Hodgkin lymphoma and non-Hodgkin lymphoma are common malignancies in children and are now highly treatable. Imaging plays a major role in diagnosis, staging and response using conventional CT and MRI ...and metabolic imaging with positron emission tomography (PET)/CT and PET/MRI. Cross-sectional imaging has replaced staging laparotomy and splenectomy by demonstrating abdominal nodal groups and organ involvement. F-182-fluoro-2-deoxyglucose (FDG) PET provides information on bone marrow involvement, and MRI elucidates details of cortical bone and confirmation of bone marrow involvement. The staging system for Hodgkin lymphoma is the Ann Arbor system with Cotswald modifications and is based on imaging, whereas the non-Hodgkin staging system is the St. Jude Classification by Murphy or the more recent revised International Pediatric Non-Hodgkin Lymphoma Staging System (IPNHLSS). Because all pediatric lymphomas are metabolically FDG-avid and identify all nodal, solid organ, cortical bone and bone marrow disease, staging evaluations require FDG PET as PET/CT or PET/MRI in both Hodgkin and non-Hodgkin lymphoma. Both diseases have in common issues of airway compromise at presentation demonstrated by imaging. Differences exist in that Hodgkin lymphoma has several independent poor prognostic factors seen by imaging such as large mediastinal adenopathy, Stage IV disease, systemic symptoms, pleural effusion and pericardial effusion. Non-Hodgkin lymphoma includes more organ involvement such as renal, ovary, central nervous system and skin. Early or interim PET-negative scans are a reliable indicator of improved clinical outcome and optimize risk-adapted therapy and patient management; imaging may not, however, predict who will relapse. A recent multicenter trial has concluded that it is usually sufficient for pediatric lymphoma at staging and interim assessment to evaluate children with PET imaging from skull base to mid-thigh. Various systems of assessment of presence of disease or response are used, including the Deauville visual scale, where avidity is compared to liver; Lugano, which includes size change as part of response; or quantitative PET, which uses standardized uptake values to define more accurate response. Newer methods of immunotherapy can produce challenges in FDG PET evaluation because of inflammatory changes that may not represent disease.
Summary
The Children's Oncology Group AHOD0831 study used a positron emission tomography (PET) response‐adapted approach in high‐risk Hodgkin lymphoma, whereby slow early responders (SERs) received ...more intensive therapy than rapid early responders (RERs). We explored if baseline PET‐based characteristics would improve risk stratification. Of 166 patients enrolled in the COG AHOD0831 study, 94 (57%) had baseline PET scans evaluable for quantitative analysis. For these patients, total body metabolic tumour volume (MTV), total lesion glycolysis (TLG), maximum standardized uptake value (SUVmax) and peak SUV (SUVpeak) were obtained. MTV/TLG thresholds were an SUV of 2.5 (MTV2.5/TLG2.5) and 40% of the tumour SUVmax (MTV40%/TLG40%). TLG2.5 was associated with event‐free survival (EFS) in the complete cohort (p = 0.04) and in RERs (p = 0.01), but not in SERs (p = 0.8). The Youden index cut‐off for TLG2.5 was 1841. Four‐year EFS was 92% for RER/TLG2.5 up to 1841, 60% for RER/TLG2.5 greater than 1841, 74% for SER/TLG2.5 up to 1841 and 79% for SER/TLG2.5 greater than 1841. Second EFS for RER/TLG2.5 up to 1841 was 100%. Thus, RERs with a low baseline TLG2.5 experienced excellent EFS with less intensive therapy, whereas RERs with a high baseline TLG2.5 experienced poor EFS. These findings suggest that patients with a high upfront tumour burden may benefit from intensified therapy, even if they achieve a RER.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Patients with primary refractory Hodgkin's 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 Hodgkin's 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 Hodgkin's lymphoma or early relapse.
In this Children's Oncology Group, multicentre, single-arm, phase 1–2 trial, we recruited patients with Hodgkin's 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.
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.
Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkin's lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials.
National Institutes of Health and the St. Baldrick's Foundation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Children's Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated ...the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). “Rapid early responders” (RERs) had a negative PET1 (PET1−); “slow early responders” (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as “within the PET1+ site” or “initially involved but outside the PET1+ site.” Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.
•Patients with a slow early response by PET1 have a significantly higher rate of relapse, which can be mitigated by adding 21-Gy IFRT.•With relapses common in the PET1+ site, there is a role for up-front alternative systemic therapy and/or target RT intensification.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose We evaluated outcomes of nonoperative management of primary nonrefluxing megaureter at long-term followup to identify clinical predictors of spontaneous resolution. Materials and Methods A ...total of 75 patients (88 primary megaureters) were diagnosed between 1990 and 2005 and followed for more than 6 months. Of the patients 63 (74 primary megaureters) were included in the main study population. Indications for surgery were obstructive hydroureteronephrosis, functional impairment and persistent symptoms. Results Of the 74 primary megaureters 20 (27%) required surgery up to 7 years after diagnosis. Surgery was not indicated in 82% of primary megaureters with grade I or II hydronephrosis vs 62.9% of those with grade III or higher hydronephrosis (difference not significant), nor in 76.5% of types I and II primary megaureters vs 33.3% of type III primary megaureters (p = 0.040), 78.7% of renal units with differential function 40% or greater vs 0% with differential function less than 40% (p = 0.027), 80% of primary megaureters with a nonobstructive washout pattern vs 44.4% with an intermediate/obstructive pattern (p = 0.032), 67.9% of patients with perinatal presentation vs 25% with postneonatal presentation (p = 0.008) or 63.2% of patients presenting with symptoms vs 76.4% of those who were asymptomatic (difference not significant). On multivariate analysis age at presentation and washout pattern were significant predictors of spontaneous resolution. Conclusions Most cases of primary megaureter resolve spontaneously or improve without loss of function or development of symptoms. Careful observation allows surgery to be delayed beyond the neonatal period in most patients. Long-term followup is recommended because symptoms can develop years later. Washout pattern and age at presentation are statistically significant predictors of spontaneous resolution.
