Kathleen McCarten

Dose-Intensive Response-Based Chemotherapy and Radiation Therapy for Children and Adolescents With Newly Diagnosed Intermediate-Risk Hodgkin Lymphoma: A Report From the Children's Oncology Group Study AHOD0031

PURPOSE The Childrens Oncology Group study AHOD0031, a randomized phase III study, was designed to evaluate the role of early chemotherapy response in tailoring subsequent therapy in pediatric intermediate-risk Hodgkin lymphoma. To avoid treatment-associated risks that compromise long-term health and to maintain high cure rates, dose-intensive chemotherapy with limited cumulative doses was used. PATIENTS AND METHODS Patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation. Rapid early responders (RERs) received two additional ABVE-PC cycles, followed by complete response (CR) evaluation. RERs with CR were randomly assigned to involved-field radiotherapy (IFRT) or no additional therapy; RERs with less than CR were nonrandomly assigned to IFRT. Slow early responders (SERs) were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). All SERs were assigned to receive IFRT. RESULTS Among 1,712 eligible patients, 4-year event-free survival (EFS) was 85.0%: 86.9% for RERs and 77.4% for SERs (P < .001). Four-year overall survival was 97.8%: 98.5% for RERs and 95.3% for SERs (P < .001). Four-year EFS was 87.9% versus 84.3% (P = .11) for RERs with CR who were randomly assigned to IFRT versus no IFRT, and 86.7% versus 87.3% (P = .87) for RERs with positron emission tomography (PET) -negative results at response assessment. Four-year EFS was 79.3% versus 75.2% (P = .11) for SERs who were randomly assigned to DECA versus no DECA, and 70.7% versus 54.6% (P = .05) for SERs with PET-positive results at response assessment. CONCLUSION This trial demonstrated that early response assessment supported therapeutic titration (omitting radiotherapy in RERs with CR; augmenting chemotherapy in SERs with PET-positive disease). Strategies directed toward improved response assessment and risk stratification may enhance tailoring of treatment to patient characteristics and response.

BEACOPP chemotherapy is a highly effective regimen in children and adolescents with high-risk Hodgkin lymphoma: a report from the Children's Oncology Group

Dose-intensified treatment strategies for Hodgkin lymphoma (HL) have demonstrated improvements in cure but may increase risk for acute and long-term toxicities, particularly in children. The Childrens Oncology Group assessed the feasibility of a dose-intensive regimen, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) in children with high-risk HL (stage IIB or IIIB with bulk disease, stage IV). Rapidity of response was assessed after 4 cycles of BEACOPP. Rapid responders received consolidation therapy with guidelines to reduce the risk of sex-specific long-term toxicities of therapy. Females received 4 cycles of COPP/ABV (cyclophosphamide, vincristine, procarbazine, prednisone, doxorubicin, bleomycin, vinblastine) without involved field radiation therapy (IFRT). Males received 2 cycles of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) with IFRT. Slow responders received 4 cycles of BEACOPP and IFRT. Ninety-nine patients were enrolled. Myelosuppression was frequent. Rapid response was achieved by 74% of patients. Five-year event-free-survival is 94%, IFRT with median follow-up of 6.3 years. There were no disease progressions on study therapy. Secondary leukemias occurred in 2 patients. Overall survival is 97%. Early intensification followed by less intense response-based therapy for rapidly responding patients is an effective strategy for achieving high event-free survival in children with high-risk HL. This trial is registered at http://www.clinicaltrials.gov as #NCT00004010.

PROCESSES FOR QUALITY IMPROVEMENTS IN RADIATION ONCOLOGY CLINICAL TRIALS

Quality assurance in radiotherapy (RT) has been an integral aspect of cooperative group clinical trials since 1970. In early clinical trials, data acquisition was nonuniform and inconsistent and computational models for radiation dose calculation varied significantly. Process improvements developed for data acquisition, credentialing, and data management have provided the necessary infrastructure for uniform data. With continued improvement in the technology and delivery of RT, evaluation processes for target definition, RT planning, and execution undergo constant review. As we move to multimodality image-based definitions of target volumes for protocols, future clinical trials will require near real-time image analysis and feedback to field investigators. The ability of quality assurance centers to meet these real-time challenges with robust electronic interaction platforms for imaging acquisition, review, archiving, and quantitative review of volumetric RT plans will be the primary challenge for future successful clinical trials.

