Ha Dang

Revised Risk Classification for Pediatric Extracranial Germ Cell Tumors Based on 25 Years of Clinical Trial Data From the United Kingdom and United States

PURPOSE To risk stratify malignant extracranial pediatric germ cell tumors (GCTs). PATIENTS AND METHODS Data from seven GCT trials conducted by the Childrens Oncology Group (United States) or the Childrens Cancer and Leukemia Group (United Kingdom) between 1985 and 2009 were merged to create a data set of patients with stage II to IV disease treated with platinum-based therapy. A parametric cure model was used to evaluate the prognostic importance of age, tumor site, stage, histology, tumor markers, and treatment regimen and estimate the percentage of patients who achieved long-term disease-free (LTDF) survival in each subgroup of the final model. Validation of the model was conducted using the bootstrap method. RESULTS In multivariable analysis of 519 patients with GCTs, stage IV disease (P = .001), age ≥ 11 years (P < .001), and tumor site (P < .001) were significant predictors of worse LTDF survival. Elevated alpha-fetoprotein (AFP) ≥ 10,000 ng/mL was associated with worse outcome, whereas pure yolk sac tumor (YST) was associated with better outcome, although neither met criteria for statistical significance. The analysis identified a group of patients age > 11 years with either stage III to IV extragonadal tumors or stage IV ovarian tumors with predicted LTDF survival < 70%. A bootstrap procedure showed retention of age, tumor site, and stage in > 94%, AFP in 12%, and YST in 27% of the replications. CONCLUSION Clinical trial data from two large national pediatric clinical trial organizations have produced a new evidence-based risk stratification of malignant pediatric GCTs that identifies a poor-risk group warranting intensified therapy.

Outcome of Patients With Recurrent Osteosarcoma Enrolled in Seven Phase II Trials Through Children's Cancer Group, Pediatric Oncology Group, and Children's Oncology Group: Learning From the Past to Move Forward

PURPOSE The use of radiographic response as the primary end point in phase II osteosarcoma trials may limit optimal detection of treatment response because of the calcified tumor matrix. We performed this study to determine if time to progression could be used as an end point for subsequent studies. PATIENTS AND METHODS We performed a retrospective analysis of outcome for patients with recurrent/refractory osteosarcoma enrolled in one of seven phase II trials conducted by the Childrens Oncology Group and predecessor groups from 1997 to 2007. All trials used RECIST or WHO radiographic response criteria and the primary end point of response rate. The following potential prognostic factors-age, trial, number of prior chemotherapy regimens, sex, and race/ethnicity-were evaluated for their impact on event-free survival (EFS). We used data from a phase II study (AOST0221) of patients with osteosarcoma who were given inhaled granulocyte-macrophage colony-stimulating factor with first pulmonary recurrence who had an EFS as well as biologic end point to determine the historical disease control rate for patients with fully resected disease. RESULTS In each included trial, the drugs tested were determined to be inactive on the basis of radiographic response rates. The EFS for 96 patients with osteosarcoma and measurable disease was 12% at 4 months (95% CI, 6% to 19%). There was no significant difference in EFS across trials according to number of prior treatment regimens or patient age, sex, and ethnicity. The 12-month EFS for the 42 evaluable patients enrolled in AOST0221 was 20% (95% CI, 10% to 34%). CONCLUSION The EFS was uniformly poor for children with recurrent/refractory osteosarcoma in these single-arm phase II trials. We have now constructed baseline EFS outcomes that can be used as a comparison for future phase II trials for recurrent osteosarcoma.

Is adjuvant chemotherapy indicated in ovarian immature teratomas? A combined data analysis from the Malignant Germ Cell Tumor International Collaborative

There is a debate regarding the management of ovarian immature teratomas (ITs). In adult women, postoperative chemotherapy is standard except for stage I, grade 1 disease, whereas surgery alone is standard in pediatric patients. To determine the role of chemotherapy, a pooled analysis of pediatric and adult clinical trials was conducted.

