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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
Abstract
Purpose:
The Children's 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.
... These factors include the location and laterality of the affected lymph nodes on either or both sides of the diaphragm, the number of lymph nodes involved, the involvement of contiguous lymph nodes, and the presence of bulky disease (defined as a mediastinal mass >1/3 the size of the intrathoracic diameter on a posterior-anterior chest X-ray or any mass ≥10 cm on a computed tomography [CT] scan at diagnosis [74]). Of note, the Children's Oncology Group has a lower threshold for bulky disease and defines it as a mass greater than or equal to 6 cm in pediatric populations in the presence or absence of B symptoms [75]. ...
... Radiation has been a cornerstone of HL therapy since the early 1900s [80]. However, because of the high survivability of the disease (the 5-year relative survival for patients diagnosed with cHL at age 0-19 years is higher than 95% [81]) and the high rate of long-term side effects, efforts have been made in recent years to reduce the usage of radiation in pediatric populations [75]. ...
... The pediatric intermediate-risk HL population was investigated in the COG phase 3 trial AHOD0031, which evaluated early chemotherapy response assessments as a means of dictating subsequent therapy [75]. Two cycles of ABVE with prednisone and cyclophosphamide (ABVE-PC) were administered to patients with newly discovered, intermediaterisk HL; the patients then received an early response assessment (ERA) using a PET or CT scan. ...
Hodgkin lymphoma, a hematological malignancy of lymphoid origin that typically arises from germinal-center B cells, has an excellent overall prognosis. However, the treatment of patients who relapse or develop resistant disease still poses a substantial clinical and research challenge, even though current risk-adapted and response-based treatment techniques produce overall survival rates of over 95%. The appearance of late malignancies after the successful cure of primary or relapsed disease continues to be a major concern, mostly because of high survival rates. Particularly in pediatric HL patients, the chance of developing secondary leukemia is manifold compared to that in the general pediatric population, and the prognosis for patients with secondary leukemia is much worse than that for patients with other hematological malignancies. Therefore, it is crucial to develop clinically useful biomarkers to stratify patients according to their risk of late malignancies and determine which require intense treatment regimens to maintain the ideal balance between maximizing survival rates and avoiding late consequences. In this article, we review HL’s epidemiology, risk factors, staging, molecular and genetic biomarkers, and treatments for children and adults, as well as treatment-related adverse events and the late development of secondary malignancies in patients with the disease.
... These strategies have included using less-intensive chemotherapy regimens and responseadapted protocols to identify patients for whom radiotherapy (RT) can be omitted. [4][5][6][7][8][9][10][11][12] To de-escalate treatment, the Children's Oncology Group developed AHOD0431 for early-stage, low-risk cHL. The study examined whether reducing up-front treatment, by using a response-based approach with minimal initial chemotherapy and omission of involved-field RT (IFRT), in patients with a complete response (CR) could maintain overall survival and event-free survival (EFS) while reducing late toxicity. ...
... Over the past 15 years, the most popular paradigm has been PET response-adapted treatment, which has often focused on eliminating the use of RT for RERs and intensifying treatment for SERs (supplemental Table 2). [4][5][6][7][8][9][10][11][12][13][14][15][16][17] Although, in the present study, early PET response was used to adapt therapy initially, the results demonstrated that, in this treatment paradigm, the PET1 response was a more sensitive predictor of PFS than the end-of- When evaluating outcomes in AHOD0431 for patients who were RER by PET1, it is evident that those who received combinedmodality therapy (10-year PFS, 96.6%) and chemotherapy alone (10-year RFS, 84.1%) compare favorably with patients enrolled in the 3 other major trials, conducted to analyze the role of PET2 or PET3 in guiding treatment reduction for early-stage cHL in adults and using chemotherapy of comparable intensity (supplemental Table 2). In the EORTC H10 study, which used interim PET2 to determine treatment adaptation, favorable-risk patients (H10F) who received 3 cycles of ABVD followed by 30-Gy IFRT in the standard arm had a 5-year PFS rate of 99.0% compared with a 5-year PFS rate of 87.1% among those in the experimental arm with a negative PET2 who received 4 cycles of ABVD without RT (P , .05). ...
... Similarly, the ABVE-PC regimen reported by Friedman et al (AHOD0031) examined a population of patients with intermediate-risk features that were mutually exclusive to the concurrently run AHOD0431 trial. 10 Small series using the ABVD regimen in the pediatric population have been published with good outcomes and limited use of radiation. 23 The authors acknowledge that optimization of the chemotherapy regimen may lead to improved overall outcomes, although the observations related to RT use would be likely to remain unchanged. ...
Children's Oncology Group trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classical Hodgkin lymphoma. We investigated the impact of PET response after 1 cycle (PET1) and IFRT on outcomes and relapse pattern. Patients on AHOD 0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). "Rapid early responders" (RER) had a negative PET1; "slow early responders" (SER) had a positive PET1. Patients with a partial response (PR) by CT and functional imaging following 3 chemotherapy cycles received 21-Gy IFRT, while complete responders (CR) had no IFRT. Progression-free survival (PFS) was evaluated for RER and SER patients treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as "within PET1+ site" or "initially involved but outside PET1+ site". Median follow-up was 118 months. The 10-year PFS rate among RER patients was 96.6% with IFRT and 84.1% without IFRT (p=.10), while SER patients were 80.9% with IFRT and 64.0% without IFRT (p=.03). Among 90 RER patients who did not receive IFRT, all 14 relapses included an initial site. Among 45 SER patients receiving no IFRT, 14/16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5/10 relapses were in the PET1+ site. Following 3 cycles of AVPC alone, RER patients experienced favorable results. Conversely, SER patients experienced unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. Radiotherapy remains an important component of treatment for patients who are SER. Trial Registration: Combination Chemotherapy Followed by Radiation Therapy in Treating Young Patients with Newly Diagnosed Hodgkin's' Lymphoma; https://clinicaltrials.gov/ct2/show/NCT00302003; NCT00302003.
... 14,17,18 The COG AHOD0031 (n = 1712) study reported bulky disease in 73.4% of patients. 19 In a study from New Delhi, India, the EFS in patients with bulky mediastinal disease was significantly lower on univariate but not multivariate analysis. 17 In our study, bulky disease was noted in 58.9% of patients, among whom 89% had bulky nodal disease, and 11% had bulky mediastinal disease. ...
... 24 In the COG AHOD0031 (n = 1712) study, patients received two cycles of doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, and prednisone (ABVE-PC) followed by response evaluation. 19 Slow early responders were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). 19 The COG AHOD0031 study reported FN in 24.9% of patients and 2 deaths due to infections in the setting of non-prolonged neutropenia. ...
... 19 Slow early responders were randomly assigned to receive two additional ABVE-PC cycles with or without two cycles of dexamethasone, etoposide, cisplatin, and cytarabine (DECA). 19 The COG AHOD0031 study reported FN in 24.9% of patients and 2 deaths due to infections in the setting of non-prolonged neutropenia. 19 In the GPOH-HD-2002 study, neutropenia was observed in 81.5% and 22.5% of patients who received OEPA and COPDAC, respectively. ...
ABVD regimen for Hodgkin lymphoma (HL) is frequently used in children and young adults in low-middle income countries (LMIC). The feasibility and safety data for 'non-ABVD' protocols from LMIC is limited. The retrospective study was conducted in a single center in India. The Euronet PHL-C1 based protocol was administered during 2010-19. A PET-CT was performed at diagnosis and following two OEPA cycles. Radiotherapy was administered for inadequate PET response. During the 10-year period, 143 patients with HL were treated. The mean age was 7.8 ± 2.5 years. Bulky disease was observed in 82 (59%). Treatment abandonment was recorded in 13 (9.1%). The median follow-up duration was 46.4 months. An inadequate PET response was observed in 41/119 (34.4%), of which 56.1% received radiotherapy. Twelve (29.3%) patients who were supposed to receive radiotherapy received 2-cycles of COPDAC instead. Sixty-nine episodes of febrile neutropenia were observed in 54 patients. Treatment-related mortality (TRM) was observed in 7 (5.3%). The majority of episodes of febrile neutropenia (61%) and TRM (86%) occurred in the first cycle of OEPA. The 4-year event-free survival (EFS) and overall survival (OS) were 86.2 ± 3.4% and 93.5 ± 2.2%, respectively. Nine (6.3%) patients relapsed. Bulky disease lacked association with inadequate PET response (p = .800) or relapse (p = 1.000). OEPA/COPDAC regimen and response assessment by PET-CT permitted therapy reduction, including radiotherapy. Febrile neutropenia and resultant TRM (5.3%) are concerning and occurred frequently in the first cycle of OEPA. The support system for managing febrile neutropenia should be optimized for administering OEPA in LMIC.
... В других случаях использование vDS привело к изменению балла у 31 (27,0%) пациента (в 25 случаях было выставлено 2 балла по qDS против 3 баллов по vDS; в 6 -3 балла по qDS против 4 баллов по vDS). Факторами, независимо связанными с бессобытийной выживаемостью, являлись значение vDS (отношение рисков 2,49 (1,93); p = 0,009), а также наличие объемной опухолевой массы (отношение рисков 3,12 (1,10-9,64); p = 0,048). Проведенный нами сравнительный анализ выявил различия в результатах, полученных при использовании vDS и qDS, но ни в одном случае при таком подходе не было отмечено занижения балла при оценке по vDS и, как следствие, не было деэскалации терапии. ...
... При хорошем сокращении объема опухоли по данным КТ, но сомнительных результатах оценки промежуточной ПЭТ/КТ по vDS (особенно при DS4 или DS3) следует использовать программное обеспечение для оценки по qDS. Ключевые слова: лимфома Ходжкина, позитронно-эмиссионная томография, совмещенная с компьютерной томографией, Deauville score, выживаемость, химиотерапия В структуре детских злокачественных заболеваний лимфома Ходжкина (ЛХ) составляет около 5-7% и является одной из самых прогностически благоприятных злокачественных опухолей у детей и подростков с общей 5-летней выживаемостью около 90% [1,2]. К сожалению, прекрасные результаты лечения пациентов с ЛХ могут быть скомпрометированы поздними побочными эффектами и осложнениями как непосредственно от проводимой химиотерапии, так и от ее комбинации с лучевой терапией (ЛТ). ...
The use of risk-adaptive therapy in patients with Hodgkin lymphoma (HL) makes it possible to de-escalate treatment protocols, thereby decreasing the incidence of long-term adverse effects. Metabolic remission as detected by interim positron emission tomography/computed tomography (PET/CT) performed after 2 cycles of chemotherapy is a prognostic factor that could guide further treatment. The generally accepted Deauville 5-point scale (DS) used for the visual assessment of interim PET/CT scans may be prone to inaccuracies. One of the suggested ways to address this problem is to use a quantitative evaluation method (qPET).
The aim of our study was to determine the level of discrepancy between DS assigned after visual (vDS) and quantitative (qDS) assessment of detected lesions on interim PET/CT images in children with HL.
The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Interim PET/CT scans of 115 patients with HL (the median age was 14 years) were retrospectively analyzed using the quantitative (qPET) method to determine qDS. Baseline PET/CT scan findings and medical history data were available for all patients. All imaging studies were performed at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology between June 2016 and March 2023. Our results showed that with the above approach (availability of initial PET/CT scans and access to the patient’s medical history), discordance between vDS and qDS was about 30%. There was no difference in the patients with a DS of 4 and 5. In other cases, in 31 (27%) patients, vDS and qDS differed by one score: 25 patients with a qDS of 2 had a vDS of 3; 6 patients with a qDS of 3 had a vDS of 4. Factors independently associated with event-free survival were vDS (hazard ratio (HR) 2.49 (1.26–4.93), p = 0.009) and the presence of a bulky tumor (HR 3.12 (1.10–9.64), p = 0.048). Our comparative analysis revealed a discrepancy between the findings obtained by the visual and quantitative assessment methods. In our study, there were no cases of vDS underestimation and, as a consequence, no patients underwent treatment de-escalation. In HL patients with good tumor volume reduction on CT but ambiguous results of interim PET/CT evaluation performed using the vDS (especially in case of DS4 or DS3), quantification software should be used.
... Hodgkin lymphoma (HL) is a rare cancer in children under 15 years of age, but it is the most common cancer among adolescents 15-19 years of age [1,2]. Treatment of HL has become a great success in modern oncology, with survival rates exceeding 90% for patients irrespective of the stage of disease [3][4][5][6][7][8][9][10]. Survivors of classical Hodgkin lymphoma (cHL) are at high risk of secondary malignancies and cardiovascular disease [1,[11][12][13][14][15][16][17]. ...
... Dietrich Stoevesandt 1 · Christiane Ludwig 2 · Christine Mauz-Körholz 3,4 · Dieter Körholz 3 · Dirk Hasenclever 5 · Kathleen McCarten 6,7 · Jamie E. Flerlage 8 ...
Background
Disseminated pulmonary involvement in pediatric Hodgkin lymphoma (pHL) is indicative of Ann Arbor stage IV disease. During staging, it is necessary to assess for coexistence of non-malignant lung lesions due to infection representing background noise to avoid erroneously upstaging with therapy intensification.
Objective
This study attempts to describe new lung lesions detected on interim staging computed tomography (CT) scans after two cycles of vincristine, etoposide, prednisolone, doxorubicin in a prospective clinical trial. Based on the hypothesis that these new lung lesions are not part of the underlying malignancy but are epiphenomena, the aim is to analyze their size, number, and pattern to help distinguish true lung metastases from benign lung lesions on initial staging.
Materials and methods
A retrospective analysis of the EuroNet-PHL-C1 trial re-evaluated the staging and interim lung CT scans of 1,300 pediatric patients with HL. Newly developed lung lesions during chemotherapy were classified according to the current Fleischner glossary of terms for thoracic imaging. Patients with new lung lesions found at early response assessment (ERA) were additionally assessed and compared to response seen in hilar and mediastinal lymph nodes.
Results
Of 1,300 patients at ERA, 119 (9.2%) had new pulmonary lesions not originally detectable at diagnosis. The phenomenon occurred regardless of initial lung involvement or whether a patient relapsed. In the latter group, new lung lesions on ERA regressed by the time of relapse staging. New lung lesions on ERA in patients without relapse were detected in 102 (7.8%) patients. Pulmonary nodules were recorded in 72 (5.5%) patients, the majority (97%) being<10 mm. Consolidations, ground-glass opacities, and parenchymal bands were less common.
Conclusion
New nodules on interim staging are common, mostly measure less than 10 mm in diameter and usually require no further action because they are most likely non-malignant. Since it must be assumed that benign and malignant lung lesions coexist on initial staging, this benign background noise needs to be distinguished from lung metastases to avoid upstaging to stage IV disease. Raising the cut-off size for lung nodules to ≥ 10 mm might achieve the reduction of overtreatment but needs to be further evaluated with survival data. In contrast to the staging criteria of EuroNet-PHL-C1 and C2, our data suggest that the number of lesions present at initial staging may be less important.
