Transplant‐related mortality following allogeneic hematopoeitic stem cell transplantation for pediatric acute lymphoblastic leukemia: 25‐year retrospective review

Background

Over the last 25 years, donor source, conditioning, graft‐versus‐host disease prevention and supportive care for children undergoing hematopoeitic stem cell transplantation (HSCT) have changed dramatically. HSCT indications for acute lymphoblastic leukemia (ALL) now include high‐risk patients in first and subsequent remission. There is a large burden of infectious and pre‐HSCT morbidities, due to myelosuppressive therapy required for remission induction. We hypothesized that, despite these trends, overall survival (OS) had increased.

Procedure

A retrospective audit of allogeneic pediatric HSCT for ALL was performed in our institution over 25 years. Outcomes for 136 HSCTs were analyzed in three consecutive 8‐year periods (Period 1: 1/1/1984–31/8/1992, Period 2: 1/9/1992–30/4/2001, Period 3: 1/5/2001–31/12/2009).

Results

Despite a significant increase in unrelated donor HSCT, event‐free and OS over 25 years improved significantly. (EFS 31.6–64.8%, P = 0.0027; OS 41.8–78.9%, P < 0.0001) Concurrently, TRM dropped from 33% to 5% (P = 0.0004) whilst relapse rate was static (P = 0.07). TRM reduced significantly for matched sibling and unrelated cord blood transplantation (UCT) in Period 3 compared with earlier periods (P = 0.036, P = 0.0098, respectively). Factors leading to improved survival in patients undergoing UCT include better matching, higher total nucleated cell doses, and significantly faster neutrophil engraftment. Length of initial HSCT admission was similar over time.

Conclusion

EFS and OS have increased significantly despite heightened HSCT complexity. This survival gain was due to TRM reduction. Contemporary patients have benefited from refined donor selection and improved supportive care. Overall rates of leukemic relapse post‐HSCT are unchanged, and remain the focus for improvement. Pediatr Blood Cancer 2013;160:1520–1527. © 2013 Wiley Periodicals, Inc.     

Toxicity and outcome of children with treatment related acute myeloid leukemia

Background

The aim of this study was to evaluate the clinical course and outcome of children with treatment related acute myeloid leukemia (tAML) and compare them to children with primary AML (pAML).

Procedure

We retrospectively reviewed the demographic, treatment, toxicity, and outcome data of children with tAML and treatment related myelodysplastic syndrome (tMDS), treated at our institution between 1975 and 2005. We compared these parameters with matched controlled children with pAML. Finally we compared overall survival (OS) for tAML with all pAML children treated at the study era in our institution.

Results

Twenty‐one patients with tAML (n = 19) and tMDS (n = 2) were identified. Three years event‐free survival (EFS) and OS were both 14 ± 8%. Compared to pAML patients, tAML had a higher rate of adverse cytogenetics (P < 0.008) and inferior OS (P = 0.027) but no significant difference in treatment toxicity or death. All survivors were treated with allogeneic hematopoietic stem cell transplantation (HSCT).

Conclusions

In this population based report of pediatric tAML, outcome was poor and was related to a higher probability of poor cytogenetic features rather than excessive toxicities or inability to deliver therapy. HSCT should be considered for patients with tAML. These preliminary findings should set the stage for prospective cooperative studies. Pediatr Blood Cancer 2008;50:17–23. © 2007 Wiley‐Liss, Inc.     

Treatment of young children with CNS‐positive acute lymphoblastic leukemia without cranial radiotherapy

Background

Due to the long‐term sequelae of cranial radiotherapy (CRT), contemporary treatment protocols for children with acute lymphoblastic leukemia (ALL) aim to limit the use of prophylactic CRT. For patients with central nervous system (CNS) involvement with ALL at diagnosis, the use of CRT remains common. Children <5 years of age are a particularly challenging subgroup in whom the consequences of CRT can be devastating.

Procedure

This study retrospectively describes the overall (OS) and event‐free survival (EFS) of young children (1–5 years) who were treated for CNS‐positive ALL at the Hospital for Sick Children between 2000 and 2013.

Results

Of a total of 19 patients, two were treated with upfront CRT, both as part of the conditioning regimen prior to HSCT. All patients received intensification of CNS‐directed chemotherapy by triple intra‐thecal chemotherapy (84.2%), use of dexamethasone in induction (57.9%) and maintenance (66.7%), and high‐dose methotrexate (77.8%). The OS was 84.2 ± 8.4% and EFS was 79.0 ± 9.4% with a median follow‐up time of 4.3 years (range, 2.6–8.2). The cumulative incidence of CNS relapse was 5.2 ± 5.1%.

