Health-Related Quality of Life of Adolescent and Young Adult-Aged Childhood Cancer Survivors in a South African Cohort: A Pilot Study Using the Minneapolis-Manchester Quality of Life Instrument.

Purpose: We investigated the health-related quality of life (HRQoL) of an adolescent and young adult (AYA)-aged South African childhood cancer survivor (CCS) cohort. Methods: Participants completed the Minneapolis-Manchester Quality of Life adolescent and adult forms. The overall Cronbach's alpha coefficients were 0.81 (adolescent form) and 0.92 (adult form). The scale-level content validity indexes were acceptable (0.88 and 0.89 for the adolescent and adult forms, respectively). The total domain and overall HRQoL scores were calculated. Results: Sixty-two survivors completed the adolescent form and 30 completed the adult form. The median age was 17.5 years (range 13-34 years), and the median time from diagnosis was 12 years (male:female ratio 1:1.2). Risk factors for poor physical functioning included age at study visit (p = 0.015), solid tumor diagnosis (p = 0.012), radiotherapy (p = 0.021), and surgery (p = 0.006). Six or more late effects impacted most domains negatively; severe late effects (p = 0.020) decreased physical functioning. Lower socioeconomic status was associated with poorer physical (p = 0.006) and cognitive (p = 0.047) functioning. The adult form cohort had poorer psychological (p = 0.014) and social functioning (p = 0.005) and body image (p = 0.016) than the adolescent form cohort. Conclusion: Older age, radiotherapy, surgery, solid tumor diagnosis, and the number and severity of late effects negatively influenced HRQoL in AYA-aged CCSs. A long-term follow-up (LTFU) risk stratification system should include HRQoL status to assist with holistic LTFU care.

SACCSG HL-2018. Barriers and enablers of a harmonized treatment protocol for childhood and adolescent Hodgkin lymphoma in South Africa.

Introduction: Collaborative studies have contributed to improved survival of pediatric Hodgkin lymphoma in well-resourced settings, but few are documented in resource-constrained countries. The South Africa Children's Cancer Study Group initiated harmonization of management protocols in 2015. This article analyzes barriers and enablers of the process. Methods: Clinician-researchers at 11 state-funded pediatric oncology units completed preparatory questionnaires in June 2018. Parameters included infrastructure, access to therapeutic modalities and clinician numbers. A reassessment of 13 sites (two new pediatric oncology unit) in February 2021 ascertained changes in resources and identified challenges to full participation. Questions investigated the presence and quality of diagnostic radiology, availability of surgeons, cytology/pathology options and hematology laboratory facilities. Results: The response rate was 11/11 to survey 1 and 13/13 to survey 2. The anticipated pre-study barriers to participation of pediatric oncology units included time constraints and understaffing. PET-CT was unavailable to two centers. The majority of pediatric oncology units met the minimum criteria to participate. The interim survey confirmed chemotherapy and radiotherapy availability nearly 100% of the time. One site reported improved access to radiotherapy while another reported improved access to PET-CT. Barriers to participation included excessive times to obtain regulatory approvals, time constraints and lack of dedicated research staff. Enablers include the simple management algorithm and communication tools. Conclusion: This study demonstrates that multicenter collaboration and harmonization of management protocols are achievable in a middle-income setting. Minimal funding is required but full participation to run high-quality studies requires more financial investment. Focused funding and increased prioritization of research may address systemic barriers to full participation.

The pre-surgical factors that determine the decision to proceed to resection in children diagnosed with high-risk neuroblastoma in a resource limited setting.