... Nonetheless refractory disease or relapse are the therapeutic challenge for treating physicians. [2]. The standard of care for relapsed or refractory (r/r) HL in pediatrics is a risk-adapted approach using high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (auto-HSCT). ...
Citation: Kozlov AV, Komarova YV, Potanin AA, et al. Autologous hematopoietic stem cell transplantation after immune checkpoint inhibitor therapy in pediatric relapsed/refractory Hodgkin lymphoma. Summary Effective treatment of relapsed/refractory Hodgkin lym-phoma (r/r HL) in children is still a challenge, especially in case of failure after several therapy lines. The present study demonstrates high effectiveness of auto-HSCT in heavily pretreated children with HL after immune checkpoint inhibitor (ICIs) therapy. Overall 16 children with r/r HL received auto-HSCT after ICIs with OS and PFS of 93.8% and 73.1%, respectively (median follow-up, 1.3 years). The transplantation procedure was generally well tolerated, with only one death (6.3%) due to sepsis. Thus, auto-HSCT after ICIs is a promising option in pediatric r/r HL but longer follow-up is mandatory to draw valid conclusions.
... Pretreatment of malignancies with steroids before biopsy has been shown to contribute to diagnostic uncertainty, and in some clinical trials, pretreatment assigns patients to higher-intensity regimens. [6][7][8][9] Managing patients with anterior mediastinal masses can be challenging and requires coordination among multiple teams, including oncology, pediatric general surgery (PGS), anesthesia, interventional radiology (IR), and pediatric intensive care (PICU). [10][11][12] Communication can be challenging, with multiple specialists needing to be contacted several times to coordinate care for these high-risk patients. ...
Background
Mediastinal masses in children with cancer present unique challenges, including the risk of respiratory and hemodynamic compromise due to the complex anatomy of the mediastinum. Multidisciplinary communication is often a challenge in the management of these patients. After a series of patients with mediastinal masses were admitted to Riley Hospital for Children Pediatric Intensive Care Unit, the time from presentation to biopsy and pathology was greater than expected. We aimed to reduce the time to biopsy by 25% and demonstrate improved multidisciplinary communication within 6 months of protocol implementation for patients presenting to Riley Hospital for Children Emergency Department with an anterior mediastinal mass.
Methods
Quality improvement methodology created a pathway that included early multidisciplinary communication. The pathway includes communication between the emergency department and multiple surgical and medical teams via a HIPPA-compliant texting platform. Based on patient stability, imaging findings, and sedation risks, the approach and timing of the biopsy were determined.
Results
The pathway has been used 20 times to date. We successfully reduced the time to biopsy by 38%, from 25.1 hours to 15.4 hours. There was no statistically significant reduction in time to pathology. The multidisciplinary team reported improved communication from a baseline Likert score of 3.24 to 4.
Conclusions
By initiating early multidisciplinary communication, we reduced the time to biopsy and pathology results, improving care for our patients presenting with anterior mediastinal masses.
... In the recent AHOD0831 and AHOD0031 protocols from the Children's Oncology Group (COG), < 5% of pediatric/ adolescent patients developed Grade 3 or higher vincristine-induced peripheral neuropathy, based on clinical grading scales. Rates of mild to moderate CIPN (≤ Grade 2) were not routinely collected [20,21], and validated tools to measure patient report of CIPN have been lacking [22] in younger patients. While younger children may not possess the vocabulary with which to describe their symptoms, we posit that older children and adolescents are likely to be capable of providing self-report, using existing validated measures. ...
Background
Chemotherapy-induced peripheral neuropathy (CIPN) is an under-recognized complication of several chemotherapy agents used as part of curative-intent therapy for Hodgkin Lymphoma (HL). In the absence of validated self- or proxy-report measures for children and adolescents, CIPN reporting has relied on clinician rating, with grading scales often restricted to severe manifestations. In a proof-of-concept study, we assessed the feasibility and psychometric performance of the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx), a unidimensional CIPN symptom scale widely used adults with CIPN, in pediatric HL at risk for CIPN.
Methods
Youth (11+ years) and parents of all children (5–17.9 years) with newly diagnosed high-risk HL enrolled on Children’s Oncology Group AHOD1331 (NCT02166463) were invited to complete the FACT-GOG-Ntx and a health-related quality of life (HRQL) measure at pre-treatment (Time 1), and during cycles 2 (Time 2) and 5 (Time 3) of chemotherapy during the first half of study accrual. Clinical grading of CIPN by providers was also assessed using the Balis Pediatric Neuropathy Scale. We evaluated Cronbach’s alpha, construct validity, and agreement between raters. Change in FACT-GOG-Ntx scores over time was assessed using a repeated measures model.
Results
306 patients had at least one completed FACT-GOG-Ntx with time-specific completion rates of > 90% for both raters. Cronbach’s alpha was > 0.7 for youth and parent-proxy report at all time points. Correlations between FACT-GOG-Ntx and HRQL scores were moderate (0.41–0.48) for youth and parent-proxy raters across all times. Youth and parent-proxy raters both reported worse FACT-GOG-Ntx scores at Time 3 for those who had clinically-reported CIPN compared to those who did not. Agreement between raters was moderate to high. Compared to baseline scores, those at Time 3 were significantly lower for youth (β = − 2.83, p < 0.001) and parent-proxy raters (β = − 1.99, p < 0.001).
Conclusions
High completion rates at all time points indicated feasibility of eliciting youth and parent report. Psychometric performance of the FACT-GOG-Ntx revealed acceptable reliability, evidence of validity, and strong inter-rater agreement, supporting the use of this self- or proxy-reported measure of CIPN in youth with high-risk HL exposed to tubulin inhibitors, as part of a Phase 3 clinical trial.
Clinical trial information : Clinical Trials Registry, NCT02166463. Registered 18 June 2014, https://clinicaltrials.gov/ct2/show/study/NCT02166463
... Although the prognosis for children with Hodgkin lymphoma (HL) is excellent, up to 25% of patients experience relapse and require salvage therapy. [1][2][3] In the largest retrospective series, event-free survival (EFS) for patients with relapsed or refractory disease after high-dose therapy with autologous stem cell transplantation (ASCT) is only 42% to 57%, thus there is an urgent clinical need for improved therapies. 1,[4][5][6][7][8][9] One approach to reducing the risk of posttransplantation recurrence is through the use of post-ASCT consolidative therapy. ...
Outcomes for children and adolescents with relapsed and refractory Hodgkin lymphoma (HL) are poor, with approximately 50% of patients experiencing a subsequent relapse. The anti-CD30 antibody-drug conjugate brentuximab vedotin improved progression-free survival (PFS) when used as consolidation after autologous stem cell transplant (ASCT) in adults with high-risk relapsed/refractory HL. Data on brentuximab vedotin as consolidative therapy after ASCT in pediatric patients with HL are extremely limited, with only 11 patients reported in the literature. We performed a retrospective analysis of 67 pediatric patients who received brentuximab vedotin as consolidation therapy following ASCT for the treatment of relapsed/refractory HL to describe the experience of this regimen in the pediatric population. This is the largest cohort reported to date. We found that brentuximab vedotin was well tolerated with a safety profile similar to adult patients. With a median follow up of 37 months, the 3-year PFS was 85%. These data suggest a potential role for the use of brentuximab vedotin as consolidation therapy after ASCT for children with relapsed/refractory Hodgkin lymphoma.
... The Hodgkin and Reed-Sternberg tumor cells involved are surrounded by a dense and complex microenvironment that supports their survival and proliferation [2,3]. Current HL therapies achieve high cure rates, but also carry a risk of therapy-related toxicities [4][5][6], especially in cases of relapsing/refractory disease, which can be cured with high-dose therapy, as reviewed in Daw et al. [7]. In the clinical management of HL, one of the main goals is to reduce the long-term toxicities of radiotherapy and chemotherapy by minimizing the treatments' intensity based on the risk category of the disease. ...
Classical pediatric Hodgkin Lymphoma (HL) is a rare malignancy. Therapeutic regimens for its management may be optimized by establishing treatment response early on. The aim of this study was to identify plasma protein biomarkers enabling the prediction of relapse in pediatric/adolescent HL patients treated under the pediatric EuroNet-PHL-C2 trial. We used untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomics at the time of diagnosis—before any therapy—as semiquantitative method to profile plasma proteins specifically associated with relapse in 42 children with nodular sclerosing HL. In both the exploratory and the validation cohorts, six proteins (apolipoprotein E, C4b-binding protein α chain, clusterin, fibrinogen γ chain, prothrombin, and vitronectin) were more abundant in the plasma of patients whose HL relapsed (|fold change| ≥ 1.2, p < 0.05, Student’s t-test). Predicting protein function with the Gene Ontology classification model, the proteins were included in four biological processes (p < 0.01). Using immunoblotting and Luminex assays, we validated two of these candidate biomarkers—C4b-binding protein α chain and clusterin—linked to innate immune response function (GO:0045087). This study identified C4b-binding protein α chain and clusterin as candidate early plasma biomarkers of HL relapse, and important for the purpose of shedding light on the molecular scenario associated with immune response in patients treated under the EuroNet-PHL-C2 trial.
... The secondary endpoint of this study was the achievement of complete remission at the interim PET scan. In the non-European Network-Paediatric Hodgkin Lymphoma-C1/ C2 (EuroNet-PHL-C1/C2) treatment protocols, instead of a PET scan, ultrasound evaluation or a computed tomography (CT) scan was used for interim evaluation (20,21). A sub-analysis was done for the secondary outcome to try to reduce the chance of bias, only including patients treated according to the current EuroNet-PHL-C1/C2 protocols. ...
Immunohistochemical markers are associated with treatment outcome in adults with classical Hodgkin Lymphoma (cHL). Studies in children are scarce and inconsistent. We investigated in 67 children with cHL, whether the expression of CD15, CD30, PAX5, PD-1, PD-L1, CD68, CD163 and TARC at diagnosis is associated with disease free survival (DFS) and with interim remission status. Low CD15 and low TARC expression were associated with relapsed disease. Low expression of PD-L1 was associated with complete remission at interim PET-scan. Our data suggest a difference between pediatric and adult cHL. This underlines the importance of future research into specific prognostic factors in pediatric cHL, indispensable for improvement of treatment in this population.
... A new initiative is being developed to house patient care data in a uniform format to develop programs in artificial intelligence in both our clinics and translational science laboratories. We understand that artificial intelligence will only be successful if built on strong datasets with complete information, otherwise we will be committed to continue to make the mistakes of the past limiting our credibility with colleagues from other disciplines (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). ...
The future of radiation oncology is exceptionally strong as we are increasingly involved in nearly all oncology disease sites due to extraordinary advances in radiation oncology treatment management platforms and improvements in treatment execution. Due to our technology and consistent accuracy, compressed radiation oncology treatment strategies are becoming more commonplace secondary to our ability to successfully treat tumor targets with increased normal tissue avoidance. In many disease sites including the central nervous system, pulmonary parenchyma, liver, and other areas, our service is redefining the standards of care. Targeting of disease has improved due to advances in tumor imaging and application of integrated imaging datasets into sophisticated planning systems which can optimize volume driven plans created by talented personnel. Treatment times have significantly decreased due to volume driven arc therapy and positioning is secured by real time imaging and optical tracking. Normal tissue exclusion has permitted compressed treatment schedules making treatment more convenient for the patient. These changes require additional study to further optimize care. Because data exchange worldwide have evolved through digital platforms and prisms, images and radiation datasets worldwide can be shared/reviewed on a same day basis using established de-identification and anonymization methods. Data storage post-trial completion can co-exist with digital pathomic and radiomic information in a single database coupled with patient specific outcome information and serve to move our translational science forward with nimble query elements and artificial intelligence to ask better questions of the data we collect and collate. This will be important moving forward to validate our process improvements at an enterprise level and support our science. We have to be thorough and complete in our data acquisition processes, however if we remain disciplined in our data management plan, our field can grow further and become more successful generating new standards of care from validated datasets.
... With the advent of the National Cancer Institute sponsored National Clinical Trials Network (NCTN), there is also the opportunity for further collaboration between pediatric and adult cooperative groups in the United States. Table 1 reviews some of these more recent studies from pediatric and adult cooperative groups (9)(10)(11)(12)(13)(14)(15)(16). The next generation of investigation builds upon these studies with incorporation of more biologically-targeted approaches. ...
Since the initial treatment with radiation therapy in the 1950s, the treatment of Hodgkin lymphoma has continued to evolve, balancing cure and toxicity. This approach has resulted in low rates of relapse and death and fewer short and late toxicities from the treatments used in pursuit of cure. To achieve this balance, the field has continued to progress into an exciting era where the advent of more targeted therapies such as brentuximab vedotin, immunotherapies such as PD-1 inhibitors, and chimeric antigen receptor T-cells (CAR-T) targeted at CD30 are changing the landscape. As in the past, cooperative group and international collaborations are key to continuing to drive the science forward. Increased focus on patient-reported outcomes can further contribute to the goal of improved outcomes by examining the impact on the individual patient in the acute phase of therapy and on long-term implications for survivors. The goals of this review are to summarize recent and current clinical trials including reduction or elimination of radiation, immunotherapies and biologically-targeted agents, and discuss the use of patient-reported outcomes to help discern directions for new therapeutic regimens and more individualized evaluation of the balance of cure and toxicity.
Classical Hodgkin lymphoma is a lymphoproliferative disease with a good prognosis mainly seen in young people. Nevertheless secondary malignancy, cardiac disease and infertility may affect the long survivors with significant impact on quality of life, morbidity and overall survival. In the last decades several treatment strategies were evaluated to reduce the toxicity of first line treatment such as avoiding radiotherapy or its reduction in terms of dosage and extension. Many trials including interim Positron Emission Tomography evaluation fail to compare efficacy between combined modality treatment versus chemotherapy alone in particular in early stage disease. In this review we analyze which subset of patients could take advantage from proton therapy in terms of toxicity and cost effectiveness.
Importance
Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain.
Objective
To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials.
Design, Setting, and Participants
For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children’s Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023.
Exposures
All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane.
Main Outcomes and Measures
Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease.
Results
The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines.
Conclusions and Relevance
In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.
Hodgkin lymphoma (HL) represents one of the more common cancers occurring in adolescent and young adults (AYAs) age 15-39 years. Despite a generally high cure rate, age-related differences in HL biology and the optimal therapeutic approaches including supportive care and risks for long-term adverse effects in the AYA population remain understudied. After an overview of HL epidemiology and biology in the AYA population, this review will cover frontline pediatric and adult treatment approaches. Recently completed and ongoing studies will foster harmonization of risk group definition and trial eligibility criteria across the AYA spectrum, enabling more rapid progress. In addition to treatment approaches, an evolving holistic care approach to AYA HL will result in enhanced understanding of unique challenges, and continued improved short- and long-term outcome for these patients.
