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.