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This topic addresses the management of recurrent Hodgkin lymphoma. While autologous stem cell transplantation may be appropriate for select cases of recurrent disease following comprehensive combined-modality therapy, other options exist for patients treated with lower-dose therapy for early-stage disease. Additionally, innovative targeted therapies provide newer salvage options to consider. The American College of Radiology Appropriateness Criteria[R] are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation, or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the complex decisionmaking associated with the management of recurrent Hodgkin lymphoma., Summary of Literature Review Introduction/Background Classical Hodgkin lymphoma is a highly curable cancer, even in advanced stages. Although radiation therapy (RT) alone improved disease-free survival (DFS) for many years, the [...]

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.

Children’s Oncology Group (COG) trial AHOD0431 reduced systemic therapy and used response-adapted involved-field radiotherapy (IFRT) in early-stage pediatric classic Hodgkin lymphoma. We investigated the impact of positron emission tomographic response after 1 cycle (PET1) and on IFRT outcomes and pattern of relapse. Patients in AHOD0431 underwent PET1 response assessment after AVPC (doxorubicin, vincristine, prednisone, and cyclophosphamide). “Rapid early responders” (RERs) had a negative PET1 (PET1−); “slow early responders” (SERs) had a positive PET1 (PET1+). Patients with a partial response by computed tomographic and functional imaging after 3 chemotherapy cycles received 21-Gy IFRT, whereas complete responders had no IFRT. Progression-free survival (PFS) was evaluated for RERs and SERs treated with or without IFRT. Recurrence sites were initial, new, or both. Relapses involving initial sites were characterized as “within the PET1+ site” or “initially involved but outside the PET1+ site.” Median follow-up was 118 months. The 10-year PFS rate among RERs was 96.6% with IFRT and 84.1% without IFRT (P = .10), whereas SERs were 80.9% with IFRT and 64.0% without IFRT (P = .03). Among 90 RERs who did not receive IFRT, all 14 relapses included an initial site. Among 45 SERs receiving no IFRT, 14 of 16 relapses were in the initial site (9 PET1+ site only). Among 58 patients receiving IFRT, 5 of 10 relapses were in the PET1+ site. After 3 cycles of AVPC alone, RERs showed favorable results. Conversely, SERs had unfavorable outcomes with AVPC alone, although they improved with 21-Gy IFRT. RT remains an important component of treatment for SERs. This trial was registered at www.clinicaltrials.gov as #NCT00302003.

Testicular cancer represents the most curable solid tumor, with a 10-year survival rate of more than 95%. Given the young average age at diagnosis, it is estimated that effective treatment approaches, in particular, platinum-based chemotherapy, have resulted in an average gain of several decades of life. This success, however, is offset by the emergence of considerable long-term morbidity, including second malignant neoplasms, cardiovascular disease, neurotoxicity, nephrotoxicity, pulmonary toxicity, hypogonadism, decreased fertility, and psychosocial problems. Data on underlying genetic or molecular factors that might identify those patients at highest risk for late sequelae are sparse. Genome-wide association studies and other translational molecular approaches now provide opportunities to identify testicular cancer survivors at greatest risk for therapy-related complications to develop evidence-based long-term follow-up guidelines and interventional strategies. We review research priorities identified during an international workshop devoted to testicular cancer survivors. Recommendations include 1) institution of lifelong follow-up of testicular cancer survivors within a large cohort setting to ascertain risks of emerging toxicities and the evolution of known late sequelae, 2) development of comprehensive risk prediction models that include treatment factors and genetic modifiers of late sequelae, 3) elucidation of the effect(s) of decades-long exposure to low serum levels of platinum, 4) assessment of the overall burden of medical and psychosocial morbidity, and 5) the eventual formulation of evidence-based long-term follow-up guidelines and interventions. Just as testicular cancer once served as the paradigm of a curable malignancy, comprehensive follow-up studies of testicular cancer survivors can pioneer new methodologies in survivorship research for all adult-onset cancer. DOI: 10.1093/jnci/djq216

Background: Women treated with therapeutic chest radiation may develop breast cancer. Purpose: To summarize breast cancer risk and breast cancer surveillance in women after chest radiation for pediatric or young adult cancer. Data Sources: Studies from MEDLINE, EMBASE, the Cochrane Library, and CINAHL (1966 to December 2008). Study Selection: Articles were selected to answer any of 3 questions: What is the incidence and excess risk for breast cancer in women after chest radiation for pediatric or young adult cancer? For these women, are the clinical characteristics of breast cancer and the outcomes after therapy different from those of women with sporadic breast cancer in the general population? What are the potential benefits and harms associated with breast cancer surveillance among women exposed to chest radiation? Data Extraction: Three investigators independently extracted data and assessed study quality. Data Synthesis: Standardized incidence ratios ranged from 13.3 to 55.5; cumulative incidence of breast cancer by age 40 to 45 years ranged from 13% to 20%. Risk for breast cancer increased linearly with chest radiation dose. Available limited evidence suggests that the characteristics of breast cancer in these women and the outcomes after diagnosis are similar to those of women in the general population; mammography can detect breast cancer, although sensitivity is limited. Limitation: The quality of evidence for key questions 2 and 3 is limited by substantial study heterogeneity, variation in study design, and small sample size. Conclusion: Women treated with chest radiation have a substantially elevated risk for breast cancer at a young age, which does not seem to plateau. In this high-risk population, there seems to be a benefit associated with early detection. Further research is required to better define the harms and benefits of lifelong surveillance. Primary Funding Source: National Cancer Institute. Ann Intern Med. 2010;152:444-455. www.annals.org For author affiliations, see end of text.