Objectives
Bleomycin is a chemotherapeutic agent also used as a sclerosant for the management of vascular malformations. Although effective and with a low complication profile, the safety and monitoring necessary for this indication is still controversial. This study examines routine periprocedural laboratory results on a cohort of patients undergoing bleomycin sclerotherapy.
Methods
Retrospective chart review of prospectively collected data was performed on patients who underwent bleomycin sclerotherapy for vascular malformations from 2011 to 2018. Complete blood count and liver function were assessed before and after sclerotherapy.
Results
Forty-six patients were identified who underwent a total of 71 sclerotherapy sessions with bleomycin. A median dose of 5 U/m ² of bleomycin was used per procedure (8 U total). No difference between preprocedure and postprocedure values was detected for white blood cell count (7.7–7.9; P = .63) or absolute neutrophil count (4009–4414; P = .20). A nominal difference was found in hemoglobin (12.7–13.0; P = .001), hematocrit (37.0–38.6; P = .001), and platelet counts (278–302; P = .001). No patient had absolute neutrophil count levels below 500 cells/μL. On liver function tests, no change was detected for direct bilirubin (0.19–0.17; P = .4). A small decrease in total bilirubin (0.49–0.41; P = .004), aspartate aminotransferase (32.1–26.9; P < .001), and alanine aminotransferase (31.2–24.3; P < .001) was shown.
Conclusion
This study suggests that laboratory assessment of immune and liver function, as commonly performed in chemotherapy protocols, is not required following intralesional bleomycin sclerotherapy. Clinically relevant abnormalities are unlikely to be detected as demonstrated in this cohort of patients with vascular malformations.
Clinical trials have been the center of progress in modern medicine. In oncology, we are fortunate to have a structure in place through the National Clinical Trials Network (NCTN). The NCTN provides the infrastructure and a forum for scientific discussion to develop clinical concepts for trial design. The NCTN also provides a network group structure to administer trials for successful trial management and outcome analyses. There are many important aspects to trial design and conduct. Modern trials need to ensure appropriate trial conduct and secure data management processes. Of equal importance is the quality assurance of a clinical trial. If progress is to be made in oncology clinical medicine, investigators and patient care providers of service need to feel secure that trial data is complete, accurate, and well-controlled in order to be confident in trial analysis and move trial outcome results into daily practice. As our technology has matured, so has our need to apply technology in a uniform manner for appropriate interpretation of trial outcomes. In this article, we review the importance of quality assurance in clinical trials involving radiation therapy. We will include important aspects of institution and investigator credentialing for participation as well as ongoing processes to ensure that each trial is being managed in a compliant manner. We will provide examples of the importance of complete datasets to ensure study interpretation. We will describe how successful strategies for quality assurance in the past will support new initiatives moving forward.
Hypodense volumes (HDV) in mediastinal thymic lesions can be visualized in a computed tomography scan in Hodgkin lymphoma.
We analyzed staging CT scans of 1178 patients with mediastinal involvement from the EuroNet-PHL-C1 trial and explored correlations of HDV with patient characteristics, mediastinal tumor volume and progression-free survival.
HDV occurred in 350 of 1178 patients (29.7%), typically in larger mediastinal volumes. There were different patterns in appearance with single lesions found in 243 patients (69.4%), multiple lesions in 107 patients (30.6%). Well delineated lesions were found in 248 cases (70.1%), diffuse lesions were seen in 102 cases (29.1%).
Clinically, B symptoms occurred more often in patients with HDV (47.7% compared to 35.0% without HDV (p=0.039)) and patients with HDV tended to be in higher risk groups. Inadequate overall early-¹⁸F-FDG-PET-response was strongly correlated with the occurrence of hypodense lesions (p<0.001).
Patients with total HDV > 40ml (n=80) had a 5-year PFS of 79.6% compared to 89.7% (p=0.01) in patients with HDV < 40ml or no HDV. This difference in PFS is not caused by treatment group alone.
HDV is a common phenomenon in HL with mediastinal involvement Further research should be considered for validation as an independent prognostic factor for PFS.
The goal of therapy in pediatric Hodgkin lymphoma (HL) is to maximize overall survival while minimizing the morbidity of curative therapy. Key findings from recent Children's Oncology Group (COG) trials include: (i) superior event-free survival with the addition of brentuximab vedotin (Bv) in frontline regimens for high-risk disease, (ii) successful reduction in myeloablative regimens with demonstrated safety and efficacy of Bv and checkpoint inhibitor therapy in relapsed disease, and (ii) the potential to select a population that can be salvaged after relapse without receiving a stem cell transplant. The COG HL committee will lead a National cancer Institute National Clinical Trials Network phase 3 trial to evaluate the combination of Bv/nivolumab in early-stage disease. Ongoing advances in technology and blood biomarkers are increasing the ability to deliver biologically driven, personalized treatment for HL.
Purpose:
Clear indications do not exist for consolidative radiotherapy (CRT) in relapsed and refractory pediatric Hodgkin lymphoma (rrpHL). Increasing numbers of rrpHL patients are radiation naïve, as response-adapted front-line therapies omit CRT for favorable responses. We evaluated practice patterns among treating oncologists for rrpHL.
Methods and materials:
A survey developed by pediatric and radiation oncologists was distributed to Children's Oncology Group (COG) Hodgkin Lymphoma Committee members during the Fall 2021 COG meeting. Questions ascertained respondent specialty and annual rrpHL patient volumes. Respondents provided treatment recommendations for two cases. Case 1: 21-year-old female with stage IIB bulky mediastinal HL treated with ABVDx6 without initial radiotherapy with neck and mediastinal relapse and Deauville 4 (D4) response after 2 second-line chemotherapies. Case 1 was modified (modCase1) to a D2 response after second-line therapy. Case 2: 21-year-old female with non-bulky stage IIB disease treated with ABVDx6 without initial radiotherapy with splenic, mediastinal, and neck relapse and D4 activity in those sites after 2 second-line therapies. Descriptive statistics are presented.
Results:
20 (83%) pediatric hematologist/oncologists and 4 (17%) radiation oncologists completed the survey. After autologous stem cell transplant (ASCT) for Case 1, 58% recommended CRT followed by brentuximab vedotin (Bv) maintenance and 33% recommended involved-site radiotherapy (ISRT) alone. For modCase1, 63% would consider CRT instead of ASCT. With ASCT, 21% would recommend CRT to bulk and 38% to all sites at initial relapse. After ASCT for Case 2, 75% recommended ISRT followed by Bv and 17% ISRT alone.
Conclusions:
In a sample of predominantly pediatric-oncologist COG members, most respondents considered that CRT has a role for patients with radiation-naive rrpHL both for groups with D4 disease as well as D2 disease pre-ASCT.
Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare variant of Hodgkin lymphoma characterized by a persistent risk of relapse but an excellent overall survival. Historically, it was treated similarly to classic Hodgkin lymphoma, but efforts have been made to deintensify treatment due to risk of late toxicity associated with intensive therapy. For patients with completely resected stage IA NLPHL, no further treatment may be considered, particularly for pediatric patients. For those with stage I-II NLPHL without risk factors such as B symptoms, sites>2, or variant pattern histology, lower intensity treatment with radiotherapy or chemotherapy alone may be sufficient. However, combined modality therapy is a standard treatment for favorable and unfavorable risk stage I-II NLPHL associated with excellent progression-free and overall survival rates. For patients with advanced stage NLPHL, the optimal chemotherapy is not defined, but R-CHOP appears to be an effective treatment. Efforts to study NLPHL through multicenter collaborative efforts are crucial to develop evidence based and individualized treatments for patients with NLPHL.
Biology-guided radiation therapy is an emerging field whereby delivery of external beam radiotherapy incorporates biological/molecular imaging to inform radiation treatment. At present, there is evidence for the use of functional imaging such as PET to evaluate treatment response in patients both during and after radiation treatment as well as to provide a method of adapting or selecting patient-specific treatments. Examples in thoracic, gastrointestinal, and hematologic malignancies are provided. Improvements in PET metrics, thresholds, and novel radiotracers will further move this novel field forward.
Purpose:
We investigated the impact of central review of the interim fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) scan response (iPET) assessment on treatment allocation on the risk-based, response-adapted, Children's Oncology Group study AHOD1331 (ClinicalTrials.gov: 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 (RRL), 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 RRLs 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 by using the Cohen kappa statistic (κ; a κ >0.80 was considered very good agreement; >0.60-0.80, good agreement).
Results:
The concordance rate (514/573 [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 radiotherapy. 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 radiotherapy.
Conclusions:
Central review is integral to PET response-adapted clinical trials for children with Hodgkin lymphoma. Continued support of central imaging review and education on DS is needed.
Background:
Children and adolescents with early-stage classical Hodgkin lymphoma have a 5-year event-free survival of 90% or more with vincristine, etoposide, prednisone, and doxorubicin (OEPA) plus radiotherapy, but late complications of treatment affect survival and quality of life. We investigated whether radiotherapy can be omitted in patients with adequate morphological and metabolic responses to OEPA.
Methods:
The EuroNet-PHL-C1 trial was designed as a titration study and recruited patients at 186 hospital sites across 16 European countries. Children and adolescents with newly diagnosed stage IA, IB, and IIA classical Hodgkin lymphoma younger than 18 years of age were assigned to treatment group 1 to be treated with two cycles of OEPA (vincristine 1·5 mg/m2 intravenously, capped at 2 mg, on days 1, 8, and 15; etoposide 125 mg/m2 intravenously, on days 1-5; prednisone 60 mg/m2 orally on days 1-15; and doxorubicin 40 mg/m2 intravenously on days 1 and 15). If no adequate response (a partial morphological remission or greater and PET negativity) had been achieved after two cycles of OEPA, involved-field radiotherapy was administered at a total dose of 19·8 Gy (usually in 11 fractions of 1·8 Gy per day). The primary endpoint was event-free survival. The primary objective was maintaining a 5-year event-free survival rate of 90% in patients with an adequate response to OEPA without radiotherapy. We performed intention-to-treat and per-protocol analyses. The trial was registered at ClinicalTrials.gov (NCT00433459) and with EUDRACT, (2006-000995-33) and is completed.
Findings:
Between Jan 31, 2007, and Jan 30, 2013, 2131 patients were registered and 2102 patients were enrolled onto EuroNet-PHL-C1. Of these 2102 patients, 738 with early-stage disease were allocated to treatment group 1. Median follow-up was 63·3 months (IQR 60·1-69·8). We report on 714 patients assigned to and treated on treatment group 1; the intention-to-treat population comprised 713 patients with 323 (45%) male and 390 (55%) female patients. In 440 of 713 patients in the intention-to-treat group who had an adequate response and did not receive radiotherapy, 5-year event-free survival was 86·5% (95% CI 83·3-89·8), which was less than the 90% target rate. In 273 patients with an inadequate response who received radiotherapy, 5-year event-free survival was 88·6% (95% CI 84·8-92·5), for which the 95% CI included the 90% target rate. The most common grade 3-4 adverse events were neutropenia (in 597 [88%] of 680 patients) and leukopenia (437 [61%] of 712). There were no treatment-related deaths.
Interpretation:
On the basis of all the evidence, radiotherapy could be omitted in patients with early-stage classical Hodgkin lymphoma and an adequate response to OEPA, but patients with risk factors might need more intensive treatment.
Funding:
Deutsche Krebshilfe, Elternverein für Krebs-und leukämiekranke Kinder, Gießen, Kinderkrebsstiftung Mainz of the Journal Oldtimer Markt, Tour der Hoffnung, Menschen für Kinder, Mitteldeutsche Kinderkrebsforschung, Programme Hospitalier de Recherche Clinique, and Cancer Research UK.
Background:
The increasing number of childhood cancer survivors necessitates continued follow-up to monitor for long-term complications. Inequities in loss to follow-up for patients enrolled on pediatric clinical trials have not been well studied.
Methods:
This was a retrospective study of 21,084 patients residing in the United States enrolled on phase 2/3 and phase 3 Children's Oncology Group (COG) trials between January 1, 2000 and March 31, 2021. Rates of loss to follow-up to COG were evaluated using log-rank tests and multivariable Cox proportional hazards regression models with adjusted hazard ratios (HRs). Demographic characteristics included age at enrollment, race, ethnicity, and zip code level socioeconomic data.
Results:
Adolescent and young adult (AYA) patients 15-39 years old at diagnosis had an increased hazard of loss to follow-up compared to patients 0-14 years old (HR, 1.89; 95% confidence interval (CI), 1.76-2.02). In the overall cohort, non-Hispanic Blacks were found to have an increased hazard of loss to follow-up compared to non-Hispanic Whites (HR, 1.56; 95% CI, 1.43-1.70). Among AYAs, the highest loss to follow-up rates were among non-Hispanic Blacks (69.8% ± 3.1%), patients on germ cell tumor trials (78.2% ± 9.2%), and patients living in zip codes with a median household income ≤150% of the federal poverty line at diagnosis (66.7% ± 2.4%).
Conclusions:
AYAs, racial and ethnic minority patients, and those living in lower socioeconomic status areas had the highest rates of loss to follow-up among clinical trial participants. Targeted interventions are warranted to ensure equitable follow-up and improved assessment of long-term outcomes.
Plain language summary:
Little is known about disparities in loss to follow-up for pediatric cancer clinical trial participants. In this study, we found that participants who were adolescents and young adults when treated, those who identified as a racial and/or ethnic minority, or those residing in areas with lower socioeconomic status at diagnosis were associated with higher rates of loss to follow-up. As a result, the ability to assess their long-term survival, treatment-related health conditions, and quality of life is hindered. These findings suggest the need for targeted interventions to improve long-term follow-up among disadvantaged pediatric clinical trial participants.
Advances in the management of Hodgkin lymphoma in children, adolescents and young adult have resulted in survival outcomes exceeding 90%. The risk of late toxicity, however, remains a significant concern for survivors of HL and the focus of modern trials have been to advance cure rates while reducing long term toxicity. This has been accomplished through response-adapted treatment approaches and the incorporation of novel agents, many of which target the unique interaction between the Hodgkin and Reed Sternberg cells and the tumor microenvironment. In addition, an improved understanding of prognostic markers, risk stratification, and the biology of this entity in children and AYAs may allow us to further tailor therapy. This review focuses on the current management of HL in the upfront and relapsed settings, recent advances in novel agents that target HL and the tumor microenvironment, and promising prognostic markers that may help guide the future management of HL.
