Abstract
Background:
AHOD 1331 was a clinical trial investigating brentuximab vedotin in conjunction with chemotherapy and response adapted radiation therapy (RT) in pediatric patients with high-risk classic Hodgkin lymphoma (cHL). RT was delivered using 3D conformal RT (3DCRT), intensity modulated radiation therapy (IMRT), or proton therapy. This analysis evaluated dosimetric and clinical outcomes for patients treated across these different RT modalities.
Methods:
After five cycles of systemic therapy, patients received 21 Gy of RT to sites including bulky mediastinal disease at diagnosis or partial metabolic responses after two cycles. A 9 Gy boost was delivered to sites with partial responses at the end of therapy. Clinical and dosimetric outcomes prospectively collected and were compared for 3D-CRT, IMRT, and proton therapy in a post hoc analysis.
Results:
Of 587 enrolled patients, 317 (54%) received protocol-directed RT: 29% with 3D-CRT, 41% with IMRT, 26% with proton therapy, and 4% with mixed modalities. Proton therapy use increased from 16% to 26% to 36% among the first, second, and third tertiles of patients irradiated. (P=0.045). At a median follow-up of 43 months, 3-year progression-free survival rates were equivalent across modalities (P=0.77): 86.6% for 3DCRT, 87.6% for IMRT, and 87.9% for proton therapy. No significant differences were observed in acute grade 3 or higher toxicities. Proton therapy delivered significantly lower mean doses to the heart, breast, and lung compared to IMRT or 3D-CRT, while IMRT resulted in higher mean doses to the lungs and breasts compared to 3D-CRT.
Conclusion:
Selective use of RT combined with chemotherapy, including brentuximab vedotin, led to excellent outcomes for pediatric patients with high-risk HL. Proton therapy utilization increased during the study, showing similar disease control and toxicity outcomes as 3D-CRT and IMRT. Long-term follow-up is essential to evaluate the risks of secondary malignancies and cardiac toxicity across radiation techniques.
Introduction
Combined modality therapy, including chemotherapy followed by radiation therapy (RT), has been the standard of care for managing “High Risk” pediatric classic Hodgkin lymphoma (cHL) for decades. While RT has been associated with increased risk of late effects among long term survivors, the risk has primarily been driven by antiquated RT that included the large RT fields, such as total and subtotal nodal irradiation, and high doses of RT (40–45 Gy).1,2 To mitigate these risks, the Children’s Oncology Group (COG) has explored ways to reduce the number of patients receiving RT in clinical studies through PET response adapted treatment algorithms and integration of novel targeted therapies.3
An additional strategy to minimize risk of late effects of RT is to lower the RT dose to the critical organs at risk (OAR), such as the heart, breasts, and lungs. Several approaches have been employed to achieve this reduction.3,4 Lowering RT prescription dose from 40–45 Gy to 21–30 Gy is crucial due to the dose dependent relationship between RT exposure and toxicity.5,6 Additionally, utilizing smaller radiation fields, such as involved field radiation therapy (IFRT) in AHOD 0031 & AHOD 0431, and limited RT to only high-risk sites of disease including initial bulky disease and slowly responding sites on AHOD 0831 rather than the large extended RT fields used in the POG 9425 study.7 These reductions in RT field design are expected to decrease the risk of late effects, especially risk of secondary breast cancers and heart disease.1
Another key method to reduce OAR RT doses is using highly conformal radiation techniques and technologies, including IMRT and proton therapy. Dosimetric studies have shown that IMRT can decrease doses to OARs in patients with cHL compared to conventional 3D conformal radiotherapy (3D-CRT).8 Furthermore, proton therapy has demonstrated even greater reductions in RT dose to OARs compared to IMRT.9–12 Yet, the high conformality of these techniques, which allows rapid dose fall-off near critical structures, raises concerns among some clinicians about the potential for “unintentional misses,” of the lymphoma target potentially leading to worse disease outcomes.13 Clinical outcomes for IMRT and proton therapy in both pediatric and adult cHL are limited and predominately retrospective, with long-term data on late effects still requiring time to mature.14–17
In this post-hoc analysis of a prospective clinical trial with RT central review, we evaluate the impact of different RT techniques and technologies on patients who received RT on AHOD 1331, focusing on both the dosimetric and disease control outcomes.
