Recommended testing algorithms for NTRK gene fusions in pediatric and selected adult cancers: Consensus of a Singapore Task Force.

The occurrence of neurotrophic tyrosine receptor kinase (NTRK) gene fusions in a wide range of tumor types presents an attractive opportunity for using a tropomyosin receptor kinase (TRK) inhibitor as cancer therapy. Recent clinical studies have demonstrated highly efficacious outcomes associated with the use of TRK inhibitors, such as larotrectinib and entrectinib in NTRK fusion-bearing cancers, in both adult and pediatric populations. While NTRK gene fusions are commonly found in some uncommon adult and pediatric malignancies, they are also found, albeit rarely, in a wide range of more common malignancies. The potential value of testing for NTRK gene fusions in practically all advanced malignancies is underpinned by the remarkable therapeutic outcomes that TRK inhibitors offer. This requirement presents practical and financial challenges in real-world oncological practice. Furthermore, different testing platforms exist to detect NTRK gene fusions, each with its advantages and disadvantages. It is, therefore, imperative to develop strategies for NTRK gene fusion testing in an attempt to optimize the use of limited tissue specimen and financial resources, and to minimize the turnaround time. A multidisciplinary task force of Singapore medical experts in both public and private sectors was convened in late 2020 to propose testing algorithms for adult colorectal tumors, sarcomas, non-small cell lung cancer, and pediatric cancers, with particular adaptation to the Singapore oncological practice. The recommendations presented here highlight the heterogeneity of NTRK-fusion positive cancers, and emphasize the need to customize the testing methods to each tumor type to optimize the workflow.

Treatment of hepatic veno-occlusive disease in children with N-acetylcysteine.

In our institution, hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) has been treated with N-acetylcysteine (NAC) since 2008-a loading dose of 150 mg/kg, followed by 12 doses of 70 mg/kg 6 hourly. Nine children were diagnosed with hepatic VOD/SOS. Hepatic VOD/SOS occurred in seven children after stem cell transplantation and two were receiving chemotherapy for Wilms tumor. Their clinical severity was classified as moderate in two and severe in seven by the European Society for Blood and Marrow Transplantation criteria. All children recovered and were discharged from 4 to 16 days after diagnosis. No side effects were observed. Intravenous NAC is an effective treatment for hepatic VOD/SOS.

Osteogenic sarcoma in children and young adults.

INTRODUCTION: More than 80% of children with osteogenic sarcoma (OS) relapse and 35% to 40% of them die within the first 2 years after diagnosis due to relapse. We investigated the incidence, treatment modalities used and the outcome of patients with OS treated in Singapore. MATERIALS AND METHODS: Patients with OS treated in Department of Paediatrics KK Women's and Children's Hospital (KKH) and National University Hospital (NUH) between January 1994 and June 2011 were reviewed. Chemotherapy was as per the European Osteosarcoma Intergroup (EOI) and as per the Memorial Sloan-Kettering Cancer Centre's (MSKCC) T12 protocols. Overall and event-free (EFS) 5-year survivals were calculated using Kaplan-Meier analysis and Cox proportional hazards regression analysis. RESULTS: Of 66 patients with OS, 19 (29%) of them presented with metastatic OS. The median age of diagnosis was 12.1 years with 5-year overall survival of 61.7% (95% CI, 48.1 to 75.3). The 5-year overall survival for those with non-metastatic and metastatic OS was 73.1% (95% CI, 58.1 to 88.1) and 34.7% (95% CI, 8.7 to 60.7, P=0.007) respectively. The 5-year overall survival for those treated as per the MSKCC T12 and EOI was 72.4% (95% CI, 52.6 to 92.2) and 54.3% (95% CI, 36.3 to 72.3, P=0.087) respectively. After controlling for confounding factors, patients with non-metastatic OS had higher 5-year EFS (HR, 0.228, 95% CI, 0.096 to 0.541, P=0.001) and overall survival (HR, 0.294, 95% CI, 0.121 to 0.713, P=0.007) compared to those with metastatic OS. Non-metastatic OS patients treated as per EOI regimen had lower 5-year EFS (HR, 2.397, 95% CI, 1.012 to 6.678, P=0.047) compared to those treated per MSKCC T12 regimen. CONCLUSION: Multidrug combination chemotherapy including high-dose methotrexate (HD-MTX) and a multidisciplinary team approach introduced in 2003 in Singapore is well tolerated and can be safely delivered. The survival benefit between the 2 regimens still needs to be explored.

