Importance of Central Imaging Review in a Pediatric Hodgkin Lymphoma Trial Using Positron Emission Tomography Response Adapted Radiation Therapy.

PURPOSE: We investigated the effects of central review of the interim fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan response (iPET) assessment on treatment allocation in the risk-based, response-adapted, Children's Oncology Group study AHOD1331 (ClinicalTrials.gov identifier: NCT02166463) for pediatric patients with high-risk Hodgkin lymphoma. METHODS AND MATERIALS: Per protocol, after 2 cycles of systemic therapy, patients underwent iPET, with visual response assessment by 5-point Deauville score (DS) at their treating institution and a real-time central review, with the latter considered the reference standard. An area of disease with a DS of 1 to 3 was considered a rapid-responding lesion, whereas a DS of 4 to 5 was considered a slow-responding lesion (SRL). Patients with 1 or more SRLs were considered iPET positive, whereas patients with only rapid-responding lesions were considered iPET negative. We conducted a predefined exploratory evaluation of concordance in iPET response assessment between institutional and central reviews of 573 patients. The concordance rate was evaluated using the Cohen κ statistic (κ > 0.80 was considered very good agreement and κ > 0.60-0.80, good agreement). RESULTS: The concordance rate (514 of 573 [89.7%]) had a κ of 0.685 (95% CI, 0.610-0.759), consistent with good agreement. In terms of the direction of discordance, among the 126 patients who were considered iPET positive by institutional review, 38 (30.2%) were categorized as iPET negative by central review, preventing overtreatment with radiation therapy. Conversely, among the 447 patients who were considered iPET negative by institutional review, 21 patients (4.7%) were categorized as iPET positive by the central review and would have been undertreated without radiation therapy. CONCLUSIONS: Central review is integral to PET response-adapted clinical trials for children with Hodgkin lymphoma. Continued support of central imaging review and education about DS are needed.

Brentuximab Vedotin with Chemotherapy in Pediatric High-Risk Hodgkin's Lymphoma.

BACKGROUND: In adults with advanced-stage Hodgkin's lymphoma, the CD30-directed antibody-drug conjugate brentuximab vedotin combined with multiagent chemotherapy has been shown to have greater efficacy, but also more toxic effects, than chemotherapy alone. The efficacy of this targeted therapy approach in children and adolescents with Hodgkin's lymphoma is unclear. METHODS: We conducted an open-label, multicenter, randomized, phase 3 trial involving patients 2 to 21 years of age with previously untreated Hodgkin's lymphoma of stage IIB with bulk tumor or stage IIIB, IVA, or IVB. Patients were assigned to receive five 21-day cycles of brentuximab vedotin with doxorubicin, vincristine, etoposide, prednisone, and cyclophosphamide (brentuximab vedotin group) or the standard pediatric regimen of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (standard-care group). Slow-responding lesions, defined by a score of 4 or 5 (on a 5-point scale, with scores of 1 to 3 indicating rapid-responding lesions), were identified on centrally reviewed positron-emission tomography-computed tomography after two cycles. Involved-site radiation therapy was administered after the fifth cycle of therapy to slow-responding lesions and to large mediastinal adenopathy that was present at diagnosis. The primary end point was event-free survival, defined as the time until disease progression occurred, relapse occurred, a second malignant neoplasm developed, or the patient died. Safety and overall survival were assessed. RESULTS: Of 600 patients who were enrolled across 153 institutions, 587 were eligible. At a median follow-up of 42.1 months (range, 0.1 to 80.9), the 3-year event-free survival was 92.1% (95% confidence interval [CI], 88.4 to 94.7) in the brentuximab vedotin group, as compared with 82.5% (95% CI, 77.4 to 86.5) in the standard-care group (hazard ratio for event or death, 0.41; 95% CI, 0.25 to 0.67; P<0.001). The percentage of patients who received involved-site radiation therapy did not differ substantially between the brentuximab vedotin group and the standard-care group (53.4% and 56.8%, respectively). Toxic effects were similar in the two groups. Overall survival at 3 years was 99.3% (95% CI, 97.3 to 99.8) in the brentuximab vedotin group and 98.5% (95% CI, 96.0 to 99.4) in the standard-care group. CONCLUSIONS: The addition of brentuximab vedotin to standard chemotherapy resulted in superior efficacy, with a 59% lower risk of an event or death, and no increase in the incidence of toxic effects at 3 years. (Funded by the National Institutes of Health and others; AHOD1331 ClinicalTrials.gov number, NCT02166463.).