Group-Wide, Prospective Study of Ototoxicity Assessment in Children Receiving Cisplatin Chemotherapy (ACCL05C1): A Report From the Children’s Oncology Group

Purpose Optimal assessment methods and criteria for reporting hearing outcomes in children who receive treatment with cisplatin are uncertain. The objectives of our study were to compare different ototoxicity classification systems, to evaluate the feasibility of including otoacoustic emissions and extended high frequency audiometry, and to evaluate a central review mechanism for audiologic results for cisplatin-treated children in the cooperative group setting. Patients and Methods Eligible participants were 1 to 30 years, with planned cisplatin-containing treatment. Hearing evaluations were conducted at baseline, before each cisplatin cycle, and at the end of therapy. Audiologic results were assessed and graded by the testing audiologist and by two central review audiologists using the American Speech-Language-Hearing Association Ototoxicity Criteria (ASHA), Common Terminology Criteria for Adverse Events, version 3.0 (CTCAE), and Brock Ototoxicity Grades (Brock). One central reviewer also used the International Society of Pediatric Oncology Ototoxicity Scale (SIOP). Results At the end of treatment, the prevalence of any degree of ototoxicity ranged from 40% to 56%, and severe ototoxicity ranged from 7% to 22%. Compared with CTCAE, SIOP detected significantly more ototoxicity ( P = .004), whereas Brock criteria detected significantly fewer patients with any or severe ototoxicity ( P < .001 for both). SIOP detected ototoxicity earlier than did the other scales. Agreement between the central reviewers and the institutional audiologist was almost perfect for ASHA and Brock, whereas the poorest agreement occurred with CTCAE. Conclusion The SIOP scale may be superior to ASHA, Brock, and CTCAE scales for classifying ototoxicity in pediatric patients who were treated with cisplatin. Future studies should evaluate inter-rater reliability of the SIOP scale.

Adolescents and Young Adults With a “Rare” Cancer: Getting Past Semantics to Optimal Care for Patients With Germ Cell Tumors

Because the tumors of adolescence and young adulthood (AYA) are distinct from those that occur earlier and later in life, the most common tumors in this age group are termed “rare.” We offer a collaborative, cross-disciplinary, evidence-based approach, advocated and funded by civil society, to advance the field of germ cell tumor and potentially to apply to other rare AYA tumors.

Caphosol for prevention of oral mucositis in pediatric myeloablative haematopoietic cell transplantation

Background:The primary objective was to determine whether topically administered Caphosol, rinsed orally four times daily at the initiation of conditioning, reduces the duration of severe oral mucositis (OM) compared with placebo among children and adolescents undergoing haematopoietic cell transplantation (HCT).Methods:This was a Children’s Oncology Group multicentre randomised double-blinded placebo-controlled clinical trial. Patients between the ages of 4 and 21 years who were scheduled to undergo myeloablative HCT for any indication were randomised to Caphosol or placebo saline rinses four times daily from initiation of conditioning through day +20. Subjects were assessed daily for OM using the World Health Organisation (WHO) Oral Toxicity Scale, Mouth Pain Categorical Scale (0–10) and the Oral Mucositis Daily Questionnaire (OMDQ). The primary end point was duration of severe OM (WHO ⩾3).Results:The study enrolled 220 participants with a median age of 13.7 years (range 4.0–21.9); 163 (74%) received allogeneic HCT. The mean (±s.d.) duration of severe OM was not reduced among Caphosol (4.5±5.0 days) vs placebo (4.5±4.8; P=0.99) recipients. The incidence of severe OM in the Caphosol and placebo arms was 63% (57 out of 91) and 68% (62 out of 91), respectively (P=0.44). There were no significant differences in any of the secondary end points between the groups.Conclusions:Caphosol did not reduce severe OM when compared with placebo among children and adolescents undergoing myeloablative HCT. Studies to identify effective interventions for OM are needed in this population.

Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan‐cyclophosphamide‐melphalan (Bu‐Cy‐Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less‐toxic myeloablative conditioning regimen containing busulfan‐fludarabine (Bu‐Flu) would be associated with equivalent outcomes.

Effect of Levofloxacin Prophylaxis on Bacteremia in Children With Acute Leukemia or Undergoing Hematopoietic Stem Cell Transplantation: A Randomized Clinical Trial

Importance Bacteremia causes considerable morbidity among children with acute leukemia and those undergoing hematopoietic stem cell transplantation (HSCT). There are limited data on the effect of antibiotic prophylaxis in children. Objective To determine the efficacy and risks of levofloxacin prophylaxis in children receiving intensive chemotherapy for acute leukemia or undergoing HSCT. Design, Setting, and Participants In this multicenter, open-label, randomized trial, patients (6 months-21 years) receiving intensive chemotherapy were enrolled (September 2011-April 2016) in 2 separate groups—acute leukemia, consisting of acute myeloid leukemia or relapsed acute lymphoblastic leukemia, and HSCT recipients—at 76 centers in the United States and Canada, with follow-up completed September 2017. Interventions Patients with acute leukemia were randomized to receive levofloxacin prophylaxis for 2 consecutive cycles of chemotherapy (n = 100) or no prophylaxis (n = 100). Those undergoing HSCT were randomized to receive levofloxacin prophylaxis during 1 HSCT procedure (n = 210) or no prophylaxis (n = 214). Main Outcomes and Measures The primary outcome was the occurrence of bacteremia during 2 chemotherapy cycles (acute leukemia) or 1 transplant procedure (HSCT). Secondary outcomes included fever and neutropenia, severe infection, invasive fungal disease, Clostridium difficile–associated diarrhea, and musculoskeletal toxic effects. Results A total of 624 patients, 200 with acute leukemia (median [interquartile range {IQR}] age, 11 years [6-15 years]; 46% female) and 424 undergoing HSCT (median [IQR] age, 7 years [3-14]; 38% female), were enrolled. Among 195 patients with acute leukemia, the likelihood of bacteremia was significantly lower in the levofloxacin prophylaxis group than in the control group (21.9% vs 43.4%; risk difference, 21.6%; 95% CI, 8.8%-34.4%, P = .001), whereas among 418 patients undergoing HSCT, the risk of bacteremia was not significantly lower in the levofloxacin prophylaxis group (11.0% vs 17.3%; risk difference, 6.3%; 95% CI, 0.3%-13.0%; P = .06). Fever and neutropenia were less common in the levofloxacin group (71.2% vs 82.1%; risk difference, 10.8%; 95% CI, 4.2%-17.5%; P = .002). There were no significant differences in severe infection (3.6% vs 5.9%; risk difference, 2.3%; 95% CI, −1.1% to 5.6%; P = .20), invasive fungal disease (2.9% vs 2.0%; risk difference, −1.0%; 95% CI, −3.4% to 1.5%, P = .41), C difficile–associated diarrhea (2.3% vs 5.2%; risk difference, 2.9%; 95% CI, −0.1% to 5.9%; P = .07), or musculoskeletal toxic effects at 2 months (11.4% vs 16.3%; risk difference, 4.8%; 95% CI, −1.6% to 11.2%; P = .15) or at 12 months (10.1% vs 14.4%; risk difference, 4.3%; 95% CI, −3.4% to 12.0%; P = .28) between the levofloxacin and control groups. Conclusions and Relevance Among children with acute leukemia receiving intensive chemotherapy, receipt of levofloxacin prophylaxis compared with no prophylaxis resulted in a significant reduction in bacteremia. However, there was no significant reduction in bacteremia for levofloxacin prophylaxis among children undergoing HSCT.

Is Adjuvant Chemotherapy necessary in Ovarian Immature Teratoma? A Combined Data Analysis from The Malignant Germ Cell Tumors International Collaborative (MaGIC)

This is the author accepted manuscript. The final version is available from Wiley at http://dx.doi.org/10.1002/cncr.29732.