Singapore rhabdomyosarcoma (RMS) experience: shall we change our practice?

INTRODUCTION: Although rhabdomyosarcoma (RMS) constitutes nearly 4% of all children diagnosed with cancer in the ethnically diverse small island city of Singapore, it is unknown how children with RMS fare. MATERIALS AND METHODS: This study investigated 50 children with RMS from April 1993 to December 2010 from KK Women's and Children's Hospital (KKH) and National University Hospital (NUH). They were treated either as per Intergroup Rhabdomyosarcoma Study Group (IRSG) or Société Internationale Pediatrique D'Oncologie (SIOP) regimens. RESULTS: Median age of diagnosis was 5.1 years (range, 0.1 to 17.3 years) with a median follow-up of 3.3 years (range, 0.4 to 15.6 years). According to IRSG classifi cation, 18 (36%) were staged as low-risk (LR); 19 (38%) were intermediate-risk (IR), 12 (24%) were high-risk (HR) and it was unknown in 1 patient. Twenty-nine (58%) were of embryonal subtype, 17 (34%) were alveolar and subclassification was not available in 4. The primary sites of tumour were: head and neck region (n = 22); genitourinary (n = 19); extremity (n = 10); and abdomen/retroperitoneal (n = 5). At the time of analysis, 80% were alive with no evidence of disease, 9 were dead of disease, and 2 were alive with disease. By disease risk group, the 5-year event-free survival (EFS) for LR group disease was 81.3% (95% CI, 62.0 to 100.0), IR group was 61.4% (95% CI, 32.3 to 90.4) and HR group was 25.0% (95% CI, 0.0 to 49.5) respectively (P <0.001). The 5-year EFS for risk by chemotherapy received as per SIOP vs per IRSG revealed: LR 83.3% vs 75.0% (P = 0.787); IR 83.3% vs 43.8% (P = 0.351); HR 0.0% vs 42.9% (P = 0.336) respectively. Of 15 relapses (HR, n = 7), at median of 2 years, 4 of 6 patients treated as per SIOP regimen were dead of disease and 3 of 8 treated as per IRSG were alive. CONCLUSION: Radiation therapy (RT) can be avoided in LR classification although those in higher risk classification need RT to local and distant metastatic disease. The outcome of children with RMS in Singapore can be further improved by coming together as a cooperative group to provide the best total care. Improved communication, multidisciplinary team collaboration, standardisation of protocols and rigorous data collection are keys.

Quality of life following amputation or limb preservation in patients with lower extremity bone sarcoma.

PURPOSE: Although functional differences have been described between patients with lower extremity bone sarcoma with amputation and limb-preservation surgery, differences have not clearly been shown between the two groups related to quality of life. The purpose of the study was to determine if there is a difference in overall quality of life in lower extremity bone sarcoma survivors related to whether they had an amputation or a limb-preservation procedure while identifying psychological differences for further evaluation. The main hypothesis was that sparing a person's limb, as opposed to amputating it, would result in a better quality of life. PATIENTS AND METHODS: Eighty-two long-term survivors of lower extremity bone sarcoma were studied to make a comparison of the overall quality of life, pain assessment, and psychological evaluations in limb preservation and amputation patients. Forty-eight patients with limb preservation and thirty-four patients with amputations were enrolled in the study. Validated psychometric measures including the Quality of Life Questionnaire (QLQ), the Minnesota Multiphasic Personality Inventory, and visual analog scales were utilized. RESULTS: The overall quality of life of patients with limb preservation was significantly higher than patients with amputation (p-value < 0.01). Significant differences were noted in the categories of material well-being, job satisfiers, and occupational relations. CONCLUSION: The overall quality of life of patients with limb-preservation appears to be better than for those patients with amputation based on the QLQ in patients surviving lower extremity bone sarcoma. Further analysis needs to verify the results and focus on the categories that significantly affect the overall quality of life.