Conclusions

We conclude that omission of CRT from the treatment of young children with ALL involving the CNS is associated with acceptable survival and avoids potentially devastating late effects in this group. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.     

Outcome and prognostic factors for children with supratentorial primitive neuroectodermal tumors treated with carboplatin during radiotherapy: A report from the Children's Oncology Group

Background

Supratentorial PNETs (sPNET) are uncommon embryonal malignancies of the central nervous system whose prognosis has historically been poor. We evaluated the outcome and prognostic factors of children with sPNET treated prospectively on a Children's Oncology Group trial.

Procedure

Following surgery, patients received craniospinal radiotherapy with concurrent carboplatin followed by six months of maintenance chemotherapy with cyclophosphamide and vincristine.

Results

Five‐year overall survival (OS) and progression‐free survival (PFS) for all patients was 58 ± 7% and 48 ± 7%. For patients with pineoblastoma (n = 23), five‐year OS and PFS was 81 ± 9% and 62 ± 11%. Extent of resection but not M‐stage was prognostic. Five‐year OS and PFS for 37 patients with non‐pineal tumors (NPsPNET) was 44 ± 8% and 39 ± 8%, significantly worse than for PB (P = 0.055 and 0.009 respectively). Extent of resection and major radiotherapy deviations were prognostic. Five year OS was 59 +/? 11.4% for those undergoing complete resection versus 10.4 +/? 7% for those who did not (P = 0.017). Central pathologic review called 14 (38%) “classic” sPNET, 8 (22%) “undifferentiated” and 13 (35%) “malignant gliomas.” There was no significant difference between the subgroups, although survival distributions approached significance when the combined “classic” and “undifferentiated” group was compared to the “malignant gliomas.”

Conclusions

Carboplatin during RT followed by 6 months of non‐intensive chemotherapy is a feasible treatment strategy for patients with sPNET. Aggressive surgical resection should be attempted if feasible. The classification of supratentorial small cell malignancies can be difficult. Pediatr Blood Cancer 2015;62:776–783. © 2015 Wiley Periodicals, Inc.

     

Central nervous system disease in pediatric acute myeloid leukemia: A report from the Children's Oncology Group

1 Background

The prognostic impact of central nervous system (CNS) involvement in children with acute myeloid leukemia (AML) has varied in past trials, and controversy exists over the degree of involvement requiring intensified CNS therapy. Two recent Children's Oncology Group protocols, AAML03P1 and AAML0531, directed additional intrathecal (IT) therapy to patients with CNS2 (≤5 white blood cell [WBC] with blasts) or CNS3 (>5 WBC with blasts or CNS symptoms) disease at diagnosis.

2 Methods

We examined disease characteristics and outcomes of the 1,344 patients on these protocols, 949 with CNS1 (no blasts), 217 with CNS2, and 178 with CNS3, with the latter two receiving additional IT therapy.

3 Results

Young age (P = 0.003), hyperleukocytosis (P < 0.001), and the presence of inversion 16 (P < 0.001) were the only factors more prevalent in patients with CNS2 or CNS3 disease. Complete remission at the end of induction (EOI) 2 was achieved less often in patients with CNS involvement (P < 0.001). From diagnosis, event‐free survival (EFS) for patients with CNS involvement was significantly worse (P < 0.001), whereas overall survival (OS) was not (P = 0.16). From the EOI1, there was a higher relapse rate (RR) and worse disease‐free survival (DFS), but less impact on OS (CNS1:DFS 58.9%, RR 34.1%, OS 69.3%; CNS2:DFS 53.2%, RR 40.9%, OS 74.7%; CNS3:DFS 45.2%, RR 48.8%, OS 60.8%; P = 0.006, P < 0.001, P = 0.045, respectively). Multivariable analysis showed that independently CNS2 and CNS3 status adversely affected RR and DFS. Traumatic diagnostic lumbar puncture was not associated with worse outcome.

4 Conclusions

CNS leukemia confers greater relapse risk despite more aggressive locally directed therapy. Novel approaches need to be investigated in this group of patients.     