Methods
The treatment protocol has been previously described and the primary endpoints reported.18 In short, AHOD 1331 was reviewed and approved by the National Cancer Institute, the pediatric Central Institutional Review Board, and the local institutional review boards, per the institutional policies of the participating sites. Written informed consent from parents or guardians and assent from children were obtained in accordance with the Declaration of Helsinki.
Patients aged 2 to 21 years old with newly diagnosed advanced stage classic Hodgkin lymphoma (Stage IIB bulky, Stage IIIB, or IV) were randomly assigned in a 1:1 ratio to receive five cycles of chemotherapy in one of two groups, including brentuximab vedotin plus doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide or the standard of care regimen including doxorubicin, vincristine, etoposide, prednisone, cyclophosphamide, and bleomycin (instead of brentuximab vedotin). An FDG-PET-CT scan was performed after 2 cycles of systemic therapy and defined sites of slow responding lesion (SRL) if they had a 4 or 5 on the 5 point metabolic response scale (5PS); a score of 1–3, was defined as a rapid responding lesion (RRL).
Within 3 weeks following completion of systemic therapy, involved site radiotherapy (ISRT) was delivered to SRL and to all initial bulky mediastinal sites according to maximal mediastinal ratio (MMR) greater than 1/3 and to a dose of 21 Gy delivered at 1.5 Gy/fraction. Additionally, sites that did not achieve a complete metabolic response after 5 cycles of systemic therapy based on a 5PS of 3–5, were to be boosted using residual pet radiotherapy (RPRT) to a dose of 9 Gy (total 30 Gy), delivered at 1.5 Gy/fraction.
Radiotherapy could be delivered using 3D conformal techniques (3D), IMRT, or with proton therapy (PT) per investigator choice. All RT data was centrally reviewed prior to delivery. Institutions treating with IMRT and/or PT had to have been credentialed for the modality through the imaging and radiation oncology core (IROC), which included successfully irradiating the IROC Houston lung phantom.
ISRT and RPRT target volumes have been previously described and were the same regardless of RT technique utilized.4,19 In short, the ISRT CTV included the lymph nodes/tissue originally involved with lymphoma but had to take into account the reduction in axial diameter that occurred with chemotherapy. For patients with a partial response at completion of systemic therapy, a 900 cGy boost was delivered to the area of imaging abnormality demonstrating the lymph node that remained PET avid, GTVPET+. A PTV margin of 0.3–15 mm was used based on the location of the target and the institutional standards. Target dose uniformity required 95% of the prescription dose to cover >99% of the CTV and no more than 10% of the CTV or PTV could receive >110% of the dose. Also, 95% of the prescription dose was to cover >95% of the PTV with a maximum dose not to exceed 120% of the prescription dose. Per protocol, dose constraints to the OARs included Lung V20 <35%, mean lung dose <15 Gy, mean ipsilateral kidney <15 Gy and 50% of contralateral kidney < 8Gy, maximum spinal cord dose of 45 Gy, and mean heart dose of <15 Gy (although exceeding heart constraint was not a protocol violation).
Imaging and plans regarding radiation therapy were centrally reviewed in real time at IROC Rhode Island to determine metabolic response and to review the delivered radiation therapy. Submission of the dose to selected OARs and dose volume histogram of the targets were required by protocol.
Post-hoc, the heart and breast (female patients only) OARs were centrally re-contoured retrospectively on each patient separately, as there was significant variation in how they were contoured by the treating physician. Radiation doses to the revised OARs were calculated based on the 21 Gy ISRT plans. Boost plans for patients with a partial response were not included due to the small sample size and the use of different modalities in some of the boost treatments..
Statistical Analysis
In our analysis, we employed a suite of statistical tests to rigorously evaluate the data post hoc. For continuous variables, we used the Wilcoxon rank-sum test and the Kruskal-Wallis test to compare groups suitable for non-normally distributed data to assess median differences. Categorical variables in both tables were analyzed using χ2 tests for overall associations, with Fisher exact test applied where small sample sizes required a more precise probability calculation. Furthermore, to investigate survival distributions, we utilized the Kaplan–Meier method for estimating survival probabilities over time and employed log-rank tests to compare progression-free survival across groups.