Risk of Cerebrovascular Events Among Childhood and Adolescent Patients Receiving Cranial Radiation Therapy: A Pediatric Normal Tissue Effects in the Clinic Normal Tissue Outcomes Comprehensive Review.

PURPOSE: Radiation-induced cerebrovascular toxicity is a well-documented sequelae that can be both life-altering and potentially fatal. We performed a meta-analysis of the relevant literature to create practical models for predicting the risk of cerebral vasculopathy after cranial irradiation. METHODS AND MATERIALS: A literature search was performed for studies reporting pediatric radiation therapy (RT) associated cerebral vasculopathy. When available, we used individual patient RT doses delivered to the Circle of Willis (CW) or optic chiasm (as a surrogate), as reported or digitized from original publications, to formulate a dose-response. A logistic fit and a Normal Tissue Complication Probability (NTCP) model was developed to predict future risk of cerebrovascular toxicity and stroke, respectively. This NTCP risk was assessed as a function of prescribed dose. RESULTS: The search identified 766 abstracts, 5 of which were used for modeling. We identified 101 of 3989 pediatric patients who experienced at least one cerebrovascular toxicity: transient ischemic attack, stroke, moyamoya, or arteriopathy. For a range of shorter follow-ups, as specified in the original publications (approximate attained ages of 17 years), our logistic fit model predicted the incidence of any cerebrovascular toxicity as a function of dose to the CW, or surrogate structure: 0.2% at 30 Gy, 1.3% at 45 Gy, and 4.4% at 54 Gy. At an attained age of 35 years, our NTCP model predicted a stroke incidence of 0.9% to 1.3%, 1.8% to 2.7%, and 2.8% to 4.1%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.2%-0.3%). At an attained age of 45 years, the predicted incidence of stroke was 2.1% to 4.2%, 4.5% to 8.6%, and 6.7% to 13.0%, respectively at prescribed doses of 30 Gy, 45 Gy, and 54 Gy (compared with a baseline risk of 0.5%-1.0%). CONCLUSIONS: Risk of cerebrovascular toxicity continues to increase with longer follow-up. NTCP stroke predictions are very sensitive to model variables (baseline stroke risk and proportional stroke hazard), both of which found in the literature may be systematically erring on minimization of true risk. We hope this information will assist practitioners in counseling, screening, surveilling, and facilitating risk reduction of RT-related cerebrovascular late effects in this highly sensitive population.

Quality of Life: A Prospective Randomized Trial of Palliative Volumetric Arc Therapy Versus 3-Dimensional Conventional Radiation Therapy.

PURPOSE: Volumetric arc therapy (VMAT) is a radiation therapy (RT) technique that spares normal tissues from high and intermediate RT doses but increases the volume of tissues receiving low doses of RT compared with 3-dimensional conformal RT (3DCRT). We hypothesized that palliative VMAT would reduce the detriment to patient quality of life (QOL) compared with palliative 3DCRT. METHODS AND MATERIALS: This phase 2 trial randomized patients to palliative RT using VMAT or 3DCRT to 1 painful site of metastatic disease in the trunk. Treating physicians could choose 8 Gy in 1 fraction or 20 Gy in 5 fractions to stratify randomization. The primary endpoint was the change in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30) global health status QOL subscale at 1 week after RT. Repeated measures analysis of variance was used to assess the relationship of patient QOL over time with other factors. RESULTS: From July 2014 to November 2017, 37 patients who underwent 3DCRT and 32 patients who underwent VMAT were randomized into the study. Median overall survival was 9 months. Overall pain responses to RT were equivalent (P = .53) between the techniques. Patient compliance in returning QOL questionnaires was 94%, 81%, and 69% at baseline, 1 week after RT, and 1 month after RT, respectively. At 1 week after RT, change in global QOL was not significantly (P = .31) different between VMAT versus 3DCRT. At 4 weeks after RT, VMAT induced significantly (P = .049) less global QOL deterioration than 3DCRT did. Patients who underwent VMAT maintained better physical (P = .012), role (P = .041), and social (P = .025) functioning, but they reported more diarrhea symptoms (P = .017) than in the 3DCRT group. CONCLUSIONS: Palliative VMAT and 3DCRT did not differ in their ability to control pain; however, palliative VMAT induced fewer QOL detriments than 3DCRT did at 4 weeks after RT.