Intensified chemotherapy without SCT in infant ALL: Results from COG P9407 (Cohort 3)

Background

Infants with acute lymphoblastic leukemia (ALL) present with aggressive disease and a poor prognosis. Early relapse within 6–9 months of diagnosis is common. Approximately 75% of infants have MLL‐rearranged (MLL‐R) ALL with event free survival (EFS) ranging from 20% to 30%. Children's Oncology Group (COG) P9407 used shortened (46 weeks), intensified therapy to address early relapse and poor EFS.

Procedure

P9407 therapy was modified three times for induction toxicity resulting in three cohorts of therapy. One hundred forty‐seven infants were enrolled in the third cohort.

Results

We report an overall 5‐year EFS and OS of 42.3 ± 6% and 52.9 ± 6.5% respectively. Poor prognostic factors included age ≤90 days at diagnosis, MLL‐R ALL and white cell count ≥50,000/μl. For infants ≤90 days of age, the 5‐year EFS was 15.5 ± 10.1% and 48.5 ± 6.7% for those >90 days (P < 0.0001). Among infants >90 days of age, 5‐year EFS rates were 43.8 ± 8% for MLL‐R versus 69.1 ± 13.6% for MLL‐germline ALL (P < 0.0001).

Conclusions

Age ≤90 days at diagnosis was the most important prognostic factor. Despite shortened therapy with early intensification, EFS remained less than 50% overall in MLL‐R ALL. Pediatr Blood Cancer 2015;62:419–426. © 2014 Wiley Periodicals, Inc.     

Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group

1 Background

The purpose of this study was to evaluate clinical characteristics, treatment, and survival of children, who were diagnosed with hepatoblastoma (HB) in their first 6 months of age, enrolled in the SIOPEL 2 and 3 protocols.

2 Methods

Seventy‐nine patients, treated between 1994 and 2006, were analyzed after stratification into three age groups: <1 month, between 1 and 3 months, and between 3 and 6 months. All received preoperative chemotherapy.

3 Results

Clinical characteristics were similar in both trials: 4 patients had pulmonary metastases at diagnosis, 4 had α‐fetoprotein <100 ng/ml, 68 were operated by partial hepatectomy, and 7 received liver transplant. Chemotherapy courses were delayed in 8.5%, 8.4%, and 11.8% of cycles in the three groups. Doses were calculated according to weight for children <5 and 5–10 kg, and further reduced in 18.1%, 6.8%, and 5.9% of cycles. Acute toxicity was manageable. Long‐term hearing loss was the major problem at follow‐up occurring in two‐thirds of children. Ten patients experienced progression or relapse, and 5 of 10 died. After a median follow‐up of 5.6 years, the 5‐year overall survival (OS) and event‐free survival (EFS) were 91% (95% confidence interval [CI]: 84–96%) and 87% (95% CI: 78–92%), respectively.

4 Conclusions

The 5‐year OS and EFS of children <6 months of age affected by HB seem to be similar to those documented in the elder children. Dose reduction does not seem to jeopardize the long‐term outcome and may explain the lower toxicity profile. Ototoxicity though appears as high as in the whole population of SIOPEL 2 and 3. The treatment for these children should be further explored in international studies, particularly focusing on prevention of hearing loss.     

Gender affects survival for medulloblastoma only in older children and adults: A study from the surveillance epidemiology and end results registry

Background

Males have a higher incidence of medulloblastoma (MB) than females, but the effect of gender on survival is unclear. Studies have yielded conflicting results, possibly due to small sample sizes or differences in how researchers defined MB. We aimed to determine the effect of gender on survival in MB using a large data set and strict criteria for defining MB.

Procedure

A sample of 1,226 subjects (763 males and 463 females) was identified from 1973 to 2002, using the Surveillance Epidemiology and End Results (SEER‐9) registry. MB was strictly defined to exclude non‐cerebellar embryonal tumors (primitive neuro‐ectodermal tumors). Because children <3 years of age are known to have worse survival, patients were stratified by age <3 years at diagnosis (95 males, 82 females) and >3 years (668 males, 381 females).

Results

Overall, there was no significant difference in survival between males and females (log rank P = 0.22). However, among subjects >3 years, females had significantly greater survival than males (log rank P = 0.02). In children <3 years, there was a non‐significant trend toward poorer survival in females (median survival: males 27 months, females 13 months; log rank P = 0.24). This interaction between age group and gender was statistically significant (P = 0.03).

