Doojduen Villaluna

Anthracycline-Related Cardiomyopathy After Childhood Cancer: Role of Polymorphisms in Carbonyl Reductase Genes—A Report From the Children's Oncology Group

PURPOSE 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. PATIENTS AND METHODS 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. RESULTS 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. CONCLUSION 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.

A risk-adapted, response-based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425

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.

Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Children's Oncology Group.

This phase 2 study was designed to assess the efficacy of single agent cixutumumab (IMC‐A12) and gain further information about associated toxicities and pharmacodynamics in children, adolescents, and young adults with recurrent or refractory solid tumors.

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

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

Physical activity and colon cancer risk among women in the California teachers study

Background: Existing data suggest that physical activity reduces colon cancer risk, but the association is not consistently observed in women. One potential explanation for this inconsistency is that hormone therapy, which is associated with lower colon cancer risk, acts as a modifier of the physical activity/colon cancer relationship. Methods: Participants in the California Teachers Study (N = 120,147), a prospective cohort of female teachers and administrators residing in California, ages 22 to 84 years at baseline and with no prior history of colon cancer were eligible for study. Between 1996 and 2002, 395 patients were diagnosed with invasive colon cancer. The relative risks (RR) associated with lifetime (high school through age 54 years or current age) and recent (past 3 years) strenuous and moderate recreational physical activity were estimated using Cox proportional hazards regression models. Results: Combined lifetime moderate and strenuous recreational physical activity was only modestly associated with colon cancer risk in the cohort [≥4 versus ≤0.5 h/wk/y: RR, 0.75; 95% confidence interval, 0.57-1.00; Ptrend = 0.23]. Lifetime physical activity reduced colon cancer risk among postmenopausal women who had never taken hormone therapy (≥4 versus ≤0.5 h/wk/y: RR, 0.51; 95% confidence interval, 0.31-0.85; Ptrend = 0.02). Postmenopausal women with histories of hormone therapy use had lower colon cancer risk, but their risk was not associated with physical activity. The likelihood ratio test for interaction between hormone use and lifetime moderate plus strenuous physical activity was of borderline statistical significance (P = 0.05). We observed no effect modification by age, body mass index, smoking status, menopausal status, or folate intake. Conclusions: Lifetime recreational physical activity may protect against colon cancer among postmenopausal women who have never used hormone therapy. Among hormone therapy users, who have lower risk of colon cancer, recreational physical activity does not seem to provide any additional benefit. With declining rates of hormone therapy use, physical activity offers one possible means for reducing womens colon cancer risk. (Cancer Epidemiol Biomarkers Prev 2007;16(3):517–25)

Surveillance After Initial Surgery for Pediatric and Adolescent Girls With Stage I Ovarian Germ Cell Tumors: Report From the Children's Oncology Group

PURPOSE To determine whether overall survival (OS) can be preserved for patients with stage I pediatric malignant ovarian germ cell tumor (MOGCT) with an initial strategy of surveillance after surgical resection. PATIENTS AND METHODS Between November 2003 and July 2011, girls age 0 to 16 years with stage I MOGCT were enrolled onto Childrens Oncology Group study AGCT0132. Required histology included yolk sac, embryonal carcinoma, or choriocarcinoma. Surveillance included measurement of serum tumor markers and radiologic imaging at defined intervals. In those with residual or recurrent disease, chemotherapy with compressed PEB (cisplatin, etoposide, and bleomycin) was initiated every 3 weeks for three cycles (cisplatin 33 mg/m(2) on days 1 to 3, etoposide 167 mg/m(2) on days 1 to 3, bleomycin 15 U/m(2) on day 1). Survivor functions for event-free survival (EFS) and OS were estimated using the Kaplan-Meier method. RESULTS Twenty-five girls (median age, 12 years) with stage I MOGCT were enrolled onto AGCT0132. Twenty-three patients had elevated alpha-fetoprotein (AFP) at diagnosis. Predominant histology was yolk sac. After a median follow-up of 42 months, 12 patients had evidence of persistent or recurrent disease (4-year EFS, 52%; 95% CI, 31% to 69%). Median time to recurrence was 2 months. All patients had elevated AFP at recurrence; six had localized disease, two had metastatic disease, and four had tumor marker elevation only. Eleven of 12 patients experiencing relapse received successful salvage chemotherapy (4-year OS, 96%; 95% CI, 74% to 99%). CONCLUSION Fifty percent of patients with stage I pediatric MOGCT can be spared chemotherapy; treatment for those who experience recurrence preserves OS. Further study is needed to identify the factors that predict recurrence and whether this strategy can be extended successfully to older adolescents and young adults.