Results
In an as treated analysis, among 586 eligible patients who were enrolled across 153 institutions between March 2015 to August 2019, 317 (54%) received protocol RT (Supplemental Table 1). Patients receiving RT were more likely to be female, have large mediastinal adenopathy, have B symptoms, and SRLs. Across both study arms Progression-free survival rates were similar among patients who received and didn’t receive radiotherapy (P=0.91) (Supplemental Figure 1).
Limited to just the 317 patients that received RT, RT was given due to large mediastinal adenopathy (69.7%), presence of a SRL (6.6%), or both (23.7%) without any difference by treatment arm. With a median follow up of 43.1 months among irradiated patients, the 3-yr PFS was 82.5% (90% CI, 78.3%–85.9%) with ABVE-PC and 92.5% (90% CI 89.5%–94.6%) with BV-AVE-PC (P =0.0002) (Supplemental Figure 2).
RT modalities included 28.7% (n=91) 3D, 41.3% (n=131) IMRT, 25.6% (n=81) PT and mixed techniques of 3.5% (n=11) 3D+IMRT, 0.6% (n=2) IMRT+PT, and 0.3% (n=1) 3D+PT. Table 1 describes the cohort characteristics according to type of RT modality. There was no significant difference in the systemic treatment arm or having slow responding lesions according to RT type. There were significantly fewer patients with Stage IV disease that received IMRT compared with proton therapy, while significantly more IMRT patients had B symptoms. Proton utilization increased over the course of the study and made up 16% of the first 100 patients treated with RT, while it was 36% of the final 100 patients treated with RT (Figure 1).
Table 1.
Patient, Disease, and Treatment Characteristics Stratified by Type of RT
| Characteristic | Overall N=317 | 3D N=91 | IMRT1 N=142 | Proton2 N=84 | P value |
|---|---|---|---|---|---|
| Age | |||||
| Median [Range] | 15.8 [3.5, 21.5] | 16 [6, 21.5] | 15.7 [6.4, 21.4] | 15.9 [3.5, 21.5] | 0.2939 |
| Sex | |||||
| Female | 173 (54.6%) | 50 (54.9%) | 80 (56.3%) | 43 (51.2%) | 0.7516 |
| Male | 144 (45.4%) | 41 (45.1%) | 62 (43.7%) | 41 (48.8%) | |
| Race | |||||
| American Indian or Alaska Native | 1 (0.3%) | 1 (1.1%) | 0.3864 | ||
| Asian | 5 (1.6%) | 1 (1.1%) | 4 (4.8%) | ||
| Black or African American | 44 (13.9%) | 14 (15.4%) | 18 (12.7%) | 12 (14.3%) | |
| Native Hawaiian or Other Pacific Islander | 3 (0.9%) | 1 (1.1%) | 1 (0.7%) | 1 (1.2%) | |
| Unknown or Not Reported | 28 (8.8%) | 9 (9.9%) | 11 (7.7%) | 8 (9.5%) | |
| White | 233 (73.5%) | 64 (70.3%) | 110 (77.5%) | 59 (70.2%) | |
| more than one race | 3 (0.9%) | 1 (1.1%) | 2 (1.4%) | ||
| Ethnicity | |||||
| Hispanic or Latino | 62 (19.6%) | 21 (23.1%) | 22 (15.5%) | 19 (22.6%) | 0.3592 |
| Not Hispanic or Latino | 241 (76.0%) | 67 (73.6%) | 111 (78.2%) | 63 (75.0%) | |
| Unknown or Not Reported | 14 (4.4%) | 3 (3.3%) | 9 (6.3%) | 2 (2.4%) | |
| Stage | |||||
| IIB with bulk | 89 (28.1%) | 22 (24.2%) | 48 (33.8%) | 19 (22.6%) | 0.0165 |
| IIIB | 62 (19.6%) | 19 (20.9%) | 29 (20.4%) | 14 (16.7%) | |
| IVA | 71 (22.4%) | 21 (23.1%) | 20 (14.1%) | 30 (35.7%) | |
| IVB | 95 (30.0%) | 29 (31.9%) | 45 (31.7%) | 21 (25.0%) | |