Clinical trials have become the primary mechanism to validate process improvements in oncology clinical practice. Over the past two decades there have been considerable process improvements in the practice of radiation oncology within the structure of a modern department using advanced technology for patient care. Treatment planning is accomplished with volume definition including fusion of multiple series of diagnostic images into volumetric planning studies to optimize the definition of tumor and define the relationship of tumor to normal tissue. Daily treatment is validated by multiple tools of image guidance. Computer planning has been optimized and supported by the increasing use of artificial intelligence in treatment planning. Informatics technology has improved, and departments have become geographically transparent integrated through informatics bridges creating an economy of scale for the planning and execution of advanced technology radiation therapy. This serves to provide consistency in department habits and improve quality of patient care. Improvements in normal tissue sparing have further improved tolerance of treatment and allowed radiation oncologists to increase both daily and total dose to target. Radiation oncologists need to define a priori dose volume constraints to normal tissue as well as define how image guidance will be applied to each radiation treatment. These process improvements have enhanced the utility of radiation therapy in patient care and have made radiation therapy an attractive option for care in multiple primary disease settings. In this chapter we review how these changes have been applied to clinical practice and incorporated into clinical trials. We will discuss how the changes in clinical practice have improved the quality of clinical trials in radiation therapy. We will also identify what gaps remain and need to be addressed to offer further improvements in radiation oncology clinical trials and patient care.
Pediatric lymphoma is the third most common childhood cancer, representing 15% of all pediatric malignancies. Evaluation of the extent of disease with imaging is essential for appropriate risk stratification and treatment planning, and has evolved extensively over the past several decades. At present, PET/CT plays a key role in the diagnostic evaluation of these patients, particularly for staging, treatment planning, and therapy response assessment. The vast majority of pediatric lymphomas are FDG avid and as a result, FDG PET/CT has a higher sensitivity for detecting sites of disease compared to conventional imaging modalities, as well as a higher sensitivity for detecting focal bone marrow lesions compared to standard bone marrow biopsy of the iliac crest. PET/CT can be used to identify early responders, helping to minimize overtreatment with intensive chemotherapy and radiotherapy, thereby reducing the risk of secondary malignancies and cardiovascular complications. Conversely, PET/CT can identify patients with an inadequate metabolic response during treatment, who can then benefit from earlier treatment intensification. A negative interim or end of treatment FDG PET/CT is highly predictive for a complete remission, although positive PET/CT scans, particularly at end of treatment, have a lower PPV and must be interpreted cautiously. Nevertheless, PET/CT is more accurate than conventional imaging alone, as well as in the case of conflicting results, such as residual lymph node enlargement and soft tissue lesions that can that can persist despite resolution of the underlying malignancy. For these reasons, FDG PET/CT has been incorporated into the standard diagnostic procedures for lymphoma staging and treatment response evaluation, using the visual Deauville 5-point scale and Lugano classification. In the future, innovations in low-dose ultrafast total-body PET/CT, increased use of PET/MR and incorporation of quantitative parameters from PET such as total metabolic tumor volume may allow even more precise prediction of response and personalized therapy while minimizing radiation exposure and adverse effects and complications of treatment.
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.).
Overview
Pediatric malignancies differ from those that occur in adults in their relative incidence, pathological type, clinical presentation, and prognosis. The last several decades of the twentieth century have been a period of enormous accomplishment in the field of pediatric cancer research and outcomes have steadily improved largely due to results from large well‐controlled clinical trials conducted by various cooperative groups at the national and international level. This article seeks to provide a broad overview of pediatric oncology, outlining the several common cancer types that are unique to the pediatric age group.
Objectives:
To compare the diagnostic and staging efficacy of PET/diagnostic-level CT (PET/DxCT) and PET/low-dose CT (PET/LDCT) in pretreatment pediatric lymphoma patients and to estimate the reduction of the CT effective dose in the PET/CT scan.
Methods:
One hundred and five pediatric patients who underwent total-body PET/CT examination were enrolled and divided into the DxCT group (n = 47) and LDCT group (n = 58) according to their dose levels. The sensitivity, specificity, PPV, and NPV of PET/DxCT and PET/LDCT for detecting the involvement of lymph node, spleen, bone marrow, and other extranodal organs in pretreatment lymphoma were compared. ROC analysis was performed to evaluate the integral efficiency. The staging accuracies based on PET/DxCT and PET/LDCT were also evaluated. Dosimetry was calculated for DxCT and LDCT, and the reduction in the effective dose was estimated.
Results:
In the diagnosis of nodal, splenic, bone marrow, and other extranodal involvement, the differences in sensitivity, specificity, PPV, and NPV between PET/LDCT and PET/DxCT were not significant (all p values ∈ [0.332, 1.000]). Both modalities had accuracies above 90% and the ROC analysis indicated good or high efficiency in diagnosing all patterns of lymphoma involvement. PET/LDCT and PET/DxCT each had a staging accuracy of 89.7% and 89.4%, respectively. LDCT had a comparable image quality score with DxCT, with a significant increase in noise (p < 0.001) and a 66.1% reduction in effective dose.
Conclusions:
PET/LDCT allowed for a 66.1% CT effective dose reduction compared to PET/DxCT in pediatric lymphoma patients without compromising the diagnostic and staging efficacy.
Key points:
• Pediatric lymphoma patients can benefit from a reduced effective dose of PET/CT. • This retrospective study showed that the diagnostic and staging efficacies of PET/low-dose CT are comparable to those of PET/diagnostic-level CT, both with satisfactory efficiency in diagnosing all patterns of lymphoma involvement. • PET/low-dose CT allowed for a 66.1% CT effective dose reduction compared to PET/diagnostic-level CT.
Hodgkin lymphoma (HL) and non‐Hodgkin lymphoma (NHL) are both malignancies originating in the lymphatic system and both affect children, but many features differ considerably, impacting workup and management. This paper provides consensus‐based imaging recommendations for evaluation of patients with HL and NHL at diagnosis and response assessment for both interim and end of therapy (follow‐up).
Clinical trials in radiation oncology have improved our translational science and patient care. All patients referred to departments of radiation oncology can be invited to participate in a clinical trial with multiple venues. Study endpoints can include intradepartmental endpoints to improve workflow and patient access as well as interdepartmental clinical translational trials that include the National Clinical Trials Network (NCTN) and industry. The quality of the trial is important to trial outcome and influences interpretation of the results of the study and how the results can be applied to patient care moving forward. Clinical trials in radiation oncology to date have accomplished much, however many important questions remain as patient care matures and systemic therapies become more sophisticated and associated with specific biomarkers and cellular expression products. In this chapter we review the history of clinical trials in radiation oncology and review the current status of the structure of quality assurance in clinical trials. We will review unanswered questions and areas to study in each disease area and how to design strategy for trials to address modern unmet needs in our discipline.
Purpose: The intrusive thoughts of cancer diagnosis, treatments, re-experiencing, and avoidance associated with post-traumatic stress symptoms (PTSS) can negatively affect Hodgkin lymphoma (HL) survivors. This study investigates the associations between experiences and beliefs and PTSS among adolescent survivors of intermediate-risk HL treated on the Children's Oncology Group (COG) AHOD0031 study. Methods: COG AHOD0031 participants completed self-report surveys at end of therapy concerning post-treatment medical conditions, activity limitations, fatigue, future concerns, exercise, and PTSS. Results: One thousand one hundred ten of 1721 participants in AHOD0031 completed the first survey at a median of 6.7 months post-diagnosis (interquartile range: 5.3-11.5 months), and of these, 736 (66.3%) completed a second survey at a median of 12.4 (10.1-17.6) months following the first. The mean PTSS score (ranging from 0 to 20) was 5.5 (standard deviation [SD] = 5.1) on survey 1 and 4.4 (SD = 4.8) on survey 2. Increased fatigue (odds ratio [OR] = 1.14, p < 0.01), concerns for the future (OR = 1.13, p < 0.01), activity limitations (OR = 1.05, p < 0.01), and relapse history (OR = 2.18, p < 0.05) were associated with higher PTSS scores in the initial survey. Increased fatigue (OR = 1.16, p < 0.01), concerns for the future (OR = 1.14, p < 0.01), activity limitations (OR = 1.05, p < 0.05), and higher PTSS scores on the first survey (OR = 1.19, p < 0.01) were associated with higher PTSS scores in the subsequent survey. Longer time since diagnosis (OR = 0.85, p < 0.05; OR = 0.84, p < 0.05) was associated with lower PTSS scores on both surveys. Conclusions: Based on our findings, future research should examine the onset and trajectory of PTSS among HL survivors, focusing on early recognition and intervention to improve quality of life.
Résumé
Notre discipline est en perpétuelle évolution technologique. Sur le plan thérapeutique, des changements majeurs en termes de prise en charge, alimentés par les nombreux essais prospectifs qui voient le jour au sein de notre communauté particulièrement dynamique en matière de recherche, permettent également d’optimiser la prise en charge des patients au quotidien. L’article présenté ici a choisi de se concentrer sur certaines localisations, à savoir la stéréotaxie, l’oncologie pédiatrique, la cancérologie thoracique, gynécologique basse et haute, ainsi que sur l’oncologie de la sphère urogénitale afin de faire le point sur les dernières données de la littérature et particulièrement les grands essais ayant marqué la ou les dernières années en oncologie-radiothérapie.
Integrated 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG) positron emission tomography (PET)/magnetic resonance (MR) imaging can provide "one stop" local tumor and whole-body staging in one session, thereby streamlining imaging evaluations and avoiding duplicate anesthesia in young children. 18F-FDG PET/MR scans have the benefit of lower radiation, superior soft tissue contrast, and increased patient convenience compared to 18F-FDG PET/computerized tomography scans. This article reviews the 18F-FDG PET/MR imaging technique, reporting requirements, and imaging characteristics of the most common pediatric bone tumors, including osteosarcoma, Ewing sarcoma, primary bone lymphoma, bone and bone marrow metastases, and Langerhans cell histiocytosis.
Little is known about the prevalence of pediatric radiation oncologists treating patients off study according to Children's Oncology Group (COG) trials before data are available regarding toxicity and efficacy of novel radiotherapy regimens. We conducted a 12‐question survey of 358 pediatric radiation oncologists to characterize practice patterns regarding ongoing and completed COG protocols off study. With 130 responses (40.3%), the prevalence of providing treatment per protocol, but off study, before data are available in abstract or peer‐reviewed form varied from 9.1% (for ACNS1422) to 88.1% (for AHOD1331). Future studies are needed to understand the effects of these practice patterns on outcomes.
Patients with therapy‐refractory or high‐risk relapsed classical Hodgkin lymphoma are typically treated with the high‐dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) to consolidate the response to salvage therapy. The combination of brentuximab vedotin with gemcitabine has recently been shown to be an effective and safe salvage regimen. While the majority of patients with complete responses to this regimen ultimately underwent HDC/ASCT consolidation, four subjects, reported herein, achieved durable complete remissions lasting more than 4 years after the study treatment but without ASCT consolidation. Further investigation of treatment strategies incorporating targeted agents may allow omission of HDC/ASCT for select patients.
Background:
Adriamycin, bleomycin, vinblastine, dacarbazine (ABVD), the de facto standard of care in adult-onset Hodgkin lymphoma (HL), has not been directly compared to doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide (ABVE-PC), a pediatric-aimed regimen designed to reduce late effects. We aimed to describe the single-institution experience of using both regimens in patients with pediatric HL.
Methods:
This retrospective cohort study evaluated a total of 224 patients diagnosed with HL between 1999 and 2018 at Children's Hospital Los Angeles (CHLA), of which 93 patients were eligible having received ABVD (n = 46) or ABVE-PC (n = 47) chemotherapy as their initial treatment. Descriptive analyses were performed using the Student's t-test or Fisher's exact test. Survival analysis used the Kaplan-Meier method. Events included death, relapse, and secondary malignancy. We also describe the use of radiation therapy, pulmonary toxicity, and cardiomyopathy determined by shortening fraction <29%. Analyses followed an intention-to-treat principle.
Results:
There was no difference in baseline characteristics between the patients receiving ABVE-PC or ABVD in regard for stage, risk group, or prognostic variables, such as the presence or absence of "B" symptoms, bulky disease, and extra-nodal involvement. A greater proportion of patients treated with ABVE-PC received consolidating external beam radiation treatment (XRT) either by randomization or by response compared to ABVD (59.6% vs. 32.6%, respectively, p = .01). While not statistically significant, response to therapy, assessed by positron emission tomography/computerized tomography (PET/CT) where available, mirrored the use for radiation (rapid response 58.3% vs. 90.0%, n = 34, p = .11). The median dose of anthracycline (doxorubicin) was the same in patients receiving ABVE-PC versus ABVD (200 vs. 200 mg/m2 , interquartile range 200-250 vs. 200-300 mg/m2 , p = .002). There was no difference in event-free survival (p = .63) or overall survival (p = .37) with a median follow-up length of 3.9 years.
Conclusions:
ABVD and ABVE-PC achieved similar survival outcomes in our single-institution cohort.
Resumen
Objetivo
Este estudio retrospectivo tuvo como objetivo evaluar el papel de los parámetros metabólicos de la ¹⁸F-FDG PET/TC en el linfoma linfoblástico pediátrico (LBL).
Métodos
Treinta pacientes con LBL se sometieron a 42 exploraciones. Los parámetros metabólicos, que incluyeron el valor máximo de captación estandarizado (SUVmax), el volumen tumoral metabólico total (TMTV) y la glucólisis de lesión total (TLG), se midieron en la PET/TC basal. Se realizaron análisis univariantes y multivariantes de la supervivencia para evaluar su valor pronóstico. Doce pacientes se sometieron a PET/TC después del régimen de reinducción, y se calcularon la sensibilidad, la especificidad, el valor predictivo positivo (VPP), el valor predictivo negativo (VPN) y la precisión de la PET/TC para predecir la recaída.
Resultados
Los pacientes con estadio IV tuvieron una TMTV más alta que los que tenían un estadio III (p = 0,031). Además, los pacientes con T-LBL o afectación mediastínica tenían una TMTV y TLG altos (p < 0,05). No hubo diferencias significativas en los parámetros metabólicos de la PET/TC entre los pacientes con diferente evolución (p > 0,05). Los niños con una TMTV baja (< 242,91 cm³) tuvieron una mejor EFS a los 3 años comparados con aquellos con una TMTV elevada (88.9% vs. 56,3%; p = 0,036). El SUVmax y el TLG no fueron predictivos de la EFS (p = 0,874; p = 0,152). Sin embargo, ninguno de los parámetros metabólicos de la PET/TC basales fueron factores pronósticos independientes para los resultados del LBL pediátrico. La PET/TC realizada después del régimen de reinducción presentó una mayor sensibilidad (50% vs. 0%) y VPN (90% vs. 83,3%) para predecir la recaída que la TC sola.
Conclusiones
Los parámetros metabólicos de la PET/TC de referencia no fueron predictivos de los resultados en los niños con LBL. La PET/TC realizada después del régimen de reinducción tuvo una mejor sensibilidad y VPN que la TC sola, y una exploración negativa podría ser un indicador fiable de remisión sostenida.