Childhood, adolescent, and young adult cancer survivors are at increased risk of reduced bone mineral density. Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve bone mineral density parameters and prevent fragility fractures. Discordances across current late effects guidelines necessitated international harmonisation of recommendations for bone mineral density surveillance. The International Late Effects of Childhood Cancer Guideline Harmonization Group therefore established a panel of 36 experts from ten countries, representing a range of relevant medical specialties. The evidence of risk factors for very low and low bone mineral density and fractures, surveillance modality, timing of bone mineral density surveillance, and treatment of very low and low bone mineral density were evaluated and critically appraised, and harmonised recommendations for childhood, adolescent, and young adult cancer survivors were formulated. We graded the recommendations based on the quality of evidence and balance between potential benefits and harms. Bone mineral density surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against bone mineral density surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and health-care provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to carry out bone mineral density surveillance using dual-energy x-ray absorptiometry at entry into long-term follow-up, and if normal (Z-score > −1), repeat when the survivor is aged 25 years. Between these measurements and thereafter, surveillance should be done as clinically indicated. These recommendations facilitate evidence-based care for childhood, adolescent, and young adult cancer survivors internationally.

Survivors of Hodgkin lymphoma (HL) have an increased risk of subsequent malignant neoplasms (SMNs). Response-adapted treatment may decrease this risk by reducing exposure to therapy associated with SMN risk. The Children’s Oncology Group study AHOD0031 evaluated response-adapted therapy for children and adolescents with intermediate-risk HL. We report the SMNs among 1711 patients enrolled in AHOD0031. Patients were treated with 4 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone, and cyclophosphamide with or without involved-field radiation therapy (RT). Patients with a slow early response to initial chemotherapy were randomized to 2 additional cycles of dexamethasone, etoposide, cisplatin and cytarabine or no additional chemotherapy, and all received RT. At a median follow-up of 7.3 years, an analysis of SMNs was performed. The 10-year cumulative incidence of SMN was 1.3% (95% confidence interval [CI], 0.6-2.0). SMNs included 3 patients with acute myeloid leukemia (AML), 11 with solid tumors, and 3 with non-Hodgkin lymphoma. Sixteen of 17 patients with an SMN had received combined modality therapy. The standardized incidence ratio for SMN was 9.5 (95% CI, 4.5-15.2) with an excess absolute risk of 1.2 per 1000 person-years. The cumulative incidence of SMNs was higher among patients who received RT (P = .037). In multivariate analysis, RT, B symptoms, and race were associated with SMN risk. Given the latency from exposure, we have likely captured all cases of secondary leukemia and myelodysplastic syndrome (MDS). Longer follow-up is needed to determine the risk of solid tumors. Avoidance of RT without sacrificing disease control should remain a goal for future therapeutic approaches. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

Advances in multimodality care for patients with pediatric cancer continues to improve long-term survival. The use of surgery, chemotherapy, and radiotherapy may lead to debilitating late effects in childhood cancer survivors. It is critically important to understand, mitigate, and screen for late effects to improve the quality of life in childhood cancer survivors. This review summarizes the use of radiotherapy in children, radiobiology of tissue injury, impact of age on late effects, important organ systems affected by radiotherapy during survivorship, and screening for radiotherapy late effects.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is an uncommon histologic variant, and the optimal treatment of stage I-II NLPHL is undefined. We conducted a multicenter retrospective study including patients ≥16 years of age with stage I-II NLPHL diagnosed from 1995 through 2018 who underwent all forms of management, including radiotherapy (RT), combined modality therapy (CMT; RT+chemotherapy [CT]), CT, observation after excision, rituximab and RT, and single-agent rituximab. End points were progression-free survival (PFS), freedom from transformation, and overall survival (OS) without statistical comparison between management groups. We identified 559 patients with median age of 39 years: 72.3% were men, and 54.9% had stage I disease. Median follow-up was 5.5 years (interquartile range, 3.1-10.1). Five-year PFS and OS in the entire cohort were 87.1% and 98.3%, respectively. Primary management was RT alone (n = 257; 46.0%), CMT (n = 184; 32.9%), CT alone (n = 47; 8.4%), observation (n = 37; 6.6%), rituximab and RT (n = 19; 3.4%), and rituximab alone (n = 15; 2.7%). The 5-year PFS rates were 91.1% after RT, 90.5% after CMT, 77.8% after CT, 73.5% after observation, 80.8% after rituximab and RT, and 38.5% after rituximab alone. In the RT cohort, but not the CMT cohort, variant immunoarchitectural pattern and number of sites >2 were associated with worse PFS (P < .05). Overall, 21 patients (3.8%) developed large-cell transformation, with a significantly higher transformation rate in those with variant immunoarchitectural pattern (P = .049) and number of involved sites >2 (P = .0006). OS for patients with stage I-II NLPHL was excellent after all treatments.

With the widespread adoption of multimodality treatment, 5-year survival of children diagnosed with cancer has improved dramatically in the past several decades from approximately 60% in 1970 to greater than 85% currently. As a result, there are an estimated nearly half a million long-term survivors of childhood cancer living in the United States today. However, survivors have, on average, significantly greater serious medical and psychosocial late effects compared with the general population. In this review, we will discuss the current epidemiology of childhood cancer survivorship, including new methods to estimate the burden of late effects and genetic susceptibility toward late effects. We will also review the development of surveillance guidelines for childhood cancer survivors and early toxicity signals from novel agents now being tested and used increasingly to treat pediatric and adult cancers. We conclude with an overview of current models of survivorship care and areas for future research.

The present guidelines review epidemiology, pathology, presentation, workup, staging, prognostic factors, and treatment options for patients with localized nodal indolent lymphoma, with an emphasis on radiation guidelines, including radiation dose, field design, and radiation techniques. Following a discussion of the current literature and available data for treatment and outcomes of patients with indolent lymphoma, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) by which the panel rates the appropriateness of imaging and treatment procedures. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment., Summary of Literature Review Introduction Patients with indolent lymphomas are predominantly found to have advanced-stage disease (stage III and IV) at diagnosis. Although effective therapies exist for patients found to [...]