Surgical control has prognostic value in neuroblastoma (NB). Advanced NB is common at diagnosis in South Africa. We investigated the pre-surgery factors that influenced decisions to perform surgical resections. We included 204 patients with high-risk NB from a national retrospective study, who completed induction chemotherapy between 2000 and 2016.The median age was 32.4 months (IQR 15.1 - 53.5 months). Primary tumor resection was achieved in 76.9% of patients between 0-18 months of age, 51.8% between 18-60 months and 51.7% older than 60 months (p < 0.001). Only 43.2% of patients with distant metastatic disease had surgery done (p < 0.001). LDH was >750 U/L in 46.8% and ferritin >120 g/dL in 53.1% of those who had surgery (p = 0.005). The majority (80.4%), who had achieved post-induction metastatic complete remission (mCR), were operated, while 28.7% without mCR had surgery (p < 0.001). The long-term overall survival in patients with mCR and primary tumor resection was 36.5% compared to those with mCR without primary tumor resection (25.4%) and without mCR (≤3.0%)(p < 0.001). Age (p < 0.001), stage (p < 0.001), mCR (p < 0.001) and treatment setting (p < 0.001) were of prognostic significance. The tumor site and MYCN-amplification did not significantly predict resection rates. Post-induction mCR and stage were associated with surgical resection and five-year OS (p < 0.001) on multivariate analysis.Patients with high-risk NB who achieved mCR and had primary tumor resections are curable in limited resourced settings. Stage and post-induction mCR were significant variables that led to surgery. These variables should be included as indications in the management of metastatic NB in resource limited settings.

High-risk neuroblastoma that achieved post-induction chemotherapy metastatic remission and have undergone resection, is curable, even in limited resource settings.Achieving metastatic complete remission was the only factor that significantly predicated if surgery was done.The age at diagnosis, stage and hospitals with expertise in neuroblastoma surgery were of prognostic significance in South Africa.If a patient with high-risk neuroblastoma achieves metastatic complete remission in a resource limited setting, it should be an indication for resection of the primary tumor.

Psychological distress of adolescent and young adult childhood cancer survivors in a South African cohort.

BACKGROUND: We investigated psychological distress in a South African childhood cancer survivor (CCS) cohort. METHODS: Adult CCSs treated at Tygerberg Hospital, Cape Town, completed the Brief Symptom Inventory-18. Internal consistency was acceptable: Cronbach's alpha values were 0.91 (Global Severity Index (GSI)), 0.85 (depression), 0.83 (somatization), and 0.75 (anxiety). We compared results utilizing different case rules (GSI T scores of ≥50, ≥57, and ≥63) for the identification of psychological distress. RESULTS: Forty CCSs (median age 24 years; median follow-up period 16 years) participated. Most (58%; 23 out of 40) completed school or tertiary education, were unmarried (90%; 36 out of 40), and unemployed (59.5%; 22 out of 37). The diagnoses included hematological malignancies (65%; 26 out of 40) and solid tumors (35%; 14 out of 40). The GSI T scores of ≥63, ≥57, and ≥50 identified 10% (four out of 40), 32.5% (13 out of 40), and 45% (18 out of 40) of survivors with psychological distress, respectively. Radiotherapy (odds ratio (OR) 4.6; p = .035), presence of ≥six late effects (OR 7.5; p = .026), and severe late effects (OR 6.6; p = .024) were significant risk factors (GSI T score ≥57). Follow-up period of 11-20 years (OR 7.3; p = .034) was significant for a GSI T score ≥50. CONCLUSION: This South African CCS cohort had higher levels of psychological distress utilizing the GSI T score ≥50 and ≥57 case rules than reported in the literature. Most were unmarried or unemployed. Significant contributing factors were radiotherapy, number and severity of late effects, and follow-up period. CCSs must be screened for psychological distress.

Diagnostic yield and accuracy of paediatric image-guided fine needle aspiration biopsy of deep organ tumours.