A phase 2 study of bortezomib in combination with ifosfamide/vinorelbine in paediatric patients and young adults with refractory/recurrent Hodgkin lymphoma: a Children's Oncology Group study

A Childrens Oncology Group clinical trial aimed to determine if bortezomib (B) increased the efficacy of ifosfamide and vinorelbine (IV) in paediatric Hodgkin lymphoma (HL). This study enrolled 26 relapsed HL patients (<30 years) treated with two to four cycles of IVB. The primary endpoint was anatomic complete response (CR) after two cycles. Secondary endpoints included overall response (OR: CR + partial response) at study completion compared to historical controls [72%; 95% confidence interval (CI): 59–83%]. Although few patients achieved the primary objective, OR with IVB improved to 83% (95% CI: 61–95%; p = 0·32). Although not statistically different, results suggest IVB may be a promising combination.

Patterns of Relapse From a Phase 3 Study of Response-Based Therapy for Intermediate-Risk Hodgkin Lymphoma (AHOD0031): A Report From the Children's Oncology Group

PURPOSE The study was designed to determine whether response-based therapy improves outcomes in intermediate-risk Hodgkin lymphoma. We examined patterns of first relapse in the study. PATIENTS AND METHODS From September 2002 to July 2010, 1712 patients <22 years old with stage I-IIA with bulk, I-IIAE, I-IIB, and IIIA-IVA with or without doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide were enrolled. Patients were categorized as rapid (RER) or slow early responders (SER) after 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). The SER patients were randomized to 2 additional ABVE-PC cycles or augmented chemotherapy with 21 Gy involved field radiation therapy (IFRT). RER patients were stipulated to undergo 2 additional ABVE-PC cycles and were then randomized to 21 Gy IFRT or no further treatment if complete response (CR) was achieved. RER without CR patients were non-randomly assigned to 21 Gy IFRT. Relapses were characterized without respect to site (initial, new, or both; and initial bulk or initial nonbulk), and involved field radiation therapy field (in-field, out-of-field, or both). Patients were grouped by treatment assignment (SER; RER/no CR; RER/CR/IFRT; and RER/CR/no IFRT). Summary statistics were reported. RESULTS At 4-year median follow-up, 244 patients had experienced relapse, 198 of whom were fully evaluable for review. Those who progressed during treatment (n=30) or lacked relapse imaging (n=16) were excluded. The median time to relapse was 12.8 months. Of the 198 evaluable patients, 30% were RER/no CR, 26% were SER, 26% were RER/CR/no IFRT, 16% were RER/CR/IFRT, and 2% remained uncategorized. The 74% and 75% relapses involved initially bulky and nonbulky sites, respectively. First relapses rarely occurred at exclusively new or out-of-field sites. By contrast, relapses usually occurred at nodal sites of initial bulky and nonbulky disease. CONCLUSION Although response-based therapy has helped define treatment for selected RER patients, it has not improved outcome for SER patients or facilitated refinement of IFRT volumes or doses.

Quality of radiotherapy reporting in randomized controlled trials of Hodgkin's lymphoma and non-Hodgkin's lymphoma: in regard to Bekelman and Yahalom (Int J Radiat Oncol Biol Phys 2009;73:492-498)