While treatment protocols for Hodgkin lymphoma (HL) are well established, there is no literature available to guide therapy or estimate prognosis for patients with Fontan physiology who develop HL. The physiology of a Fontan procedure can result in the inability to tolerate chemotherapy toxicities, supportive care, and infection. We present a series of three patients with Fontan physiology who were treated for HL and discuss their clinical course and treatment.
Background and purpose
With high survival rates for pediatric Hodgkin lymphoma (HL), attention has turned to minimizing treatment-related morbidity and mortality. Chemotherapy and dose of radiation to organs at risk (OARs) contribute to elevated risks of secondary malignancy and cardiopulmonary disease. We sought to characterize the radiation dose to OARs, toxicities, and outcomes for pediatric HL patients treated with proton therapy (PT).
Materials and methods
Fifty patients aged 11-21 with HL consecutively treated with PT were evaluated 1-2 months following completion of PT and every 6 months thereafter. Acute and late toxicities were captured retrospectively using CTCAE v5. Patterns of relapse were characterized, and survival was assessed using Kaplan-Meier method.
Results
Most (47, 94%) patients received PT to the mediastinum. Median mean heart dose was 4.3 Gy (RBE) and median bilateral lung V20Gy was 5.8%. Median integral dose was 1.7 Gy. For the 27 female patients, a median mean dose of 0.4 and 0.3 Gy (RBE) was delivered to ipsilateral and contralateral breast tissue, respectively. No on-treatment grade 3-5 toxicities were seen. At a median follow-up of 5.3 years, no PT-related grade 3-5 toxicities or secondary malignancies developed. Five patients relapsed at a median time of 9.2 months after PT (range 2.5-24.9 months; 5-year recurrence free survival 90%). Recurrences were both in- and out-of-field in all 5 cases with no marginal failures. All relapsed patients were successfully salvaged (5-year overall survival 100%).
Conclusion
For pediatric HL patients, proton treatment resulted in marked dose sparing of OARs with low rates of toxicity, no marginal failures, and excellent 5-year survival.
Primary cardiac tumors are quite rare in children, and only a small portion are malignant. Presenting symptoms may be nonspecific, often mimicking those of congestive heart failure, pulmonary embolism, and syncope. Due to location and potential detrimental outcomes, diagnosis and management are of the utmost importance. Secondary and metastatic cardiac tumors are more frequent in comparison to primary tumors of the heart. Primary Hodgkin lymphoma of the heart is exceedingly rare with no standardized approach for treatment. Here we describe a case of an adolescent girl with primary cardiac Hodgkin lymphoma.
Background
Adolescents with Hodgkin lymphoma have worse disease outcomes than children. Whether these differences persist within clinical trials is unknown. We examined survival, by age, in patients receiving response-adapted therapy for Hodgkin lymphoma on Children's Oncology Group (COG) trials.
Methods
Patients (aged 1–21 years) diagnosed with classical Hodgkin lymphoma and enrolled between Sept 23, 2002, and Jan 19, 2012, on one of three phase 3 COG trials in the USA and Canada were eligible for inclusion. The three COG trials were defined by risk group according to Ann Arbor stage, B-symptoms, and bulk (AHOD0431 [low risk; NCT00302003], AHOD0031 [intermediate risk; NCT00025259], or AHOD0831 [high risk; NCT01026220]). The outcomes of this study were event-free survival (death, relapse, or subsequent neoplasm) and overall survival. Cox proportional hazards models estimated survival, adjusting for disease and treatment factors both overall and in patients with mixed cellularity or non-mixed cellularity (nodular sclerosing and not-otherwise-specified) disease.
Findings
Of 2155 patients enrolled on the three trials, 1907 (88·4%; 968 [50·8%] male and 939 [49·2%] female; 1227 [64·3%] non-Hispanic White) were included in this analysis. After a median follow-up of 7·4 years (IQR 4·3–10·2), older patients (aged ≥15 years) had worse unadjusted 5-year event-free survival (80% [95% CI 78–83]) than did younger patients (aged <15 years; 86% [83–88]; HR 1·38 [1·11–1·71]; p=0·0038). Older patients also had worse unadjusted 5-year overall survival than did younger patients (96% [95% CI 95–97] vs 99% [98–99]; HR 2·50 [1·41–4·45]; p=0·0012). In patients with non-mixed cellularity histology, older patients had a significantly increased risk of having an event than did younger patients with the same histology (HR 1·32 [1·03–1·68]; p=0·027). Older patients with mixed cellularity had significantly worse 5-year event-free survival than did younger patients in unadjusted (77% [95% CI 65–86] for older patients vs 94% [88–97] for younger patients; HR 2·93 [1·37–6·29]; p=0·0039) and multivariable models (HR 3·72 [1·56–8·91]; p=0·0032). Overall, older patients were more likely to die than younger patients (HR 3·08 [1·49–6·39]; p=0·0025).
Interpretation
Adolescents (≥15 years) treated on COG Hodgkin lymphoma trials had worse event-free survival and increased risk of death compared with children (<15 years). Our findings highlight the need for prospective studies to examine tumour and host biology, and to test novel therapies across the age spectrum.
Funding
National Institutes of Health, St Baldrick's Foundation, and Lymphoma Research Foundation.
Purpose:
In 1995, the Children's Cancer Group (CCG) opened a trial for patients with Hodgkin's lymphoma evaluating whether low-dose involved-field radiation therapy (IFRT) improved event-free survival (EFS) for patients achieving a complete response after chemotherapy. We present the long-term study outcome using final data through March 2007.
Patients and methods:
Between January 1995 and December 1998, 826 eligible patients were enrolled onto CCG 5942. Four hundred ninety-eight patients achieving an initial complete response to chemotherapy were randomly assigned to receive IFRT or no further therapy. EFS and overall survival (OS) were assessed from the date of study entry or random assignment, as appropriate.
Results:
Ten-year EFS and OS rates for the entire cohort were 83.5% and 92.5%, respectively. In an as-treated analysis for randomly assigned patients, the 10-year EFS and OS rates were 91.2% and 97.1%, respectively, for IFRT and 82.9% and 95.9%, respectively, for no further therapy. For EFS and OS comparisons, P = .004 and P = .50, respectively. Bulk disease, "B" symptoms, and nodular sclerosis histology were risk factors for inferior EFS.
Conclusion:
With a median follow-up of 7.7 years, IFRT produced a statistically significant improvement in EFS but no improvement in OS. For individual patients, the relative risks of relapse versus late effects of IFRT must be considered. Patient and disease characteristics and early response assessment will aid in deciding which patients are most likely to benefit from IFRT.
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 Children's 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.
The contribution of specific cancer therapies, comorbid medical conditions, and host factors to mortality risk after pediatric Hodgkin lymphoma (HL) is unclear. We assessed leading morbidities, overall and cause-specific mortality, and mortality risks among 2742 survivors of HL in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study of survivors diagnosed from 1970 to 1986. Excess absolute risk for leading causes of death and cumulative incidence and standardized incidence ratios of key medical morbidities were calculated. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of risks for overall and cause-specific mortality. Substantial excess absolute risk of mortality per 10,000 person-years was identified: overall 95.5; death due to HL 38.3, second malignant neoplasms 23.9, and cardiovascular disease 13.1. Risks for overall mortality included radiation dose ≥ 3000 rad ( ≥ 30 Gy; supra-diaphragm: HR, 3.8; 95% CI, 1.1-12.6; infradiaphragm + supradiaphragm: HR, 7.8; 95% CI, 2.4-25.1), exposure to anthracycline (HR, 2.6; 95% CI, 1.6-4.3) or alkylating agents (HR, 1.7; 95% CI, 1.2-2.5), non-breast second malignant neoplasm (HR, 2.6; 95% CI 1.4-5.1), or a serious cardiovascular condition (HR, 4.4; 95% CI 2.7-7.3). Excess mortality from second neoplasms and cardiovascular disease vary by sex and persist > 20 years of follow-up in childhood HL survivors.
Vincristine, etoposide, prednisone, and doxorubicin (OEPA)-cyclophosphamide, vincristine, prednisone, and dacarbazine (COPDAC) is derived from standard vincristine, procarbazine, prednisone, and doxorubicin (OPPA)-cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) chemotherapy by replacing procarbazine with etoposide and dacarbazine for a potentially less gonadotoxic regimen for boys with Hodgkin's lymphoma (HL).
Five hundred seventy-three pediatric patients with classical HL were enrolled onto the German Society of Pediatric Oncology and Hematology-Hodgkin's Disease (GPOH-HD) -2002 study between November 2002 and December 2005. Boys received two courses of OEPA and girls received two courses of OPPA for induction. Treatment group (TG) -2 (intermediate stages) and TG-3 (advanced stages) patients received further two or four cycles COPP (girls) or COPDAC (boys), respectively. After chemotherapy all patients received involved-field irradiation with 19.8 Gy, except for patients with early-stage disease (TG-1) in complete remission.
Five hundred seventy-three patients (287 males and 286 females) were less than 18 years old and fulfilled all inclusion criteria; 195 patients (34.0%) were allocated to TG-1, 139 (24.3%) were allocated to TG-2, and 239 (41.7%) were allocated to TG-3. Toxicity of OEPA-COPDAC was tolerable overall. Hematotoxicity was more pronounced with OEPA than OPPA, whereas it was less pronounced with COPDAC compared with COPP. The median observation time was 58.6 months. Overall survival and event-free survival (EFS) rates (+/- SE) at 5 years were 97.4% +/- 0.7% and 89.0% +/- 1.4%, respectively. In TG-1, overall EFS was 92.0% +/- 2.0%. EFS of patients without irradiation (93.2% +/- 3.3%) was similar to that of irradiated patients (91.7% +/- 2.5%), confirming results of the previous GPOH-HD-95 study. In TG-2+3, EFS did not significantly differ between boys and girls (90.2% +/- 2.3 v 84.7% +/- 2.7, respectively; P = .12).
In TG-2+3, results in boys and girls are superimposable. OPPA-COPP and OEPA-COPDAC seem to be exchangeable regimens in intermediate- and advanced-stage classical HL in pediatric patients.
Current treatment strategies for Hodgkin lymphoma result in excellent survival but often confer significant long-term toxicity. We designed ABVE-PC (doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) to (1) enhance treatment efficacy by dose-dense drug delivery and (2) reduce risk of long-term sequelae by response-based reduction of cumulative chemotherapy. Efficient induction of early response by dose-dense drug delivery supported an early-response-adapted therapeutic paradigm. The 216 eligible patients were younger than 22 years with intermediate- or high-risk Hodgkin lymphoma. ABVE-PC was administered every 21 days. Rapid early responders (RERs) to 3 ABVE-PC cycles received 21 Gy radiation to involved regions; RER was documented in 63% of patients. Slow early responders received 2 additional ABVE-PC cycles before 21 Gy radiation. Five-year event-free-survival was 84%: 86% for the RER and 83% for the slow early responders (P = .85). Only 1% of patients had progressive disease. Five-year overall survival was 95%. With this regimen, cumulative doses of alkylators, anthracyclines, and epipodophyllotoxins are below thresholds usually associated with significant long-term toxicity. ABVE-PC is a dose-dense regimen that provides outstanding event-free survival/overall survival with short duration, early-response-adapted therapy.
In the HD15 trial of the German Hodgkin Study Group, the negative predictive value (NPV) of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose in advanced-stage Hodgkin lymphoma (HL) was evaluated. A total of 817 patients were enrolled and randomly assigned to receive BEACOPP-based chemotherapy. After completion of chemotherapy, residual disease measuring more than or equal to 2.5 cm in diameter was assessed by PET in 311 patients. The NPV of PET was defined as the proportion of PET(-) patients without progression, relapse, or irradiation within 12 months after PET review panel. The progression-free survival was 96% for PET(-) patients (95% confidence interval [CI], 94%-99%) and 86% for PET(+) patients (95% CI, 78%-95%, P = .011). The NPV for PET in this analysis was 94% (95% CI, 91%-97%). Thus, consolidation radiotherapy can be omitted in PET(-) patients with residual disease without increasing the risk for progression or early relapse compared with patients in complete remission. The impact of this finding on the overall survival at 5 years must be awaited. Until then, response adapted therapy guided by PET for HL patients seems to be a promising approach that should be further evaluated in clinical trials. This trial is registered at http://isrctn.org study as #ISRCTN32443041.
Early adjustment of treatment may benefit the patient. In order to guide treatment adjustment, use of early response (ER) or early complete response (ECR), judged after the few initial cycles of chemotherapy, is common in pediatric and also adult Hodgkin's and non-Hodgkin's studies. Paradoxically, almost no data support this strategy.
The influence of ECR on outcome was evaluated in three series of advanced Hodgkin's disease (HD), leading to a series of questions.
The 1982 EORTC study assessed prospectively the time frame needed to reach an apparent complete response (CR) through repeated tumor measurements. In patients assessed at mid-treatment before the fifth cycle, both 15 year freedom from progression (FFP) and overall survival (OS) were superior in ECR patients compared with other patients continued on the same treatment (61% versus 37%; P < 0.001). A series of questions arise from these observations. Question 1: is the shortening of treatment detrimental? In a randomized Swedish trial, in one arm treatment was shortened in patients evaluated from the fifth cycle as ECR as compared with the standard eight cycles arm, 10 year cause-specific-survival (CSS) was 53 versus 69% [not significant (ns)]; 10 year OS 49% versus 58% (ns). Conversely, in the EORTC 20884 study, ECR patients given only six cycles did as well as patients entering CR later and, for this reason, given eight cycles (identical 6 year event-free survival 75%). Question 2: is early treatment adaptation in patients who failed to reach ER beneficial? In the French MDH 90 trial, 15% of children failed to reach ECR after four cycles; in these children only, anthracyclines plus alkylating agents were given and the dose of radiotherapy increased, improving the results observed in the previous trial. In the EORTC 20884 study, patients who failed to reach an ECR were switched earlier to involved field RT: their results matched those of ECR patients, at the difference of the previous trial. Question 3: is ER a predicting factor that can be used with any type of treatment? Probably not, based on the German Hodgkin's Lymphoma Study Group trial HD 9: ECR is highly dependent on specific interval from treatment start and on treatment intensity.
More general questions stem from these results. Question 4: is the definition of ER secured? With conventional imaging, the different methods for response assessment at end treatment also lead to different response rates; the assessment in the middle of treatment itself and the use of newer imaging techniques may further increase the variation. Indeed, question 5 is: is ER a concept based on any biology? Correlation to markers, 99mTc uptake, PET and hematological tolerance might help to pinpoint how and why ER represents a surrogate for final outcome.
ER is a surrogate for final outcome, reflecting both tumor burden and activity. This predictability may, and possibly should, impact on treatment.
Starting from November 2001, 260 newly diagnosed patients with Hodgkin's lymphoma (HL) were consecutively enrolled in parallel Italian and Danish prospective trials to evaluate the prognostic role of an early interim 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) scan and the International Prognostic Score (IPS) in advanced HL, treated with conventional ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) therapy.