Background: Paediatric tumour cytological diagnosis by image-guided fine needle aspiration biopsy (FNAB) with rapid on-site evaluation (ROSE) has not gained wide acceptance despite increasing publications advocating the procedure. Objective: The primary aim was an audit of the diagnostic yield and accuracy of paediatric image-guided FNAB with ROSE at a single institution. Evaluation of safety was a secondary aim. Method: Details of consecutive cases of paediatric image-guided FNAB with ROSE for suspected non-benign deep-seated lesions performed from 01 January 2014 to 30 April 2020 were retrieved from the institutional radiology and laboratory databases. Diagnostic yield and accuracy were evaluated using clinico-pathological-radiological correlation and/or subsequent histological specimen diagnosis correlation. Complications and the frequency of key radiological features potentially affecting yield and accuracy were described. Results: Of 65 cases retrieved, cytology showed malignancy in 52, benign features in five and one indeterminate diagnosis; seven samples were insufficient for cytological assessment. Of the 65 cases, 58 had subsequent formal histological diagnosis. The overall diagnostic yield was 98.5%, with 94.5% sensitivity, 100.0% specificity, 100.0% positive predictive value, 75.0% negative predictive value and 95.3% diagnostic accuracy. All cases (n = 26) demonstrating restricted diffusion on MRI yielded adequate samples and cyto-histopathological correlation. Conclusion: Paediatric image-guided FNAB with ROSE has a relatively high diagnostic yield, sensitivity, specificity, positive predictive value and accuracy in the diagnosis of deep-seated tumours. The relatively low negative predictive value may reflect insufficient samples obtained from cystic and/or benign lesions. Sampling from areas of restricted MRI diffusion may enhance diagnostic yield.

Malignant extracranial germ cell tumours: A first national report by the South African Children's Cancer Study Group.

OBJECTIVE: To determine the overall survival (OS) and prognostic factors influencing outcomes in children and adolescents with malignant extracranial germ cell tumours (MEGCTs) in preparation for the development of a harmonised national treatment protocol. METHODS: A retrospective folder review was undertaken at nine South African paediatric oncology units to document patient profiles, tumour and treatment-related data and outcomes for all children with biopsy-proven MEGCTs from birth up to and including 16 years of age. RESULTS: Between 1 January 2000 and 31 December 2015, 218 patients were diagnosed with MEGCTs. Female sex (hazard ratio [HR] 0.284, p = .037) and higher socio-economic status (SES) (HR 0.071, p = .039) were associated with a significantly lower risk of death. Advanced clinical stage at diagnosis significantly affected 5-year OS: stage I: 96%; stage II: 94.3%; stage III: 75.5% (p = .017) and stage IV (60.1%; p < .001). There was a significant association between earlier stage at presentation and higher SES (p = .03). Patients with a serum alpha-fetoprotein (AFP) level of more than 33,000 ng/ml at diagnosis had significantly poorer outcomes (p = .002). The use of chemotherapy significantly improved survival, irrespective of the regimen used (p < .001). CONCLUSIONS: The cohort demonstrated a 5-year OS of 80.3% with an event-free survival (EFS) of 75.3%. Stage, the use of chemotherapy and an elevated serum AFP level of more than 33,000 ng/ml were independently predictive of outcome. The relationship between SES and outcome is important as the implementation of the new national protocol hopes to standardise care across the socio-economic divide.

Childhood Cancers Misdiagnosed as Tuberculosis in a High Tuberculosis Burden Setting.

BACKGROUND: Tuberculosis (TB) and childhood cancers have overlapping presentations and malignancies may be misdiagnosed as TB in high TB-burden settings. METHODS: This retrospective study investigated the diagnosis of TB in children with cancer registered in the Tygerberg Hospital Childhood Tumor Registry from 2008 to 2018. We studied children on anti-tuberculosis treatment (ATT) at cancer diagnosis or diagnosed with TB within 1 month of cancer diagnosis. We describe the circumstances and extent of this misdiagnosis, quantify the delay in therapy and document the outcomes of these children. RESULTS: Twenty-seven of 539 (5%) children in the registry started ATT before cancer diagnosis. Both pulmonary and extrapulmonary TB complicated the cancer diagnosis. Of the 27 patients on ATT at cancer diagnosis, 22 (81%) had contact with a TB case and in 6 of 12 children (50%) a tuberculin skin test was positive. At cancer diagnosis, 16/27 (59%) children had chest radiograph changes interpreted as TB with 11/27 (41%) regarded as suggestive of TB on expert review. The median diagnostic delay between TB and cancer diagnoses was 25 days (interquartile range 3.5-58). Of 539 children with cancer, 204 (38%) died of cancer, including 18/30 (60%) children on ATT at cancer diagnosis or diagnosed with TB within 1 month of cancer diagnosis (odds ratio 2.6; 95% confidence interval: 1.2-5.4; P = 0.012). CONCLUSIONS: The clinical and radiologic overlap of TB and cancer causes diagnostic confusion in a significant number of children with cancer and may contribute to increased mortality.