| LMA | |||||
| Yes | 296 (93.4%) | 84 (92.3%) | 135 (95.1%) | 77 (91.7%) | 0.5423 |
| No | 21 (6.6%) | 7 (7.7%) | 7 (4.9%) | 7 (8.3%) | |
| B Symptoms | |||||
| Yes | 245 (77.3%) | 70 (76.9%) | 121 (85.2%) | 54 (64.3%) | 0.0020 |
| No | 68 (21.5%) | 21 (23.1%) | 19 (13.4%) | 28 (33.3%) | |
| Unknown | 4 (1.3%) | 2 (1.4%) | 2 (2.4%) | ||
| Histology | |||||
| Nodular sclerosis | 251 (79.2%) | 78 (85.7%) | 105 (73.9%) | 68 (81.0%) | 0.2811 |
| Mixed cellularity | 11 (3.5%) | 2 (2.2%) | 7 (4.9%) | 2 (2.4%) | |
| Classic HL NOS | 51 (16.1%) | 11 (12.1%) | 26 (18.3%) | 14 (16.7%) | |
| Lymphocyte-rich | 4 (1.3%) | 4 (2.8%) | |||
| Study Arm | |||||
| ABVE-PC | 162 (51.1%) | 44 (48.4%) | 79 (55.6%) | 39 (46.4%) | 0.3368 |
| BV-AVE-PC | 155 (48.9%) | 47 (51.6%) | 63 (44.4%) | 45 (53.6%) | |
| Response after 2 cycles | |||||
| RRL | 221 (69.7%) | 64 (70.3%) | 95 (66.9%) | 62 (73.8%) | 0.5445 |
| SRL | 96 (30.3%) | 27 (29.7%) | 47 (33.1%) | 22 (26.2%) |
includes 131 treated with IMRT alone & 11 treated with IMRT + 3D,
includes 81 treated with proton alone & 1 treated with proton + 3D & 2 treated with proton + IMRT.
Figure 1.
Distribution of Type of RT Use Broken Down by Groups of 50 Consecutive Patients (A) and Cumulative Over the Course of the Study (B).
The 3-yr PFS by RT modality were not significantly different (P=0.77): 3D (86.6%, 95% CI 77.6%–91.2%), IMRT (87.6%, 80.8%–92.1%), PT (87.9%, 95% CI 78.7% – 93.3%%) (Figure 2). No differences were observed in severe grade 3 and higher acute toxicities among patients according to RT modality (5.5% for 3D, 9.9% for IMRT, 8.3% for proton therapy, P=0.51). Additionally, there was no significant differences in the development of second malignancies or grade 3 or higher thyroid toxicities (Table 2 and Supplemental Table 2).
Figure 2.
Progression-Free Survival According to RT Modality Used on AHOD 1331.
Table 2.
Grade 3 and Higher Acute Toxicities During RT and Second Cancer Development During Follow-Up
| 3D-CRT (N=91) | IMRT (N=142) | Proton Therapy (N=84) | Overall (N = 317) | P value | |
|---|---|---|---|---|---|
| Grade 3+ AE during RT | 5 (5.5%) | 14 (9.9%) | 7 (8.3%) | 26 (8.2%) | 0.51 |
| SMN during follow-up | 2 (2.2%) | 2 (1.4%) | 1 (1.2%) | 5 (1.6%) | 0.86 |
Among the 317 patients that received RT, 299 patients (94%) had thoracic RT plans available with RT doses to the OARs. The dose to the heart, breasts, and thyroid for each cohort of patients are shown in Table 3 according to modality. The mean heart dose was 10.6 Gy, 10.0Gy, and 7.5 Gy for patients receiving IMRT, 3D-CRT, and PT. The mean breast dose was 5.6Gy, 3.1Gy, and 2.3 Gy for female patients treated with IMRT, 3D-CRT, and PT. The mean lung dose was 9.3 Gy, 8.2 Gy, and 6.5 Gy for patients receiving IMRT, 3D-CRT, and PT. Patients receiving PT had significantly lower doses to the heart, breast, and lung compared with either 3D or IMRT (all P<0.01). Patients receiving 3D had significantly lower doses to the lung and breast compared with IMRT. The thyroid dose was not significantly different among the 3 RT modalities.