Identification of MET genomic amplification, protein expression and alternative splice isoforms in neuroblastomas.

BACKGROUND: Crizotinib, a dual anaplastic lymphoma kinase (ALK) and mesenchymal-epithelial transition (MET) tyrosine kinase inhibitor, is currently being evaluated for the treatment of neuroblastoma. Its effects are thought to be mediated mainly via its activity against ALK. Although MET genomic/protein expression status might conceivably affect crizotinib efficacy, this issue has hitherto not received attention in neuroblastomas. AIMS/METHODS: MET genomic and protein expression status was characterised by silver in situ hybridisation and immunohistochemistry (IHC) respectively, in a cohort of 54 neuroblastoma samples. MET splice isoforms were characterised in 15 of these samples by quantitative PCR. RESULTS: One case (1/54; prevalence 1.85%) displayed MET genomic amplification, while another case (1/54; prevalence 1.85%) displayed strong membranous MET protein expression (IHC score 3+). Alternative exon 10-deleted and exon 14-deleted MET splice isoforms were identified. CONCLUSIONS: MET amplification and protein expression, although low in prevalence, are present in neuroblastomas. This has implications when crizotinib is employed as a therapeutic agent in neuroblastomas. Additionally, the existence of alternatively spliced MET isoforms may have clinical and biological implications in neuroblastomas.

The hidden impact of childhood cancer on the family: a multi-institutional study from Singapore.

INTRODUCTION: The care of children with cancer creates emotional and financial hardships for their families. There is a lack of information on the impact of childhood cancer on the family as a whole in Singapore. Thus, we set out to assess the financial impact as well as its psychosocial impact in our local context. MATERIALS AND METHODS: All patients diagnosed and treated for cancer at the Departments of Paediatrics, KK Women's and Children's Hospital and National University Hospital, Singapore were eligible for this study. Families of these patients completed 2 self-administered questionnaires: (i) About-you and your-family and (ii) the Impact-On-Family scale. For the latter, the total score was obtained by the summation of all scores, where high scores correlated to high impact. RESULTS: Seventy-nine parents were enrolled during the study period from October 2008 to February 2009. Being of Malay/Indian origin was associated with a high overall family burden. On the other hand, being of Malay/Indian origin was also associated with most successful at mastery when a child was diagnosed with cancer (P = 0.001). In addition, when compared to caregivers who remained employed, those who were asked to quit their job, experienced a higher Financial Burden (P = 0.03), a high Familial/Social Burden (P = 0.05) and a high Personal Strain (P = 0.03). CONCLUSION: Childhood cancer impacted family life in Singapore at many levels. In particular, the factors involved are various cultural discourses; employment status of caregivers; and those whose leave/pay are affected.

Diagnostic delay in pediatric solid tumors: a population based study on determinants and impact on outcomes.

BACKGROUND: Despite socioeconomic and clinical progress, pediatric tumors continue to present in advanced stage, and may be due to delays in diagnosis. This study aimed to identify factors associated with diagnostic delay (time between symptom onset and diagnosis) in pediatric tumors in a population-based study, and to assess the impact of delay on subsequent outcome. PROCEDURE: Natural logarithm of delay was retrospectively described for 390 newly diagnosed tumors reported to the Singapore Childhood Cancer Registry from 1997 to 2007. Delay was correlated with socio-demographic, disease and healthcare-system factors using multivariate linear regression, and with event-free survival (EFS) using Cox regression analysis. RESULTS: Total median delay was 5.3 weeks (range 0.1-283.1). Shorter delay was independently associated with younger patient age (P = 0.006), abdominal and pelvic sites (P < 0.001 and P = 0.036, respectively), incidental diagnoses by healthcare staff (P = 0.002), and when pediatric emergency units were the first contacted healthcare facilities and the first to raise suspicion of malignancy (P = 0.034, and P = 0.018, respectively). These factors explained only a small percentage of variance in delay times (21%). Delay was not associated with EFS and disease stage, with 24% of tumors presenting in stage 4. CONCLUSIONS: Diagnostic delay was independently associated with age and site of presentation, and points of first symptom detection, first healthcare contact, and first suspicion of malignancy. The broad range of clinical variables analyzed could only account in a small way for differences in delay times observed. While overall delay times were short, they did not influence disease stage at presentation and eventual outcome.

