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.