Table 3.
Radiation Dose to the Organs at Risk by RT Modality
| OAR | 3D-CRT N Mean (STD) Median (25%, 75%) | IMRT N Mean (STD) Median (25%, 75%) | Proton N Mean (STD) Median (25%, 75%) | 3D vs IMRT P value | 3D vs PT P value | IMRT vs PT P value |
|---|---|---|---|---|---|---|
| Heart | N=89 9.95 (3.95) 10.26 (7.30, 13.01) |
N=133 10.58 (3.58) 10.91 (8.39, 13.24) |
N=77 7.45 (4.05) 7.14 (3.96, 10.34) |
0.243 | 0.0001 | <0.0001 |
| Lung | N=89 8.16 (2.71) 8.40 (6.40, 9.90) |
N=133 9.27 (2.61) 9.40 (7.20, 10.90) |
N=77 6.53 (2.28) 6.50, (4.80, 8.50) |
0.005 | <0.0001 | <0.0001 |
| Breast | N=48 3.12 (1.86) 2.67 (1.9, 3.85) |
N=74 5.62 (2.67) 4.83 (3.57, 7.79) |
N=39 2.27 (2.28) 1.35 (0.89, 2.90) |
<0.0001 | 0.002 | <0.0001 |
| Thyroid | N=89 11.75 (8.04) 11.50 (3.32, 20.07) |
N=133 11.95 (7.58) 12.23 (4.95, 19.65) |
N=77 13.75 (7.84) 16.4 (7.50, 21.02) |
0.896 | 0.244 | 0.144 |
Discussion
In addition to establishing a new standard of care for pediatric classic HL with BV-AVEPC systemic therapy, AHOD 1331 took significant steps to reduce organ at risk exposure as means to reduce the risk of late effects from RT. These measures resulted in irradiating fewer patients compared to previous pediatric HL studies, limiting RT fields to sites known to be at high risk for relapse in PET adapted approaches with historic conventional chemotherapy, and utilizing highly conformal radiation techniques, including IMRT and proton therapy. This study was the first COG lymphoma trial to prospectively include PT as a modality. The findings indicate lower doses to the OARs with PT versus IMRT and 3D and acceptable and similar rates of relapse and toxicity within first 3 years of follow up.
Over the last decade, numerous studies have correlated RT dose to OAR with both acute and late toxicities, with a generally linear relationship observed between mean dose and toxicity risk.20 Consequently, OAR dose has been a reliable surrogate for predicting toxicity rates. Various RT treatment planning studies have compared OAR doses in mediastinal HL patients of 3D-CRT, IMRT, and proton therapy. Traditional 3D-CRT treatment typically delivers RT through AP/PA fields to the planned target volume (PTV). In contrast, IMRT, tomotherapy, and volumetric modulated arc therapy (VMAT) deliver RT from multiple different field angles (+/− modulation of the field), which can significantly reduce the amount of normal tissue receiving higher doses of RT. However, these techniques can increase the “low dose bath”, potentially redistributing but not reducing the integral dose, the total dose received by the body, an important factor in the risk of secondary cancers. Furthermore, expertise in planning and evaluating the RT plans are needed as one must often consider the exact field arrangements that can best spare the breasts, lung, and heart for a patient. Proton therapy, by contrast, operates differently. With a finite range within the body, it allows for reduction of high dose regions without increasing the low dose exposure. This results in approximately a 40% reduction in integral dose.8
In AHOD 1331, patients treated with proton therapy consistently had lower doses to the heart, lung, and breast compared with either 3D or IMRT, with median mean heart dose of 10.6 Gy vs 7.14 Gy for IMRT versus proton therapy, respectively. Past analyses have demonstrated that reductions from 10 Gy mean heart dose to 7.6 Gy would result in ≥2% reductions in future risks of major cardiovascular events.21 A surprising finding from this study was the higher doses to the lungs and breast observed in IMRT compared to 3D-CRT. This finding may reflect patient selection, with bulkier tumors more commonly referred for IMRT, while patients treated with 3D-CRT likely had less bulky tumors. Alternatively, the increased lung and breast doses could result from suboptimal IMRT planning, which is an area warranting further investigation.