Conclusion

Females with MB have a survival advantage only in subjects >3 years. In children <3 years, females may even have poorer outcome. The effect of gender on survival and incidence in MB warrants additional biologic investigation, and may differ in very young children with MB. Pediatr Blood Cancer 2009;52:60–64. © 2008 Wiley‐Liss, Inc.     

Defibrotide for the treatment of hepatic veno‐occlusive disease/sinusoidal obstruction syndrome following nontransplant‐associated chemotherapy: Final results from a post hoc analysis of data from an expanded‐access program

1 Background

Hepatic veno‐occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) but can occur after nontransplant‐associated chemotherapy. Following HSCT, VOD/SOS with multi‐organ dysfunction (MOD) may be associated with >80% mortality. Defibrotide is approved to treat severe hepatic VOD/SOS post‐HSCT in patients aged >1 month in the European Union and hepatic VOD/SOS with renal or pulmonary dysfunction post‐HSCT in the United States. Prior to US approval, defibrotide was available to treat VOD/SOS through an expanded‐access treatment (T‐IND) program. A post hoc analysis of nontransplant‐associated VOD/SOS patients treated with defibrotide initiated within 30 days of starting chemotherapy and followed for 70 days is presented.

2 Procedure

Patients were diagnosed by Baltimore or modified Seattle criteria or biopsy, and received defibrotide 25 mg/kg/day in four divided doses (≥21 days recommended).

3 Results

Of the 1,154 patients in the T‐IND, 137 had nontransplant‐associated VOD/SOS, 82 of whom developed VOD/SOS within 30 days of starting chemotherapy. Of them, 66 (80.5%) were aged ≤16 years. Across all the 82 patients, Kaplan–Meier estimated day +70 survival was 74.1%, 65.8% in patients with MOD (n = 38), and 81.3% in patients without MOD (n = 44). By age group, Kaplan–Meier estimated day +70 survival was 80.1% in pediatric patients (n = 66) and 50.0% in adults (n = 16). Treatment‐related adverse events occurred in 26.8%.

4 Conclusions

In this post hoc analysis of 82 patients initiating defibrotide within 30 days of starting chemotherapy, Kaplan–Meier estimated survival was 74.1% at 70 days after defibrotide initiation. Safety profile was consistent with prior defibrotide studies.     

High‐dose treatment for malignant rhabdoid tumor of the kidney: No evidence for improved survival—The Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH) experience

1 Background

Malignant rhabdoid tumor of the kidney (MRTK) is the most aggressive childhood renal tumor with overall survival (OS) rates ranging from 22% to 42%. Whether high‐dose chemotherapy with autologous stem‐cell transplantation (HDSCT) in an intensive first‐line treatment offers additional benefit is an ongoing discussion.

2 Methods

A retrospective analysis of all 58 patients with MRTK from Austria, Switzerland, and Germany treated in the framework of consecutive, prospective renal/rhabdoid tumor studies SIOP9/GPO, SIOP93‐01/GPOH (where SIOP is International Society of Pediatric Oncology and GPOH is German Society of Pediatric Oncology and Hematology), SIOP2001/GPOH, and European Rhabdoid Tumor Registry from 1991 to 2014.

3 Results

Median age at diagnosis was 11 months. Fifty percent of patients had metastases or multifocal disease at diagnosis (Stage IV). Local stage distribution was as follows: not done/I/II/III—1/6/11/40. Fifteen (26%) patients underwent upfront surgery. Thirty‐seven (64%) patients achieved a complete remission, 17 (29%) relapsed, 34 (59%) died of disease progression, and two (3%) died of treatment‐related complication. Mean time to the first event was 3.5 months. Two‐year EFS/OS (where EFS is event‐free survival) for the whole group was 37 ± 6%/38 ± 6%. Metastases/multifocal disease, younger age, and local stage III were associated with significantly inferior survival. Eleven (19%) patients underwent HDSCT (carboplatin + thiotepa, n = 6; carboplatin + etoposide + melphalan, n = 4; others, n = 1); 2‐year OS in this group was 60 ± 15% compared to 34 ± 8% in the non‐HDSCT group (P = 0.064). However, the time needed from radiologic to histologic diagnosis, stem‐cell harvest, and HDSCT must also be taken into account to avoid selection bias by excluding the highest risk group with early progression (<90 days). Thus, 2‐year EFS only for patients without progression until day 90 was 60 ± 16% consolidated by HDSCT compared to 62 ± 11% without (P = 0.8).