Radiotherapy (RT) can be curative in patients with localized follicular lymphoma (FL), with historical series showing a 10-year disease-free survival of 40 to 50%. As 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography with computerized tomography (PET-CT) upstages 10 to 60% of patients compared to CT, we sought to evaluate outcomes in patients staged by PET-CT, to determine if more accurate staging leads to better patient selection and results. We conducted a multicenter retrospective study under the direction of the International Lymphoma Radiation Oncology Group (ILROG). Inclusion criteria were: RT alone for untreated stage I to II FL (grade 1-3A) with dose equivalent ≥24 Gy, staged by PET-CT, age ≥18 years, and follow-up ≥3 months. End points were freedom from progression (FFP), local control, and overall survival (OS). A total of 512 patients treated between 2000 and 2017 at 16 centers were eligible for analysis; median age was 58 years (range, 20-90); 410 patients (80.1%) had stage I disease; median RT dose was 30 Gy (24-52); and median follow-up was 52 months (3.2-174.6). Five-year FFP and OS were 68.9% and 96%. For stage I, FFP was 74.1% vs 49.1% for stage II (P < .0001). Eight patients relapsed in-field (1.6%). Four had marginal recurrences (0.8%) resulting in local control rate of 97.6%. On multivariable analysis, stage II (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.44-3.10) and BCL2 expression (HR, 1.62; 95% CI, 1.07-2.47) were significantly associated with less favorable FFP. Outcome after RT in PET-CT staged patients appears to be better than in earlier series, particularly in stage I disease, suggesting that the curative potential of RT for truly localized FL has been underestimated.

ObjectiveCancer survivors treated with abdominal/pelvic radiation therapy (ART) have increased the risks of colorectal cancer (CRC), although evidence supporting early CRC screening for these patients is lacking. We sought to determine whether there is an elevated prevalence of adenomatous colorectal polyps in young survivors prior to the age when screening would be routinely recommended.DesignWe conducted a prospective study of early colonoscopic screening in cancer survivors aged 35–49 who had received ART ≥10 years previously. The planned sample size was based on prior studies reporting a prevalence of adenomatous polyps of approximately 20% among the average-risk population ≥50 years of age, in contrast to ≤10% among those average-risk people aged 40–50 years, for whom screening is not routinely recommended.ResultsColonoscopy was performed in 54 survivors, at a median age of 45 years (range 36–49) and after median interval from radiation treatment of 19 years (10.6–43.5). Forty-nine polyps were detected in 24 patients, with 15 patients (27.8%; 95% CI 17.6% to 40.9%) having potentially precancerous polyps. Fifty-three per cent of polyps were within or at the edge of the prior ART fields.ConclusionsYoung survivors treated with ART have a polyp prevalence comparable with the average-risk population aged ≥50 years and substantially higher than previously reported for the average-risk population aged 40–50 years. These findings lend support to the early initiation of screening in these survivors.Clinical trial registration numberNCT00982059; results.

This topic addresses the treatment of newly diagnosed patients with favorable prognosis stage I and II Hodgkin lymphoma. In most cases, combined modality therapy (chemotherapy followed by involved site radiation therapy) constitutes the current standard of care. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. By combining the most recent medical literature and expert opinion, this revised guideline can aid clinicians in the appropriate use of combined modality therapy for favorable prognosis stage I and II Hodgkin lymphoma. Increasing information about the late effects of treatment has led to attempts to decrease toxicity by using less chemotherapy (decreased duration and/or intensity or different agents) and less radiation therapy (reduced volume and/or dose) while maintaining excellent efficacy.

This multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT). Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. Patients who achieved a negative positron emission tomography (PET) scan (Deauville score of 1-3) received 30 Gy ISRT. Thirty patients received treatment and were assessable for toxicity. Twenty-nine patients completed 4 cycles of BV + AVD, and 25 patients BV + AVD + 30 Gy ISRT. No clinically significant noninfectious pneumonitis was observed. Serious adverse events (≥grade 3) were reported in 4 patients, including febrile neutropenia, peripheral neuropathy, and hypertension. After 2 and 4 cycles of BV + AVD, 90% (26 of 29) and 93% (27 or 29) of patients achieved a negative PET scan, respectively. Two patients with biopsy-proven primary refractory HL were treated off-study. All 25 patients who completed BV + AVD + ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, 84-102). Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients (≥90%) achieved negative interim PET scans after 2 and 4 cycles of BV + AVD. Excluding the 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk. This trial was registered at www.clinicaltrials.gov as #NCT01868451.

These guidelines review the historical evolution of treatment for early-stage Hodgkin lymphoma (HL) with current standards that rely on prognostic factors to risk stratify and direct current treatment schemes that includes differentiation of favorable and unfavorable presentations. The major clinical trials for unfavorable early-stage HL are reviewed. Patients in this heterogenous subgroup of classic HL are best managed with sequential chemotherapy and radiotherapy. The role of imaging response assessment as a means to modify therapy is a strategy under investigation. Tailoring the radiation treatment volume and radiation dose prescription along with selective use of modern conformal techniques is expected to help reduce long-term toxicities. Many patients are well served receiving involved-site radiotherapy to 30 Gy after appropriate systemic therapy intensity; but, there are nuances for which some variations in the chemotherapy and radiotherapy specifics are appropriately individualized. Following a discussion of the current evidence-based treatment algorithms, several different example cases are reviewed to help physicians make appropriate treatment decisions. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

The management of diffuse large B-cell lymphoma depends on the initial diagnosis including molecular and immunophenotypic characteristics, Ann Arbor staging, and International Prognostic Index (IPI score). Treatment approaches with different chemotherapy regimens used is discussed in detail. The role of radiation as a consolidation is discussed including: (1) the prerituximab randomized trials that challenged the role of radiation, (2) recent prospective studies (UNFOLDER/RICOVER-60), and (3) retrospective studies; the last 2 showed a potential benefit of radiation both for early and advanced stage. The document also discusses the role of positron emission tomography/computed tomography for predicting outcome and potentially guiding therapy. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment.

