Current Challenges of Asian National Children's Cancer Study Groups on Behalf of Asian Pediatric Hematology and Oncology Group.

In Asia, a few countries have a long and established history of collaborative clinical trials successfully formed national children's cancer study groups, but many still do not have such groups. The process of forming national children's cancer groups is fraught with many hurdles, which varies among the countries. One of the basic requirements for running clinical trials is an affordable health care system in which most of the children with cancer can receive the proposed treatment. The health insurance coverage for children with cancer varies from <20% to as high as 100% among Asian countries, and the operation of clinical trials must also be adjusted accordingly. Shortage of research personnel is common, including medical, nursing, research coordinators, and data managers. The establishment of the Asian Pediatric Hematology and Oncology Group aims to provide a good platform for promotion of international clinical trials in the Asian countries.

Surgical treatment confers prognostic significance in pediatric malignant mediastinal germ cell tumors.

BACKGROUND: Primary malignant mediastinal germ cell tumors (GCTs) are rare pediatric tumors that have a poorer prognosis compared to GCTs occurring elsewhere in the body. The current study aimed to assess the prognostic factors and treatment outcomes of children with primary malignant mediastinal GCT in Taiwan. METHODS: The authors retrospectively reviewed children 0-18 years old who were newly diagnosed with primary malignant mediastinal GCT between January 1, 2005 and December 31, 2019 and were registered in the Taiwan Pediatric Oncology Group patient registry. The impact of presenting characteristics, including sex, age, tumor stage, histology subtype, surgical treatment, and chemotherapy regimens of the patients were analyzed. RESULTS: This study enrolled 52 children with malignant mediastinal GCT who had a median age of 16.0 (range, 6.0-17.9) years at diagnosis. The most common histological subtypes were mixed GCTs (n = 20) and yolk sac tumors (n = 15). Advanced disease stage and choriocarcinoma histology subtype were associated inferior outcomes. Children who received surgical treatment exhibited better outcomes compared to those who did not (5-year overall survival, 78% vs. 7%, p < .001). After comparing patients who received first-line cisplatin- and carboplatin-based chemotherapy, no difference in treatment outcomes was observed. Multivariate analysis showed that surgical management was the only independent predictor for superior OS. CONCLUSIONS: Surgical treatment is recommended for mediastinal GCT. Cisplatin-based chemotherapy was not superior to carboplatin-based chemotherapy as first-line treatment and may be avoided due to toxicity concerns.

Characteristics and outcomes of second cancers in patients with childhood cancer: A report from the Taiwan Pediatric Oncology Group.

BACKGROUND: Patients with childhood cancer are at increased risk for the development of second cancers. METHODS: A national multicenter survey of second cancers conducted by the Taiwan Pediatric Oncology Group retrieved retrospective data from the database at the Children Cancer Foundation in Taiwan beginning in 1995. The characteristics of second cancers and associations of patient demographic and clinical characteristics with time to death due to a second cancer were analyzed. RESULTS: We examined the records of 8782 patients with a primary cancer diagnosed between January 1, 1995 and December 31, 2013, and a total of 99 patients with a second cancer were identified. The most common type of second cancer was acute myeloid leukemia (n = 35), followed by acute lymphoblastic leukemia (n = 15), central nervous system (CNS) tumors (n = 15), and sarcomas (n = 10). Secondary hematological malignancies occurred earlier than other secondary cancers. The frequencies of second CNS tumors and second bone cancers and sarcomas were notably increased when prior radiation doses increased from zero, low dose to high dose. The overall 5-year survival of patients with a second cancer was poor (33.7%). Multivariate survival analysis revealed that the year of primary diagnosis ≤2002, secondary hematological malignancies, and age at second cancer diagnosis ≤9.3 years or >26.8 years increased the risk of death following second cancer. CONCLUSION: Children who develop a second cancer have an unfavorable outcome. Early detection and improved treatment for second cancers are needed.

Treatment outcomes of pediatric acute myeloid leukemia: a retrospective analysis from 1996 to 2019 in Taiwan.