Health-related quality of life in children with cancer undergoing treatment: a first look at the Singapore experience.

INTRODUCTION: With intensive chemotherapy and increased survival, quality of life in our paediatric population is of increasing concern. The aim of this study was to assess the children's quality of life during the treatment process. MATERIALS AND METHODS: Patients between the ages of 7 and 18 years old who are undergoing cancer treatment in the Division of Paediatric Haematology-Oncology, Department of Paediatrics, National University Health System, were identified. The child self-reported his/her health-related quality of life (HRQOL) using the PedsQL Paediatric Quality of Life Inventory and Cancer module as a validated assessment tool. RESULTS: Thirty-two patients were enrolled over a 3-week period in November 2007. The median age was 11 years (range, 7 to 17). There was 1 non-responder (3%). Fourteen (45%) boys and 17 (55%) girls were interviewed. There were 8 (26%) and 23 (74%) patients with solid and haematologic malignancies, respectively. For the Cognitive Problem Dimension score, 86% of patients with haematologic malignancy and 50% of those with solid malignancy scored below the 75th percentile (82), [OR 0.72 (0.01-0.8), P = 0.03]. For the Physical Health Summary score, patients with solid malignancy scored worse, 25% below the 10th percentile, as compared to 4.3% of patients with haematologic malignancy. This is reflected by a worse Pain and Hurt Dimension score for patients with solid malignancy. For the Perceived Appearance Dimension score, patients with solid malignancy (75%) scored lower than the median score (67) compared to those with haematologic malignancy (44%). CONCLUSIONS: The domains of HRQOL are affected to different extents for the patients with solid and those with haematologic malignancy. This is most likely to be due to the differences in treatment strategies and clinical course. Healthcare professionals should be aware of the effects of treatment on HRQOL and take practical steps to address these issues.

A report from the Singapore Childhood Cancer Survivor Study (SG-CCSS): a multi-institutional collaborative study on long-term survivors of childhood cancer, initial analysis reporting for the SG-CCSS.

INTRODUCTION: Worldwide, the survival rates among childhood cancer patients are increasing. As such, assessing the risk of late effects and complications are increasingly becoming more important. The degree of risk of late effects may be influenced by various treatment-related factors. MATERIALS AND METHODS: The Singapore Childhood Cancer Survivor Study (SGCCSS) consists of all individuals who survived at least 2 or more years after treatment for cancer diagnosed during childhood or adolescence. Phase I of SG-CCSS is the identification of all eligible patients between 1981 and 2005. RESULTS: There were a total of 1440 patients registered in the Singapore Childhood Cancer Registry. Among these, 704 (48.9%) patients were from the KK Women's and Children's Hospital (KKH) and 626 (43.5%) were from the National University Hospital (NUH). Of all the registered patients, the most common cancer in childhood was leukaemia [42.6% (n = 613)] and the second most common was brain tumour [14.9% (n = 215)]. A total of 1043 (72.4%) patients were surviving, of whom 839 (80.4%) were long-term survivors. Haematological malignancies were found in 492 (58.6%) survivors whilst 347 (41.4%) were diagnosed with various solid tumours. Among leukaemic patients (n = 613), 65.6% (n = 402) were long-term survivors. Acute lymphoblastic leukaemia (ALL) (n = 484) had the highest percentage of [80.9% (n = 392)] of surviving patients, of whom 73.4% were long term-survivors. For brain tumour (n = 215), there were 95 (44.2%) long-term survivors. CONCLUSION: Preliminary analysis revealed that 58.3% of patients were long-term survivors. Our hope is to tailor all future therapy for childhood cancers, optimising cure rates whilst minimising long-term side-effects.