A phase 2 trial of trabectedin in children with recurrent rhabdomyosarcoma, Ewing sarcoma and non-rhabdomyosarcoma soft tissue sarcomas: A report from the Children’s Oncology Group

PURPOSE To determine the toxicity, efficacy and pharmacokinetics of trabectedin given over 24h every 3 weeks to children with recurrent rhabdomyosarcoma, Ewing sarcoma, or non-rhabdomyosarcoma soft tissue sarcomas. PATIENTS AND METHODS Trabectedin was administered as a 24-h intravenous infusion every 21 days. Two dose levels were evaluated (1.3 and 1.5mg/m(2)) for safety; efficacy was then evaluated using a traditional 2-stage design (10+10) at the 1.5mg/m(2) dose level. Pharmacokinetics (day 1 and steady state) were performed during cycle 1. RESULTS Fifty patients were enrolled, eight patients at 1.3mg/m(2) and 42 at 1.5mg/m(2). Dose limiting toxicities (DLTs) in the dose finding component included fatigue and reversible GGT elevation in 1/6 evaluable patients at 1.3mg/m(2) and 0/5 at 1.5mg/m(2). Efficacy was evaluated in 42 patients enrolled at the 1.5mg/m(2) dose of whom 22% experienced reversible grade 3 or 4 toxicities that included AST, ALT, or GGT elevations, myelosuppression and deep venous thrombosis. One patient with rhabdomyosarcoma had a partial response and one patient each with rhabdomyosarcoma, spindle cell sarcoma and Ewing sarcoma had stable disease for 2, 3 and 15 cycles, respectively. CONCLUSION Trabectedin is safe when administered over 24h at 1.5mg/m(2). Trabectedin did not demonstrate sufficient activity as a single agent for children with relapsed paediatric sarcomas.

Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: effects on disease-free survival and immunomodulation. a report from the Children's Oncology Group.

Purpose: Osteosarcoma most commonly recurs in the lung. Based on preliminary data on the antitumor effects of granulocyte-macrophage colony stimulating factor (GM-CSF) in animal models, and promising phase I trials, we embarked on a feasibility study of inhaled GM-CSF in patients with first isolated pulmonary recurrence of osteosarcoma. Experimental Design: Forty-three eligible patients received inhaled GM-CSF at doses from 250 to 1,750 μg twice daily on alternate weeks. Following two cycles, patients underwent thoracotomy to resect tumor and analyze pulmonary nodules for expression of Fas/Fas ligand (Fas/FasL), and the presence of dendritic cells by immunostaining for CD1a, clusterin, and S100. Following surgery, patients received 12 additional cycles of therapy on alternating weeks or until progression. Event-free survival and survival, and feasibility of therapy delivery were evaluated. Results: Dose escalation to 1,750 μg twice daily was feasible with no dose-limiting toxicity. Mean scores for Fas/FasL in nodules from patients with bilateral recurrence who underwent unilateral thoracotomy pretreatment (using a scoring system of 0-3) were 1.3 and 0.88, respectively, compared with 0.78 and 0.62 in nodules resected following two cycles of therapy. Only 11 of 30 nodules postinhalation were positive for CD1a, 4 of 30 for S100, and 6 of 30 for clusterin. Event-free and overall survival at 3 years were 7.8% and 35.4%, respectively. Conclusions: Inhalation of GM-CSF at doses from 250 to 1,750 μg twice daily on alternate weeks was feasible with low toxicity. However, no detectable immunostimulatory effect in pulmonary metastases or improved outcome postrelapse was seen. Clin Cancer Res; 16(15); 4024–30. ©2010 AACR.