Improvement in outcomes of children with acute myeloid leukemia (AML) is attributed to several refinements in clinical management. We evaluated treatment outcomes of Taiwanese pediatric AML patients in the past 20 years. Overall, 860 de novo AML patients aged 0-18 years and registered in the Childhood Cancer Foundation of R.O.C during January 1996-December 2019 were included. Survival analysis was performed to identify factors that improved treatment outcomes. Regardless of treatment modalities used, patients during 2008-2019 had better 5-year event-free survival (EFS) and overall survival (OS) rates than patients during 1996-2007. For patients received the TPOG-AML-97A treatment, only 5-year OS rates were significantly different between patients diagnosed before and after 2008. Patients with RUNX1-RUNX1T1 had similar relapse-free survival rates, but 5-year OS rates were better during 2008-2019. However, the survival of patients who received hematopoietic stem-cell transplantations (HSCT) did not differ significantly before and after 2008. For patients without relapse, the 5-year OS improved during 2008-2019. Non-relapse mortality decreased annually, and cumulative relapse rates were similar. In conclusion, 5-year EFS and OS rates improved during 2008-2019, though intensities of chemotherapy treatments were similar before and after 2008. Non-relapse mortality decreased gradually. Further treatment strategies including more intensive chemotherapy, novel agents' use, identification of high-risk patients using genotyping and minimal residual disease, early intervention of HSCT, and antibiotic prophylaxis can be considered for future clinical protocol designs in Taiwan.

Outcome and prognosis of anaplastic large cell lymphoma in children: a report from the Taiwan Pediatric Oncology Group.

Studies of childhood anaplastic large cell lymphoma (ALCL) are less reported from East Asian countries. Clinical features and outcome of 90 children with ALCL in Taiwan were analyzed. The median age at diagnosis was 11.7 years. The most common presentation was lymph node involvement (86.7%). Advanced diseases accounted for 70% of patients at diagnosis. Most patients (93.1%) had positive staining for anaplastic lymphoma kinase. The five-year overall survival and event-free survival (EFS) rates were 79.7% and 73.3%, respectively. Bone marrow involvement, advanced stage, and thoracopulmonary ALCL were adverse prognostic factors for EFS (p=.05, .04, and .03, respectively). In multivariate analysis, only thoracopulmonary ALCL had a marginal significance on worse EFS (p= .054). We suggested that children with thoracopulmonary ALCL may need to intensify the treatment, and introduction of new targeted therapies for relapsed/refractory disease will be required.

Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG-ALL-2002 study.

BACKGROUND: To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL). METHODS: This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 [2002-2008] with CrRT and era 2 [2009-2012] with delayed first TIT and no CrRT). RESULTS: There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non-CNS-1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2. CONCLUSIONS: The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status.

Pediatric acute lymphoblastic leukemia with t(1;19)/TCF3-PBX1 in Taiwan.

BACKGROUND: In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3-PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan. PROCEDURE: In Taiwan Pediatric Oncology Group 2002 ALL studies, genotypes were determined by cytogenetic analysis and/or reverse transcriptase polymerase chain reaction assay. Based on presenting features, immunophenotype and genotype, patients were assigned to one of the three risk groups: standard risk (SR), high risk (HR), or very high risk (VHR). The patients with t(1;19)/TCF3-PBX1 were treated in the HR arm receiving more intensive chemotherapy. The outcomes of patients with t(1;19)/TCF3-PBX1 were compared to that of patients with other subtypes of B-precursor ALL (B-ALL). RESULTS: Of the 1,129 patients with B-ALL, 64 (5.7%) had t(1;19)/TCF3-PBX1; 51 of whom were treated in the HR arm, but 11 were treated in the VHR and 2 in the SR arm because of physician's preference. As a group, 64 patients with t(1;19)/TCF3-PBX1 had similar 5-year event-free survival (83.3 ± 4.8%) as those with TEL-AML1 (85.2 ± 3.4%, P = 0.984) or those with hyperdiploidy >50 (84.0 ± 3.1%, P = 0.748). The cumulative risk of any (isolated plus combined) central nervous system relapse among patients with t(1;19)/TCF3-PBX1 (8.7 ± 3.8%) tended to be higher than that of patients with TEL-AML1 (5.8 ± 2.3%, P = 0.749) or those with hyperdiploidy (4.1 ± 1.8%, P = 0.135), albeit the differences did not reach statistical significance. CONCLUSIONS: With contemporary intensive chemotherapy, children with t(1;19)/TCF3-PBX1 fared as well as those with favorable genotypes (TEL-AML1 or hyperdiploidy).

Treatment for childhood acute lymphoblastic leukemia in Taiwan: Taiwan Pediatric Oncology Group ALL-2002 study emphasizing optimal reinduction therapy and central nervous system preventive therapy without cranial radiation.