Retinoblastoma: a recent experience at the National University Hospital, Singapore.

INTRODUCTION: Retinoblastoma is a very rare disease. There were 30 cases of retinoblastoma diagnosed and treated at National University Hospital (NUH). MATERIALS AND METHODS: A retrospective chart review was performed on the medical records of 30 patients who were diagnosed with retinoblastoma between 1995 and 2008 at the Department of Paediatrics, National University Hospital, Singapore. RESULTS: The median age at diagnosis was 1.6 years (range, 0-5.9) with a median follow-up of 1.8 years (range, 0.1 to 11.6). The median time from presenting signs to the time of diagnosis was 5.2 months (range, 0-25.2). Common presenting signs of retinoblastoma were identified; the most common of which were leukocoria (50.0%), squinting (13.3%), poor vision (10.0%), strabismus (6.6%) and unknown (33.3%). Of the 30 patients, 10 were from Singapore whilst the other 20 patients were from the surrounding countries. Twelve patients had bilateral disease at the time of diagnosis, while 18 had unilateral disease. Staging information was available in 27 patients. Enucleation was performed in 25 of 30 patients. Radiation therapy was given in 3 patients in 1995 (bilateral disease), 2001 (bilateral disease) and 2003 (unilateral disease). At the time of analysis, 19 patients were alive with no evidence of disease. Overall 5-year survival for the cohort was 88.1% [95% confidence interval (CI), 88.0-100] and event-free survival for the whole cohort was 74.2% (95% CI, 55.8-92.6). CONCLUSION: In our limited experience, the importance of collaboration and standardisation of the staging system, raising awareness and education of primary healthcare providers and parents are strongly stressed.

Improved outcome in childhood acute myeloid leukemia in Singapore with the MRC AML 10 protocol.

BACKGROUND: The introduction of the United Kingdom Medical Research Council's 10th AML trial (MRC AML 10) protocol incorporating high-dose anthracycline therapy has improved outcome of children with acute myeloid leukemia (AML). In this study, we review the results of childhood AML therapy in a Singapore university hospital over the last 17 years emphasizing toxicity and outcome. PROCEDURE: Retrospective analysis revealed 34 children with AML between 1988 and 2003. Prior to September 1996, therapy consisted of: POG-8498 (n = 10), others (n = 9). From September 1996, all but one of 15 children received MRC AML 10 treatment. RESULTS: At the time of analysis, 17 had died from disease, and 17 patients were alive among whom 2 had relapsed. MRC AML 10-treated patients (n = 14) had significantly better 3-year overall, event-free, and disease-free survival (74% vs. 35%, 77% vs. 20%, 83% vs. 31%; P = 0.019, P = 0.002, and P = 0.010, respectively) and were likelier to achieve complete remission (CR) than non-MRC AML 10 patients (P = 0.102). Among patients who achieved CR, MRC AML 10-treated patients were significantly more likely to achieve CR after only one cycle of chemotherapy (P = 0.016). Hematologic toxicity was similar among the different regimens (P = 0.9). CONCLUSIONS: These findings suggest that MRC AML 10 treatment results in significantly superior survival, without excess toxicity. Future studies should attempt to elucidate the relative importance of individual MRC AML 10 components and reduce the high cumulative anthracycline dose without compromising outcome.

Metachronous skeletal osteosarcoma in patients treated with adjuvant and neoadjuvant chemotherapy for nonmetastatic osteosarcoma.