4 Conclusion

Our retrospective analysis suggests comparable outcomes for patients with and without HDSCT, if adjusted for early disease progression.     

Both location and age predict survival in ependymoma: A SEER study

Background

Studies have suggested that supratentorial ependymomas have better survival than infratentorial tumors, with spinal tumors having the best prognosis, but these data have been based on small samples. Using a population‐based registry of ependymomas, we analyzed how age, gender, location, race and radiotherapy influence survival in children.

Methods

We queried the Surveillance Epidemiology End Results database (SEER‐17) from 1973 to 2003, strictly defining ependymomas by histology. Site codes were used to distinguish between supratentorial, infratentorial, and spinal tumors when available. Outcomes were compared by location, age, gender, race and radiotherapy, using Kaplan–Meier analysis and logrank tests. Cox regression was completed, incorporating all significant covariates from univariate analysis.

Results

Six hundred thirty‐five children were identified with an overall 5‐year survival of 57.1 ± standard error (SE) 2.3%. Increasing age was associated with improved survival (P < 0.0001). Five‐year survival by location was 59.5 ± SE 5.5% supratentorial, 57.1 ± SE 4.1% infratentorial and 86.7 ± SE 5.2% spinal. Radiotherapy of the infratentorial tumors resulted in significantly improved survival in both univariate analysis (logrank P < 0.018) and multivariate analysis restricted to this tumor location (P = 0.033). Using multivariate analysis that incorporated all tumor locations, age (P < 0.001) and location (P = 0.020) were significant predictors for survival.

Conclusions

Age and location independently influence survival in ependymoma. Spinal tumors are associated with a significantly better prognosis than both supratentorial and infratentorial tumors, and may represent a distinct biological entity. Radiotherapy appears beneficial for survival in patients with infratentorial ependymoma. Pediatr Blood Cancer 2009;52:65–69. © 2008 Wiley‐Liss, Inc.     

Osteosarcoma in patients younger than 12 years old without metastases have similar prognosis as adolescent and young adults

Background

Childhood cancer is relatively rare and tends to present specific age distribution, as a prognostic factor for some of these diseases. Information on how young age affects prognosis, response to chemotherapy, and local control options in children versus AYA with osteosarcoma (OST) is minimal.

Methods

In order to identify the main differences in clinicalpathologic features, surgical approaches and survival rates of primary high grade OST of the extremity between children (n = 156; <12 years old) and AYA (n = 397; 12–30 years old), the institutional database with 553 patients treated by BOTG studies over 15 years were reviewed.

Results

There were no differences in metastasess at diagnosis, tumor size, and grade of necrosis between the two age groups. The rate of amputation was 30% higher in the children group (P = 0.018). The rate of limb salvage surgery using reconstruction with allograft or autograft was 70% higher in the children group (P = 0.018) while endoprosthesis rate was 40% higher in the AYA group (P = 0.018). The log rank test revealed that survival is similar between the two age groups for non‐metastatic patients (P = 0.424 for OS and P = 0.393 for EFS). Metastatic patients of both ages group had higher risk of dying compared to non‐metastatic (HR 3.283 95% CI 2.581–4.177; P < 0.001). Children with metastases at diagnosis had less OS time (P = 0.049) and EFS time (P = 0.032) than adolescents.

Conclusion

Non‐metastatic OST in preadolescent patients does not appear to be significantly differentfrom those seen in AYA patients, but has local control challenges. Children presenting with metastases should be considered an ultra‐high‐risk group. Pediatr Blood Cancer 2015;62:1209–1213. © 2015 Wiley Periodicals, Inc.     

Dose‐escalation is needed for gross disease in high‐risk neuroblastoma

1 Background

Locoregional failure is common after subtotal resection in high‐risk neuroblastoma. Although a dose of 21 Gy radiation therapy (RT) is standard for treatment of high‐risk neuroblastoma after gross total resection, the dose needed for local control of patients with gross residual disease at the time of RT is unknown. We sought to evaluate local control after 21–36 Gy RT in patients with high‐risk neuroblastoma undergoing subtotal resection.

2 Methods

All patients with high‐risk neuroblastoma who received RT to their primary site from 2000 to 2016 were reviewed. Of the 331 patients who received consolidative RT to their primary site, 19 (5.7%) underwent subtotal resection and were included in our analysis. Local failure (LF) was correlated with biologic prognostic factors and dose of RT.

