Extramedullary leukemia in children with acute myeloid leukemia: A population‐based cohort study from the Nordic Society of Pediatric Hematology and Oncology (NOPHO)

1 Background

The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified.

2 Procedure

This population‐based study included 315 children from the NOPHO‐AML 2004 trial.

3 Results

At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma, 22 (7%) had central nervous system disease, and 12 (4%) had both. EML was associated with young age (median age: 2.6 years), a high white blood cell count (median: 40 × 10⁹/l), M5 morphology (40%), and 11q23/MLL (KMT2A) rearrangements (34%). No patient received involved field radiotherapy. Five‐year event‐free survival did not differ significantly between the EML and the non‐EML patients (54% vs. 45%, P = 0.57), whereas 5‐year overall survival (OS) was significantly lower in the EML group (64% vs. 73%, P = 0.04). The risk of induction death was significantly higher for EML patients (8% vs. 1%, P = 0.002). There was a trend toward a lower risk of relapse for EML patients (5‐year cumulative incidence of relapse 33% vs. 49%, P = 0.16). Traumatic lumbar puncture did not adversely affect survival in this cohort.

4 Conclusions

EML was associated with increased risk of induction death impacting the OS. No patients relapsed at the primary site of the myeloid sarcoma despite management without radiotherapy.     

Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma

BACKGROUND: Survival after relapse in patients with Ewing sarcoma is very poor and this retrospective study attempts to identify of prognostic factors predicting survival after relapse. PROCEDURE: A total of 191 patients with localised Ewing sarcoma were registered in the ET-2 trial of the United Kingdom Children's Cancer Study Group (UKCCSG). All patients received standardised primary treatment with chemotherapy and surgery and or radiotherapy as local modality treatment. Sixty-four patients who relapsed are included in this report. Treatment at relapse was variable and included chemotherapy, surgery, radiotherapy and high dose therapy (HDT) or megatherapy with peripheral stem cell transplantation (PBSCT) or autologous bone marrow transplantation (ABMT) in various combinations. A subgroup of patients had only non-specific symptomatic treatment at relapse. Both univariate and multivariate methods were used to investigate variables affecting survival after relapse. RESULTS: The overall actuarial median survival from relapse for all patients was 14 months (95% CI 11-16 months). Univariate analysis showed that males had a longer survival (median, 16 months vs. 11 months); patients who relapsed while on treatment did worse (median, 3 months vs. 16 months) and patients who had a longer disease-free interval (DFI) prior to relapse had a better outcome (DFI <1 year, median survival = 3 months; DFI 1-2 years, survival = 8 months; DFI > 2 years, median survival = 24 months, P < 0.001). Multivariate analysis confirmed that duration of first remission was the only factor associated with longer survival after relapse. CONCLUSIONS: These data suggest that although aggressive therapy may delay disease progression after relapse for some children, the course of the disease after relapse is usually fatal. International co-operative studies are needed to evaluate new strategies.     

Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study

BACKGROUND: The Cooperative Ewing Sarcoma Study (CESS 86), conducted by the German Society of Pediatric Oncology and Hematology (GPOH), was planned on the basis of the results of the preceding CESS 81 study. The prognostic significance of tumor volume in localized Ewing sarcoma of bone was well documented in the CESS 81 trial. As a consequence, the treatment intensity was adapted to volume in the follow-up CESS 86 trial: the four-drug combination used in CESS 81 was amended for patients with large tumor volume (> or = 100 ml), where ifosfamide was substituted for cyclophosphamide. PROCEDURE: From January 1986 to June 1991, 177 protocol patients with localized Ewing sarcoma of bone were registered in CESS 86. The prognostic implication of tumor volume and several covariates was evaluated using Kaplan-Meier life table analysis and Cox's proportional hazard model. RESULTS: The estimated 5- and 8-year event-free survival (EFS) rates were both 59%. Age, gender, tumor site, and a tumor volume of 100 ml did not distinguish groups of patients with different prognosis. However, the prognosis of patients with tumors >200 ml (8-year EFS rate: 42%) was significantly inferior compared to patients with tumors both of 100 to 200 ml (70%) and of <100 ml (63%). In contrast to CESS 81, the histological response to chemotherapy was no longer a significant prognostic factor (EFS: 64% for good and 50% for poor responders, respectively). CONCLUSIONS: Despite risk-adapted treatment intensity, tumor volume retained its prognostic significance; the cut point, however, was shifted toward larger volumes.     