The implementation of a national paediatric oncology protocol for neuroblastoma in South Africa.

PURPOSE: The aim of the World Health Organization-International Paediatric Oncology Society is to improve childhood cancer survival in low- and middle-income countries to 60% by 2030. This can be achieved using standardised evidence-based national treatment protocols for common childhood cancers. The aim of the study was to describe the development and implementation of the SACCSG NB-2017 neuroblastoma (NB) treatment protocol as part of the treatment harmonisation process of the South African Children's Cancer Study Group. METHODS: The Consolidated Framework for Implementation Research was used to identify factors that could influence the implementation of the national NB protocol as a health care intervention. The evaluation was done according to five interactive domains for implementation: intervention characteristics, inner setting, outer setting, individual or team characteristics and the implementation process. RESULTS: The protocol was developed over 26 months by 26 physicians involved in childhood cancer management. The process included an organisational phase, a resource identification phase, a development phase and a research ethics approval phase. Challenges included nationalised inertia, variable research ethical approval procedures with delays and uncoordinated clinical trial implementation. CONCLUSION: The implementation of the national NB protocol demonstrated the complexity of the implementation of a national childhood cancer treatment protocol. However, standardised paediatric cancer treatment protocols based on local expertise and resources in limited settings are feasible.

Sex Cord Stromal Tumors in Children and Adolescents: A First Report by The South African Children's Cancer Study Group (1990-2015).

OBJECTIVES: Pediatric sex cord stromal tumors (SCSTs) are extremely rare and there are no reported data from Africa. The authors evaluated the outcomes of children and adolescents with biopsy-proven SCSTs in preparation for the introduction of a national protocol. MATERIALS AND METHODS: Retrospective data were collated from 9 South African pediatric oncology units from January 1990 to December 2015. Kaplan-Meier analysis was performed to estimate overall survival (OS) and event-free survival. RESULTS: Twenty-three patients were diagnosed with SCSTs, 3 male and 20 female individuals, during the study period. Histologies included 1 thecoma, 9 Sertoli-Leydig cell tumors, and 13 juvenile granulosa cell tumors. Stage I tumors predominated (n=14; 60.9%), with 2 stage II (8.7%), 5 stage III (21.7%), and 2 stage IV tumors (8.7%). The upfront resection rate was 91.3% with no reported surgical morbidity or mortality and an OS of 82.1%. Chemotherapy approaches were not standardized. Most children (81.8%), except 2, had recognized platinum-based regimens. Chemotherapy-related toxicity was minimal and acceptable. Assessment of glomerular filtration rate and audiology assessments were infrequent and not standardized. Three patients were lost to follow-up. CONCLUSIONS: Although the numbers in this cohort are small, this study represents the first national cohort in Africa. The 5-year OS of 82.1% was encouraging. Standardized management of rare tumors like SCSTs is critical to improve ensure OS and address potential long-term sequelae.

Prognostic factors affecting survival in children and adolescents with HIV and Hodgkin lymphoma in South Africa.