3 Results

Median follow‐up among surviving patients was 6.0 years. Median RT dose was 25 Gy (range, 21 Gy–36 Gy). The 5‐year cumulative incidence of LF among all patients was 17.2%. LF at 5 years was 30% in those who received <30 Gy versus 0% in those who received 30–36 Gy (P = 0.12). There was a trend towards improved local control in patients with tumor size ≤10 cm at diagnosis (P = 0.12). The 5‐year event‐free and overall survival were 44.9% and 68.7%, respectively.

4 Conclusion

After subtotal resection, patients who received less than 30 Gy had poor local control. Doses of 30–36 Gy are likely needed for optimal control of gross residual disease at the time of consolidative RT in high‐risk neuroblastoma.     

Treatment results for patients with localized,completely resected (Group I) alveolar rhabdomyosarcoma on Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols III and IV, 1984–1997: A report from the Children's Oncology Group

Purpose

To assess local control, event‐free survival (EFS), and overall survival (OS) rates in 71 patients with localized, completely resected (Group I) alveolar rhabdomyosarcoma (ALV RMS) and their relation to radiation therapy (RT) on IRSG Protocols III and IV, 1984–1997.

Methods

Chart review and standard statistical procedures.

Patients and Tumors

Patients were 1–18 years at diagnosis (median, 6 years). Primary tumor sites were extremity/trunk (N = 54), head/neck (N = 9), genitourinary tract (N = 7), and perineum (N = 1). Thirty patients received VA ± C with RT; 41 received VA ± C alone. RT was assigned, not randomized.

Results

Fifty‐four patients had Stage 1 (favorable site, any size) or Stage 2 (unfavorable site, ≤5 cm) tumors. Eight‐year EFS was 90%, with 100% local control for 17 patients given RT. Eight‐year EFS was 88%, with 92% local control for 37 patients without RT; P = 0.52 for EFS comparisons, 0.3 for local control comparisons. In 17 Stage 3 patients (unfavorable site, tumors >5 cm, N0), 8‐year EFS was 84% with 100% local control in 13 patients given RT; 8‐year EFS was only 25% and local control 50% in 4 patients without RT. Local recurrence was the most common site of first failure in non‐irradiated patients.

Conclusion

Patients with Stage 1–2 ALV RMS had slightly but statistically insignificantly improved local control, EFS, and OS rates when local RT was given. The need for local RT in Stage 1–2 patients deserves evaluation in a randomized study. Local control, EFS, and OS rates were significantly improved in Stage 3 patients receiving local RT. Pediatr Blood Cancer. 2010;55:612–616. © 2010 Wiley‐Liss, Inc.     

Sparing strategy does not compromise prognosis in pediatric localized synovial sarcoma: experience of the International Society of Pediatric Oncology, Malignant Mesenchymal Tumors (SIOP-MMT) Working Group

Background

The aim of this analysis was to identify if the modified indications of radiotherapy (RT) or radical surgery compromised survival in pediatric synovial sarcoma (SS).

Procedure

Children with non‐metastatic SS, prospectively enrolled in three trials, were analyzed. After primary surgery or biopsy, they received chemotherapy. RT was planned after chemotherapy in patients who had not achieved a complete response (CR). The considered outcome was 5‐year overall survival (OS) and event‐free survival (EFS).

Results

Eighty‐eight patients were identified. Primary tumors were mainly located in limbs (66%). The first‐line therapy for 65 patients was primary resection. Of the 49 patients who had gross tumor resection, 43 received adjuvant chemotherapy, and 8 had RT. All of the 39 patients with macroscopic residual disease received chemotherapy, then only surgery (n = 12) ± RT (n = 22). The 5‐year EFS and OS rates were 68% and 85%, respectively. The TNM stage was a prognostic factor for relapse, whereas primary site of the tumor and TNM stage were prognostic factors for death.

Conclusions

Only 32% of survivors received RT. OS was similar to published data. Omission of RT may be considered in younger children, to limit the potential sequelae in patients with tumors less than 5 cm in size initially submitted to marginal resection. This strategy may also be considered in initially unresected cases, when the tumor is resected at delayed surgery with microscopically free margins, and in patients in complete remission after primary chemotherapy. Pediatr Blood Cancer 2011; 57: 1130–1136. © 2011 Wiley Periodicals, Inc.     

Risk Factors for Microbiologically-documented Infections,Mortality and Prolonged Hospital Stay in Children with Febrile Neutropenia

Objective

To analyze the risk factors for microbiologically documented infection, mortality and hospital stay more than 5 days in children with febrile neutropenia.

