Discussion
In recent years, a number of retrospective studies have shown that irinotecan-containing regimens have a certain effect in recurrent Wilms tumor, but most of them are retrospective studies, the number of enrolled subject is small, and the combination of irinotecan and chemotherapy drugs is notuniform19,21-23。A SIOP retrospective study showed that 14 patients with evaluable relapsed Wilms tumor who received Irinotecan-containing regimens (including VCR, TMZ, bevacizumab, ect.) had an ORR of 21.4%, and the effective rate was not high23. Anthracyclines are effective chemotherapeutics for patients with Wilms’ tumor. Concerns about the cardiotoxicity of anthracyclines have restricted the dose of anthracyclines. Studies revealed that doxorubicin-induced HF occurs in 3% to 5% with 400 mg/m227.Cumulative doses of doxorubicin in patients with Wilms tumor in COG and SIOP studies were no more than 250 mg/m220,28.Doxorubicin hydrochloride liposome is a novel formulation of doxorubicin encapsulated in polyethylene glycol-coated liposome and its PK are markedly different from those of doxorubicin. Study showed that patients exposed to relatively high cumulative doses, 540–840 mg/m2, did not have evidence of acute congestive heart failure, which suggests that doxorubicin hydrochloride liposome might be less cardiotoxic than doxorubicin29. Doxorubicin hydrochloride liposome may become a potentially effective chemotherapeutic drug for children with relapsed and refractory Wilms tumor. Alternating the doxorubicin hydrochloride liposome to conventional anthracycline may improve the prognosis of the relapsed or refractory WT patients. Irinotecan combined with doxorubicin hydrochloride liposome may become an effective rescue chemotherapy for relapsed and refractory Wilms tumor. Study showed that the maximum tolerated dose of doxorubicin hydrochloride liposome administered every 4 weeks to pediatric patients was 60 mg/m2 25.According to our experience in doxorubicin hydrochloride liposome, in this study we accepted the regimen of doxorubicin hydrochloride liposome as 40mg /m2 for 1 single day treatment.
In this study, among the 14 evaluable patients, 2 patients achieved CR and 5 achieved PR after AI regimen chemotherapy, and the ORR of the AI regimen was 50%, indicating that the AI ​​regimen was effective for relapsed and refractory Wilms’ tumor. However, the SIOP study showed that irinotecan-containing regimens had poor efficacy in relapsed Wilms tumor, with an ORR of 21.4%23. The curative effect of this study on patients with relapsed and refractory Wilms tumor is better than that of SIOP clinical research. The reason may be that the curative effect of irinotecan combined with doxorubicin hydrochloride liposome is better than other Irinotecan-containing regimens (such as VCR, TMZ, Bevacizumab, etc.).
The COG AREN0321 clinical study showed that irinotecan combined with VCR showed good efficacy in newly treated DA WT patients20. The SIOP clinical study enrolled 14 patients with evaluable efficacy, 8 patients were first relapse, and 9 patients had HR histological type, including 4 diffuse anaplasia (DA) WT and 5 blastemal type (BT). The ORR of IR and HR WT patients was 33.3% and 11.1%, respectively. The results of SIOP study indicate that the relapsed HR WT patients was not sensitive to the irinotecan-containing salvage regimens. In the present study, none of the patient was diagnosed as HR WT. If AI regimen is effective for HR WT need to be further explored.
In this study, 2 CR patients achieved longer survival after AI regimen chemotherapy; 4 out of 5 PR patients who achieved CR after further clinical management (surgery or radiotherapy) survived at the last follow-up, the response to the AI regimen can converted into survival benefit; 5 PD patients had poor survival, most of them were died within 2 years and needed to find a new therapeutic strategy.
In this study, the median number of treatment courses for patients receiving AI regimen was 3 (1 to 8 courses), and the median cumulative dose of doxorubicin hydrochloride liposome was 120 mg/m2 (40-240 mg/m2). 7 patients had mild abnormalities in the electrocardiogram, but none of the patients had severe cardiotoxicity (such as heart failure, arrhythmia, etc.). Because of the short follow-up time, long time was needed to follow up the long-term cardiotoxicity. In the study, most patients relapsed more than 2 times and received high-intensity chemotherapy in the past, and concerning that the AI ​​regimen may cause severe bone marrow suppression, all patients were given long-acting granulocyte stimulating factor to prevent neutropenia. The most common grade 3 and 4 side effects observed in this study including alopecia (62%), leucopenia (40%), abdominal pain (38%), diarrhea (23%), Mucositis (16%). None of the patients delayed treatment due to toxicity. Studies have shown that the dose-limiting toxicity of doxorubicin hydrochloride liposome is mucositis. The incidence of mucositis in this study is not high, suggesting that doxorubicin hydrochloride liposome 40mg/m2 is safe for relapsed and refractory Wilms tumor25. Whether increasing the dose of doxorubicin hydrochloride liposome can further improve the efficacy is worthy to explore.
Of note, this is the first time to report this therapeutic regimen to combine these two agents. In this study, we noted the adverse effect are commonly self-limited and easily controllable with routinely intervention, and this therapeutic regimen was generally continued without delayed therapy. Still, we acknowledge some limitations are existed. As a single-arm study, the comparison could not be performed because this study is lack of control group, it may arise selection bias as non-randomized design. Furthermore, limited sample sizes were enrolled in this study. However, all patients with manageable adverse effects could continue the therapeutic regimen without delay of therapy, and this study provided valuable experience for the treatment of relapsed or refractory Wilms’ tumor.
In conclusion, the combination regimen of irinotecan and doxorubicin hydrochloride liposome indicates promising efficacy for relapsed or refractory WT patients with tolerable toxicities, especially for FH group WT. Prospective clinical trial is warranted.