South African children with Hodgkin lymphoma (HL) and human immunodeficiency virus (HIV) have low 5-year overall survival (OS) rates. In this retrospective multicenter study, 271 South African pediatric patients with HL were studied to determine OS and prognostic factors in those with HIV and HL. Univariate risk factor analysis was performed to analyze prognostic factors. The 29 HIV-infected patients were younger (p = .021), more likely to present with wasting (0.0573), stunting (0.0332), and Stage IV disease (p = .000) than HIV-uninfected patients. The 5- and 10-year OS of HIV-infected patients of 49% and 45% versus 84% and 79%, respectively for HIV-uninfected patients (p = .0001) appeared to be associated with hypoalbuminemia (<20 g/dL) and CD4 percentage of <15%. Causes of death in the HIV-infected group included disease progression (6/14), infection (4/14), unknown (3/14), and second malignancy (1/14). HIV-infected pediatric patients with HL experience increased mortality due to post-therapy opportunistic and nosocomial infections.

The evaluation of induction chemotherapy regimens for high-risk neuroblastoma in South African children.

Achieving remission after induction therapy in high-risk neuroblastoma (HR-NB) is of significant prognostic importance. This study investigated remission after induction-chemotherapy using three standard neuroblastoma protocols in the South African (SA) setting. Retrospective data of 261 patients with HR-NB diagnosed between January 2000 and December 2016, who completed induction chemotherapy with standard treatment protocols were evaluated. The treatment protocols were either OPEC/OJEC or the St Jude NB84 protocol (NB84) or rapid COJEC (rCOJEC). The postinduction metastatic complete remission (mCR) rate, 2-year overall survival (OS) and 2-year event free survival (EFS) were determined as comparative denominators. The majority (48.3%; n = 126) received OPEC/OJEC, while 70 patients received (26.8%) rCOJEC and 65 (24.9%) NB84. Treatment with NB84 had the best mCR rate (36.9%), followed by OPEC/OJEC (32.5%) and rCOJEC (21.4%). The 2-year OS of treatment with NB84 was 41% compared to OPEC/OJEC (35%) and rCOJEC (24%) (p = 0.010). The 2-year EFS of treatment with NB84 was 37% compared to OPEC/OJEC (35%) and rCOJEC (18%) (p = 0.008). OPEC/OJEC had the least treatment-related deaths (1.6%) compared to rCOJEC (7.1%) and NB84 (7.5%) (p = 0.037). On multivariate analysis LDH (p = 0.023), ferritin (p = 0.002) and INSS stage (p = 0.006) were identified as significant prognostic factors for OS. The induction chemotherapy was not significant for OS (p = 0.18), but significant for EFS (p = 0.08) Treatment with NB84 achieved better mCR, OS and EFS, while OPEC/OJEC had the least treatment-related deaths. In resource-constrained settings, OPEC/OJEC is advised as induction chemotherapy in HR-NB due to less toxicity as reflected in less treatment-related deaths.

Overall survival for neuroblastoma in South Africa between 2000 and 2014.

BACKGROUND: Outcome data for neuroblastoma in sub-Saharan Africa are minimal, whereas poor outcome is reported in low- and middle-income countries. A multi-institutional retrospective study across South Africa was undertaken to determine outcome. METHODS: Patients treated between January 2000 and December 2014 in nine South African pediatric oncology units were included. Kaplan-Meier curves and Cox regression models were employed to determine two-year survival rates and to identify prognostic factors. RESULTS: Data from 390 patients were analyzed. The median age was 39.9 months (range, 0-201 months). The majority presented with stage 4 disease (70%). The main chemotherapy regimens were OPEC/OJEC (44.8%), St Jude NB84 protocol (28.96%), and Rapid COJEC (22.17%). Only 44.4% had surgery across all risk groups, whereas only 16.5% of high-risk patients received radiotherapy. The two-year overall survival (OS) for the whole cohort was 37.6%: 94.1%, 81.6%, and 66.7%, respectively, for the very-low-risk, low-risk, and intermediate-risk groups and 27.6% for the high-risk group (P < 0.001, 95% CI). The median survival time for the whole group was 13 months (mean, 41.9 months; range, 0.1-209 months). MYCN-nonamplified patients had a superior two-year OS of 51.3% in comparison with MYCN-amplified patients at 37.3% (P = 0.002, 95% CI). CONCLUSIONS: Limited disease had an OS comparable with high-income countries, but advanced disease had a poor OS. South Africa should focus on early diagnosis and implementation of a national protocol with equitable access to treatment.

