FN is associated with an increased risk of prolonged hospitalization, worse clinical outcomes, and life-threatening complications. Chemotherapeutic regimens that are associated with a high incidence of FN (> 20%) in chemo-naïve patients are considered as being high-risk regimens, and prophylactic administration of G-CSF is recommended in such patients . Therefore, mFOLFIRINOX was devised to reduce the incidence of toxicities, including neutropenia and FN, associated with FOLFIRINOX. In this study, we retrospectively evaluated the incidence of FN and severe neutropenia associated with mFOLFIRINOX therapy, in order to identify the risk factors for severe neutropenia. The single-institution study was undertaken using the same unified method for tumor staging and identical treatment regimens and the same protocol for follow-up of blood sampling and administration of granulocyte colony stimulating factor products, and we provided supportive care throughout, which enabled us to confirm important predictive factors.
The patient selection criteria for this study were broader than those of previous Japanese phase II studies, because this retrospective study was conducted in clinical practice. But, the patients homozygosity for UGT1A1*28 or UGT1A1*6 or double-variant heterozygosity for UGT1A1*28 and UGT1A1*6 were excluded from this analysis, because these patients treated with reduced dose of FOLFIRINOX in clinical practice. As compared to the Japanese phase II study of FOLFIRINOX, the median age of the enrolled patients was higher (65.0 years vs. 61.5 years) and the treatment line was not limited to 1st line treatment in this study. Nonetheless, the incidence of severe neutropenia and FN were lower than those reported for FOLFIRINOX , and the results were consistent with those in the Japanese phase II study of mFOLFIRINOX . The RDIs of oxaliplatin, irinotecan and continuous intravenous infusion of 5-FU in this study were comparable to those reported for FOLFIRINOX  (Table 3). In addition, in 69% and 70% of cases, respectively, the severe neutropenia and FN occurred during the first cycle of treatment in this study. In the Japanese phase II study of FOLFIRINOX , FN only occurred during the first cycle of treatment, so that the tendency seemed to be similar. Even in modified regimen, it is important to pay careful attention to severe neutropenia and FN especially during the first cycle and to undergo appropriate dose modification against the toxicities in the subsequent cycles.
In this study, we found that a low baseline WBC count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism were significant independent risk factors for the development of severe neutropenia during treatment with mFOLFIRINOX. The NCCN guideline mentions higher age, history of prior chemotherapy or radiotherapy, preexisting infection or neutropenia, tumor involvement of the bone marrow, poor PS, and comorbidities including renal and liver dysfunction . In this study, the baseline WBC count was associated with the risk of severe neutropenia, this result was consistent with other chemotherapeutic regimens in previous studies [14–17]. On the other hand, we considered that low baseline neutrophil and low baseline WBC counts were cofounding factors, and low baseline neutrophil count was identified as one of the significant risk factors by univariate, but not by multivariate analysis.
UGT1A1 is known to be involved in the metabolism of SN-38, an active metabolite of irinotecan, and double-variants of UGT1A1 have been often reported to be risk factors for severe myelosuppression . There are significant racial differences in the distribution of UGT1A1 polymorphisms among Asians, Caucasians, and Africans. The frequency of UGT1A1*28 in Asians (16%) is one-third that in Caucasians (29%-45%), and UGT1A1*6 is not detected at all in Caucasians or Africans, but is as frequent as the *28 allele in Asians (15%-20%) . Several studies have suggested that the incidence of severe neutropenia is significantly higher in patients with double-variant UGT1A1*28 and *6 heterozygosity than in those with the wild-type genotype. A meta-analysis suggested that the incidence of severe neutropenia is significantly higher in patients who heterozygous for UGT1A1*28 or *6 polymorphism than in patients with the wild-type genotype [19, 20]. A previously reported prospective study on pancreatic cancer showed that the incidence of grade 3–4 hematological adverse events was higher in patients who were heterozygous for UGT1A1 *6 or UGT1A1 *28 than in patients with wild-type UGT1A1, although the difference did not reach statistical significance. However, the study suggested that the incidence of diarrhea was significantly higher in patients with heterozygous polymorphisms of UGT1A1*6 or *28 than in patients with the wild-type genotype . Therefore, there appears to be convincing evidence to suggest that patients who are heterozygous for UGT1A1*6 or *28 polymorphism are at an increased risk for irinotecan toxicity as compared to patients with wild-type UGT1A1.
There were some limitations of this study. Firstly, the relatively small number of patients and there were only 27 patients who were heterozygous for UGT1A1*28 or UGT1A1*6 in the study made it difficult to draw any definitive conclusions. Furthermore, the study was a single-center and retrospective study, influenced by local individual clinician practices. Therefore, further clinical investigation, such as a multicenter trial is warranted to evaluate the risk factors for severe neutropenia associated with mFOLFIRINOX therapy in patients. Secondly, the safety data of mFOLFIRINOX were not evaluated in patients who were homozygous for UGT1A1*28 or UGT1A1*6 or heterozygous for both UGT1A1*6 and UGT1A1*28 in this study. However, a multicenter retrospective study of FOLFIRINOX in advanced pancreatic cancer patients with double-variant type UGT1A1*28 and *6 polymorphism was conducted by our colleagues and they recommend that the initial dose of irinotecan should be further reduced to ≤ 120 mg/m2 of body surface area in such patients .
In conclusion, the incidences of severe neutropenia and FN were lower in the patients who received mFOLFIRINOX as compared to those reported for patients treated with FOLFIRINOX, despite the absence of significant differences in the relative dose intensities of the component drugs. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline WBC count and heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism. Therefore, mFOLFIRINOX should be administered with caution in patients with these risk factors.