Predictive Factor Analysis of Response-Adapted Radiation Therapy for Chemotherapy-Sensitive Pediatric Hodgkin Lymphoma: Analysis of the Children's Oncology Group AHOD 0031 Trial.

PURPOSE: To evaluate whether clinical risk factors could further distinguish children with intermediate-risk Hodgkin lymphoma (HL) with rapid early and complete anatomic response (RER/CR) who benefit significantly from involved-field RT (IFRT) from those who do not, and thereby aid refinement of treatment selection. METHODS AND MATERIALS: Children with intermediate-risk HL treated on the Children's Oncology Group AHOD 0031 trial who achieved RER/CR with 4 cycles of chemotherapy, and who were randomized to 21-Gy IFRT or no additional therapy (n=716) were the subject of this study. Recursive partitioning analysis was used to identify factors associated with clinically and statistically significant improvement in event-free survival (EFS) after randomization to IFRT. Bootstrap sampling was used to evaluate the robustness of the findings. RESULT: Although most RER/CR patients did not benefit significantly from IFRT, those with a combination of anemia and bulky limited-stage disease (n=190) had significantly better 4-year EFS with the addition of IFRT (89.3% vs 77.9% without IFRT; P=.019); this benefit was consistently reproduced in bootstrap analyses and after adjusting for other prognostic factors. CONCLUSION: Although most patients achieving RER/CR had favorable outcomes with 4 cycles of chemotherapy alone, those children with initial bulky stage I/II disease and anemia had significantly better EFS with the addition of IFRT as part of combined-modality therapy. Further work evaluating the interaction of clinical and biologic factors and imaging response is needed to further optimize and refine treatment selection.

Anti-Müllerian hormone screening to assess ovarian reserve among female survivors of childhood cancer.

PURPOSE: Anti-Müllerian hormone (AMH) is an indicator of oocyte reserve in healthy females. The role of AMH testing in oncology remains investigational, although its sensitivity and stability over the menstrual cycle make it an attractive screening test for fertility assessment among female cancer survivors. We measured AMH level in survivors of childhood cancer and evaluated its association with treatment and patient factors. METHODS: Participants were adult female survivors of childhood malignancy treated with chemotherapy. Serum AMH was measured at a random day of the menstrual cycle. Multivariate analysis was used to evaluate the association between AMH level, alkylating agent exposure using the cyclophosphamide equivalent dose (CED), and other covariates. RESULTS: Sixty-six females with a median attained age of 23.3 years were eligible for analysis. Median AMH was 25.5 pM (range 0.5-108.0), at a median time of 11.5 years (range 1.4-25.1) since cancer diagnosis. Twenty-three patients (34.8%) had low AMH, including a significant proportion that reported normal menstrual cycles. Compared to ALL survivors, sarcoma survivors had significantly lower AMH levels. Among alkylating agents evaluated, procarbazine had the greatest adverse effect on AMH. In multivariate analysis, higher CED (p = 0.001), older age at diagnosis (p < 0.001), and use of oral contraceptive pills (p = 0.04) remained significantly associated with lower AMH. CONCLUSIONS: Random AMH can reveal evidence of oocyte depletion among female survivors reporting normal cycles, although low AMH should be interpreted cautiously among those taking oral contraception. Age at exposure and CED can aid identification of those more likely to have low AMH, although CED may underestimate the effect of procarbazine on oocyte reserve. IMPLICATIONS FOR CANCER SURVIVORS: Measurement of AMH can reveal apparent depletion of ovarian reserve in female childhood cancer survivors reporting normal menstrual cycles. Sarcoma survivors and those exposed to procarbazine may benefit from targeted AMH evaluation in an outpatient setting, and thereby allow appropriate fertility counseling before the onset of premature ovarian failure. The cyclophosphamide equivalent dose may facilitate comparison of the potential effect of different regimens on fertility.