Predictive Indicators to Identify High-Risk Paediatric Febrile Neutropenia in Paediatric Oncology Patients in a Middle-Income Country.

PURPOSE: To validate a clinical risk prediction score (Ammann score) to predict adverse events (AEs) in paediatric febrile neutropenia (FN). PATIENTS AND METHODS: Patients <16 years of age were enrolled. A risk prediction score (based on haemoglobin ≥ 9 g/dl, white cell count (WCC) < 0.3 G/l, platelet count <50 G/l and chemotherapy more intensive than acute lymphoblastic leukaemia maintenance therapy) was calculated and AEs were documented. RESULTS: In total, 100 FN episodes occurred in 52 patients, male:female ratio was 1.8:1 and median age was 56 months. At reassessment, AEs occurred in 18 of 55 (45%) low-risk FN episodes (score < 9) and 21 of 42 (55%) high-risk episodes (score ≥9) (sensitivity 60%, specificity 65%, positive predictive value 53%, negative predictive value 71%). Total WCC and absolute monocyte count (AMC) were significantly associated with AEs. CONCLUSION: This study identified total WCC and AMC as significantly associated with AEs but failed to validate the risk prediction score.

Treatment outcomes of children with Hodgkin lymphoma between 2000 and 2010: First report by the South African Children's Cancer Study Group.

BACKGROUND: Children with Hodgkin lymphoma (HL) have excellent survival rates in high-income countries, but there are minimal outcome data in South African patients. Differing approaches to treatment are used in centres across South Africa, and the South African Children's Cancer Study Group (SACCSG) embarked on a programme to audit outcomes to improve survival rates. PATIENTS AND METHODS: A multicentre study was conducted to analyse outcomes and prognostic factors of children with HL in South Africa. Ten dedicated South African paediatric oncology units participated in a retrospective data review. All patients with HL treated consecutively between January 2000 and December 2010 were included. Kaplan-Meier curves and Cox regression model were employed to determine survival rates and prognostic factors. RESULTS: Two hundred and ninety-four patients were eligible for inclusion. The median age at presentation was 9.6 years (range 2.9-18.8); 55.4% of the patients presented with Stage III and IV disease and 9.9% were human immunodeficiency virus (HIV) positive. First-line therapy consisted of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in 158 patients, vincristine, procarbazine/etoposide, prednisone and doxorubicin in 97 and adriamycin, bleomycin, vincristine and dacarbazine-chlorambucil, vinblastine, prednisone and procarbazine in 23 patients. The 5-year overall survival (OS) was 79% (95% confidence interval 73-84%). Multivariate analysis demonstrated that HIV infection (P = 0.018) and Ann Arbor Stage III and IV disease (P = 0.006) conferred a poor prognosis, while treatment with ABVD was associated with higher survival rates (P = 0.028). CONCLUSION: OS rates are encouraging for a middle-income country, although economic disparities continue to impact negatively on outcomes. Study results will form the basis for the development of national protocol and continued advocacy to rectify disparities.

Childhood cancer in Africa.

The majority of children with cancer live in low- and middle-income countries (LMICs) with little or no access to cancer treatment. The purpose of the paper is to describe the current status of childhood cancer treatment in Africa, as documented in publications, dedicated websites and information collected through surveys. Successful twinning programmes, like those in Malawi and Cameroon, as well as the collaborative clinical trial approach of the Franco-African Childhood Cancer Group (GFAOP), provide good models for childhood cancer treatment. The overview will hopefully influence health-care policies to facilitate access to cancer care for all children in Africa.