In the S0313 trial, we evaluated the impact of adding ibritumomab tiuxetan consolidation to 3 cycles of standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy plus involved field radiotherapy (IFRT) in patients with limited-stage aggressive B-cell non-Hodgkin lymphoma (LD-NHL). Patients with at least 1 stage-modified adverse risk factor (nonbulky stage II, age >60 years, elevated lactate dehydrogenase, or World Health Organization performance status of 2) were treated with CHOP on days 1, 22, and 43, followed 3 weeks later by 40 to 50 Gy of IFRT. An ibritumomab tiuxetan regimen was initiated 3 to 6 weeks following IFRT. Forty-six patients were registered and eligible, with median follow-up of 7.3 years. The progression-free survival estimate is 89% at 2 years, 82% at 5 years, and 75% at 7 years. The overall survival estimate is 91% at 2 years, 87% at 5 years, and 82% at 7 years. Grade 4 adverse events occurring more than once included neutropenia (8), leukopenia (5), and lymphopenia (2). Febrile neutropenia was observed in 4 patients. No cases of treatment-related myeloid neoplasms were noted. In conclusion, patients with high-risk LD-NHL treated with 3 cycles of CHOP plus IFRT followed by ibritumomab tiuxetan consolidation had outcomes that compare favorably to our historical experience. The clinical trial was registered at www.clinicaltrials.govas #NCT00070018.

Although most patients (pts) with newly diagnosed stage III or IV Hodgkin lymphoma (HL) will be cured with initial therapy (tx), about 20-25% of pts will have relapsed or refractory (R/R) HL. The standard initial tx for adults with advanced stage HL, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), is associated with pulmonary toxicity due to bleomycin. Recent studies have demonstrated that in pts with a negative interim PET scan, the omission of bleomycin after 2 cycles is non-inferior with regards to survival. However, a significant proportion of pts have a positive interim PET scan and require escalation to BEACOPP - an effective but toxic regimen associated with secondary malignancies and infertility. Recently, the addition of brentuximab vedotin (BV) to AVD chemotherapy (BV-AVD) demonstrated improved modified and traditionally-defined progression-free survival (PFS) compared to ABVD. However, the BV-AVD regimen was associated with higher rates of neutropenia, sepsis, and peripheral neuropathy compared to ABVD, and there still was a ~20% failure rate. In adolescent and young adult pts with advanced stage HL, there is a similar ~20% failure rate using ABVE-PC (AB, vincristine, etoposide, prednisone, cyclophosphamide) and response-adapted radiation therapy (RT) - with RT use in a majority of pts. There remains room to improve outcomes in pediatric and adult pts with newly diagnosed advanced stage HL.

The brain is highly vulnerable to neurotoxic agents during the prime learning period of a child's life. Paediatric patients with brain tumours who are treated with cranial radiation therapy (CRT) often go on to develop neurocognitive deficits, which are reflected in poor academic achievement and impaired memory, attention and processing speed. The extent of these delayed effects varies with radiation dose, brain volume irradiated, and age at treatment, and might also be influenced by genetic factors and individual susceptibility. CRT-induced impairment involves axonal damage and disruption of white matter growth, and can affect brain structures implicated in memory function and neurogenesis, such as the hippocampus. In this article, we review the underlying mechanisms and clinical consequences of CRT-induced neurocognitive damage in survivors of paediatric brain tumours. We discuss the recent application of neuroimaging technologies to identify white matter injury following CRT, and highlight new radiation techniques, pharmacological and neurological interventions, as well as rehabilitation programmes that have potential to minimize neurocognitive impairment following CRT.

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. This trial was registered at www.clinicaltrials.govas #NCT00005578.

Introduction

Introduction: Sequential Hodgkin lymphoma (HL) trials of the Children's Oncology Group (COG) have tested treatment strategies intended to reduce late toxicity while maintaining high rates of cure. However, the long latency of the relevant late effects makes it impossible to observe in a timely way the degree to which modifications to protocol-directed treatment will achieve this goal. The purpose of this study was to estimate late cardiac disease risk associated with sequential COG trial protocols using established risk models.

The late effects of current treatments for childhood cancer increase the risk of morbidity and mortality and diminish the quality of life in long-term survivors. We selectively review the negative late cardiac, endocrine, and neurological effects of childhood cancer and its treatments and comment on current research and recommendations for the care of long-term survivors of childhood cancer.

We questioned whether children with optic pathway tumors (OPTs) have an increased frequency of other CNS tumors on the basis of experience with a number of such children treated at our institution. The medical records of all patients with OPTs treated at Golisano Children's Hospital at Strong at the University of Rochester from 1957 to 2000 were reviewed to determine the incidence of additional CNS tumors in these children and whether the occurrence of these other CNS tumors is associated with any risk factors. Twenty-six children had OPTs. Twelve of the 26 children had biopsy-proved tumors; the remaining 14 were diagnosed on the basis of CT or MRI scans. Eight of the 26 patients (31%) had a total of 11 additional CNS tumors. (One child had 2 additional CNS neoplasms, and a second child had 3.) Nine were biopsy proved (3 glioblastoma, 3 anaplastic astrocytoma, 3 low-grade astrocytoma), and 2 were diagnosed by imaging studies alone (acoustic neuromas). Eight of the 11 tumors occurred at a median of 5 years (0.8-25 years) subsequent to the diagnosis of the OPTs; 3 were diagnosed simultaneously with the OPT. Of the 17 children with neurofibromatosis (NF) and OPTs, 8 (47%) had additional CNS tumors, while none of the 9 children (0%) without NF had other CNS tumors (P = 0.023). There was no association between radiation treatment of the primary OPT and subsequent development of other CNS tumors in the group as a whole, or when the analysis was confined to children with NF. Despite this lack of statistical association, all 7 CNS tumors that occurred following radiation arose in irradiated areas. The risk of simultaneous or subsequent CNS tumors in children with NF and OPTs is high. These children should be closely monitored for the simultaneous or subsequent occurrence of other CNS tumors.

ObjectiveTo investigate the impact of modifications to contemporary cancer protocols, which minimize exposures to cardiotoxic treatments and preserve long term health, on serious cardiac outcomes among adult survivors of childhood cancer.DesignRetrospective cohort study.Setting27 institutions participating in the Childhood Cancer Survivor Study.Participants23 462 five year survivors (6193 (26.4%) treated in the 1970s, 9363 (39.9%) treated in the 1980s, and 7906 (33.6%) treated in the 1990s) of leukemia, brain cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, renal tumors, neuroblastoma, soft tissue sarcomas, and bone sarcomas diagnosed prior to age 21 years between 1 January 1970 and 31 December 1999. Median age at diagnosis was 6.1 years (range 0-20.9) and 27.7 years (8.2-58.3) at last follow-up. A comparison group of 5057 siblings of cancer survivors were also included.Main outcome measuresCumulative incidence and 95% confidence intervals of reported heart failure, coronary artery disease, valvular heart disease, pericardial disease, and arrhythmias by treatment decade. Events were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events. Multivariable subdistribution hazard models were used to estimate hazard ratios by decade, and mediation analysis examined risks with and without exposure to cardiotoxic treatments.ResultsThe 20 year cumulative incidence of heart failure (0.69% for those treated in the 1970s, 0.74% for those treated in the 1980s, 0.54% for those treated in the 1990s) and coronary artery disease (0.38%, 0.24%, 0.19%, respectively), decreased in more recent eras (P<0.01), though not for valvular disease (0.06%, 0.06%, 0.05%), pericardial disease (0.04%, 0.02%, 0.03%), or arrhythmias (0.08%, 0.09%, 0.13%). Compared with survivors with a diagnosis in the 1970s, the risk of heart failure, coronary artery disease, and valvular heart disease decreased in the 1980s and 1990s but only significantly for coronary artery disease (hazard ratio 0.65, 95% confidence interval 0.45 to 0.92 and 0.53, 0.36 to 0.77, respectively). The overall risk of coronary artery disease was attenuated by adjustment for cardiac radiation (0.90, 0.78 to 1.05), particularly among survivors of Hodgkin lymphoma (unadjusted for radiation: 0.77, 0.66 to 0.89; adjusted for radiation: 0.87, 0.69 to 1.10).ConclusionsHistorical reductions in exposure to cardiac radiation have been associated with a reduced risk of coronary artery disease among adult survivors of childhood cancer. Additional follow-up is needed to investigate risk reductions for other cardiac outcomes.Trial registrationClinicalTrials.gov NCT01120353.

Introduction:The standard therapy for early stage, unfavorable risk Hodgkin lymphoma (HL) with disease bulk is combined modality therapy, typically 4-6 cycles of ABVD followed by 30Gy involved-site radiotherapy (ISRT) (Eich JCO 2010). In this pilot study with four sequential cohorts, we studied whether consolidative radiotherapy could be reduced or eliminated in early stage, unfavorable risk HL patients treated with brentuximab vedotin (BV) and AVD chemotherapy. In the first cohort, we demonstrated that BV+AVD and 30Gy ISRT had an acceptable safety profile without significant pulmonary toxicity and promising efficacy (Kumar Blood 2016). In subsequent cohorts, we tested whether the ISRT dose could be reduced to 20Gy (cohort 2), the RT field could be reduced with consolidation volume radiation (CVRT; cohort 3), and whether radiation therapy could be eliminated (cohort 4).

Persky: Sandoz: Consultancy; Morphosys: Other: Member, Independent Data Monitoring Committee; Debiopharm: Other: Member, Independent Data Monitoring Committee; Bayer: Consultancy. Stephens:Acerta: Research Funding; Karyopharm: Research Funding; Gilead: Research Funding. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Bartlett:Seattle Genetics: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Pfizer: Research Funding; Millenium: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Genenetech: Research Funding; Immune Design: Research Funding; Gilead: Research Funding; Forty Seven: Research Funding; Janssen: Research Funding; Affimed: Research Funding; Merck: Research Funding; Pharmacyclics: Research Funding. Swinnen:Pharmacyclics: Consultancy; AbbVie: Consultancy. Barr:Celgene: Consultancy; Merck: Consultancy; Seattle Genetics: Consultancy; Genentech: Consultancy; Verastem: Consultancy; Gilead: Consultancy; Astra Zeneca: Consultancy, Research Funding; Janssen: Consultancy; AbbVie: Consultancy; Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Leonard:Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy; Miltenyi: Consultancy; ADC Therapeutics: Consultancy; Nordic Nanovector: Consultancy; Akcea Therapeutics: Consultancy; Sandoz: Consultancy; ADC Therapeutics: Consultancy; Miltenyi: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Karyopharm Therapeutics: Consultancy; Epizyme, Inc: Consultancy; Sutro Biopharma: Consultancy; AstraZeneca: Consultancy; AstraZeneca: Consultancy; Bayer Corporation: Consultancy; Bayer Corporation: Consultancy; Celgene: Consultancy; Epizyme, Inc: Consultancy; Celgene: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Karyopharm Therapeutics: Consultancy; Gilead: Consultancy; Sutro Biopharma: Consultancy; BeiGene: Consultancy; Merck: Consultancy; MorphoSys: Consultancy; Sandoz: Consultancy. Kahl:TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy; BeiGene: Consultancy. Fisher:Celgene: Consultancy; AstraZeneca: Consultancy; Barclays: Honoraria; prIME: Honoraria. Rimsza:NanoSting: Patents & Royalties: Named inventor on a patent licensed to NanoSting [Institution]. Smith:Portola Pharmaceuticals: Research Funding. Friedberg:Bayer: Honoraria, Other: Data & Safety Monitoring Committee; Acerta: Other: Data & Safety Monitoring Committee.Ibritumomab tiuxetan in diffuse large B-cell lymphoma

No abstract.

Background:The role of radiation therapy (XRT) for advanced stage Hodgkin lymphoma (HL) is controversial. In the HD15 trial, the German Hodgkin Study Group (GHSG) administered XRT for PET-positive residual disease ≥2.5 cm at least 2 weeks after completion of chemotherapy and showed 91.5 % in-field control rate with a median follow-up of 102 months (Engert, A; personal communication). However, there is no comparison arm where patients with PET-positive residual disease ≥2.5 cm did not receive XRT. SWOG S0816 was a US intergroup trial utilizing ABVD-based therapy with response adaptation based on interim PET imaging; XRT was not allowed per protocol, and counted as an event. In this analysis, we identified patients in S0816 who would have met HD15 criteria for XRT, but did not receive XRT per design. We then modeled the potential impact of XRT on disease control.

Introduction

Kumar: Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Casulo: Gilead: Honoraria, Other: travel support; Celgene: Research Funding; Infinity: Consultancy. Advani: Sutro: Consultancy; Nanostring: Consultancy; Celgene: Research Funding; Agensys: Research Funding; Spectrum: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Juno Therapeutics: Consultancy; Gilead: Consultancy; Regeneron: Research Funding; Millennium: Research Funding; Bayer Healthcare Pharmaceuticals: Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Genentech: Research Funding; Merck: Research Funding; Infinity: Research Funding; Kura: Research Funding; Cell Medica: Research Funding; Pharmacyclics: Consultancy. Barr: Gilead: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Infinity: Consultancy; Seattle Genetics: Consultancy; Novartis: Consultancy; Celgene: Consultancy; AbbVie: Consultancy, Research Funding. Chen: Affimed: Research Funding; Pfizer: Consultancy; Merck: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Speakers Bureau; Pharmacyclics: Consultancy, Research Funding. Drullinsky: Seattle Genetics: Honoraria, Other: Ad Board. Friedberg: Bayer HealthCare Pharmaceuticals.: Other: Data and Safety Monitoring Board: Bayer HealthCare Pharmaceuticals.. Gerecitano: Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Aratana: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Royal Bank of Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Arcus Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees; Samus Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Orexo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mass Medical International: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hamlin: Gilead: Consultancy, Honoraria; Seattle Geneitcs: Other: research support; Incyte: Other: research support; Novartis: Other: research support; Celgene: Consultancy, Honoraria; Portola: Consultancy, Honoraria, Other: research support. Horwitz: Kyowa Hakko Kirin: Consultancy, Research Funding; BMS: Consultancy; Mundipharma: Consultancy; Aileron Therapeutics: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; HUYA: Consultancy; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; Spectrum Pharmaceuticals: Research Funding; Millennium Pharmaceuticals, Inc.: Consultancy; ADCT Therapeutics: Research Funding; Celgene: Consultancy, Research Funding. Moskowitz: ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Incyte: Research Funding; Takeda: Honoraria; Seattle Genetics: Honoraria, Research Funding. Noy: Pharmacyclics LLC, an AbbVie Company: Honoraria, Other: Travel, Accommodation, Expenses, Research Funding, Speakers Bureau. Palomba: Merck: Consultancy. Straus: Received consulting fee from Seattle Genetics for involvement in the research: Consultancy. Younes: Takeda Millenium: Honoraria; Johnson & Johnson: Research Funding; Roche: Consultancy, Honoraria, Other: Third-party medical writing assistance, under the direction of Anas Younes, was provided by Scott Malkin of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd.; Curis: Research Funding; Seattle Genetics: Honoraria; Sanofi: Honoraria; Merck: Honoraria; Janssen: Honoraria; Incyte: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Bayer: Honoraria; Novartis: Research Funding. Zelenetz: Celgene: Consultancy; Amgen: Consultancy. Moskowitz: Genentech BioOncology: Consultancy; Pharmacyclics: Research Funding; Merck: Consultancy, Research Funding; Seattle Genetics: Consultancy, Other: Ad Board, Research Funding; Celgene: Consultancy.

Introduction

Porcu: miRagen: Other: Investigator in a clinical trial; celgene: Other: Investigator in a clinical trial; Millenium: Other: investigator in a clinical trial; Innate Pharma: Other: Investigator in a clinical trial. Winter:Pharmacyclics: Research Funding; Medivation: Other: Provision of investigational agent for clinical trial; Seattle Genetics: Research Funding; GSK: Research Funding. Kahl:This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under the following award number: Research Funding. Smith:Juno: Consultancy; TGTX: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Gilead: Consultancy; Portola: Consultancy; Amgen: Other: Educational lecture to sales force; Pharmacyclics: Consultancy. Rimsza:NCI/NIH: Patents & Royalties: L.M. Rimsza is a co-inventor on a provisional patent, owned by the NCI of the NIH, using Nanostring technology for determining cell of origin in DLBCL.. Fisher:Gilead: Consultancy; Seattle Genetics: Consultancy; Johnson and Johnson: Consultancy. Friedberg:Bayer: Honoraria, Other: Data Safety Monitoring Board.

Asselin: Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Lipshultz:Clinigen Group: Consultancy, Other: Travel/accommodations for consulting related meeting; Pfizer: Research Funding; Roche Diagnostics: Research Funding.

No relevant conflicts of interest to declare.

The major risk for patients with recurrent or refractory Hodgkin Disease (HD) who receive standard treatment with high-dose chemotherapy and autologous hematopoietic stem cell rescue (ASCR) is relapse. However, in HD, the allogeneic graft-vs.-lymphoma effect is offset by high transplant-related mortality. The Children’s Oncology Group has completed a pilot study of immunotherapy using cyclosporine, interferon-γ, and interleukin-2 to induce autologous graft-vs.-host disease (auto GVHD) in an effort to reduce the relapse rate without excessive morbidity and mortality. From 11/2003 to 2/2005, 24 patients with biopsy-confirmed recurrent/refractory HD were enrolled at 13 COG stem cell transplant institutions. One patient was inevaluable because of errors in protocol administration. At initial diagnosis, 5 were stage IV, 8 stage III, 7 stage II, 1 stage 1, and 3 unknown; 16 had B symptoms, and 15 had bulky disease. All patients had failed intensive multi-agent chemotherapy, and most had received prior radiation therapy. High risk patterns of relapse included extranodal disease (8), B symptoms (3), and bulky disease (2). We have previously presented the tolerability of this regimen, with the expected reversible complications and 4% non-relapse mortality. Moreover, we detected circulating autoreactive lymphocytes in vitro from the majority of patients during immunotherapy. These autoreactive lymphocytes respond to the HLA class II invariant peptide (CLIP). We therefore isolated these cells from selected patients by flow cytometry after staining with CLIP-DR2 tetramers, and demonstrated high perforin expression in CD8+ effector cells early in the course of immunotherapy, and a subsequent rise of FOXP3 expression in CD4+ regulatory T cells later in the course of immunotherapy. Importantly, CLIP was strongly expressed on the surface of Hodgkin Reed-Sternberg cells, as demonstrated by monoclonal antibody LN2 immunostaining of tumor samples from 8/9 patients for whom adequate tissue was submitted. To date, only 6 relapses have been reported. Updated event-free and overall survival data will be presented. We conclude that this immunotherapy regimen is tolerable, induces autoreactivity in a majority of patients, targets a molecule expressed consistently on Hodgkin Reed-Sternberg cells, and has produced encouraging clinical outcomes. We will proceed to test the efficacy of this immunotherapy regimen by randomizing patients with chemosensitive recurrent/refractory HD to receive immunotherapy or not after BEAM and ASCR.

Introduction: Patients with recurrent or refractory Hodgkin (HL) and non-Hodgkin lymphoma (NHL) treated with high dose chemotherapy and autologous stem-cell rescue (ASCR) commonly relapse (post-ASCR) (70–90%) in sites of previous disease. Although adjuvant involved field radiation therapy (IFRT) to sites of previous recurrence might be expected to enhance local control, translation of this into improved disease-free (DFS) or overall survival (OS) is controversial. We sought to evaluate IFRT following ASCR in terms of patterns of recurrence, OS and DFS. Methods and Materials: All 281 patients with recurrent or refractory HL and NHL who underwent ASCR between 5/92 and 7/03 were analyzed. Disease stratification at the time of transplant included HL, 24%, aggressive NHL (ANHL) 62%, and indolent NHL (INHL) 14%. Most, 46% underwent ASCR after 1st relapse, 18% after 2nd relapse, 4% after 3rd relapse and 26% had refractory disease at ASCR. IFRT was administered to 129 patients (46%). Physician and patient choice determined which patients received IFRT. Dose ranged from 20–36 Gy depending on response to salvage therapy before ASCR and the presence of visible imaging abnormalities following ASCR. For end point analysis 39 patients (14%) including 11 HL, 23 ANHL, and 5 INHL had insufficient data and were excluded. Results: Mean follow-up was 3 years (.3 – 12). The median age at ASCR was 45 years (8 – 73). Male to female ratio was 1.3:1. Thirty five percent of patients had prior RT. On univariate analysis, OS and DFS following IFRT for ANHL was superior (or approached this statistically) at 5 years. For HL, improved OS approached significance, whereas DFS did not despite an apparent benefit by disease-free percentages. IFRT appears to be disadvantageous in INHL, but patient numbers were very small. OS and DFS at 5 years are in the table. Survival Table 5-year OS (%) 5-year DFS (%) HL With IFRT 62 79 Without IFRT 37 68 p-value .07 .41 Aggressive NHL With IFRT 57 65 Without IFRT 37 49 p-value .02 .07 Indolent HNL With IFRT 50 67 Without IFRT 85 88 p-value .06 .30 On multivariate analysis, for ANHL, IFRT was protective (p = .002, Hazard Ratio = 0.39) and bulky disease was adverse (p = .04, HR = 2.04). For HL, an advantage of IFRT did not reach statistical significance (p = .63, HR = .8). For INHL, IFRT was associated with an inferior outcome (p = .23, HR = 4.9). Conclusion: Recognizing that bias exists in patient selection for IFRT post-ASCR (in both directions), a survival benefit appears to exist for patients with ANHL, and potentially for those with HL. The absence of a difference in DFS may relate to relapses in other sites or competing events with censored data. Longer follow-up or larger patient numbers are necessary to confirm a long- term improvement. INHL did not benefit from IFRT as might be expected since this group is more likely to have occult disseminated, chemotherapy insensitive disease. Determination of specific patterns of disease recurrence is in progress.

Conditioning regimens utilized in reduced intensity transplants are designed to optimize immune suppression to allow a graft vs. tumor effect. One reduced intestiy regimen reported to result in a reduced incidence of GVHD while demonstrating disease response consists of extracorporeal photopheresis, pentostatin, 4 mg/m2/day X 2, and reduced dose total body irradiation(TBI; 600 cGy given in 3 fractions) (Miller KB et al; BMT 2004; 34:881–9). This regimen has been utilized in our center in 45 patients who have at least 6 months of follow up. All were ineligible for a conventional conditioning regimen, and from 3/03, this regimen was utilized for all reduced intensity transplants with exception of those wherein prior radiation precluded this dose of TBI. The median age of the patients was 55 years with age range 27 through 67 years. Thirty-three of the patients were 50 years of age or older. Twenty-five patients received sibling and 20 an unrelated donor (UD) transplant. All but one sibling transplant was a 6/6 match, whereas 8/20 of the UD transplants involved mismatched loci. GVHD prophylaxis consisted of tacrolimus and short course methotrexate in 43, tacrolimus/MMF in 1, and tacrolimus/sirolimus in 1. Seventeen patients had AML, 3 MDS, 2 ALL, 2 CML, 11 CLL, and 8 NHL. One had HD, and one had Waldenstrom's. Eight of the 45 had prior stem cell transplantation. The median number of CD34+ cells infused was 4.54 X 106/kg recipient weight. Nine patients were transplanted in CR or early disease phase. The remainder had more advanced stages of disease. Five patients died before anticipated neutrophil recovery. Two others had no neutrophil nadir, and median time to neutrophil engraftment in the remainder was 14.5 days. In those evaluable for platelet engraftment, the median time to engraftment was 18.7 days. For those surviving to approximately Day+30, the median donor chimerism as assessed by VNTRs was 94% (range 34%–100%). The overall Day 100 survival was 69% (31/45), with 80%(20/25) of sibling graft recipients alive and 55% (11/20) of UD recipients still living. Twelve patients developed regimen related toxicity. In five, this manifested as ARDS or multi-organ failure with a capillary leak syndrome, and 2 had renal failure. Ten patients had disease resistance or relapse after transplant, and all of those have died. The overall survival to date is 42%; 48% for sibling transplant recipients and 35% for UD recipients with range of follow up in survivors from 283 to 1366 days (median 535 days). Acute GVHD of grade III or IV was seen in only 3 patients. For those surviving past 100 days, 27% had extensive GVHD. No patients transplanted with this regimen for AML not in remission survived. Only one patient with NHL not in CR or a chemotherapy sensitive relapse state survived. This conditioning regimen of extracorporeal photopheresis, pentostatin, and TBI therefore appears most effective for patients with AML in first or greater remission or for CLL patients in early relapse with responsive disease. The regimen was associated with a capillary leak/organ failure syndrome in seven patients but was otherwise well-tolerated. Its long-term effects on GVHD incidence and coincident graft vs. malignancy benefit remain to be better understood as compared to other reduced intensity regimens which do not contain extracorporeal photopheresis.

For patients with recurrent and refractory Hodgkin Disease (HD), the major risk after standard treatment with high-dose chemotherapy and autologous hematopoietic stem cell rescue (ASCR) is relapse. In the setting of allogeneic SCT, the graft-vs.-lymphoma effect is offset by high transplant-related mortality. The Children’s Oncology Group has therefore undertaken a study of immunotherapy to induce autologous graft-vs.-host disease (auto GVHD) in an effort to reduce the relapse rate without excessive morbidity and mortality. The objectives of part I of the study were to determine the toxicity and feasibility of inducing auto GVHD with cyclosporine, interferon-γ , and IL-2 after high-dose BEAM. Twenty-four patients with biopsy-confirmed recurrent/refractory HD were enrolled at 13 institutions. One patient was inevaluable because of a protocol violation. At initial diagnosis, 5 were stage IV, 8 stage III, 7 stage II, 1 stage I, and 3 unknown; 16 had B symptoms, and 15 had bulky disease. All patients had failed intensive multi-agent chemotherapy, and most had received prior radiation therapy. At relapse, 3 patients had B symptoms and 2 had bulky disease, and 8 had extranodal disease. All patients received full doses of the preparative regimen, with the expected reversible complications of febrile neutropenia, pancytopenia, nausea, vomiting, anorexia, mucositis, and electrolyte disturbances. In addition to fever, fatigue, and cytopenias, two patients developed pneumonitis after receiving immunotherapy, one of whom died of respiratory failure 6 wks after study entry. Of note, this patient received only 2 doses of IL-2 before developing pneumonitis. Bronchoalveolar lavage failed to demonstrate an etiology, but a culture obtained by open lung biopsy was positive for staphylococcus epidermidis. One patient developed a rash and one patient developed liver function abnormalities during the immunotherapy consistent with auto GVHD. Toxicities Toxicity RT/BEAM/ASCR Immunotherapy n = 16 n = 15 Febrile neutropenia 11 (69%) 4 (27%) Nausea/vomiting/anorexia 10 (63%) 3 (20%) Mucositis 7 (44%) 2 (13%) Metabolic/lab 8 12 Pneumonitis 0 2 (13%) Fever 0 2 (13%) Fatigue 0 2 (13%) Hypotension 1 (6%) 0 Blood was requested at weekly intervals during immunotherapy administration to test for autoreactivity in mixed lymphocyte cultures and by cytokine assays with autologous stimulator cells. The sample submission rate was 90%. In 11 of 14 patients, there was significant in vitro lymphocyte autoreactivity. We conclude that this immunotherapy regimen is tolerable and induces autoreactivity in a sufficient proportion of patients to warrant proceeding with part II of the study. Part II will test the efficacy of immunotherapy by randomizing patients with chemosensitive recurrent/refractory HD to receive immunotherapy or not after BEAM and ASCR.

Hodgkin Lymphoma (HL) is a B cell malignancy, highly curable in the modern era (1989–2004). It is the most common cancer in the 15–19 age range. In the United States, adolescents with de novo HL may be treated on either pediatric or adult protocols. To identify outcomes of adolescents with HL, we conducted a comprehensive literature review and statistical analysis of all treatment trials (N > 50 pts) published in the past 15 years. Trials were selected for their relevance to treatment and disease outcome in adolescents with the following search criteria: Hodgkins disease, therapy, treatment, adolescents (13–18 years), and adults (19–44 years). The search retrieved 120 randomized control trials and 57 Phase II trials. 117 trials were eliminated due to inappropriate histology, non-clinical endpoints, topic reviews or otherwise not meeting established criteria. 79 studies were eligible for analysis. 15 pediatric treatment protocols (13 multi-center, 7 randomized) met established criteria. 7 identified the number of adolescents on trial (N=958/2675; 36%). Only 3 of these studies evaluated adolescent outcome; one trial demonstrated an inferior event-free survival for the adolescent subgroup vs. all children (72.0% vs. 89.0%; p-value 0.006, Chi Square Test). 57 adult treatment studies (39 multi-center, 44 randomized) were reviewed. 7 identified the number of adolescents on trial (N=422/2522; 17%). Only one provided information on adolescent outcome, which experienced a superior overall survival compared with the entire population (86.0% vs. 73.1%; p-value 0.030, Chi Square Test). None of the trials with both pediatric and adult subjects (7 multi-center, 4 randomized) provided information on the adolescent subgroup. In comparing pediatric and adult trials, we found remarkable differences in therapeutic approaches (all pediatric studies included XRT as a treatment component compared to 58% of adult studies) and in trial design (77% of adult studies were randomized compared to 47% of pediatric studies; p-value 0.0234, Fishers Exact Test). The adolescent population with HL is significantly understudied despite reasonable clinical trial participation and relatively high prevalence. In fact, only 4 published trials provided outcome information on adolescents with HL; in 2, outcome was statistically different from the rest of the study population, suggesting this subgroup may benefit from a specialized treatment approach. It is critical for future treatment trials to analyze results of the adolescent population to determine whether unique biological features, therapeutic practices, or host factors contribute to prognosis and outcome.

The complexity of the field of pediatric oncology is reflected by the need for a variety of professionals to provide an integrated approach to the care of a child with cancer. In Pediatric Oncology, Philip Lanzkowski has successfully selected and arranged information that will be useful to clinicians involved in treating children with malignant neoplasms. The text is concise, practical, and readable, with generous use of appropriate tables and figures. All but two chapters were written by persons from the editor's institution, the State University of New York at Stony Brook School of Medicine/Long Island Jewish-Hillside Medical Center. The result is a consistency in approach and organization of the specific tumor-oriented chapters, which cover incidence, etiology, pathogenesis, pathology, clinical manifestations, diagnostic techniques, treatment, complications, and strategies for long-term follow-up of all commonly encountered pediatric malignant neoplasms.Individual chapters present a wealth of practical information not commonly found in texts of