosing and scheduling, have promising results and are well tolerated by the patients19, 20. Together, these data reveal that the adverse events of a triplet chemotherapy treatment may be manageable if it is provided as a supportive treatment.
This study showed the group at risk for FN. Worse dysphagia score and lower CCr were correlated with the incidence of FN, while lower platelet count was correlated with mucositis. Dysphagia is one of the most frequent symptoms occurring in patients with ESCC. The degree of dysphagia was correlated with the risk of aspiration leading to aspiration pneumonia. Dysphagia might cause FN through aspiration pneumonia. Our study also indicated that lower CCr (<80mg/mL) have a tendency of risk for FN. Although CCr correlates with the risk of neutropenia in some drugs, for example, carboplatin, no correlation was found between the level of CCr and grade 4 neutropenia in this analysis (data not shown). Lower CCr seems to reflect the patient’s nutritional status including fluid intake, which may be one of the causes of FN.
There are two essential points to consider before introducing DCF: (i) the prevention of severe adverse events and (ii) the selection of patients.
Several methods have been used to prevent the adverse events. Among them, prophylactic antibiotics were used to prevent FN. A previous meta-analysis of randomized clinical trials revealed that prophylactic antibiotics in the course of intensive chemotherapy reduced the number of patients with infections21. Although a previous phase II study reported that preoperative DCF led to grade 3/4 neutropenia (83%), anorexia (7%), and stomatitis (5%)14, FN was reduced to 3% by prophylactic use of antibiotics on days 5–15 in all patients. In our analysis, most of the patients – except those who cannot take drugs orally – received prophylactic antibiotics. The substantial difference in the incidence of FN (3% for phase II vs 17% for this study) might be caused by the differences in the background of the patients who had more advanced cases. For example, only patients with resectable disease were enrolled in the phase II trial, while 17% of T4 patients were enrolled in this analysis although dysphagia score was not reported. Recently, the risk factor of FN during DCF therapy was reported in a retrospective manner, where dysphagia score at diagnosis was the independent predictive factor for FN and severe diarrhea22. Although the relationship of diarrhea and dysphagia score was unclear in our study, further advanced T stage and severe dysphagia may increase the risk for inspiration pneumonia and lower nutritional status. Dysphagia score may reflect these factors and was an independent risk factor for FN in our study.
To reduce the incidence of neutropenia and non-hematological toxicity associated with docetaxel, the divided dose of docetaxel was evaluated in previous clinical trials23, 24. A phase I/II clinical trial, JCOG0807, of biweekly DCF for metastatic cancer reported that the common grade 3-4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%)12. No FN was reported among 53 patients. The response rate was 62%, and the overall survival of the metastatic patients in this study was 11.1 months; patients received 30 or 40 mg/m2 of docetaxel on days 1 and 15, which indicate that administering docetaxel in two doses might have reduced the incidence of hematological adverse events without reducing the efficacy. However, no pathological efficacy data reported the use of divided dose of docetaxel in neoadjuvant triplet regimen.
One more solution is the use of G-CSF as prophylactic treatment. In this study, 5 (5%) patients used G-CSF after the onset of FN, while none of the patients received G-CSF as prophylactic treatment. The prophylactic use of G-CSF is recommended when the risk of FN is 20% or higher25, 26. Based on the ASCO guidelines, the DCF regimen should be administered together with a prophylactic drug in patients with risk factors of FN. Due to the higher cost of G-CSF, patients who really benefit should be strictly selected. Results of our analysis indicated that the patients who had dysphagia, and/or lower CCr, may have a risk of FN superior to 20%. For these patients, prophylactic use of G-CSF might be adequate to prevent FN and to keep the dose intensity of DCF. Another issue is the timing of G-CSF administration. Usually, G-CSF is usually administered 24 h after the discontinuing the administration of chemotherapeutic drugs, but this might eliminate the effect of G-SCF. A previous report for day 5 administration of Peg-G-CSF showed that it does not reduce the incidence of grade 3/4 neutropenia associated with DCF therapy, because the nadir of DCF mainly appears at days 7 to 10. The investigators concluded that earlier administration of peg-G-CSF is more suitable for patients receiving the DCF regimen, and clinical trials should be conducted for further investigation27.
Mucositis and esophagitis are common adverse events in patients receiving chemotherapy containing 5-FU and docetaxel. Based on the results of clinical trials of ESCC, gastric cancer, and head and neck cancer, 4.6%–21% of grade 3-4 stomatitis was reported during the course of DCF10, 11, 13, 14. Risk factor of mucositis induced by chemotherapy and chemoradiotherapy was reported in many articles 28-30. The risk factors have been attributed to both therapy and patient characteristics and varied across cancer types and treatment regimens. With regard to the therapeutic factor, intensive chemotherapy, radiotherapy, and radiation were major the risk factors. Meanwhile, the patients’ factor is more complex, and the individual differences are more intense; however, age, gender, nutritional status, comorbidities, dentition, neutrophil count, hemoglobin, and others have been reported.
Results of our analysis indicated that lower platelet count is the risk factor of severe stomatitis, and the potential of lower neutrophil count and anemia. For the patients with these risk factors, the prophylactic use of oral hygiene or topical therapy might be considered during DCF therapy. However, the exact cut-off level of the risk factors should be evaluated in another study using a larger sample size, since this is a limitation of our study.
There were also other limitations in this retrospective analysis. This study was conducted in a single institution, and the patients’ purpose of receiving DCF varied. Moreover, blood examination was conducted in an unscheduled time point. Further analysis might be needed in a larger prospective cohort, such as a phase III trial of neoadjuvant DCF regimen15.