Feasibility and dose discovery analysis of zoledronic acid with concurrent chemotherapy in the treatment of newly diagnosed metastatic osteosarcoma: A report from the Children’s Oncology Group

AIM Patients with metastatic osteosarcoma (OS) have a poor outcome with conventional therapies. Zoledronic acid (ZA) is a third-generation bisphosphonate that reduces skeletal-related events in many adult cancers, and pre-clinical data suggest a possible benefit in OS. This study assessed the maximum tolerated dose (MTD) and the feasibility of ZA when combined with chemotherapy in patients with metastatic OS. PATIENTS AND METHODS Patients with a histological diagnosis of OS were eligible if they were <40 years of age, had initially metastatic disease and met organ function requirements. Treatment combined surgery and a conventional chemotherapy regimen. ZA was given concurrent with chemotherapy for a total of eight doses over 36 weeks. Three dose levels of ZA were tested: 1.2 mg/m(2) [max 2 mg], 2.3 mg/m(2) [max 4 mg] and 3.5 mg/m(2) [max 6 mg]. The MTD was determined during induction. Six patients were to be treated at each dose level, with an additional six patients treated with the MTD to help assess post-induction feasibility. RESULTS Twenty-four patients (median age 13.5 years [range, 7-22]; 16 females) were treated. Five patients experienced dose-limiting toxicities (DLTs) during induction, including three patients treated with 3.5 mg/m(2). DLTs included hypophosphatemia, hypokalemia, hyponatremia, mucositis, limb pain and limb oedema. There were no reports of excessive renal toxicity or osteonecrosis of the jaw. The MTD was defined as 2.3 mg/m(2) (max 4 mg). CONCLUSIONS ZA can be safely combined with conventional chemotherapy with an MTD of 2.3 mg/m(2) (max 4 mg) for patients with metastatic osteosarcoma.

Effects of sodium thiosulfate versus observation on development of cisplatin-induced hearing loss in children with cancer (ACCL0431): a multicentre, randomised, controlled, open-label, phase 3 trial

BACKGROUND Sodium thiosulfate is an antioxidant shown in preclinical studies in animals to prevent cisplatin-induced hearing loss with timed administration after cisplatin without compromising the antitumour efficacy of cisplatin. The primary aim of this study was to assess sodium thiosulfate for prevention of cisplatin-induced hearing loss in children and adolescents. METHODS ACCL0431 was a multicentre, randomised, open-label, phase 3 trial that enrolled participants at 38 participating Childrens Oncology Group hospitals in the USA and Canada. Eligible participants aged 1-18 years with newly diagnosed cancer and normal audiometry were randomly assigned (1:1) to receive sodium thiosulfate or observation (control group) in addition to their planned cisplatin-containing chemotherapy regimen, using permuted blocks of four. Randomisation was initially stratified by age and duration of cisplatin infusion. Stratification by previous cranial irradiation was added later as a protocol amendment. The allocation sequence was computer-generated centrally and concealed to all personnel. Participants received sodium thiosulfate 16 g/m2 intravenously 6 h after each cisplatin dose or observation. The primary endpoint was incidence of hearing loss 4 weeks after final cisplatin dose. Hearing was measured using standard audiometry and reviewed centrally by audiologists masked to allocation using American Speech-Language-Hearing Association criteria but treatment was not masked for participants or clinicians. Analysis of the primary endpoint was by modified intention to treat, which included all randomly assigned patients irrespective of treatment received but restricted to those assessable for hearing loss. Enrolment is complete and this report represents the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00716976. FINDINGS Between June 23, 2008, and Sept 28, 2012, 125 eligible participants were randomly assigned to either sodium thiosulfate (n=61) or observation (n=64). Of these, 104 participants were assessable for the primary endpoint (sodium thiosulfate, n=49; control, n=55). Hearing loss was identified in 14 (28·6%; 95% CI 16·6-43·3) participants in the sodium thiosulfate group compared with 31 (56·4%; 42·3-69·7) in the control group (p=0·00022). Adjusted for stratification variables, the likelihood of hearing loss was significantly lower in the sodium thiosulfate group compared with the control group (odds ratio 0·31, 95% CI 0·13-0·73; p=0·0036). The most common grade 3-4 haematological adverse events reported, irrespective of attribution, were neutropenia (117 [66%] of 177 participant cycles in the sodium thiosulfate group vs 145 [65%] of 223 in the control group), whereas the most common non-haematological adverse event was hypokalaemia (25 [17%] of 147 vs 22 [12%] of 187). Of 194 serious adverse events reported in 26 participants who had received sodium thiosulfate, none were deemed probably or definitely related to sodium thiosulfate; the most common serious adverse event was decreased neutrophil count: 26 episodes in 14 participants. INTERPRETATION Sodium thiosulfate protects against cisplatin-induced hearing loss in children and is not associated with serious adverse events attributed to its use. Further research is needed to define the appropriate role for sodium thiosulfate among emerging otoprotection strategies. FUNDING US National Cancer Institute.