While many studies have demonstrated significant reductions in RT dose to the OARs, few clinical studies on proton therapy in Hodgkin lymphoma have been reported. One prospective clinical trial demonstrated 3 year relapse free survival of 93%, but the small sample size (n=15) and limited follow up time precluded a comprehensive assessment of late effects.22 Multiple retrospective studies, single & multi-institutional, have shown favorable disease control rates of approximately 90% .16,23,24 However, these studies were similarly limited by small sample sizes and short follow-up durations. A recent study using the National Cancer Database (NCDB) assessed the risk of second malignancies among patients treated with 3D-CRT, IMRT, and proton therapy across various cancers, including 2992 Hodgkin lymphoma survivors (1621 3D-CRT, 1293 IMRT, and 78 proton therapy).25 Proton therapy was associated with significantly lower adjusted odds ratio of 0.62 (95% CI, 0.55–0.69, P<0.0001) for development of second cancers compared to IMRT. While second cancers and hypothyroidism were reported in this study, the follow up period is too short to make any meaningful conclusions. Long term follow-up of patients on AHOD 1331 will hopefully help inform us whether proton therapy reduces the rate of late effects for these patients.
The incorporation of PT to manage Hodgkin lymphoma has been clinically employed since 2005, yet, was severely limited, due to limited number of proton centers and insurance approval.26–29 While AHOD1331 began enrolling patients in 2015, the rate of access to PT for lymphoma patients in COG centers was unknown at the time. Interestingly, the growth increased from 16% among the first 100 patients irradiated to 36% of patients among the last 100 patients treated. This increase likely reflects growing comfort by treating physicians in using proton therapy for mediastinal lymphoma patients; we also previously demonstrated broader insurance approval for pediatric and adolescent patients, and expanding availability of proton therapy centers in the US.30
Although this is not a randomized controlled study comparing 3D, IMRT, and proton therapy, the large patient population in AHOD 1331 provides a valuable opportunity for exploratory analyses of RT questions that are unlikely to be the primary focus of future front-line lymphoma studies. This study demonstrated similar PFS rates across different RT modalities in both arms of the study, providing the strongest evidence to date. Furthermore, future long-term data from this study could potentially be combined with other large trials of advanced stage Hodgkin lymphoma that included significant use of proton therapy, providing even more comprehensive insights.10,31
Conclusion
The selective use of RT in combination with chemotherapy, including the antibody drug conjugate, brentuximab vedotin, results in excellent outcomes for pediatric patients with high-risk HL. Throughout the study, proton therapy utilization increased as an RT modality and results demonstrate that proton therapy maintains similar disease control rates and acute toxicity profiles as 3D-CRT and IMRT. Long term follow-up (>10 years) will be critical to fully assess the risk of secondary malignancies and cardiac toxicity across the different radiotherapy techniques.
Supplementary Material
Acknowledgements:
Portions of this manuscript were edited to improve readability with the assistance of ChatGPT.
