DISCUSSION
Across an 11-year period at our institution, fourteen patients (5 with
single kidney) were treated with an intensive ifosfamide-containing
VDC-ICE treatment plan. This regimen was well tolerated, with no patient
experiencing toxicities severe enough to prevent completion of planned
therapy, and no significant renal toxicity occurred in any patient.
Although only 9 out of 14 patients completed all 8 intended cycles of
chemotherapy, early termination of VDC-ICE chemotherapy was only due to
disease progression, not lack of tolerability. There were no toxic
deaths or severe organ toxicities. While examining outcomes was not our
primary objective, our results add to existing evidence of an
association of improved outcomes with the use of intensified treatment.
The COG clinical trial, AREN0321, found that chemotherapy regimens (UH-1
and UH-2) containing nearly all of the same agents as VDC-ICE, with the
notable omission of ifosfamide, improved relapse-free survival for
stages II-IV DAWT. The UH-1 and UH-2 regimens were accompanied by
significant treatment-related CTCAE grade 4 toxicities and mortality –
with four patients with DAWT (6%) dying of toxicities – prompting a
reduction in regimen intensity and eventual early termination of the
trial. As VDC-ICE is similar or even more intense than UH-1
(Supplemental Table S3), we examined the toxicities experienced by our
patients receiving VDC-ICE. Importantly, we did not observe any
non-hematologic grade 4 or 5 toxicities. As the most significant
complications of AREN0321 were related to cardiac and pulmonary
dysfunction, we hypothesize that the universal use of the
cardioprotectant dexrazoxane in our study, which was allowed but not
recommended on AREN0321, may have contributed to the lack of grade 4 and
5 toxicities. However, future studies are needed to confirm this
hypothesis. Additional supportive care, including administration of
prophylactic infectious measures may have helped decrease infectious
complications, but these were not administered in a standardized way.
Kidney function may have been protected by extended home hydration
implementation.
The potential nephrotoxicity of ifosfamide-containing regimens like
VDC-ICE is a major concern in patients with HRR tumors, especially those
with single kidneys. In our cohort, kidney injury was rare, with just a
single episode of temporary grade 1 acute kidney injury due to an
episode of dehydration associated with carboplatin-induced delayed
nausea and vomiting, which resolved in 24 hours. Six of our patients had
primary renal tumors, all of whom underwent bilateral partial or
unilateral nephrectomies prior to the majority of their chemotherapy.
All six completed the intended 8 cycles of VDC-ICE, making the lack of
severe toxicity or renal insufficiency noteworthy in light of the
inclusion of the potentially nephrotoxic ifosfamide in VDC-ICE as
compared to the AREN0321 regimens. Possible explanations include
improvements in antiemetic management with more widespread use of
aprepitant and the ability to provide home hydration via nasogastric
tube or intravenous fluids. We acknowledge that our institution’s
catchment area has excellent home nursing resources, enabling us to
offer these options to our patients.
Despite meticulous supportive care, the VDC-ICE regimen is not without
toxicities. Not surprisingly, given the myelosuppression expected with
the agents and doses administered, all but one patient (who only
received 3 cycles of VDC-ICE due to disease progression) experienced at
least one CTCAE grade 3 toxicity, each having at least one
hospitalization for febrile neutropenia. Half of our patients had grade
3 nausea/vomiting/dehydration, and more than half had anorexia requiring
nutritional support through a nasogastric tube. Other significant
toxicities were rare and limited to one episode of uncomplicated
bacteremia, hepatotoxicity in patients with tumors of their livers, and
admissions to the ICU. While 14% (2/14) of patients requiring ICU
admission seems substantial, none were thought to be related to VDC-ICE
chemotherapy.
Although all patients treated with this regimen required significant
supportive care (e.g., unplanned ED/clinic visits, transfusion, and
nutritional support), it appears that overall, the complications and
toxicities observed in our cohort were manageable. Even though treatment
delays of greater than a week were observed in 50% of our patients,
these were mostly due to delayed count recovery. Furthermore, this is
not entirely unexpected given the intensity of this regimen and does not
justify considering this regimen as intolerable. Other regimens, such as
standard of care for Ewing sarcoma (interval compressed alternating
cycles of VDC and ifosfamide/etoposide), are also plagued by the need
for significant symptomatic and supportive care, treatment delays, and
admissions for febrile neutropenia. Yet, this regimen has been used for
years as the standard of care for this disease, lasts longer than
VDC-ICE (28 versus 24 weeks) and has higher cumulative doses of
doxorubicin (375 mg/m2), cyclophosphamide (8400
mg/m2), ifosfamide (63 g/m2), and
etoposide (3500 mg/m2).
Our findings are limited by the small number of patients and their
management at our single institution. It is possible that the lack of
toxic deaths we have seen is due to chance alone. For example, given
toxic deaths on AREN0321 were rare, if the toxic death rate of VDC-ICE
were comparable to UH-1 and UH-2 regimens, we would have expected to see
just 1 toxic death in our 14 patients. Even discounting toxic death
rates, it is notable that our patients experienced no grade 4
toxicities. Because these tumors are rare, the challenge of low patient
numbers is difficult to overcome even through multicenter trials.
Nevertheless, we represent a high-volume center, and this is the largest
cohort of patients with HRR/INI- tumors described with this chemotherapy
regimen. The other similarly-sized cohort of pediatric oncology patients
treated with VDC-ICE comprised patients with Ewing sarcoma who were much
older, lacked renal tumors, and thus would have been expected to
tolerate the regimen better than our cohort.9
Additionally, because this represents a retrospective analysis,
controlling for differences in patient characteristics, treatment
regimen administration, or supportive care is difficult. Each patient’s
treatment plan was developed by our center’s disease-specific expert in
renal tumors and MRT, with some patients receiving customized dosing or
the addition of other chemotherapy agents based on individual
characteristics. Therefore, whether our experience is generalizable
remains an important question.
Our findings suggest that VDC-ICE chemotherapy can be safely used for
children with HRR and INI-deficient tumors, with comparable toxicity to
other widely accepted pediatric oncology regimens. Most notably, use of
ifosfamide was tolerated without nephrotoxicity in a population
generally thought of as being at unacceptably high-risk of renal
toxicity. Despite the known activity of ifosfamide in HRR/INI- tumors,
the use of post-nephrectomy ifosfamide has been reserved for the
relapsed setting. Yet for patients with these aggressive malignancies,
for whom death is overwhelmingly due to progressive and relapsed disease
rather than treatment toxicity, withholding effective agents is
difficult to justify. With our findings of excellent tolerance of
VDC-ICE combined with no meaningful chance of post-relapse survival for
patients with these tumors, inclusion of ifosfamide in upfront treatment
regimens is imperative. The use of this regimen has been adopted as our
standard of care for these rare malignancies and should be considered as
a reasonable option until future studies identify more promising
treatments. Furthermore, we believe this regimen warrants further
evaluation at a greater scale through a prospective, multicenter
clinical trial.