Most patients with metastatic prostate cancer (mPC) initially responded positively to androgen suppression, however, invariably became resistant to hormone manipulation after 18 ~ 24 months from treatment[8]. Therefore, it is important to study effective treatments to delay the progress of mHSPC to mCRPC.
At present, a number of foreign research results confirm that mHSPC benefits from DTX combined with ADT, especially in the HVD-mHSPC population. GETUG-AFU15 was the first randomized controlled trial to evaluate the use of DTX in the treatment of mHSPC patients. The results showed that the combined DTX group had a 10-month extension of bPFS (22.9 months vs 12.9 months, P < 0.001), and the high-volume disease group had a 6-month extension of bPFS (15.2 months vs 9.2 months, P < 0.001)[9]. Sub-group analysis of CHAARTED showed that patients with high-volume disease benefited more obviously from treatment, the median OS increased by 17 months (49.2 months vs 32.2 months, P < 0.001) and the median time to CRPC was prolonged by 8.5 months (20.2 months vs 11.7 months, P < 0.001)[4]. Compared with ADT alone, the median OS of the DTX group was prolonged by 15 months (60 months vs 45 months, P < 0.001), and FFS was prolonged by 17 months (37 months vs 20 months, P < 0.001) in subgroup analysis of STAMPEDE[3].All the results confirm that ADT combined with DTX chemotherapy significantly prolongs the overall survival of patients with mHSPC, especially those with high-volume disease. At present, there are very few reports about DTX chemotherapy combined with ADT used to treat HVD-mHSPC patients in China. The latest prospective single-arm, single-center phase II clinical study[7] showed that the PSA response rate was 30.9% at 6 months and 25.5% at 12 months in patients who underwent combined DTX treatment. The 1-year PFS rate was 66.5%, and the median OS and PFS was not reached. In our study, although patients in the combined DTX group had advantages in age and physical strength, there was no significant difference in gleason score and TNM stage between the two groups. The results showed that PFS in the combined DTX group was 5.7 months longer than that of the ADT group. This is basically consistent with the extension of PFS by 6 months and 8.5 months in the GETUG-AFU15 and CHAARTED high-volume disease subgroup analyses[10, 11]. When comparing the GETUG-AFU15 and CHAARTED trials, which were prospective randomized controlled trials with uniform inclusion criteria, there was no significant difference in baseline level. However, in this study, considering the difference in patients' tolerance to chemotherapy, there were differences in baseline levels between the groups. There were similar real-world retrospective studies conducted abroad where the baseline levels were also different of the median age was 68 and 81 years (P = 0.001) [5]. A higher PSA reaction rate indicates higher OS in the treatment of prostate cancer[12]. The newly diagnosed PSA level of the combined DTX group was higher, indicating that tumor load was higher. However, the time taken to reach PSA nadir was shorter than that of the ADT group, indicating that the combined DTX group can benefit even in high levels of PSA.
The most common adverse reaction of DTX was hematological toxicity, and FN accounted for 33% of delays in this therapeutic method. According to other research statistics, 17% of patients with DTX in mHSPC had grade 3 ~ 4 FN[5]. 12 cases (19%) had grade 3 ~ 4 neutropenia, and 6 cases (9.5%) had FN, all of whom recovered after timely G-CSF treatment. As the median time for neutrophils to reach nadir after DTX administration is 7 days, this interval can be shortened in patients undergoing multiple treatments[6]. FN patients were prone to life-threatening infections. This should be closely monitored with care.
Other adverse reactions caused by DTX mainly include allergic reaction, fluid retention, neurotoxicity, skin toxicity, liver function damage and fatigue[13]. In this study, three patients delayed chemotherapy due to grade 3 hepatic insufficiency. This occurred because DTX was being metabolized through the liver, causing increased liver load during the combined endocrine drug treatment. Other adverse reactions were gradually relieved by close follow-up, symptomatic treatment and appropriate psychological intervention.
As both groups were treated with continuous ADT, there were varying degrees of hot flashes and fatigue. There was no significant difference between the two groups, and no special intervention measures were required. Although there were no bone-related events in the study, more than half of the patients suffered from high-volume bone metastasis. The risk of osteoporosis based on ADT treatment should be minimized. It was recommended that calcium 1200mg/d and vitamin D800-1000IU/d be supplemented routinely, and bisphosphate should be given when necessary[14].
In conclusion, the safety and efficacy of first-line DTX in HVD-mCRPC shown in the this study are comparable to some previous clinical trials. However, the fact that this study is a single-center retrospective study should be noted as a limitation. Patients in the combined DTX group had favorable age, physical fitness and tolerance to treatment than those in the simple ADT group. The overall number of cases in this study is small, and the long-term follow-up results to confirm any OS benefits have not yet been completed. Patients progressed to mCRPC were treated with different novel hormonal therapies including abiraterone, apalutamide or enzalutamide etc., it was not possible to determine whether total OS benefited from docetaxel treatment, which was an inadequacy of the study. The real-world data of Chinese HVD-mHSPC patients undergoing ADT combined with DTX is very limited. While referring to foreign data for clinical practice, analyzing relevant data from the Chinese population in time will better guide clinical practice in the future. We still need to further carry out prospective randomized controlled clinical research with multi-centers, increase the number of research subjects and reduce the selection bias to improve the safety of applying ADT combined with DTX in HVD-mHSPC patients.