Most patients (n = 190) presented with advanced disease (stages IIB through IVB), whereas 70 presented in stage IIA with adverse prognostic factors. All but 11 patients were treated with standard ABVD therapy followed by consolidation radiotherapy in case of bulky presentation or residual tumor mass. Conventional radiologic staging was performed at baseline. FDG-PET scan was performed at baseline and after two courses of ABVD (PET-2). No treatment change was allowed on the basis of the PET-2 results.
After a median follow-up of 2.19 years (range, 0.32 to 5.18 years), 205 patients were in continued complete remission and two patients were in partial remission. Forty-three patients progressed during therapy or immediately after, whereas 10 patients relapsed. The 2-year progression-free survival for patients with positive PET-2 results was 12.8% and for patients with negative PET-2 results was 95.0% (P < .0001). In univariate analysis, the treatment outcome was significantly associated with PET-2 (P < .0001), stage IV (P < .0001), WBC more than 15,000 (P < .0001), lymphopenia (P < .001), IPS as a continuous variable (P < .0001), extranodal involvement (P < .0001), and bulky disease (P = .012). In multivariate analyses, only PET-2 turned out to be significant (P < .0001).
PET-2 overshadows the prognostic value of IPS and emerges as the single most important tool for planning of risk-adapted treatment in advanced HL.
PURPOSETo determine whether the addition of low-dose total-nodal irradiation (TNI) in pediatric patients with advanced-stage Hodgkin's disease who have received eight cycles of alternating mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) will improve the event-free survival (EFS) and overall survival (OS) when compared with patients who have received chemotherapy only.PATIENTS AND METHODS
At diagnosis, 183 children and adolescents with stages IIB, IIIA2, IIIB, and IV Hodgkin's disease were randomized to receive eight cycles of alternating MOPP-ABVD with or without low-dose TNI.RESULTSOf 183 patients, four were rendered ineligible before treatment was initiated. One hundred sixty-one of 179 patients (90%) were in complete remission (CR) at the completion of eight cycles of alternating MOPP-ABVD; 81 were in the chemotherapy-only group and proceeded to observation off therapy, whereas 80 of 161 were to receive combined modality t...
The Ann Arbor classification for describing the stage of Hodgkin's disease at initial presentation has formed the basis upon which treatment is selected and has allowed comparison of results achieved by different investigators for almost two decades. A meeting was convened to review the classification and modify it in the light of experience gained in its use and new techniques for evaluating disease. It was concluded that the structure of the classification be maintained. It was particularly recommended: (1) that computed tomography (CT) be included as a technique for evaluating intrathoracic and infradiaphragmatic lymph nodes; (2) that the criteria for clinical involvement of the spleen and liver be modified to include evidence of focal defects with two imaging techniques and that abnormalities of liver function be ignored; (3) that the suffix 'X' to designate bulky disease (greater than 10 cm maximum dimension) be introduced; and (4) that a new category of response to therapy, unconfirmed/uncertain com...
Hodgkin lymphoma is highly curable but associated with significant late effects. Reduction of total treatment would be anticipated to reduce late effects. This aim of this study was to demonstrate that a reduction in treatment was possible without compromising survival outcomes.
Protocol P9426, a response-dependent and reduced treatment for low risk Hodgkin lymphoma (stages I, IIA, and IIIA(1) ) was designed in 1994 based on a previous pilot project. Patients were enrolled from October 15, 1996 to September 19, 2000. Patients were randomized to receive or not receive dexrazoxane and received two cycles of chemotherapy consisting of doxorubicin, bleomycin, vincristine, and etoposide. After two cycles, patients were evaluated for response. Those in complete response (CR) received 2,550 cGy of involved field radiation therapy (IFRT). Patient with partial response or stable disease, received two more cycles of chemotherapy and IFRT at 2,550 cGy.
There were 294 patients enrolled, with 255 eligible for analysis. The 8-year event free survival (EFS) between the dexrazoxane randomized groups did not differ (EFS 86.8 ± 3.1% with DRZ, and 85.7 ± 3.3% without DRZ (P = 0.70). Forty-five percent of patients demonstrated CR after two cycles of chemotherapy. There was no difference in EFS by histology, rapidity of response, or number of cycles of chemotherapy. Six of the eight secondary malignancies in this study have been previously reported.
Despite reduced therapy and exclusion of most patients with lymphocyte predominant histology, EFS and overall survival are similar to other reported studies. The protocol documents that it is safe and effective to reduce therapy in low-risk Hodgkin lymphoma based on early response to chemotherapy with rapid responding patients having the same outcome as slower-responding patients when given 50% of the chemotherapy. Pediatr Blood Cancer 2012; 59: 1259-1265. © 2012 Wiley Periodicals, Inc.
As pediatric Hodgkin lymphoma (HL) survival rates approach > 95%, treatment decisions are increasingly based on minimizing late effects. Using a model-based approach, we explored whether the addition of radiotherapy contributes to improved overall long-term survival. We developed a state-transition model to simulate the lifetime HL clinical course, and we compared 2 treatment strategies: chemotherapy alone (CT) and chemoradiotherapy (CRT). Data on HL relapse, late recurrence, and excess second cancer and cardiac late-effects mortality were estimated from the published literature and databases. Outcomes included conditional life expectancy, cause-specific mortality, and proportion alive at age 50. For a hypothetical cohort of HL patients (diagnosis age 15), conditional life expectancy was 57.2 years with CT compared with 56.4 years with CRT. Estimated lifetime HL mortality risk was 3.6% with CT versus 2.2% with CRT. In contrast, combined risk of excess late-effects mortality was lower for CT (1.8% vs 7.4% with CRT). Among those alive at age 50, only 9.2% of those initially treated with CT were at risk for radiation-related late effects (100% for CRT). Initial treatment with CT may be associated with longer average per-person life expectancy. These results support the need for careful consideration of the risk-benefit profile of radiation as frontline therapy in pediatric patients.
More than 90% of children with favorable-risk Hodgkin lymphoma can achieve long-term survival, yet many will experience toxic effects from radiation therapy. Pediatric oncologists strive for maintaining excellent cure rates while minimizing toxic effects.
To evaluate the efficacy of 4 cycles of vinblastine, Adriamycin (doxorubicin), methotrexate, and prednisone (VAMP) in patients with favorable-risk Hodgkin lymphoma who achieve a complete response after 2 cycles and do not receive radiotherapy.
Multi-institutional, unblinded, nonrandomized single group phase 2 clinical trial to assess the need for radiotherapy based on early response to chemotherapy. Eighty-eight eligible patients with Hodgkin lymphoma stage I and II (<3 nodal sites, no B symptoms, mediastinal bulk, or extranodal extension) enrolled between March 3, 2000, and December 9, 2008. Follow-up data are current to March 12, 2012.
The 47 patients who achieved a complete response after 2 cycles received no radiotherapy, and the 41 with less than a complete response were given 25.5 Gy-involved-field radiotherapy.
Two-year event-free survival was the primary outcome measure. A 2-year event-free survival of greater than 90% was desired, and 80% was considered to be unacceptably low.
Two-year event-free survival was 90.8% (95% CI, 84.7%-96.9%). For patients who did not require radiotherapy, it was 89.4% (95% CI, 80.8%-98.0%) compared with 92.5% (95% CI, 84.5%-100%) for those who did (P = .61). Most common acute adverse effects were neuropathic pain (2% of patients), nausea or vomiting (3% of patients), neutropenia (32% of cycles), and febrile neutropenia (2% of patients). Nine patients (10%) were hospitalized 11 times (3% of cycles) for febrile neutropenia or nonneutropenic infection. Long-term adverse effects after radiotherapy were asymptomatic compensated hypothyroidism in 9 patients (10%), osteonecrosis and moderate osteopenia in 2 patients each (2%), subclinical pulmonary dysfunction in 12 patients (14%), and asymptomatic left ventricular dysfunction in 4 patients (5%). No second malignant neoplasms were observed.
Among patients with favorable-risk Hodgkin lymphoma and a complete early response to chemotherapy, the use of limited radiotherapy resulted in a high rate of 2-year event-free survival.
clinicaltrials.gov Identifier: NCT00145600.
In lifetesting, medical follow-up, and other fields the observation of the time of occurrence of the event of interest (called a death) may be prevented for some of the items of the sample by the previous occurrence of some other event (called a loss). Losses may be either accidental or controlled, the latter resulting from a decision to terminate certain observations. In either case it is usually assumed in this paper that the lifetime (age at death) is independent of the potential loss time; in practice this assumption deserves careful scrutiny. Despite the resulting incompleteness of the data, it is desired to estimate the proportion P(t) of items in the population whose lifetimes would exceed t (in the absence of such losses), without making any assumption about the form of the function P(t). The observation for each item of a suitable initial event, marking the beginning of its lifetime, is presupposed.
For random samples of size N the product-limit (PL) estimate can be defined as follows: List and label the N observed lifetimes (whether to death or loss) in order of increasing magnitude, so that one has \(0 \leqslant t_1^\prime \leqslant t_2^\prime \leqslant \cdots \leqslant t_N^\prime .\) Then \(\hat P\left( t \right) = \Pi r\left[ {\left( {N - r} \right)/\left( {N - r + 1} \right)} \right]\), where r assumes those values for which \(t_r^\prime \leqslant t\) and for which \(t_r^\prime\) measures the time to death. This estimate is the distribution, unrestricted as to form, which maximizes the likelihood of the observations.
Other estimates that are discussed are the actuarial estimates (which are also products, but with the number of factors usually reduced by grouping); and reduced-sample (RS) estimates, which require that losses not be accidental, so that the limits of observation (potential loss times) are known even for those items whose deaths are observed. When no losses occur at ages less than t the estimate of P(t) in all cases reduces to the usual binomial estimate, namely, the observed proportion of survivors.
A randomized trial designed to compare mechlorethamine, vincristine, procarbazine, and prednisone (MOPP)/doxorubicin, bleomycin, vinblastine, and daccarbazine (ABVD) (regimen A) with ABVD plus low-dose regional (extended-field) radiation therapy (EF RT) (regimen B) for the treatment of children and adolescents with stages III and IV Hodgkin's disease was conducted by the Children's Cancer Group (CCG-521) from 1986 until 1990.
One hundred eleven eligible patients were randomized, 57 to regimen A and 54 to regimen B. All patients had pathologically verified stage III or stage IV Hodgkin's disease.
Overall survival (S) is 87% at 4 years and event-free survival (EFS) is 82%. Patients randomized to ABVD plus EF RT have a 4-year EFS of 87% compared with 77% for patients randomized to MOPP/ABVD (P = .09, two-sided). Patients randomized to ABVD plus EF RT have a 4-year S of 90% compared with 84% for patients randomized to MOPP/ABVD (P = .45, two-sided). Significant prognostic factors in multivariate analysis for EFS are stage of disease, erythrocyte sedimentation rate (ESR) at diagnosis, liver size at diagnosis, and, among stage III patients, the size of the mediastinal mass at diagnosis. The acute toxicities of treatment are largely hematopoietic in nature, whereas acute pulmonary and cardiac toxicities are modest and not limiting.
The results of this study show that, in advanced-stage Hodgkin's disease in children, equivalent results can be obtained by the addition of either MOPP or low-dose EF RT to the ABVD regimen; whether the addition of either contributes to outcome was not addressed in this study and will require additional testing. It is clear, however, that MOPP chemotherapy can safely be eliminated from front-line combination chemotherapy regimens for advanced Hodgkin's disease in pediatric patients.
To analyze the impact of mediastinal irradiation on the incidence of cardiac late effects in long-term survivors of pediatric Hodgkin disease (HD).
The study cohort comprised 1,132 survivors of HD who received treatment before 18 years of age in consecutive trials between 1978 and 1995. They had maintained remission without secondary malignancy for 3.1-29.4 years. The cumulative doxorubicin dose was uniformly 160 mg/m(2), the mediastinal radiation dose (MedRD) was 36, 30, 25, 20, or 0 Gy. Follow-up questionnaires complemented by additional contacts served to collect information on late effects from patients and physicians. A central expert panel reviewed all reported cardiac abnormalities.
By October 2008, cardiac diseases (CD) had been diagnosed in 50 of 1,132 patients aged 15.0-41.7 (median 32.2) years. The interval since HD therapy was 3.0-28.2 (median 19.5) years. Valvular defects were diagnosed most frequently, followed by coronary artery diseases, cardiomyopathies, conduction disorders, and pericardial abnormalities. The cumulative incidence of CD after 25 years was highest in the MedRD-36 group (21%) decreasing to 10%, 6%, 5%, and 3% in the lower MedRD groups (P < 0.001). Multivariate Cox analysis of several putative risk factors showed MedRD to be the only significant variable predicting for CD-free survival (P = 0.0025).
Our results indicate that lower MedRDs are less cardiotoxic. Consequently, reduction of cardiac late effects may be expected with the lower radiation doses used in current HD protocols. Longer follow-up is needed to confirm the present results.
Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.
Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.
One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (+/- SE) 5-year disease-free and overall survival were 76% +/- 12% and 85% +/- 10% with median follow-up 5 years from SMN diagnosis.
Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.
The Childhood Cancer Survivor Study (CCSS) has assembled the largest cohort to date for assessment of late mortality. Vital status and cause of death of all patients eligible for participation in CCSS was determined using the National Death Index and death certificates to characterize the mortality experience of 20,483 survivors, representing 337,334 person-years of observation. A total of 2,821 deaths have occurred as of December 31, 2002. The overall cumulative mortality is 18.1% (95% CI, 17.3 to 18.9) at 30 years from diagnosis. With time, while all-cause mortality rates have been stable, the pattern of late death is changing. Mortality attributable to recurrence or progression of primary disease is decreasing, with increases in rates of mortality attributable to subsequent neoplasms (standardized mortality ratios [SMR], 15.2; 95% CI, 13.9 to 16.6), cardiac death (SMR, 7.0; 95% CI, 5.9 to 8.2), and pulmonary death (SMR, 8.8; 95% CI, 6.8 to 11.2) largely due to treatment-related causes. In addition, the CCSS has identified specific treatment-related risk factors for late mortality. Radiotherapy (relative risk [RR], 2.9; 95% CI, 2.1 to 4.2), alkylating agents (RR, 2.2; 95% CI, 1.6 to 3.0), and epipodophyllotoxins (RR, 2.3; 95% CI, 1.2 to 4.5) increase the risk of death due to subsequent malignancy. Cardiac radiation exposure (RR, 3.3; 95% CI, 2.0 to 5.5) and high dose of anthracycline exposure (RR, 3.1; 95% CI, 1.6 to 5.8) are associated with late cardiac death. By continued longitudinal follow-up of the cohort and expansion of the cohort to include patients diagnosed between 1987 and 1999, the CCSS will remain a primary resource for assessment of late mortality of survivors of childhood cancers.