PURPOSE: The prognosis for patients who develop metachronous skeletal osteosarcoma (OS) has been considered grave compared with that for patients with relapse limited to the lungs. We investigated the incidence and outcome of metachronous skeletal OS after initial treatment of the primary tumor. PATIENTS AND METHODS: Twenty-three (median age 18.7 years) of 426 patients with nonmetastatic, high-grade primary OS treated at Memorial Sloan-Kettering Cancer Center (New York, NY) between February 1973 and May 2000 developed metachronous skeletal OS. Initial therapy included combination chemotherapy and surgery. Treatment of subsequent relapses consisted of chemotherapy or radiation alone or surgery with or without additional individualized chemotherapy. RESULTS: The median time from the diagnosis of primary OS to the development of metachronous OS was 1.4 years (range, 0.2 to 11.3 years). Median survival was 1.5 years (95% confidence interval [CI], 0.8 to 6.9 years). Two- and 5-year postmetachronous overall survival was 43.5% (95% CI, 23.2% to 63.7%) and 33% (95% CI, 13% to 53%), respectively. At last follow-up (range, 0.1 to 12.8 years), five (30.4%) patients were alive with no evidence of disease (range, 1.7 to 12.8 years; median, 4.4 years). For 11 patients who developed metachronous OS 24 months or more from initial diagnosis, 5-year postmetachronous survival rate for patients receiving combined modality versus monotherapy was 83% (95% CI, 54% to 100%) and 40% (95% CI, 0% to 83%), respectively. CONCLUSION: In a small subset of patients who developed late metachronous OS, combined-modality therapy with surgery and aggressive chemotherapy may result in long-term postmetachronous survival. This implies that principles used in treatment of primary OS may be applied to patients with late metachronous skeletal OS.

Second malignant neoplasms in long-term survivors of osteosarcoma: Memorial Sloan-Kettering Cancer Center Experience.

BACKGROUND: The authors investigated the incidence and relative risk of secondary malignant neoplasms in long-term survivors of osteosarcoma. METHODS: A comprehensive list of 509 patients with primary osteosarcoma treated at our institution between February 1973 and March 2000 was identified. All study patients received chemotherapy and/or surgery on one of six different protocols (T4, 5, 7, 10, 12, and CCG-7921/POG-9351). Chemotherapy was scheduled for up to 40 weeks with some variations in the actual treatment period and consisted of various combinations of the following agents: high-dose methotrexate, doxorubicin, bleomycin, cyclophosphamide, dactinomycin, vincristine, cisplatin, and ifosfamide. RESULTS: Secondary malignant neoplasms (SMN) occurred in 14 of 509 patients. Only one had pulmonary metastasis at diagnosis and subsequent multiple recurrences that required thoracotomies and further modification of the chemotherapy regimen. The median age at diagnosis for osteosarcoma was 16.6 years (range, 3.1-74.4 years). The median follow-up was 5.2 years (range, 0.1-25.0 years). The time interval from diagnosis of the primary osteosarcoma to the development of SMN was 1.3-13.1 years (median, 5.5; 95% confidence interval [CI], 3.6-9.6). The most common SMN occurred in the central nervous system (n = 4): anaplastic glioma, meningioma, high-grade glioma, and maxillary astrocytoma. There were two cases of acute myeloid leukemia and one case each of myelodysplastic syndrome, non-Hodgkin lymphoma, high-grade pleomorphic sarcoma, leiomyosarcoma, fibrosarcoma, breast carcinoma, and mucoepidermoid carcinoma. The overall 5 and 10-year cumulative incidences of SMNs were 1.4% +/- 1.1% and 3.1% +/- 1.8%. The standardized incidence ratio was 4.6 (95% CI, 2.53-7.78, P = 0.00001) for the cohort and 3.64 (95% CI, 1.82-6.52, P = 0.0007) when patients with a history of retinoblastoma or Rothmund-Thomson syndrome were excluded. CONCLUSIONS: The overall incidence of secondary malignancies in long-term survivors of osteosarcoma was significantly higher than the expected incidence of cancer in the general population. However, the standardized incidence ratios were much lower than those reported for Hodgkin disease and retinoblastoma. Although additional follow-up is warranted, the successes of current treatment regimens consisting of intensive, high-dose chemotherapy in combination with topoisomerase II inhibitors outweigh the risks.