The significance of addition of EMP to DTX therapy in CRPC patients is still controversial in clinical trials [3
] as well as preclinical studies [7
]. Therefore, it is reasonable to compare the clinical efficacy of DTX + EMP combination with DTX alone in EMP-refractory CRPC patients in order to elucidate the significance of addition of EMP to DTX therapy. Present retrospective study showed, for the first time, that there were no significant differences in OS, TTP, PSA response, and adverse events between group D and group DE in EMP-refractory CRPC patients, suggesting that addition of EMP to DTX therapy had no survival benefit.
The PSA response (> 50% decline in PSA) in SWOG 9916 [2
] was 50%. However, the PSA response in this study was low; only 21% patients in group D and 24% patients in group DE responded to treatment with 60 mg/m2
DTX, which was similar to the regimen of SWOG 9916. Our result is consistent with that of another study in which patients who had been treated with EMP showed a lower PSA response as compared to patients without a history of EMP treatment [11
], suggesting that treatment with EMP before DTX treatment decreases the PSA response. However, the median OS in group D was 26 months and that in group DE was 24 months. Further, these median OS are not only greater than that of nine months after treatment with 55 mg/m2
] or that of 18 months after treatment with 60 mg/m2
DTX in SWOG 9916 but also consistent with the 15-27 months median OS obtained after treatment with 70-75 mg/m2
]. The median OS of 24 months or more achieved in this study was considered to be due to the initiation of DTX therapy with low PSA value as compared with that obtained in the previous reports [1
], because multivariate analysis performed in this study and the report by Bamias et al. [15
] demonstrated that OS prolonged when PSA was low at the initiation of DTX therapy. Since the adverse events observed in this study were well tolerated, treatment with 60 mg/m2
DTX seems to be effective and safe even in EMP-refractory CRPC patients. In recent years, several novel agents such as abiraterone [16
], sipuleucel-T [17
] and MDV3100 [18
] have been developed and showed significant clinical efficacy against CRPC. Treatment with these agents would provide the survival benefit for CRPC patients.
Regarding adverse events in TAX 327 and SWOG 9916, the incidences of grade 3/4 neutropenia were 32% and 13% in TAX 327 [1
] (DTX, 75 mg/m2
) and SWOG 9916 [2
] (DTX, 60 mg/m2
), respectively. Further, the incidence of grade 3/4 neutropenia in clinical trials performed in Japan was 93% and 33% after treatment with 70 mg/m2
] and 55 mg/m2
], respectively, indicating high incidences of DTX toxicity. In addition, the incidence of neutropenia after 60 mg/m2
DTX treatment was 86% in a clinical study on Japanese pancreatic cancer patients [20
], suggesting that the incidence of neutropenia is high among Japanese patients. Although the sample size of our study was small, the incidence of grade 3/4 neutropenia was 50% and 33% in group D and DE, respectively, which were higher as compared to the values reported in SWOG 9916 using 60 mg/m2
DTX. However, no incidence of death or severe complications suggested that our treatment was well tolerated. Furthermore, grade 2 thromboembolism was observed in one patient (3%) of group DE. Since EMP increases the incidence of thromboembolism [2
], it should be used with caution. The reason why the incidence of adverse events was not significant between group D and DE might be due to the means of treatment assignment. Namely, two-thirds of patients with adverse events by EMP monotherapy and those without them were classified in group D and DE, respectively. Although addition of EMP to DTX therapy might not show any survival benefit in CRPC patients, it was of interest that addition of EMP to DTX therapy lowered the incidence of grade 3/4 neutropenia (50% in group D and 33% in group DE), though not by a significant extent. Meta-analysis [3
] of chemotherapy combined with EMP showed a significantly low incidence of neutropenia due to concomitant use of EMP in the chemothrapy. In addition, treatment with EMP showed increase in the leukocyte count in patients with hormone-naïve prostate cancer [21
] or CRPC [22
]. Taken together, it is suggested that EMP increases the leukocyte count leading to the myeloprotection in the chemotherapy, albeit under limited conditions; hence, the significance of addition of EMP to DTX therapy may be attributed to the myeloprotection rather than the survival benefit. Further studies are required to clarify this point.
Multivariate analysis performed in this study revealed that PSA at baseline, time from diagnosis to DTX chemotherapy and the number of DTX cycles were related to the prognosis. Although these factors were statistically significant, the definitive conclusions cannot be drawn because of the small number of death events observed in this study. These factors have been reported as prognostic factors in other studies [11
]; hence, DTX treatment should be introduced when PSA values are low and continued for as long as possible. However, addition of EMP did not serve as a prognostic factor.
This study has some limitations; it is a retrospective study with a small sample size and not a randomized clinical trial. However, it was concluded that addition of EMP to DTX therapy might not show any survival benefit in EMP-refractory CRPC patients although treatment with 60 mg/m2 DTX had the OS and toxicity profiles comparable to those in TAX 327 and SWOG 9916. Further studies would be needed to elucidate the significance of addition of EMP to DTX therapy.