Discussion
KHE and TA are aggressive vascular tumors that are associated with
significant morbidity and are rarely cured. Until the discovery of
efficacy of mTOR inhibition with sirolimus in KHE in mid-2000s,
vincristine and steroids were the mainstay of medical therapy. The rare
nature and widely heterogenous clinical presentation of KHE/TA have made
comparison of treatment modalities difficult. This study compares
treatment response and durability in the largest cohort of children with
KHE/TA to date.
In this cohort, we found similar rates of KMP (40.3%) but a much lower
mortality rate (1.3%) compared to historical cohorts. This may be
attributed to the introduction of sirolimus for long-term tumor
control.4,12,32,33 Sirolimus was the most common
treatment and overall treatment response rates were high
(>70% overall by 6 months), and there were no differences
in radiologic, hematologic, or clinical response between the VCR and
Siro treatment groups at 6 months. Due to chronicity of KHE/TA we also
felt it was important to try to evaluate durability of treatment
response. We found no significant differences in the rates of
progressive or recurrent disease at 3 and 6 months between the VCR and
Siro treatment groups. While increased rates of reported persistent
disease were noted in the Siro group compared to VCR, we think the lack
of a standardized definition of persistent disease across investigators
and the frequent addition of sirolimus to patients on VCR regimen
precludes confirming this as a valid finding. KHE/TA can be considered a
chronic tumor, requiring months to years of therapy with infrequent
complete cures, and persistent disease needs to be defined more
effectively in future studies.
A recent prospective trial in 73 patients with KHE with KMP showed that
upfront sirolimus therapy in combination with steroids improves time to
resolution of KMP, durability of platelet response, and overall tumor
response at 12 months.31 In this retrospective cohort,
low patient numbers limited comparison of regiments with and without
steroids. More patients reported persistent disease in the Siro +
steroid group compared to the VCR + steroid treatment group, however
again noting that nearly 50% of the patients in the VCR + steroid group
added sirolimus to their regimen later.
Different side effect profiles often influence the choice of medical
agent. Sirolimus is associated with concerns for delayed wound healing,
mucositis, neutropenia, and lymphopenia. Vincristine is associated with
constipation, jaw pain, and peripheral neuropathy. Sirolimus may be an
agent of choice or an agent of transition for some due to its increased
ease of administration, lack of need for central venous access, and
demonstrated efficacy. Although there are concerns about
immunosuppression secondary to sirolimus, we found a lower rate of
infectious complications in the Siro group compared to patients
receiving vincristine. However, high adverse event rates in the groups
receiving vincristine (VCR and VCR+Siro) could be confounded if these
patients had more severe disease leading their physicians to elect
treatment with vincristine.
With equivalent treatment response and durability at 6 months, the
decision to treat with vincristine or sirolimus, with or without
steroids, should account for additional clinical factors, including
route of administration, side effects, perceived severity of KMP or
urgency to treat, and patient/family preference. While vincristine may
bring about more rapid radiologic response and perhaps should be
considered for high urgency situations, this is not associated with
improved longer-term outcomes in these indolent tumors. Although full
surgical resection of KHE is the only curative option, we found that
many patients who underwent surgery ultimately ended up needing systemic
medical therapy. Fortunately, the high overall treatment response rates
and low mortality highlighted in this cohort demonstrate that individual
patient factors and family and physician preferences can be encouraged
in the management of this rare vascular tumor.
This study represents the largest cohort to date investigating treatment
practices and short-term response rates in patients with KHE/TA. Results
are limited by the retrospective nature of this study, the clinical
heterogeneity of KHE/TA, and variable investigator experience and
clinical perspective. Although KHE and TA have overlapping clinical and
histopathologic features, their presentation and the urgency for medical
therapy can be quite distinct, which may affect assessment of treatment
choices and duration in this cohort. Many patients with mild TA are
observed only or treated with monotherapy initially, whereas patients
who present more acutely with large KHE causing clinical compromise or
KMP, multi-modal therapy may be the initial approach. Due to this
significant disease heterogeneity, determining baseline response
parameters for this population will allow for historical comparison in
future treatment protocols. These results augment the ability to make
educated decisions for individualized medical management for patients
with KHE/TA with and without KMP, particularly when complete surgical
excision is not possible or successful. Given the rarity of these
tumors, multi-institutional studies are needed to further knowledge of
the natural history of KHE/TA and optimal treatment modalities.