In the current study, we evaluated the efficacy and safety of the PEG-G-CSF for preventing neutropenia in mCRC patients treated with FOLFOXIRI plus Bev. Despite the high ratio of poorly differentiated adenocarcinoma and patients with RAS mutant type, the ORR was relatively high. PEG-G-CSF prevented the development of severe neutropenia without any increases in adverse events.
FN is one of the life-threatening adverse events of chemotherapy. In the 1990’s, G-CSF was widely used in the clinic as a leading supportive therapy for FN. There is substantial data regarding the effectiveness of G-CSF for cancer chemotherapy15,16. Compared to conventional G-CSF, the number of visits to a hospital by patients and the work load of the medical staff both decreased when we used PEG-G-CSF. This demonstrates a great benefit for the outpatient clinic. There are several reports regarding the efficacy of PEG-G-CSF for neutropenia and FN in both mCRC and other cancers.
A Japanese double-blind placebo-controlled randomized phase 3 trial of PEG-G-CSF in 343 breast cancer patients receiving docetaxel and cyclophosphamide chemotherapy showed that the incidence of FN was significantly lower in the PEG-G-CSF group compared to that in the placebo group (1.2% vs. 68.8 %, P < 0.001) 17. A Japanese retrospective study also showed that the incidence of FN was significantly lower in a group of non small cell lung cancer patients pretreated with PEG-G-CSF compared to that in the placebo group [0/52 (0%) vs 3/9 (33%), respectively] 18.
Regarding mCRC patients, in a phase 3 double-blind trial that evaluated the efficacy of PEG-G-CSF compared to a placebo in reducing the incidence of grade 3 or 4 FN in patients with advanced CRC receiving Bev combined with first-line chemotherapy, PEG-G-CSF significantly reduced the incidence of grade 3 and grade 4 FN in the first four treatment cycles (PEG-G-CSF 2.4%, placebo, 5.7%, P = 0.014) 19. Another randomized placebo-controlled phase II study examined PEG-G-CSF efficacy and safety in patients with CRC that received chemotherapy every two weeks. Results from this study showed that PEG-G-CSF significantly reduces the incidence of grade 3 and grade 4 FN (PEG-G-CSF, 2.0%; placebo, 8.0%; P < 0.001) 20. Notably, this study demonstrated that PEG-G-CSF could prevent severe neutropenia in patients receiving FOLFOXIRI plus Bev on a two-week cycle without an increase of adverse events, consistent with previous reports. However, the safety of PEG-G-CSF had not been established when administered within 14 days before the start of chemotherapy. It is recommended that the administration interval of PEG-G-CSF should be 2 weeks or longer.
In addition, UGT1A1 polymorphism was detected in this study in eight (30.7%) of the patients (*6 in six patients, *28 in two patients). Among these patients with UGT1A1 polymorphism, six had been administered PEG-G-CSF, two after the development of grade 3 neutropenia and four prophylactically. In Japan, the incidence of UGT1A1 *6 polymorphism is higher than that in the US and European countries 21–23. In a Japanese phase 2 trial of FOLFOXIRI plus BV in mCRC patients, the frequency of neutropenia in patients with UGT1A1 *6 or *28 polymorphism is higher than that in patients with wild-type UGT1A1 13. However, in the current study, no patients experienced severe neutropenia after the administration of PEG-G-CSF, even in those patients with UGT1A1 *6 or *28 polymorphisms. Furthermore, five of 6 patients were able continue treating with FOLFOXIRI plus Bev without the need for a dose adjustment. These data suggest that the administration of PEG-G-CSF in two-week cycle may be safe and that PEG-G-CSF is able to prevent severe neutropenia in patients with UGT1A1 *6 or *28 polymorphisms.
There were several limitations to our study. For instance, it was a retrospective study with a relatively small sample size. A further large-scale study to validate the results of this study and to compare PEG-G-CSF with G-CSF in mCRC patients treated with FOLFOXIRI plus Bev is needed. However, even with the limitations, this study showed that neutropenia, which is the most common adverse events in patients being treated with FOLFOXIRI plus Bev, could be prevented using PEG-G-CSF.