Funding:
Supported in part by grants from the National Institutes of Health (U10CA098543, U10CA180899, and U10CA180886; all to the Children’s Oncology Group), the Quality Assurance Review Center (U10CA29511), Imaging and Radiology Oncology Core Rhode Island (U24CA180803), St. Baldrick’s Foundation (to the Children’s Oncology Group), and National Institutes of Health (R50CA285492–01 PI Castellino). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Footnotes
Conflict of Interest: BSH holds a leadership role (Co-Chair) NRG Hematologic Malignancies Working Group. RRP received payment/honoraria for a speakers bureau from Mevion Medical Systems. FGK participates on Aflac’s Data Safety Monitoring Board. SP received consulting fees from Seagen for stakeholder survey development and analysis and is a member of the Dana-Farber/Harvard Cancer Center Data Safety Monitoring Board. SF is a member of the Proton Collaborative Group (PCG) Data and Safety Monitoring Board; Chair of Task Group No. 427 Technical Guidelines for the Use of Proton Therapy in Clinical Trials, American Association of Physicists in Medicine (AAPM); and Co-Chair of the Lymphoma Sub-Committee, Particle Therapy Co-Operative Group (PTCOG). KMK has a grant from National Cancer Institute and subcontracts with Emory University, Washington University, Hospital for Sick Kids in Toronto, and COG/PHI (all paid to her institution); received an honoraria from the American Society of Hematology for educational events; received travel support from the Lymphoma Research Foundation and American Society of Hematology; is a member of the Bristol Meyers Squibb Data Safety Monitoring Board; holds an unpaid leadership role on the Lymphoma Research Foundation Scientific Advisory Board; holds a leadership role on the Children’s Oncology Group Scientific Council (payment to her institution from an NCI subcontract); and received drugs from Pfizer/Seagen and Bristol Meyers Squibb for NCI-sponsored NCTN clinical trial. SMC received grants from Seattle Genetics (now Pfizer)- Pediatric Advisory Board and Bristol Meyers Squibb (Pediatric Advisory Board); received payment for lectures from the St. Jude Children’s Hospital - Scientific Symposium; received travel support from the Lymphoma Research Foundation - Sci Ad Board; and holds unpaid leadership roles on the Leukemia and Lymphoma Society Board of Directors and Lymphoma Research Foundation Scientific Advisory Board. DCH has stock in Immvue Therapeutics and is the Vice-Chair of Research for the Faculty of Radiation Oncology, University of Toronto. The other authors have nothing to disclose.
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Data Availability Statement:
The Children’s Oncology Group Data Sharing policy describes the release and use of COG individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) Guidelines. Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee (DSMC) are available to be shared. Data sharing will ordinarily be considered only after the primary study manuscript is accepted for publication. For phase 3 studies, individual-level de-identified datasets that would be sufficient to reproduce results provided in a publication containing the primary study analysis can be requested from the NCTN/NCORP Data Archive at https://nctn-data-archive.nci.nih.gov/. Data are available to researchers who wish to analyze the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. For non-phase 3 studies, data are available following the primary publication. An individual-level de-identified dataset containing the variables analyzed in the primary results paper can be expected to be available upon request. Requests for access to COG protocol research data should be sent to: datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use. For all requests, no other study documents, including the protocol, will be made available and no end date exists for requests. In addition to above, release of data collected in a clinical trial conducted under a binding collaborative agreement between COG or the NCI Cancer Therapy Evaluation Program (CTEP) and a pharmaceutical/biotechnology company must comply with the data sharing terms of the binding collaborative/contractual agreement and must receive the proper approvals.
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Data Availability Statement
The Children’s Oncology Group Data Sharing policy describes the release and use of COG individual subject data for use in research projects in accordance with National Clinical Trials Network (NCTN) Program and NCI Community Oncology Research Program (NCORP) Guidelines. Only data expressly released from the oversight of the relevant COG Data and Safety Monitoring Committee (DSMC) are available to be shared. Data sharing will ordinarily be considered only after the primary study manuscript is accepted for publication. For phase 3 studies, individual-level de-identified datasets that would be sufficient to reproduce results provided in a publication containing the primary study analysis can be requested from the NCTN/NCORP Data Archive at https://nctn-data-archive.nci.nih.gov/. Data are available to researchers who wish to analyze the data in secondary studies to enhance the public health benefit of the original work and agree to the terms and conditions of use. For non-phase 3 studies, data are available following the primary publication. An individual-level de-identified dataset containing the variables analyzed in the primary results paper can be expected to be available upon request. Requests for access to COG protocol research data should be sent to: datarequest@childrensoncologygroup.org. Data are available to researchers whose proposed analysis is found by COG to be feasible and of scientific merit and who agree to the terms and conditions of use. For all requests, no other study documents, including the protocol, will be made available and no end date exists for requests. In addition to above, release of data collected in a clinical trial conducted under a binding collaborative agreement between COG or the NCI Cancer Therapy Evaluation Program (CTEP) and a pharmaceutical/biotechnology company must comply with the data sharing terms of the binding collaborative/contractual agreement and must receive the proper approvals.