Design

Cross-sectional study (July 2013-September 2014).

Setting

Government-run, tertiary-care, university hospital in Chandigarh, Northern India.

Participants

414 episodes in 264 children aged <12 years, not undergoing stem-cell transplantation.

Outcome measures

Predictors for ‘high-risk’ febrile neutropenia.

Results

Microbiologically-documented infections were observed in 82 children (19.8%); bacterial 14.2%, fungal 4.3%, polymicrobial 9.7%. Complications were documented in 109 (26%) children. 43 (10.3%) died: 8 due to fungal and 35 due to bacterial sepsis. Children admitted within 7 days of the last chemotherapy (P<0.01) and having a non-upper respiratory focus of infection (P<0.02) were at risk of developing microbiologicallydocumented infections and death. Platelet count <20000/uL (P=0.03) was an additional predictor for microbiologicallydocumented infections, while albumin <2.5 g/dL (P=0.04) and Creactive protein >90 mg/L (P=0.02) were risk factors predicting mortality. The median (IQR) duration of hospital stay was 5 (3,8) days. Hospital stay <5 days was seen in 144 (35%) children. Children with acute myeloid leukaemia (P<0.01) and admitted within 7 days of chemotherapy (P=0.02) were likely to have a prolonged hospital stay >5 days.

Conclusions

Febrile neutropenic children admitted within 7 days of completion of chemotherapy, those with a non-upper respiratory focus of infection, CRP >90 mg/dL, platelet <20000/uL and albumin <2.5 g/dL need to be considered as ‘high risk’ for complications and mortality.

     

Treatment‐related mortality in relapsed childhood acute lymphoblastic leukemia

1 Background

Treatment of relapsed childhood acute lymphoblastic leukemia (ALL) is particularly challenging due to the high treatment intensity needed to induce and sustain a second remission. To improve results, it is important to understand how treatment‐related toxicity impacts survival.

2 Procedure

In this retrospective population‐based study, we described the causes of death and estimated the risk for treatment‐related mortality in patients with first relapse of childhood ALL in the Nordic Society of Paediatric Haematology and Oncology ALL‐92 and ALL‐2000 trials.

3 Results

Among the 483 patients who received relapse treatment with curative intent, we identified 52 patients (10.8%) who died of treatment‐related causes. Twelve of these died before achieving second remission and 40 died in second remission. Infections were the cause of death in 38 patients (73.1%), predominantly bacterial infections during the chemotherapy phases of the relapse treatment. Viral infections were more common following hematopoietic stem cell transplantation (HSCT) in second remission. Independent risk factors for treatment‐related mortality were as follows: high‐risk stratification at relapse (hazard ratio [HR] 2.2; 95% confidence interval [CI] 1.3–3.9; P < 0.01), unfavorable cytogenetic aberrations (HR 3.4; 95% CI 1.3–9.2; P = 0.01), and HSCT (HR 4.64; 95% CI 2.17–9.92; P < 0.001). In contrast to previous findings, we did not observe any statistically significant sex or age differences. Interestingly, none of the 17 patients with Down syndrome died of treatment‐related causes.

4 Conclusions

Fatal treatment complications contribute significantly to the poor overall survival after relapse. Implementation of novel therapies with reduced toxicity and aggressive supportive care management are important to improve survival in relapsed childhood ALL.     

Socioeconomic status significantly impacts childhood cancer survival in South Africa

Background and aims

Significantly discrepant survival rates have been documented in single disease childhood cancer cohorts in South Africa; those from higher socioeconomic groups were shown to have a significantly lower risk of death than those from less affluent households. This study aimed to determine the impact of socioeconomic status (SES) on childhood cancer survival using pooled South African data.

Methods

Five databases spanning January 2000 to December 2021 were interrogated. SES status was assigned based on a public sector annual household income classification. H0 households (formally unemployed) received free healthcare. H1, H2 and H3 (annual income > United States Dollar [USD] 19,000) households paid for healthcare relative to their income. The Spearman test assessed correlations between SES and disease stage in patients with solid tumours. Hazard ratios were determined using Cox regression modelling. The Kaplan–Meier procedure estimated overall survival (OS).

