Discussion
In this study, we aimed to compare two chemotherapy regimens commonly
utilized at our institution for pediatric HL in regard to efficacy and
toxicity. We found that there was no significant difference in EFS
(p=0.46) or OS (p=0.37), with a median follow up length of 3.9 years.
Our results corroborate prior published literature concerning the high
overall success rate of both medication regimens and allow for direct
comparison between the two regimens.8,9
Since treatment for HL is uniformly effective, the main challenge in
developing pediatric clinical trials is to develop strategies to
maintain OS while avoiding or reducing long-term morbidity. ABVE-PC, a
pediatric regimen specifically designed to reduce late-effects in
comparison to regimens developed in adult populations, was examined in
the Children’s Oncology Group AHOD0031 trial in an effort to eliminate
radiation for a subset of patients. The 10-year follow up for the
AHOD0031 trial found excellent outcomes for rapid early responders, and
radiation therapy did not provide significant benefit in EFS over 10
years (RT 83.8% vs no RT 82.5%, p=0.26).12 Since
completion of the AHOD0031 trial however, several case series have shown
that ABVD without radiation is feasible and associated with excellent
outcomes in children with complete metabolic response on PET/CT imaging
after chemotherapy.13,14 When directly comparing the
two regimens in similar populations, we found in our cohort that a
greater proportion of patients treated with ABVE-PC received
consolidating external beam radiation treatment (XRT) compared to ABVD
in intention-to-treat analysis, but the difference was no longer
statistically significant when patients randomized to radiation were
instead analyzed as not having received radiation. Response by PET,
where available, mirrored the need for radiation although the numbers
available were limited.
Ultimately the goal of risk-adapted therapy, selective elimination of
radiotherapy and overall reduction in therapeutic intensity is to reduce
the risk of late effects and subsequent malignant
neoplasms.15 Numerous late effects such as
hyper/hypothyroidism, thyroid nodules, heart disease, pulmonary
fibrosis/pneumonitis, skin cancer in radiation field, chronic fatigue,
perceived cognitive change, peripheral neuropathy, sexual changes, and
osteoporosis have been described following therapy for pediatric
HL.16 Subsequent malignant neoplasms are also seen, as
noted in for example in the long-term results of AHOD0031 where study
authors found an excess absolute risk of 1.2 malignant neoplasms / 1000
person-years.12 Reductions in therapy intensity have
been shown to reduce the rate of late complications as
well.17 No apparent differences were seen in our
cohort in regards to commonly-screened late effects or subsequent
malignant neoplasms, although the low event rate for both regimens
precluded analysis.
It is notable that most patients identified as Hispanic ethnicity, an
expected finding that reflects the population our hospital serves as the
primary free-standing children’s hospital in Los Angeles and as part of
the safety net for vulnerable populations. Several large studies using
have shown that patients identifying with Hispanic ethnicity have had
poorer survival with HL. Kahn et al found that Hispanic patients with
pediatric HL had a higher risk of post-relapse mortality from pooled
clinical trial data (including patients from the AHOD0031); however Kahn
et al also found no difference in outcomes overall for Hispanic patients
with pediatric HL when analyzing the Surveillance, Epidemiology, and End
Results program in the United States.18,19 Grubb et al
found that Hispanic males had inferior disease specific
survival.20 Interestingly, the results of our study
indicate overall excellent outcomes for Hispanic patients that reflect
the general population with respect to EFS and OS are possible, although
our numbers are small as a single institution.
There are several limitations to our study. Primarily, as this was not a
clinical trial and chemotherapy regimens were chosen individually,
subtle selection biases may have been introduced along with variations
in number of chemotherapy courses and decisions regarding the use of
radiotherapy. Second, despite collecting all the HL patients at one of
the largest children’s hospitals in the nation over nearly two decades,
the numbers remain small due to the rarity of the disease; such numbers
continue to illustrate the need for multicenter cooperative group
trials. Also, following the intention-to-treat principle meant all
patients randomized to receive radiation were counted as events,
although the published findings of AHOD0031 likely will similar patients
in the future (RER) will not receive radiation. Additionally, the small
number of late effects precluded meaningful comparisons, although
overall the rate was low with both regimens. We were limited to our
standard length of follow-up and standard late effect surveillance study
results available given the nature of this retrospective chart review.
Finally, due to the nature of patient heath documentation maintenance,
and the lack of electronic medical records for the patients who were
treated in the earlier years, the data collection, such as radiology and
outside records, was limited for some.
In conclusion, our study demonstrated that the ABVD and ABVE-PC regimens
had similar survival outcomes without excess late effects. We found that
patients under the ABVE-PC regimen required more radiation, although the
question of radiation randomization in AHOD0031 increased the number of
patients receiving ABVE-PC that ultimately required radiotherapy.
Nonetheless, the rate of second malignant neoplasms and other late
effects appeared to be low.