Subsequent malignant neoplasms (SMNs) are a dominant cause of morbidity and mortality in children treated for Hodgkin's disease (HD). We evaluated select demographic and therapeutic factors associated with SMNs, specifically gender and radiation dose.
A total of 930 children treated for HD at five institutions between 1960 and 1990 were studied. Mean age at diagnosis was 13.6 years, and mean follow-up was 16.8 years (maximum, 39.4 years). Treatment included radiation alone (43%), chemotherapy alone (9%), or both (48%).
We found that SMNs occurred in 102 (11%) patients, with a 25-year actuarial rate of 19%. With 15,154 patient years of follow-up, only 7.18 cancers were expected (standardized incidence ratio [SIR] = 14.2; absolute excess risk [AER] = 63 cases/10,000 years). The SIR for female subjects, 19.93, was significantly greater than for males, 8.41 (p < 0.0001). After excluding breast cancer, the SIR for female patients was 15.4, still significantly greater than for male patients (p = 0.0012). Increasing radiation dose was associated with an increasing SIR (p = 0.0085). On univariate analysis, an increased risk was associated with female gender, increasing radiation dose, and age at treatment (12-16 years). Using logistic regression, mantle radiation dose increased risk, and this was 2.5-fold for female patients treated with more than 35 Gy primarily because of breast cancer.
Survivors of childhood HD are at risk for SMNs, and this risk is greater for female individuals even after accounting for breast cancer. Although SMNs occur in the absence of radiation therapy, the risk increases with RT dose.
Sixty-four patients aged 2 to 18 years with advanced-stage Hodgkin's disease (HD) were treated on a Children's Cancer Study Group (CCSG) pilot toxicity study (521-P). Therapy consisted of 12 courses of Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), bleomycin, vinblastine, and dacarbazine (ABVD), followed by low-dose (2,100 cGy in 12 fractions) regional irradiation (RT). All patients were monitored for toxicity with particular attention to the pulmonary system. Six patients (9%) developed grade 3 or 4 pulmonary toxicity. Three had grade 3 toxicity based solely on changes in carbon monoxide diffusing capacity (DLCO) and remained well for more than 3 years after diagnosis. There was one fatality among the three symptomatic cases. In five cases, toxicity occurred prior to RT. One occurred after seven courses of ABVD, one after nine courses, and three after 10 courses. In one of these five cases, ABVD was stopped. The patient was given nitrogen mustard (mechlorethamine), vincristine, prednisone, and procarbazine (MOPP). This patient subsequently developed recurrence of HD and died of overwhelming sepsis. The other four continued on study and completed their chemotherapy. Three patients had no further bleomycin, and one continued bleomycin at 50% of the assigned dose. They all received mantle RT following chemotherapy, one with a boost dose to the mediastinum to 3,800 cGy and one with added RT to both lungs (1,050 cGy). In the sixth case of pulmonary toxicity, symptoms were first noticed 2 weeks after mantle RT to 3,500 cGy. This patient died of progressive respiratory failure. The event-free survival (EFS) and overall survival is 87% at 3 years. These early results indicate that this therapy is effective in advanced HD in children but has a 9% incidence of acute pulmonary toxicity.
Sixty-two patients with advanced-stage Hodgkin's disease and a median age of 12 years (range, 3 to 22 years) were treated with four cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) alternating with four cycles of doxorubicin, vinblastine, bleomycin, and dacarbazine (ABVD) followed by low-dose radiotherapy (RT). We determined the feasibility, immediate safety, and rapidity of response of patients to this regimen, as well as the relationship between prognostic factors and the rate of complete remission (CR), event-free survival (EFS), and overall survival. Therapy was well tolerated, and the major toxicity was hematopoietic. At the end of chemotherapy, 54 of 62 patients (87%) were in CR by clinical restaging, with a biopsy of residual disease where necessary. The actuarial 3-year EFS is 77% (SE, 11%), with a median follow-up of 35 months, and the survival is 91% (SE, 7%). With respect to EFS, female patients and those with stage II or III disease fared statistically better than males and patients with stage IV disease, respectively. Six patients have died: three of progressive Hodgkin's disease, one of secondary acute myelocytic leukemia (AML), one of secondary non-Hodgkin's lymphoma (NHL), and one of overwhelming bacterial sepsis. The Pediatric Oncology Group (POG) is currently engaged in a randomized study of these eight cycles of chemotherapy with and without RT to assess the role of RT in achieving comparable results.
The Ann Arbor classification for describing the stage of Hodgkin's disease at initial presentation has formed the basis upon which treatment is selected and has allowed comparison of results achieved by different investigators for almost two decades. A meeting was convened to review the classification and modify it in the light of experience gained in its use and new techniques for evaluating disease. It was concluded that the structure of the classification be maintained. It was particularly recommended: (1) that computed tomography (CT) be included as a technique for evaluating intrathoracic and infradiaphragmatic lymph nodes; (2) that the criteria for clinical involvement of the spleen and liver be modified to include evidence of focal defects with two imaging techniques and that abnormalities of liver function be ignored; (3) that the suffix 'X' to designate bulky disease (greater than 10 cm maximum dimension) be introduced; and (4) that a new category of response to therapy, unconfirmed/uncertain complete remission (CR[u]), be introduced to accommodate the difficulty of persistent radiological abnormalities of uncertain significance.
To determine whether the addition of low-dose total-nodal irradiation (TNI) in pediatric patients with advanced-stage Hodgkin's disease who have received eight cycles of alternating mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) will improve the event-free survival (EFS) and overall survival (OS) when compared with patients who have received chemotherapy only.
At diagnosis, 183 children and adolescents with stages IIB, IIIA2, IIIB, and IV Hodgkin's disease were randomized to receive eight cycles of alternating MOPP-ABVD with or without low-dose TNI.
Of 183 patients, four were rendered ineligible before treatment was initiated. One hundred sixty-one of 179 patients (90%) were in complete remission (CR) at the completion of eight cycles of alternating MOPP-ABVD; 81 were in the chemotherapy-only group and proceeded to observation off therapy, whereas 80 of 161 were to receive combined modality therapy (CMT). Nine of 80 patients randomized at the time of diagnosis to receive CMT did not receive radiation (RT) because of a protocol violation, but were monitored for EFS and OS and included in all analyses. The estimated EFS and OS rates at 5 years for the 179 eligible patients are 79% and 92%, respectively. The actuarial EFS at 5 years was 80% for patients who received CMT and 79% for patients who received MOPP-ABVD only. The OS for the former group is estimated to be 87% and for the latter patients 96%. Age < or = 13 years of age at diagnosis and the attainment of a clinical CR after three cycles of chemotherapy were associated with a statistically significant improved EFS.
Our results indicate that after the delivery of eight cycles of MOPP-ABVD, the addition of low-dose RT does not improve the estimated EFS or OS in pediatric patients with advanced-stage Hodgkin's disease.
The incidence of secondary leukemia after epipodophyllotoxin treatment and the relationship between epipodophyllotoxin cumulative dose and risk are not well characterized. The Cancer Therapy Evaluation Program (CTEP) of the National Cancer Institute (NCI) has developed a monitoring plan to obtain reliable estimates of the risk of secondary leukemia after epipodophyllotoxin treatment.
Twelve NCI-supported cooperative group clinical trials were identified that use epipodophyllotoxins at low (<1.5 g/m2 etoposide), moderate (1.5 to 2.99 g/m2 etoposide), or higher (> or =3.0 g/m2 etoposide) cumulative doses. Cases of secondary leukemia (including treatment-related myelodysplastic syndrome) occurring on these trials have been reported to CTEP, as has duration of follow-up for all patients, thereby allowing calculation of cumulative 6-year incidence rates of secondary leukemia for each etoposide dose group.
The calculated cumulative 6-year risks for development of secondary leukemia for the low, moderate, and higher cumulative dose groups were 3.3%, (95% upper confidence bound of 5.9%), 0.7% (95% upper confidence bound of 1.6%), and 2.2%, (95% upper confidence bound of 4.6%), respectively.
Within the context of the epipodophyllotoxin cumulative dose range and schedules of administration encompassed by the monitoring plan regimens, and within the context of multiagent chemotherapy regimens that include alkylating agents, doxorubicin, and other agents, factors other than epipodophyllotoxin cumulative dose seem to be of primary importance in determining the risk of secondary leukemia. Data obtained by the CTEP secondary leukemia monitoring plan support the relative safety of using epipodophyllotoxins according to the therapeutic plans outlined in the monitored protocols.
Treatment for Hodgkin's disease (HD) is associated with a variety of thyroid abnormalities, including hypothyroidism, hyperthyroidism, and thyroid neoplasms. Due to the small sample size and short follow-up time of most published studies, it has been difficult to appreciate the full extent of the problem and to characterize the interaction between various patient and treatment variables. To overcome these limitations we have assessed thyroid status in 1,791 (959 males) HD survivors from among 13,674 participants in the Childhood Cancer Survivor Study, a cohort of 5-yr survivors of childhood and adolescent cancer diagnosed between 1970 and 1986. Thyroid abnormalities were ascertained as part of a 22-page questionnaire sent to participants. Survivors were a median of 14 yr (range, 2-20 yr) at diagnosis of HD and a median of 30 yr (range, 12-47 yr) at follow-up. Seventy-nine percent of subjects were treated with radiation (median dose of radiation to the thyroid, 3,500 cGy; range, 0.37-5,500 cGy). Control data were available from 2,808 (1,346 males) sibling controls. Thirty-four percent of the entire cohort has been diagnosed with at least one thyroid abnormality. Hypothyroidism was the most common disturbance, with a relative risk of 17.1 (P < 0.0001) compared to sibling controls. Increasing dose of radiation, older age at diagnosis of HD, and female sex were all independently associated with an increased risk of hypothyroidism. Actuarial risk of hypothyroidism for subjects treated with 4,500 cGy or more is 50% at 20 yr from diagnosis. Hyperthyroidism was reported by 5% of survivors, which was 8-fold greater (P < 0.0001) than the incidence reported by the controls. Thyroid dose of 3,500 cGy or more was the only risk factor identified for hyperthyroidism. The risk of thyroid nodules was 27 times (P < 0.0001) that in sibling controls. Female sex and radiation dose to the thyroid of 2,500 cGy or more were independent risk factors for thyroid nodules. The actuarial risk of a female survivor developing a thyroid nodule is 20% at 20 yr from diagnosis. Thyroid cancer was diagnosed in 20 survivors, which is 18 times the expected rate for the general population. After taking into account the possibility that some of the relative risk estimates may be exaggerated due to ascertainment bias, abnormalities of the thyroid are still extremely common in young adult survivors of childhood HD, particularly among females treated with high doses of radiation to the neck.
Between January 1990 and April 1993, 56 pediatric patients with Hodgkin's disease were treated on a single-arm trial at three institutions with a regimen designed to maintain high cure rates while minimizing the potential late effects of treatment, such as infertility, second malignant neoplasms, and cardiopulmonary injury.
The regimen used combined-modality therapy with six cycles of vinblastine, etoposide, prednisone, and doxorubicin (VEPA) chemotherapy and low-dose, involved-field radiation. Unfavorable features comprised bulky presentations of localized (stage I or II) disease or advanced (stage III or IV) Hodgkin's disease.
Of 56 patients enrolled, 26 (46%) had unfavorable presentations of stage I/II disease and 30 (54%) had advanced (stage III/IV) disease. Seventy-nine percent of the patients are alive without disease at a median follow-up time of 8.9 years from diagnosis. Nineteen patients had events at a median of 1.5 years (range, 0.4 to 7.9 years) from diagnosis; 17 patients relapsed, one died of cardiomyopathy, and one died of accidental injuries. Survival and event-free survival (EFS) estimates at 5 years for the entire cohort were 81.9% (SE, 5.2%) and 67.8% (SE, 6.3%), respectively. Five-year EFS by stage was 100% for stage I, 79.2% (SE, 8.3%) for stage II, 70% (SE, 14.5%) for stage III, and 49.5% (SE, 11.3%) for stage IV patients.
Combined-modality therapy with VEPA chemotherapy and low-dose, involved-field radiation is adequate for disease control of early-stage patients with unfavorable features, but it is inferior to other standard regimens for advanced-stage patients.
Current standard therapy for children and adolescents with Hodgkin's disease includes combination chemotherapy and low-dose involved-field radiation (LD-IFRT). Because radiation may be associated with adverse late effects, the Children's Cancer Group (CCG) investigated whether radiation could be omitted in patients achieving a complete response to initial chemotherapy without jeopardizing the excellent outcome obtained with combined-modality therapy.
Between January 1995 and December 1998, 829 eligible patients were enrolled onto CCG 5942. A total of 501 patients who achieved an initial complete response after risk-adapted combination chemotherapy were randomized to receive LD-IFRT or no further treatment. Event-free survival (EFS) and overall survival were assessed from the date of study entry or the date of randomization, as appropriate.
The projected 3-year EFS from study entry for the entire cohort was 87% +/- 1.2%. Among patients who achieved a complete response to initial chemotherapy, 92% +/- 1.9% of those randomized to receive LD-IFRT were alive and disease free 3 years after randomization, versus 87% +/- 2.2% for patients randomized to receive no further therapy (stratified log-rank test; P =.057). With an "as-treated" analysis, 3-year EFS after randomization for the radiation cohort was 93% +/- 1.7% versus 85% +/- 2.3% for patients receiving no further therapy (stratified log-rank test; P =.0024). Three-year survival estimates for patients treated with and without LD-IFRT were 98% +/- 1.1% for patients who received radiation and 99% +/- 0.5% for patients who did not receive radiation.
LD-IFRT after an initial complete response to risk-adapted chemotherapy improved EFS. At this time, there is no survival advantage for LD-IFRT, but follow-up remains short.
The Childhood Cancer Survivor Study is a resource that was designed to investigate long-term effects among 5-year survivors of childhood and adolescent malignancies. Previous studies have shown that exposure to chemotherapy and/or radiation can compromise pulmonary function in these survivors of childhood cancer.
Using information obtained from questionnaires from 12,390 childhood cancer survivors and 3546 randomly selected siblings, the authors evaluated the rate of first occurrence of 15 selected pulmonary conditions in three periods: during therapy, from the end of therapy to 5 years postdiagnosis, and >/= 5 years postdiagnosis. Multivariate analyses were used to determine the relative risks with 95% confidence intervals of reported pulmonary conditions by exposure to the following treatment variables: radiation therapy to the chest, bleomycin, cyclophosphamide, busulfan, lomustine (CCNU), and/or carmustine (BCNU).