Results

A total of 1598 children were eligible for analysis; 1269 had a solid tumour with a negative correlation between SES and stage (Spearman rho = −.178; p < .001). Patients with solid tumours and lower SES showed proportionately higher numbers of stage III and IV disease (p < .01). This proportion decreased with higher SES categories. In the multivariate analyses adjusted for sex, age, tumour type and stage, higher SES was associated with lower mortality risk (p < .001), indicating that the impact of SES on survival was in excess of any effect that could be explained by lower stage disease alone. There was a strong positive correlation between race and SES (Fisher's exact tests, p < .001) across all groups and all SES strata. Five-year OS was 85.3% in children from H3 households versus 46.3% in children from H0 households (p < .001).

Conclusion

SES significantly impacts childhood cancer survival for children with solid tumours in South Africa. SES is a robust surrogate for race in South Africa as a prognostic metric of disease outcome in childhood cancer. Advocacy to increase social support for impoverished patients is essential to achieve equitable improvements in outcomes treated with standardised national treatment guidelines.     

基于美国儿童肿瘤学组方案治疗68例神经母细胞瘤的中长期随访结局

目的基于美国儿童肿瘤学组(COG)危险度分级的化疗方案,探讨神经母细胞瘤(NB)患儿诊断年龄与预后的相关性。方法以2007年1月至2013年3月复旦大学附属儿科医院外科诊断为NB的连续病例为研究对象,划分低危、中危和高危,分析不同INSS分期NB患儿的5年总体生存率和5年无事件生存率(EFS),并对诊断年龄和5年EFS行受试者工作特征(ROC)曲线分析,获得与EFS相关的最佳诊断年龄界值。结果 68例NB患儿进入分析,男41例(60.3%),女27例;Ⅰ期7例(10.3%),Ⅱ期14例(20.6%),Ⅲ期11例(16.2%),Ⅳ期23例(33.8%),Ⅳs期13例(19.1%)。低危24例,中危14例,高危30例。128例高危患儿术前行诱导化疗,非常好的部分缓解率为60.7%(17/28),部分缓解率为14.3%。60/68例接受手术治疗,肉眼完整切除(GTR)率为71.7%。28例失访,32例随访至5年,5年总体生存率为65.6%,其中Ⅲ期为66.7%,Ⅳ期为22.2%;5年EFS为59.4%,其中Ⅲ期为50.0%,Ⅳ期为11.1%,GTR患儿5年EFS高于未GTR患儿(70.2%vs 57.4%)。35/30例MYCN基因扩增阳性(Ⅱ期1例,Ⅳ期4例),2年总体生存率为40%(2/5),2年EFS为20%(1/5);25例MYCN基因阴性患儿,2年总体生存率为92%(23/25),2年EFS为88%(22/25)。4诊断年龄和5年EFS的ROC曲线下面积为0.713,诊断年龄2.4岁时的敏感度为75.0%,特异度为66.7%。结论采用COG治疗方案的Ⅳ期患儿的5年总体生存率为22.2%,5年EFS为11.1%。GTR与NB的预后相关,诊断年龄2.4岁可能提示预后不良。     

Laparoscopic resection of adrenal neuroblastoma without image-defined risk factors: a prospective study on 21 consecutive pediatric patients

Background

Over the last 20 years MIS has progressively gained popularity in children with cancer. We therefore aimed at evaluating the safety of Minimally Invasive Surgery (MIS) resection in a series of children affected by adrenal neuroblastoma (NB) presenting without Image-Defined Risk Factors (IDRFs).

Methods

An Institutional protocol for MIS resection of adrenal NB in pediatric patients without IDRFs has been applied since 2008. Absence of IDRFs represented the main indication for MIS in NB, regardless of tumor size. All pediatric patients who underwent MIS for NB between January 2008 and May 2013 were included. Specific technical considerations, demographic data, and outcome have been recorded.

Results

Twenty-one patients underwent MIS resection for IDRFs-negative adrenal NB. Nine of these patients experienced preoperative downgrading of IDRFs after chemotherapy. Radiological median diameter of the mass was 30 mm (range 10–83 mm). Median operative time was 90 min. Median hospital stay was 4 days. All patients were treated successfully, without serious intraoperative complications. One mild intraoperative hemorrhage occurred and was treated without the need for conversion to open surgery nor blood transfusion was required. No postoperative complications, including port-site or peritoneal metastases were experienced.

Conclusions

This study demonstrated the safety and effectiveness of MIS for the resection of adrenal NB without IDRFs in children. Pediatric surgeons dedicated to oncology should be aware of this alternative approach to open resection.