BACKGROUND: Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or "low-risk" in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. PROCEDURE: From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol. SR patients were randomized to receive single or double reinduction courses. The patients enrolled before 2009 received CrRT, while those enrolled later did not. The Kaplan-Meier method was used to estimate survival rates and the difference between two groups was compared by the two-sided log-rank test. RESULTS: In 1,366 eligible patients, the 5-year overall survival (OS) was 81.6 ± 1.1% (standard error) and 5-year event-free survival (EFS) was 74.3 ± 1.2%. In SR patients, the 5-year OS for one and two reinduction courses was 91.6 ± 2.1% and 93.7 ± 1.8%, respectively, and the 5-year EFS was 85.2 ± 2.7% and 89.8 ± 2.3%, respectively. There were no significant differences in survival between these two groups. Patients with MLL or BCR-ABL1 had the worst outcomes: 5-year EFS was 23.4 and 31.8% and 5-year OS was 28.6 and 44.7%, respectively. There was no significant difference in CNS relapse or survival between the era with or without CrRT. CONCLUSIONS: For SR patients, one-course reinduction was adequate. Triple intrathecal therapy alone successfully prevented CNS relapse.

Epidemiology, clinical features and treatment outcome of Wilms' tumor in Taiwan: a report from Taiwan Pediatric Oncology Group.

BACKGROUND AND PURPOSE: Taiwan Pediatric Oncology Group (TPOG)-W-91 is the first multi-institutional Wilms' tumor study for children in Taiwan. This clinical trial used a multidisciplinary approach, based on and similar to the National Wilms' Tumor Study 4. The study was conducted to evaluate the epidemiological characteristics and analyze the outcome of Wilms' tumor patients treated with this protocol. METHODS: Ninety eight children with Wilms' tumor (WT) were analyzed for distributions of age, gender, associated congenital anomalies, tumor sites, histology, tumor weights, and clinical stages. Patients received individualized multimodality treatment based upon the histology of the tumor and clinicopathologic stage. The treatment included surgery, radiotherapy and 2-, 3-, and 4-agent active chemotherapeutic agents. Seventy patients were eligible for analysis of treatment outcome. The endpoints were progression-free and overall survival (PFS, OS). Patients were divided into various subgroups according to the chemotherapy regimen used, tumor stage, age at diagnosis, gender, and tumor weight. The prognostic factors were evaluated and the survival rates of various clinical subgroups were compared using log-rank test. RESULTS: The average annual incidence rate of WT was 2.9 per million children under 15 years of age. The M/F ratio was 1.04. The mean age at diagnosis was 3.7 years. All bilateral tumors occurred in females. Congenital anomalies were present in 17.3% of patients. Anaplastic histology was found in 6 of 98 cases (6.1%). The stage distribution was: I, 43.2%; II, 19.3%; III, 23.9%; IV, 6.8%; and V, 6.8%. The median follow-up time was 89.1 months (range, 1.8 to 128.1 months). The 5-year PFS rate was 0.7841 (SE, 0.0494; 53 of 70 patients) and the 5-year OS rate was 0.886 (SE, 0.038; 63 of 70 patients). Gender was found to be the only significant prognostic variable. CONCLUSIONS: This study evaluated the epidemiological characteristics, clinical features, multimodality therapy regimens, and treatment outcome of WT in Taiwan. Data obtained from this study may lead to further improvement in the prognosis of pediatric malignant solid tumor.

Childhood Langerhans cell histiocytosis increased during El Niño 1997-98: a report from the Taiwan Pediatric Oncology Group.

From 1995-1999, a nation-wide study of Langerhans cell histiocytosis (LCH) in children less than 15 years old was conducted by the Taiwan Pediatric Oncology Group. The demographic and clinical data of 55 cases were analyzed. Thirty-two cases presented from the beginning of 1997 to the end of 1998, when the most severe El Niño in the century occurred. The incidence was higher than expected during this El Niño period (32 cases versus 22 cases, p = 0.003). During 1997-98, most LCH was diagnosed in summer (n = 15), autumn (n = 8), and winter (n = 8) but rarely in spring (n = 1); coincidentally, rainfall was least in winter but peaked in summer. During 1997-98, the most significant increase occurred in the polyostotic LCH subcategory (p = 0.017), with younger ages at diagnosis (p = 0.039). The incidence of LCH cytopenia, fever, and diseases of the skin, liver, spleen or other organs did not differ significantly. Local treatment modality, disseminated diseases and diagnosis during the El Niño of 1997-98 were independent risk factors predicting the recurrence or progression of LCH. Our findings suggest that particular infections or other environmental factors associated with El Niño might be related to the etiology of childhood LCH.