Drs. Bekelman and Yahalom’s (1) paper describing radiation therapy (RT) quality assurance (QA) in lymphoma clinical trials places emphasis for RT standards. Insuring study defined dose/volume constraint compliance, RTQA requires central pre-treatment diagnostic imaging and RT plan review. This letter describes Children’s Oncology Group (COG) historical and current RTQA process for Hodgkin’s lymphoma (HL) trials. For 33 years the Quality Assurance Review Center (QARC) has performed RTQA on cooperative group trials. Process improvements demonstrate maturing of clinical trials QA in response to protocol needs. The increasingly crucial role of imaging in clinical trials QA is validated. Pediatric Oncology Group (POG) protocol 8725 (intermediate/advanced staged HL) required 8 chemotherapy cycles +/− Involved Field RT. Initial publication(2) demonstrated no advantage for RT. Retrospective data review revealed 10% survival advantage for patients receiving compliant RT.(3) 30% of patients had treatment deviations including omission of RT to involved sites. To improve compliance, POG required pre-treatment RT review for next generation advanced/early stage HL studies, P9425/P9426(4,5). Strategy improved RT compliance. P9426 required post chemotherapy imaging response treatment adaptation. Retrospective response-imaging central review established that ~50% of patients had discordance between local and central review.(6) COG AHOD0031 (intermediate risk HL) included patient response-adapted therapy. QARC initiated real time response review with integrated imaging (anatomic and metabolic) and RT review prior to RT start. Discordant local and central interpretations were resolved in real time. (7,8) 1733 patients from 251 centers worldwide were enrolled. Near uniform data submission compliance has been obtained with >95% RT compliance in ~600 cases reviewed. Process feasibility allows extension of adaptive treatments based on centrally-confirmed response for the next high risk HL study. QARC-developed an informatics platform and processes that contribute to success of these clinical trials improvements. QARC acquires and manages imaging and RT data in several digital formats(9). The QARC database houses images and RT objects in side-by-side format, enabling remote investigator access. In collaborating with Dr. Purdy and the Advanced Technology Consortium, full digital RT files are received at QARC for review and DVH analysis. Currently strategies to incorporate Dicom compatible pathology objects into the database and use of open-source format for data sharing are being evaluated. The objectives identified in this paper for developing consensus standards and peer-review are in place for cooperative groups. Applying these established programs at enterprise level insures the objectives of this publication are met.

Staging Evaluation and Response Criteria Harmonization (SEARCH) for Childhood, Adolescent and Young Adult Hodgkin Lymphoma (CAYAHL): Methodology statement

International harmonization of staging evaluation and response criteria is needed for childhood, adolescence, and young adulthood Hodgkin lymphoma. Two Hodgkin lymphoma protocols from cooperative trials in Europe and North America were compared for areas in need of harmonization, and an evidence‐based approach is currently underway to harmonize staging and response evaluations with a goal to enhance comparisons, expedite identification of effective therapies, and aid in the approval process for new agents by regulatory agencies.

Childhood Hodgkin International Prognostic Score (CHIPS) Predicts event-free survival in Hodgkin Lymphoma: A Report from the Children’s Oncology Group

Early response to initial chemotherapy in Hodgkin lymphoma (HL) measured by computed tomography (CT) and/or positron emission tomography (PET) after two to three cycles of chemotherapy may inform therapeutic decisions. Risk stratification at diagnosis could, however, allow earlier and potentially more efficacious treatment modifications.

Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1–2 trial

BACKGROUND Patients with primary refractory Hodgkins lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkins lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkins lymphoma or early relapse. METHODS In this Childrens Oncology Group, multicentre, single-arm, phase 1-2 trial, we recruited patients with Hodgkins lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m2 intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662. FINDINGS Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m2. 24 (57%) of 42 evaluable patients (95% CI 41-72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51-80]). The most common grade 3-4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths. INTERPRETATION Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkins lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials. FUNDING National Institutes of Health and the St. Baldricks Foundation.

Sonographic Upper Gastrointestinal Series in the Vomiting Infant: How We Do It

Sonography (ultrasound) is used routinely to assess an infant with nonbilious projectile emesis. Fluoroscopic upper gastrointestinal (UGI) series has been the standard method to evaluate infants with bilious emesis. We use sonographic UGI routinely to assess infants with nonbilious emesis as well as infants with bilious emesis. This essay illustrates our technique, the results obtained using this technique for normal anatomy, and the commonly encountered pathology.