CME Author: Vicki Brower
Study Authors: Sachin R. Jhawar, Zorimar Rivera-Nuñez, et al.
Target Audience and Goal Statement:
Pediatric oncologists, oncologists, family medicine specialists, and internists
The goal was to assess whether combined modality therapy (chemotherapy plus radiation therapy) was associated with improved overall survival (OS) compared with chemotherapy alone in pediatric patients with Hodgkin lymphoma (HL). The secondary endpoint was to compare the association between clinicopathologic factors and OS. There are gaps in the existing literature, and previous studies are not unanimous that combined modality therapy (CMT) improves long-term survival.
- Is there a survival benefit with CMT versus chemotherapy alone in pediatric HL patients at 5 years and, if so, is it statistically significant?
- Which, if any, group of pediatric patients did CMT benefit most?
- What is the risk/benefit ratio for pediatric patients receiving CMT versus chemotherapy alone?
- What is the recent trend in the use of CMT versus chemotherapy alone in the pediatric HL population?
Study Synopsis and Perspective:
The current study was an observational cohort analysis of 5,657 pediatric patients from the National Cancer Database (mean age 17.1 years) who were diagnosed with stage I-II classic HL from 2004 to 2015. The researchers found that CMT was associated with improved survival compared with chemotherapy alone. Patients treated with CMT had an improved OS of 2.8% compared with chemotherapy alone at 5 years, with the low-risk cohort, and patients ages ≥15 years having a particular benefit (adjusted HR 0.47, 95% CI 0.40-0.56, P<0.001).
Notably, patients ages 1-13 years derived the least additional benefit from adding radiation therapy (RT); these patients are also the most “vulnerable” to late effects from RT.
At a median follow-up of 61.8 months, patients who received CMT had a 5-year OS of 97.3% compared with 94.5% for those treated with chemotherapy alone, according to Rahul R. Parikh, MD, of Rutgers Cancer Institute of New Jersey in New Brunswick, and colleagues.
These results remained significant on multivariable analysis that accounted for patients’ age, sex, race, health insurance type, tumor stage, presence of B symptoms, and transplant procedure (adjusted HR 0.57, 95% CI 0.42-0.78, P<0.001), they reported in JAMA Oncology.
“This study demonstrates improvement in survival benefit for pediatric Hodgkin lymphoma patients,” Parikh said in a press release. “With that, physicians should be encouraged to discuss combined modality therapy as one of the many treatment options with them at the time of diagnosis.”
About half of the patients in the study received RT after chemotherapy, and patients who received CMT were significantly younger than those receiving chemotherapy alone (ages <16 years, 38.7% vs 30.4%), more likely to have stage II disease, and more likely to have private health insurance. Most of the patients were white (82.9%) and the majority were female (53%). Males were more likely to receive CMT than females (48.1% vs 43.6%). The most common RT modality was photon radiation therapy (59.0%) followed by external-beam radiation therapy (18.5%).
“As multiple disparities to the use of combined modality therapy have been identified through this work, future studies should address improving access to care for all pediatric patients,” Parikh said.
Source Reference: JAMA Oncology, Jan. 3, 2019; DOI:10.001/jamaoncol.2018.5911
Study Highlights: Explanation of Findings
The authors found that the use of RT in CMT in childhood HL decreased significantly by 24.8%, from 59.7% in 2004 to 34.9% in 2015. “The most common physician-reported reason for not using CMT was that it was not part of the planned initial treatment strategy (90.9%). Other reasons for nondelivery of radiotherapy included that it was not recommended (1.1%), refusal (1.7%), or unknown (3.7%).
They noted that “the decline is occurring despite very limited data in highly selected groups of patients, suggesting that chemotherapy alone may be an appropriate treatment regimen for all patients with early-stage HL.” In addition to finding an OS survival advantage for patients who received CMT compared to those only treated with chemotherapy, the researchers reported that CMT “was preferentially used in younger patients, male patients, those with stage II disease, and those with private insurance. However, the youngest patients appeared to benefit the least from CMT.”
The authors pointed out that these findings “are important because they represent the group most vulnerable to the effects of radiotherapy.”
They also hypothesized that the preferential use of CMT in male patients may represent a concern for treatment-related secondary breast cancers in female patients in those receiving RT. Longer term follow-up is necessary to assess whether the decreased risk of secondary cancers with newer technologies “may balance the potential benefits of consolidation radiotherapy.”
This study may be the largest data set in pediatric patients with HL, the authors noted, emphasizing the lack of data on the long-term outcomes of pediatric patients with HL.
Along with CMT, other factors associated with OS in this population were age, presence of B symptoms, use of transplant procedure, and type of health insurance. Black patients were 63% more likely to die than white patients (HR 1.63, 95% CI 1.09-2.42, P=0.02), which the authors stated did not remain statistically significant in their multivariable analysis of patients with early-stage HL. Overall, after adjustment for confounders, “treatment with CMT remained associated with improvement in OS.”
“Nationwide, there has been a notable decrease in combined modality therapy, especially in clinical trials, many of which are designed to avoid this strategy,” explained Parikh. “The question then becomes, ‘does treatment benefit outweigh the risk of long-term side effects?'”
While the authors did not answer this question definitively, they noted that “patients who survive pediatric HL are at the highest risk (50% at 30 years) of developing late toxic effects among all childhood cancers.” Citing the Childhood Cancer Survivor Study (CCSS), the authors stated that second cancers, thyroid dysfunction, and cardiac issues are the most common late effects of treatment for childhood HL, which they attributed to certain chemotherapies and thoracic RT.
While they acknowledged that reducing overall use of RT would reduce late-stage effects, they observed that the RT modalities used in CCSS “reflect obsolete modes of radiation delivery, whereby patients were treated with subtotal lymphoid irradiation and doses of 44 Gy or higher.”
More recent RT regimens mean smaller, more tailored fields, node RT, substantially reduced doses, and less exposure to heart, lung, breast, and thyroid, they stated. In the future, intensity-modulated radiotherapy, proton-beam therapy, and deep-inspiration breath-hold are expected to further reduce toxicities — including late-term — and improve efficacy, the authors noted. Still, “longer-term, prospective follow-up is necessary to measure delayed toxic effects from radiotherapy that could abrogate the beneficial effect of CMT at 5 years we have observed in the current study,” they wrote.
Given these new data on the efficacy of CMT in older pediatric patients, the use of newer RT modalities that might reveal fewer or milder late-stage effects in years to come, the jury is still out on whether the risk/benefit ratio skews in favor of treating early-stage, older pediatric patients with CMT. The authors wrote that CMT “may be discussed” with HL pediatric patients, and prospective clinical trials should be conducted in the future, which could include CMT as a standard arm.
Study limitations included its retrospective design, and the fact that the data set lacked information on certain prognostic factors, such as systemic symptoms of the lymphoma, number of nodal sites, presence of fever, the presence of bulky disease, and other unknown confounders.
Also, the short follow-up did not fully capture late effects associated with use of RT, and there was no data on PET-based staging to measure interim response to induction chemotherapy, which would reveal which patients are most likely to benefit from consolidation RT, the authors stated. In addition, patients selected for CMT may have been the most high-risk with respect to tumor bulk or more slow responders to chemotherapy. These and other possible factors may have biased the outcomes of the cohort that only received chemotherapy, they stated.
Original story for MedPage Today by Ian Ingram
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco