Lu Chen

Children's Oncology Group, Monrovia, California, United States

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Publications (15)148.7 Total impact

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    ABSTRACT: 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.
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 10/2014;
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    ABSTRACT: Background We assessed the safety and efficacy of ifosfamide and vinorelbine (IV) as a less toxic and effective reinduction regimen for pediatric patients with relapsed or refractory Hodgkin Lymphoma.ProcedureThis multi-center Children's Oncology Group phase II pilot study enrolled patients <30 years of age with biopsy-proven Hodgkin Lymphoma in relapse or refractory disease after front-line therapy. Treatment consisted of ifosfamide 3,000 mg/m2 intravenous infusion over 24 hr on Days 1–4 and vinorelbine 25 mg/m2/dose intravenous push on Days 1 and 5 of each 21 day cycle with cytokine support. The study endpoints included estimation of key toxicities (cardiac, hepatic, or renal toxicity or toxic death), the rate of successful peripheral stem cell harvesting, and response after two cycles of therapy.ResultsSixty-six patients received a median of two cycles of IV. Sixty-four of 66 were heavily pretreated, 4 had refractory disease, 55% were male and 79% had nodular sclerosis HL. The primary toxicities were hematologic. Harvested peripheral stem cells were sufficient for autologous transplantation in 46 of 54 patients for whom stem cell collection was attempted. The overall response rate (72%; 95% CI 59–83%) permitted the majority of patients to undergo subsequent stem cell transplantation.ConclusionsIV is a safe and effective re-induction regimen for salvage of pediatric patients with relapsed or refractory Hodgkin Lymphoma with an excellent response rate and success of post chemotherapy stem cell harvest. It avoids the use of etoposide, an agent associated with secondary malignancy after stem cell transplantation. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 10/2014; · 2.35 Impact Factor
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    ABSTRACT: The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed. By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease. By using a matched case-control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 × 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09). Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure.
    Journal of Clinical Oncology 01/2014; · 18.04 Impact Factor
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    ABSTRACT: Platinum-based therapy is the mainstay for management of high-risk neuroblastoma. Prevalence of platinum-related ototoxicity has ranged from 13% to 95% in previous reports; variability is attributable to small samples and disparate grading scales. There is no consensus regarding optimal ototoxicity grading. Furthermore, prevalence and predictors of hearing loss in a large uniformly treated high-risk neuroblastoma population are unknown. We address these gaps in our study. Audiologic testing was completed after administration of cisplatin alone (< 400 mg/m(2); exposure one) or after cisplatin (400 mg/m(2)) plus carboplatin (1,700 mg/m(2); exposure two). Hearing loss was graded using four scales (American Speech-Language-Hearing Association; Brock; Chang; and Common Terminology Criteria for Adverse Events, version 3 [CTCAEv3]). Of 489 eligible patients, 333 had evaluable audiologic data. Median age at diagnosis was 3.3 years. Prevalence of severe hearing loss differed by scale. For those in the exposure-one group, prevalence ranged from 8% per Brock to 47% per CTCAEv3 (Brock v CTCAEv3 and Chang, P < .01; CTCAEv3 v Chang, P = .16); for those in the exposure-two group, prevalence ranged from 30% per Brock to 71% per CTCAEv3 (all pair-wise comparisons, P < .01). In patients requiring hearing aids, hearing loss was graded as severe in 49% (Brock), 91% (Chang), and 100% (CTCAEv3). Risk factors for severe hearing loss included exposure to cisplatin and carboplatin compared with cisplatin alone and hospitalization for infection. Severe hearing loss is prevalent among children with high-risk neuroblastoma. Exposure to cisplatin combined with myeloablative carboplatin significantly increases risk. The Brock scale underestimates severe hearing loss and should be used with caution in this setting.
    Journal of Clinical Oncology 01/2014; · 18.04 Impact Factor
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    ABSTRACT: Therapy for childhood acute myeloid leukemia (AML) has historically included chemotherapy with or without autologous bone marrow transplant (autoBMT) or allogeneic hematopoietic stem cell transplantation (alloBMT). We sought to compare health-related quality-of-life (HRQOL) outcomes between these treatment groups. Five-year survivors of AML diagnosed before age 21 and enrolled and treated from 1979 to 1995 on one of 4 national protocols were interviewed. These survivors or proxy caregivers completed a health questionnaire and an HRQOL measure. Of 180 survivors, 100 were treated with chemotherapy only, 26 with chemotherapy followed by autoBMT, and 54 with chemotherapy followed by alloBMT. Median age at interview was 20 years (range 8-39). Twenty-one percent reported a severe or life-threatening chronic health condition (chemotherapy-only 16% vs. autoBMT 21% vs. alloBMT 33%; P = 0.02 for chemotherapy-only vs. alloBMT). Nearly all (95%) reported excellent, very good or good health. Reports of cancer-related pain and anxiety did not vary between groups. HRQOL scores among 136 participants ≥14 years of age were similar among groups and to the normative population, though alloBMT survivors had a lower physical mean summary score (49.1 alloBMT vs. 52.2 chemotherapy-only; P = 0.03). Multivariate analyses showed the presence of severe chronic health conditions to be a strong predictor of physical but not mental mean summary scores. Overall HRQOL scores were similar among treatment groups, although survivors reporting more health conditions or cancer-related pain had diminished HRQOL. Attention to chronic health conditions and management of cancer-related pain may improve QOL. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 11/2013; · 2.35 Impact Factor
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    ABSTRACT: In childhood Hodgkin lymphoma, estimated 5 years survival rates exceed 90%. Long-term survival continues to decline from delayed toxicities. Key findings from recent Children's Oncology Group trials include: (1) Radiotherapy selection may be based on early chemotherapy response assessed by both FDG-PET and CT imaging, (2) A new prognostic factor score stratifies patients into risk categories; and (3) novel retrieval regimens were identified. A phase I/II trial is investigating Brentuximab vedotin (Bv) with gemcitabine in relapsed patients. A phase 3 trial will modify conventional chemotherapy and radiotherapy approaches through the addition of Bv, while incorporating translational biology to identify molecular targets. Pediatr Blood Cancer © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 12/2012; · 2.35 Impact Factor
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    ABSTRACT: Treatment of pediatric lymphocyte-predominant Hodgkin lymphoma (LPHL) is controversial but has typically consisted of both chemotherapy and radiation. Radiation therapy is associated with potential late effects in children and adolescents. We examined the impact of radiation therapy on long-term outcome of patients with LPHL treated on CCG-5942, a large pediatric cooperative group study of Hodgkin lymphoma (HL). Eighty-two patients with LPHL were registered on CCG-5942. Fifty-two patients (63%) received chemotherapy alone; 29 patients (35%) received chemotherapy followed by involved-field radiation therapy (IFRT). The median follow-up of the LPHL patients is 7.7 years; 63 patients (77%) have >5 years of follow-up. The 5-year event-free survival (EFS) and overall survival (OS) were 97% and 100%. Two relapses occurred, both in patients who did not receive IFRT. There were no significant differences in EFS or OS between patients who received or did not receive IFRT. This subset analysis demonstrates the chemosensitivity of pediatric LPHL. Patients who had a complete response to chemotherapy had an excellent EFS and OS without the addition of radiotherapy. Pediatr Blood Cancer 2012; 59: 1284-1289. © 2012 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 07/2012; 59(7):1284-9. · 2.35 Impact Factor
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    ABSTRACT: PURPOSE Children with Hodgkin's lymphoma (HL) routinely undergo surveillance computed tomography (CT) imaging for up to 5 years after therapy, resulting in cost and radiation exposure, without clear benefit. The objective of this study was to determine the contribution of surveillance CT, as compared with clinical findings, to detection of disease recurrence. PATIENTS AND METHODS Two hundred sixteen patients, age ≤ 21 years old, were treated on the multicenter Pediatric Oncology Group 9425 trial. Data for patients who experienced relapse were retrospectively reviewed to determine whether imaging or clinical events prompted suspicion of disease recurrence. Correlation was made to disease stage, time to recurrence, relapse site, and overall survival (OS). Results With a median follow-up time of 7.4 years, 25 (11.6%) of 216 patients had experienced a relapse, of whom 23 experienced local relapse. Median time to relapse was 7.6 months (range, 0.2 to 48.9 months). Nineteen relapses (76%) were detected based on symptoms, laboratory or physical examination findings, and two relapses (8%) were detected by imaging within the first year after therapy. Only four patients (16%) had their recurrence detected exclusively by surveillance imaging after the first year. Six deaths occurred, all in patients who experienced relapse within the first year after therapy. No patient with a recurrence after 1 year off treatment has died, regardless of how the recurrence was detected. CONCLUSION The majority of pediatric HL relapses occurred within the first year after therapy or were detected based on change in clinical status. Detecting late relapse, whether by imaging or clinical change, did not affect OS. These findings indicate that CT is overused for routine surveillance of patients with HL.
    Journal of Clinical Oncology 06/2012; 30(21):2635-40. · 18.04 Impact Factor
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    ABSTRACT: 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.
    Journal of Clinical Oncology 05/2012; 30(26):3174-80. · 18.04 Impact Factor
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    ABSTRACT: Carbonyl reductases (CBRs) catalyze reduction of anthracyclines to cardiotoxic alcohol metabolites. Polymorphisms in CBR1 and CBR3 influence synthesis of these metabolites. We examined whether single nucleotide polymorphisms in CBR1 (CBR1 1096G>A) and/or CBR3 (CBR3 V244M) modified the dose-dependent risk of anthracycline-related cardiomyopathy in childhood cancer survivors. One hundred seventy survivors with cardiomyopathy (patient cases) were compared with 317 survivors with no cardiomyopathy (controls; matched on cancer diagnosis, year of diagnosis, length of follow-up, and race/ethnicity) using conditional logistic regression techniques. A dose-dependent association was observed between cumulative anthracycline exposure and cardiomyopathy risk (0 mg/m(2): reference; 1 to 100 mg/m(2): odds ratio [OR], 1.65; 101 to 150 mg/m(2): OR, 3.85; 151 to 200 mg/m(2): OR, 3.69; 201 to 250 mg/m(2): OR, 7.23; 251 to 300 mg/m(2): OR, 23.47; > 300 mg/m(2): OR, 27.59; P(trend) < .001). Among individuals carrying the variant A allele (CBR1:GA/AA and/or CBR3:GA/AA), exposure to low- to moderate-dose anthracyclines (1 to 250 mg/m(2)) did not increase the risk of cardiomyopathy. Among individuals with CBR3 V244M homozygous G genotypes (CBR3:GG), exposure to low- to moderate-dose anthracyclines increased cardiomyopathy risk when compared with individuals with CBR3:GA/AA genotypes unexposed to anthracyclines (OR, 5.48; P = .003), as well as exposed to low- to moderate-dose anthracyclines (OR, 3.30; P = .006). High-dose anthracyclines (> 250 mg/m(2)) were associated with increased cardiomyopathy risk, irrespective of CBR genotype status. This study demonstrates increased anthracycline-related cardiomyopathy risk at doses as low as 101 to 150 mg/m(2). Homozygosis for G allele in CBR3 contributes to increased cardiomyopathy risk associated with low- to moderate-dose anthracyclines, such that there seems to be no safe dose for patients homozygous for the CBR3 V244M G allele. These results suggest a need for targeted intervention for those at increased risk of cardiomyopathy.
    Journal of Clinical Oncology 11/2011; 30(13):1415-21. · 18.04 Impact Factor
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    ABSTRACT: The International Harmonization Project defined complete response (CR) after treatment for Hodgkin disease (HD) by absence of fluorodeoxyglucose avidity, regardless of the size of residual masses. Residual avidity after initial treatment is known to predict inferior survival. In the setting of retrieval therapy, early positron emission tomography (PET) scans may improve assessment of treatment efficacy. Retrospective analysis after 2 cycles of gemcitabine and vinorelbine for refractory HD revealed 6 CR among 13 patients by PET and 1 CR in 13 by computed tomography (CT). No relationship between PET response and event-free or overall survival could be discerned, presumably because of the heterogeneity of subsequent therapies.
    Pediatric Hematology and Oncology 11/2010; 27(8):650-7. · 0.90 Impact Factor
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    ABSTRACT: Survivors of childhood acute myeloid leukemia (AML) face increased risks of chronic disease and secondary malignancies. Substance exposure may compound these risks. Participants were diagnosed with AML at <21 years of age and survived > or =5 years following diagnosis. All underwent chemotherapy alone or followed by autologous BMT (chemo +/- autoBMT) or underwent allogeneic BMT (alloBMT) if an HLA-matched related donor was available. Survivors completed a health questionnaire and a Youth Risk Behavior Survey (YRBS). Of eligible survivors, 117 were > or =18 years of age and completed a YRBS. Survivors were a mean age of 10 years at diagnosis and 24 years at interview. Of the substance exposures assessed by YRBS, tobacco, alcohol, and marijuana were most common. Twenty-two percent (22%) had smoked cigarettes in the last 30 days. One-quarter (25%) reported binge drinking in the last month. None of these exposures varied by treatment group. Less than 10% of survivors reported cocaine, heroin, or methamphetamine use. Men were more likely to report high substance exposure (P = 0.004). Sadness/suicidality score was associated with cancer-related anxiety (P = 0.006) and multiple health conditions (P = 0.006). This analysis reveals exposure to tobacco, alcohol, and marijuana in young adults with few differences based on treatment received. Survivors with cancer-related anxiety or multiple health conditions were more likely to report sadness/hopelessness.
    Pediatric Blood & Cancer 03/2010; 55(1):157-64. · 2.35 Impact Factor
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    ABSTRACT: For the majority of children with acute lymphoblastic leukemia (ALL), CNS prophylaxis consists of either intrathecal (IT) methotrexate or triple IT therapy (ie, methotrexate with both cytarabine and hydrocortisone). The long-term neurotoxicities of these two IT strategies have not yet been directly compared. In this multisite study, 171 children with standard-risk ALL, age 1 to 9.99 years at diagnosis, previously randomly assigned to IT methotrexate (n = 82) or to triple IT therapy (n = 89) on CCG 1952, underwent neurocognitive evaluation by a licensed psychologist at a mean of 5.9 years after random assignment. Patients who received IT methotrexate had a mean Processing Speed Index that was 3.6 points lower, about one fourth of a standard deviation, than those who received triple IT therapy (P = .04) after analysis was adjusted for age, sex, and time since diagnosis. Likewise, 19.5% of children in the IT methotrexate group had a Processing Speed Index score in the below-average range compared with 6.9% in the triple IT therapy group (P = .02). Otherwise, the groups performed similarly on tests of full-scale intelligence quotient, academic achievement, attention/concentration, memory, and visual motor integration. The association of treatment with measures of cognitive functioning was not modified by sex or age at diagnosis. In the post-therapy period, there were no group differences in special education services, neurologic events, or use of psychotropic medications. This study did not show any clinically meaningful differences in neurocognitive functioning between patients previously randomly assigned to IT methotrexate or triple IT therapy except for a small difference in processing speed in the IT methotrexate group.
    Journal of Clinical Oncology 11/2009; 27(35):5986-92. · 18.04 Impact Factor
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    ABSTRACT: In previous clinical trials of childhood acute lymphoblastic leukemia (ALL), dexamethasone resulted in higher event-free survival rates than prednisone, presumably due to greater central nervous system penetration. Dexamethasone's association with long-term neurocognitive toxicity is unknown. In this multisite study, we measured neurocognitive functioning in 92 children with standard-risk ALL, 1 to 9.99 years at diagnosis, at a mean of 9.8 years after randomization to prednisone (n = 41) or dexamethasone (n = 51) on Children's Cancer Group (CCG) 1922. No significant overall differences in mean neurocognitive and academic performance scores were found between the prednisone and dexamethasone groups after adjusting for age, sex, and time since diagnosis. The exception was that patients receiving dexamethasone scored one-third of a standard deviation worse on word reading (98.8 +/- 1.7 vs 104.9 +/- 1.8; P = .02). There were no group differences in the distribution of test scores or the parents' report of neurologic complications, psychotropic drug use, and special education. Further analyses suggested for the dexamethasone group, older age of diagnosis was associated with worse neurocognitive functioning; for the prednisone group, younger age at diagnosis was associated with worse functioning. In conclusion, our study did not demonstrate any meaningful differences in long-term cognitive functioning of childhood ALL patients based on corticosteroid randomization. This study is registered with http://www.clinicaltrials.gov under NCT00085176.
    Blood 07/2009; 114(9):1746-52. · 9.78 Impact Factor
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    ABSTRACT: The Children's Oncology Group conducted this phase II study to assess the efficacy and toxicity of gemcitabine and vinorelbine (GV) in pediatric patients with heavily pretreated relapsed/refractory Hodgkin's disease. Both agents have significant single-agent response rates in this setting. GV was given on days 1 and 8 of each 21-day treatment cycle: vinorelbine 25 mg/m(2)/dose administered via intravenous (IV) push before gemcitabine 1,000 mg/m(2)/dose IV over 100 minutes. Any patients who demonstrated a measurable response (complete response [CR], very good partial response [VGPR], or partial response [PR]) were considered to have experienced a response to GV. Response was evaluated after every two cycles. A two-stage minimax rule was used to test the null hypothesis that the response rate is <or= 40% against an alternative hypothesis of a response rate more than 65%. Thirty eligible patients with a median age of 17.7 years (range, 10.7 to 29.4 years) were enrolled. All patients had received at least two prior chemotherapy regimens, and 17 patients had undergone prior autologous stem-cell transplantation. Hematologic toxicity was predominant in all treatment cycles. Nonhematologic grade 3 to 4 toxicity, including elevated hepatic enzymes and hyperbilirubinemia, was less common. Pericardial and pleural effusions developed in one patient after cycles 4 and 5 of GV, consistent with gemcitabine-induced radiation recall. There were no toxic deaths. Measurable responses were seen in 19 (76%) of 25 assessable patients (95% exact binomial CI, 55% to 91%), including six CRs, 11 VGPRs, and two PRs. GV is an effective and well-tolerated reinduction regimen for children with relapsed or refractory Hodgkin's disease.
    Journal of Clinical Oncology 02/2009; 27(9):1456-61. · 18.04 Impact Factor

Publication Stats

152 Citations
148.70 Total Impact Points

Institutions

  • 2010–2014
    • Children's Oncology Group
      Monrovia, California, United States
  • 2010–2013
    • Children's Hospitals and Clinics of Minnesota
      Minneapolis, Minnesota, United States
  • 2012
    • Boston Children's Hospital
      Boston, Massachusetts, United States
  • 2011
    • University at Buffalo, The State University of New York
      Buffalo, New York, United States
  • 2009
    • Yale University
      New Haven, Connecticut, United States
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States