Purpose
For pediatric lymphoma, quantitative FDG PET/CT imaging features such as metabolic tumor volume (MTV) are important for prognosis and risk stratification strategies. However, feature ...extraction is difficult and time-consuming in cases of high disease burden. The purpose of this study was to fully automate the measurement of PET imaging features in PET/CT images of pediatric lymphoma.
Methods
18
F-FDG PET/CT baseline images of 100 pediatric Hodgkin lymphoma patients were retrospectively analyzed. Two nuclear medicine physicians identified and segmented FDG avid disease using PET thresholding methods. Both PET and CT images were used as inputs to a three-dimensional patch-based, multi-resolution pathway convolutional neural network architecture, DeepMedic. The model was trained to replicate physician segmentations using an ensemble of three networks trained with 5-fold cross-validation. The maximum SUV (SUV
max
), MTV, total lesion glycolysis (TLG), surface-area-to-volume ratio (SA/MTV), and a measure of disease spread (Dmax
patient
) were extracted from the model output. Pearson’s correlation coefficient and relative percent differences were calculated between automated and physician-extracted features.
Results
Median Dice similarity coefficient of patient contours between automated and physician contours was 0.86 (IQR 0.78–0.91). Automated SUV
max
values matched exactly the physician determined values in 81/100 cases, with Pearson’s correlation coefficient (
R
) of 0.95. Automated MTV was strongly correlated with physician MTV (
R
= 0.88), though it was slightly underestimated with a median (IQR) relative difference of − 4.3% (− 10.0–5.7%). Agreement of TLG was excellent (
R
= 0.94), with median (IQR) relative difference of − 0.4% (− 5.2–7.0%). Median relative percent differences were 6.8% (
R
= 0.91; IQR 1.6–4.3%) for SA/MTV, and 4.5% (
R
= 0.51; IQR − 7.5–40.9%) for Dmax
patient
, which was the most difficult feature to quantify automatically.
Conclusions
An automated method using an ensemble of multi-resolution pathway 3D CNNs was able to quantify PET imaging features of lymphoma on baseline FDG PET/CT images with excellent agreement to reference physician PET segmentation. Automated methods with faster throughput for PET quantitation, such as MTV and TLG, show promise in more accessible clinical and research applications.
The Children's Oncology Group protocol AHOD0831, for pediatric patients with high-risk classical Hodgkin lymphoma (cHL), used response-adapted radiation fields, rather than larger involved-field ...radiation therapy (IFRT) that were historically used. This retrospective analysis of patterns of relapse among patients enrolled in the study was conducted to study the potential effect of a reduction in RT exposure.
From December 2009 to January 2012, 164 eligible patients under 22 years old with stage IIIB (43%) and stage IVB (57%) enrolled on AHOD0831. All patients received 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC). Those patients with a slow early response (SER) after the first 2 ABVE-PC courses were nonrandomly assigned to 2 intensification cycles with ifosfamide/vinorelbine before the final 2 ABVE-PC cycles. Response-adapted RT (21 Gy) was prescribed to initial areas of bulky disease and SER sites. Rapid early response (RER) sites without bulk were not targeted. Imaging studies at the time of progression or relapse were reviewed centrally for this retrospective analysis. Relapses were characterized with respect to site (initial, new, or both; and initial bulk or initial nonbulk), initial chemotherapy response, and radiation field (in-field, out-of-field, or both).
Of the entire cohort, 140 patients were evaluable for the patterns of failure analyses. To investigate the pattern of failure, this analysis focuses on 23 patients who followed protocol treatment and suffered relapses at a median 1.05 years with 7.97-year median follow-up time. These 23 patients (11 RER and 12 SER) experienced a relapse in 105 total sites (median, 4; range, 1-11). Of the 105 relapsed sites, 67 sites (64%) occurred within an initial site of involvement, with 12 of these 67 sites (18%) at an initial site of bulky disease and 63 of these 67 relapses (94%) occurring in sites that were not fluorodeoxyglucose (FDG)-avid after 2 cycles of ABVE-PC (PET2-negative). Of the 105 relapsed sites, 34 sites (32%) occurred in a new site of disease (that would not have been covered by RT); and, overall, only 4 of 140 patients (2.8%) (occurring in 3 RER and 1 SER) experienced isolated out-of-field relapses that would have been covered by historical IFRT.
For a cohort of high-risk patients with cHL patients, most failures occurred in nonbulky, initially involved sites, largely due to response-based consolidation RT delivered to patients with bulky disease. In this analysis, we discovered low rates of failures outside of these modern risk-adapted radiation treatment volumes. Also, FDG uptake on PET2 did not identify most relapse sites.
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