Compared with siblings, survivors had a statistically significant increased relative risk (RR) of lung fibrosis, recurrent pneumonia, chronic cough, pleurisy, use of supplemental oxygen, abnormal chest wall, exercise-induced shortness of breath, bronchitis, recurrent sinus infection, and tonsillitis for all three periods. During the period of >or= 5 years postdiagnosis, statistically significant associations were present for lung fibrosis and chest radiation (RR, 4.3; P = 0 001); for supplemental oxygen use and chest radiation (RR, 1.8; P < 0.001), BCNU (RR, 1.4; P = 0.05), bleomycin (RR, 1.7; P = 0.001), busulfan (RR, 3.2; P = 0.002), CCNU (RR, 2.1; P < 0.001), and cyclophosphamide (RR, 1.5; P = 0.01); for recurrent pneumonia and chest radiation (RR, 2.2; P = 0.001) and cyclophosphamide (RR, 1.6; P = 0.04); for chronic cough and chest radiation (RR, 2.0; P < 0.001), bleomycin (RR, 1.9; P < 0.001), and cyclophosphamide (RR, 1.3; P = 0.004); and for pleurisy and chest radiation (RR, 1.4; P = 0.02) and busulfan (RR, 5.1; P = 0.02). Chest radiation was associated with a 3.5% cumulative incidence of lung fibrosis at 20 years after diagnosis.
For self-report of pulmonary conditions, treatment-related factors that continue to manifest > 5 years after diagnosis and treatment are important determinants of risk. Continued follow-up of childhood cancer survivors is needed to evaluate the impact of pulmonary conditions on quality of life.
Purpose:
The identification of risk factors is required for risk-adapted treatment strategies in the treatment of Hodgkin's disease. To assess the influence of bulky disease at diagnosis as compared with other risk factors on event-free survival (EFS) in pediatric Hodgkin's disease such as stage, B-symptoms, number of involved lymph node regions, histology, and remission status after chemotherapy, we analyzed the outcome of 552 patients treated with a risk-adapted treatment strategy consisting of OPPA(OEPA)/COPP (vincristine, procarbazine, etoposide, prednisone, adriamycin, cyclophosphamide) and involved-field radiotherapy.
Methods and materials:
Between 1990 and 1995, 578 patients with primary Hodgkin's disease (HD) were enrolled in the German/Austrian Pediatric Hodgkin's Disease Study Group (DAL) Multicenter Study (HD-90). Patients were stratified into three treatment groups (TGs) for early, intermediate, and advanced stage. All patients received induction chemotherapy (CT) with two cycles of OEPA for boys and two cycles of OPPA for girls. Patients in TG2 and TG3 received another two or four cycles, respectively, of COPP. Chemotherapy was followed by involved-field radiotherapy. The radiation field, which was prescribed by the study center, was treated with a dose of 25 Gy/25 Gy/20 Gy (TG1/TG2/TG3), and in case of insufficient remission with a local boost of 5 Gy to 10 Gy. The following prognostic factors were analyzed with regard to their impact on EFS: bulky disease, mediastinal tumor, number of involved lymph node regions, histology, treatment group, B-symptoms, sex, age, and remission status after chemotherapy.
Results:
Significant univariate predictive factors for the EES were: nodular sclerosis type 2 (NS2) histology (relative risk [RR] 3.43; p = 0.0002), presence of B-symptoms (RR 2.70; p = 0.0014), number of involved regions (1.55; p = 0.019), and treatment groups (RR 1.33; p = 0.017). There was a higher risk (RR 1.92; p = 0.040) for patients with bulky compared with nonbulky disease (5-year EFS 89.6%/94.6%). In the multiple regression model, only NS2 and B-symptoms remained strong predictive factors. The remission status after chemotherapy did not correlate with EFS (p = 0.66).
Conclusion:
Treatment strategies in Hodgkin's disease have an impact on different risk factors. In the risk-adapted treatment strategy of the HD-90 study, tumor burden indicated as bulky disease or as number of involved lymph nodes loses its importance, whereas NS2 histology and B-symptoms have a major impact on treatment outcome. Bulky disease at diagnosis might require higher radiation doses only in case of insufficient remission.
In 5 consecutive pediatric and adolescent Hodgkin's disease trials DAL-HD since 1978 the invasive diagnostic procedures and the radiotherapy have gradually been reduced and chemotherapy modified to minimize toxicity and the risk of late effects. Since 1982 the overall survival increased up to 95%. In this trial the possibility of reducing local radiation doses to 20 Gy in patients with good response to chemotherapy and omitting radiotherapy totally for patients with complete remission after chemotherapy was tested.
Over a period of 6 years, from August 1995 to July 2001, 1018 children and adolescents with Hodgkin's disease from Germany, Austria,Switzerland, the Netherlands, Sweden, Norway and Denmark were enrolled in this trial. The chemotherapy was equivalent to previous trial DAL-HD 90. The treatment group (TG) 1 (stages I and IIA) received 2 cycles OPPA for girls and 2 cycles OEPA for boys, TG2 (stages IIEA, IIB, IIIA) and TG3 (stages IIEB, IIIEA, IIIB, IV) received additional 2 or 4 cycles COPP respectively. In contrast to trial DAL-HD 90 boys in stage IIIB and IIIEB received OPPA instead of OEPA. The initial staging as well as the restaging for evaluating tumor volume reduction after chemotherapy was reviewed by the study center. Radiotherapy was planned accordingly: patients with complete remission after chemotherapy were not irradiated (21.9%); all other patients received local radiotherapy to the initially involved sites, depending on the tu-mor response. Patients with a partial remission of> 75 tumor regression were irradiated with 20 Gy (50AX), partial remission of< 75% with 30 Gy (4.1 %), and residual masses of > 50 ml were boosted up to 35 Gy (20.2 %).
36 tumor progressions and 49 relapses occurred over a period of 7 1/2 years (median followup 3 years, data deadline 12/19/02). Kaplan-Meier-analysis after 5 years showed a probability for event-free survival (pEFS) for all patients of 0.88 and for overall survival (pOS) of 0.97. For the total group the pDFS (disease free survival) was lower in 222 non irradiated patients than in the 758 irradiated patients (0.88 vs. 0.92,p - 0.049). But there was a difference between the individual treatment groups. In TG 1 there was no difference between nonirradiated and irradiated patients (0.97 vs. 0.94) and the non-ir-radiated patients showed a better trend. In TG 2, and in TG 2 and TG 3 combined, the pDFS was significantly worse for non irradiated patients in comparison with the irradiated patients (TG2:0.78 vs. 0.92; TG 2 +3:0.79 vs. 0.91). Compared to former DAL-HD trials the pOS stayed stable despite therapy reduction.
A reduction of radiotherapy to 20 Gy for patients in all stages with good response to chemotherapy is possible without deterioration of the results. The omission of radiotherapy for patients in complete remission after chemotherapy is recommended only for patients in early stages (TG1). In future trials the possibility of a wider selection for chemotherapy alone for this group needs to be evaluated. In intermediate (TG2) and advanced (TG3) stages omission of radiotherapy for patients incomplete remission results in a lower pEFS, but the pOS is not significantly reduced. Only with knowledge of the long term effects of today's therapy we can give a satisfactory answer to the question whether in future trials the primary aim should be pEFS as high as possible due to front-line-therapy or reduction of late effects.
We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkin's disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up.
Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years.
An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio [SIR], 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy.
Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.
With advances in multimodality therapy, survival from Hodgkin lymphoma (HL) now exceeds 80%, resulting in a large cohort of survivors who are at risk for adverse long-term sequelae of therapy. This risk is complicated by possible endogenous predispositions to developing late effects, which relate to the patient's underlying susceptibility to HL. Finally, the impact of HL on the host can compromise organ function. This article reviews the possible dominant late effects for survivors of HL and strategies for monitoring and screening. As therapy for HL has changed and evolved, so has the spectrum of late effects. Mortality from HL has decreased, whereas delayed effects of therapy have increased. Refinements in therapy to decrease toxicity have occurred in response to the success in curing HL. Thus, modifications in therapeutic protocols using a risk-adapted strategy have reduced the use of alkylating agents, anthracyclines, and radiotherapy, which are associated with adverse long-term sequelae. The most clinically evident sequelae are those involving the endocrine and cardiovascular systems, and the most morbid are hematologic and solid second malignancies. Primary and secondary prevention strategies can be developed as knowledge of delayed effects of therapy increases.
To determine if 6 courses of chemotherapy alone could achieve the same or better outcome than 4 courses of chemotherapy followed by radiation therapy (chemoradiotherapy) in pediatric and adolescent patients with Hodgkin disease. Children < or =21 years old with biopsy-proven, pathologically staged I, IIA, or IIIA1 Hodgkin disease were randomly assigned 6 courses of alternating nitrogen mustard, oncovin, prednisone, and procarbazine/doxorubicin, bleomycin, vinblastine, and dacarbazine (treatment 1) or 4 courses of alternating nitrogen mustard, oncovin, prednisone, and procarbazine/doxorubicin, bleomycin, vinblastine, and dacarbazine +2550 cGy involved-field radiotherapy (treatment 2). The complete response rate was 89%, with a complete response and partial response rate of 99.4%. There was no statistically significant difference in event-free survival (EFS) or overall survival between arms. The EFS for those who achieved an early complete response was significantly higher than for those who did not. For pediatric patients with asymptomatic low-stage and intermediate-stage Hodgkin disease, chemotherapy and chemoradiotherapy both resulted in 3-year EFS of approximately 90% and statistically indistinguishable 8-year EFS and overall survival, without significant long-term toxicity. Early response to therapy was associated with higher EFS, a concept that has led to the Children's Oncology Group paradigm of response-based risk-adapted therapy for pediatric Hodgkin disease.
Childhood cancer survivors who retain ovarian function after completing cancer treatment are at increased risk of developing premature menopause, defined as cessation of menses before age 40 years. However, published data pertaining to the risk and frequency of premature menopause are limited.
We assessed the incidence of and risk factors for premature menopause in 2819 survivors of childhood cancer who were older than 18 years and were participants in the multicenter Childhood Cancer Survivor Study (CCSS). The comparison group was 1065 female siblings of participants in the CCSS. A multiple Poisson regression model was constructed to determine risk factors for nonsurgical premature menopause. All statistical tests were two-sided.
A total of 126 childhood cancer survivors and 33 control siblings developed premature menopause. Of these women, 61 survivors (48%) and 31 siblings (94%) had surgically induced menopause (rate ratio [RR] = 0.8, 95% confidence interval [CI] = 0.52 to 1.23). However, the cumulative incidence of nonsurgical premature menopause was higher for survivors than for siblings (8% versus 0.8%; RR = 13.21, 95% CI = 3.26 to 53.51; P<.001). A multiple Poisson regression model showed that risk factors for nonsurgical premature menopause included attained age, exposure to increasing doses of radiation to the ovaries, increasing alkylating agent score (based on number of alkylating agents and cumulative dose), and a diagnosis of Hodgkin lymphoma. For survivors who were treated with alkylating agents plus abdominopelvic radiation, the cumulative incidence of nonsurgical premature menopause approached 30%.
The results of this study will facilitate counseling current survivors about their future risk of premature menopause and aid in designing new regimens that seek to diminish late ovarian toxicity.
To evaluate outcome and assess complications in children and adolescents with low-risk Hodgkin's disease treated with vinblastine, doxorubicin, methotrexate, and prednisone (VAMP) chemotherapy and low-dose, involved-field radiation therapy (IFRT).
One hundred ten children with low-risk Hodgkin's disease were treated with four cycles of VAMP and 15 Gy IFRT for those who achieved a complete response (CR) or 25.5 Gy for those with a partial response after two cycles of VAMP.
With median follow-up of 9.6 years (range, 1.7 to 15.0), 5- and 10-year overall survival were 99.1% and 96.1%, respectively, and 5-and 10-year event-free survival (EFS) were 92.7% and 89.4%. Factors contributing to 10-year EFS were: early CR (P = .02), absence of B symptoms (P = .01), lymphocyte predominant histologic subtype (P = .04), and less than three initial sites of disease (P = .02). Organ toxicity has been limited to correctable hypothyroidism in 42% of irradiated patients, and one case of cardiac dysfunction. Seventeen healthy babies have been born to 106 survivors. There have been two malignant tumors: one thyroid cancer within the radiation therapy field and one Ewing's sarcoma outside the radiation therapy field.
Risk-adapted, combined-modality therapy using VAMP chemotherapy with radiation is effective and well tolerated. Pediatric patients with low-risk Hodgkin's disease can be cured with therapy without an alkylating agent, bleomycin, etoposide, or high-dose, extended-field radiotherapy. Thus, these children are expected to retain normal fertility, organ function, and be at low risk of a second malignant tumor.
To correlate [(18)F]fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) status after chemotherapy, but before radiation, with outcome in patients treated with the Stanford V regimen.
We analyzed retrospectively 81 patients with Hodgkin's disease who had serial [(18)F]FDG-PET scans performed at baseline and again at the completion of Stanford V chemotherapy, before planned radiotherapy. Patients with favorable stage I/II (nonbulky mediastinal disease) and those with bulky mediastinal disease or stage III/IV were scanned after 8 and 12 weeks of chemotherapy, respectively. Radiotherapy fields were determined before starting chemotherapy based on baseline computed tomography scans.
After chemotherapy, six of 81 patients had residual [(18)F]FDG-PET-positive sites, all in sites for which radiotherapy was planned. Four of the six patients with positive [(18)F]FDG-PET scans after chemotherapy experienced relapse compared with just three of 75 patients with negative [(18)F]FDG-PET scans. At a median follow-up of 4 years, the freedom from progression (FFP) was 96% in postchemotherapy [(18)F]FDG-PET-negative patients versus 33% in [(18)F]FDG-PET-positive patients (P < .0003). In a bivariate Cox model, [(18)F]FDG-PET positivity after chemotherapy remained a highly significant predictor of progression-free survival even after controlling for bulky disease and International Prognostic Score more than 2.
These data indicate that PET status after chemotherapy is strongly predictive of FFP with the Stanford V regimen despite the use of consolidative radiotherapy. These results have implications for the design of clinical trials adapted to functional imaging.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest Schwartz Provision of study materials or patients
- Debra L Friedman
- Suzanne Wolden
- Pedro A De
- Allen R Alarcon
- Nathan Chen
- Peter Kobrinsky
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thresholds for late toxicity, this represents a highly significant reduction of therapy and associated long-term toxicities. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Debra L. Friedman, Suzanne Wolden, Pedro A. De Alarcon, Allen R. Chen, Nathan Kobrinsky, Peter Ehrlich, Louis S. Constine, Cindy L. Schwartz Provision of study materials or patients: Debra L. Friedman, Suzanne Wolden, Cindy L. Schwartz Collection and assembly of data: Debra L. Friedman, Suzanne Wolden, Thomas J. FitzGerald, Sandra Kessel, Robert E. Hutchison, Cindy L. Schwartz Data analysis and interpretation: Debra L. Friedman, Lu Chen, Suzanne Wolden, Allen Buxton, Kathleen McCarten, Thomas J. FitzGerald, Peter Ehrlich, Cindy L. Schwartz Manuscript writing: All authors German-Austrian DAL-HD studies. Pediatr Blood Cancer 55:1145-1152, 2010
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