Active breathing control for patients receiving mediastinal radiation therapy for lymphoma: Impact on normal tissue dose.

PURPOSE: Active breathing control (ABC) is emerging as a tool to reduce heart and lung dose for lymphoma patients receiving mediastinal radiation therapy (RT). The objective of this study was to report our early institutional experience with this technique, with emphasis on quantifying the changes in normal tissue dose and exploring factors that could be used to select patients with the greatest benefit. METHODS AND MATERIALS: Patients receiving mediastinal involved-field RT (IFRT) for lymphoma were eligible. The ABC was performed using a moderate deep-inspiration breath-hold (mDIBH) technique. All patients were replanned with free-breathing (FB) computed tomographic data sets and comparisons of lung, cardiac, and female breast tissue doses were made between mDIBH and FB plans. Logistic regression models were used to identify factors associated with improvement in mean lung and heart dose with mDIBH. RESULTS: Forty-seven patients were analyzed; the majority (87.2%) had Hodgkin lymphoma. Median prescribed dose was 30 Gy (range, 20-36 Gy), with 78.7% of cases being treated with parallel-opposed beams. The use of mDIBH significantly improved average mean lung dose (FB: 11.0 Gy; mDIBH: 9.5 Gy; P < .0001), lung V20 (28% vs 22%; P < .0001), and mean heart dose (14.3 Gy vs 11.8 Gy; P = .003), but increased the mean breast dose (FB: 3.0 Gy; mDIBH 3.6 Gy; P = .0005). The magnitude of diaphragmatic excursion on the inhale scan was significantly associated with dosimetric improvement in both heart and lung dose with mDIBH. CONCLUSIONS: Mediastinal IFRT for lymphoma delivered with mDIBH can significantly reduce lung and heart dose compared with FB, although not for all patients, and may increase breast dose in females. Its implementation is achievable in both adult and pediatric populations. Further work is necessary to better predict which patients benefit from this technique.

A multi-institutional study of factors influencing the use of stereotactic radiosurgery for brain metastases.

PURPOSE: Stereotactic radiosurgery (SRS) for brain metastases is a relatively well-studied technology with established guidelines regarding patient selection, although its implementation is technically complex. We evaluated the extent to which local availability of SRS affected the treatment of patients with brain metastases. METHODS AND MATERIALS: We identified 3030 patients who received whole-brain radiation therapy (WBRT) for brain metastases in 1 of 7 cancer centers in Ontario. Clinical data were abstracted for a random sample of 973 patients. Logistic regression analyses were performed to identify factors associated with the use of SRS as a boost within 4 months following WBRT or at any time following WBRT. RESULTS: Of 898 patients eligible for analysis, SRS was provided to 70 (7.8%) patients at some time during the course of their disease and to 34 (3.8%) patients as a boost following WBRT. In multivariable analyses, factors significantly associated with the use of SRS boost following WBRT were fewer brain metastases (odds ratio [OR] = 6.50), controlled extracranial disease (OR = 3.49), age (OR = 0.97 per year of advancing age), and the presence of an on-site SRS program at the hospital where WBRT was given (OR = 12.34; all P values were <.05). Similarly, availability of on-site SRS was the factor most predictive of the use of SRS at any time following WBRT (OR = 5.98). Among patients with 1-3 brain metastases, good/fair performance status, and no evidence of active extracranial disease, SRS was provided to 40.3% of patients who received WBRT in a hospital that had an on-site SRS program vs 3.0% of patients who received WBRT at a hospital without SRS (P<.01). CONCLUSIONS: The availability of on-site SRS is the factor most strongly associated with the provision of this treatment to patients with brain metastases and appears to be more influential than accepted clinical eligibility factors.