Reactivation of TWIST1 contributes to Ewing sarcoma metastasis

1 Background

Ewing sarcoma is a cancer of bone and soft tissue. Despite aggressive treatment, survival remains poor, particularly in patients with metastatic disease. Failure to treat Ewing sarcoma is due to the lack of understanding of the molecular pathways that regulate metastasis. In addition, no molecular prognostic markers have been identified for Ewing sarcoma to risk stratify patients.

2 Procedure

Ewing sarcoma patients were divided into high or low Twist1 gene expression and survival curves were generated using the R2 microarray‐based Genomic Analysis platform ( http://r2.amc.nl ). Tumors from Ewing sarcoma patients were also evaluated for TWIST1 expression by immunohistochemistry. Ewing sarcoma xenografts were established to evaluate the role of TWIST1 in metastasis. The effects of Twist1 on migration and invasion were evaluated using migration and invasion assays in A673 and RDES cells.

3 Results

Twist1 expression was a negative prognostic marker for overall survival in a public Ewing sarcoma patient data set based on Twist1 mRNA levels and in patient tumor samples based on Twist1 immunohistochemistry. TWIST1 is detected in significantly higher percentage of patients with metastatic diseases than localized disease. Using Ewing sarcoma tumor xenografts in mice, we found that suppressing TWIST1 levels suppressed metastasis without affecting primary tumor development. Knockdown of Twist1 inhibited the migration and invasion capability, while overexpression of Twist1 promoted migration and invasion in Ewing sarcoma cells.

4 Conclusion

These results suggest that TWIST1 promotes metastasis in Ewing sarcoma and could be used as a prognostic marker for treatment stratification; however, further validation is required in a larger cohort of patients.     

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.     

Sentinel node biopsy in pediatric soft tissue sarcomas of extremities

Background

Sentinel Node Biopsy is an established staging technique in many adult malignancies. However, only few reports describe this procedure for the evaluation of regional lymph nodes in childhood and adolescents. Our experience with sentinel node biopsy in soft tissue sarcomas of extremities in children is reported.

Methods

Seventeen children were evaluated with sentinel node biopsy between 2002 and 2007: 11 at initial surgery, 5 at primary re‐excision, 1 at local relapse. The diagnosis was rhabdomyosarcoma in 5 and other soft tissue sarcomas in 12: Ewing/PNET sarcoma 6, epithelioid sarcoma 1, malignant peripheral‐nerve‐sheath tumor 1, undifferentiated sarcoma 1, myxoid liposarcoma 2, adult‐type fibrosarcoma 1. Primary sites included lower limbs (8), upper limbs (9). Mapping of nodes was performed with lymphoscintigraphy plus intra‐operative injections with blue‐dye in 14 cases, with lymphoscintigraphy and intra‐operative injections alone in 2 and 1, respectively.

Results

Of the 17 lymphatic regions (9 axilla, 8 inguinal), 16 were identified with lymphoscintigraphy, 15 by intra‐operative injections. Thirty‐five lymph nodes were removed. Nodes were positive for metastasis in two patients with alveolar rhabdomyosarcoma and undifferentiated sarcoma. There were no complications. No further lymph node metastases were recognized either at diagnosis or during the follow‐up (6–78 months).

Conclusions

Sentinel node biopsy was technically feasible, reliable, and free of complications. It could be an alternative to aggressive or random biopsies for extremity rhabdomyosarcoma and it can contribute to define those non‐rhabdomyosarcoma soft tissue sarcomas that spread to regional nodes. Pediatr Blood Cancer 2009;52:51–54. © 2008 Wiley‐Liss, Inc.     

Treatment of Ewing sarcoma family of tumors with a modified P6 protocol in children and adolescents

Background

Reported overall survival (OS) rates of patients with localized Ewing sarcoma family of tumors (ESFT) are >80% when treated with the MSKCC P6 protocol. However, it has been associated with a 5.8% incidence of secondary leukemias. A modified P6 (mP6) protocol with reduced exposure to chemotherapy is presented.

Procedure

Thirty‐one newly diagnosed ESFT patients were enrolled onto this phase II, single‐arm, non‐randomized protocol. Courses 1, 2 and 4 consisted of cyclophosphamide 4.2 g/m², doxorubicin 75 mg/m², and vincristine 2 mg/m² (CDV). Cycles 3 and 5 consisted of ifosfamide 9 g/m² and etoposide 500 mg/m² (IE). Course 5 ifosfamide was 14 g/m² if necrosis was <90%.

Results

Twenty‐four patients had loco‐regional disease and seven had metastases. The 4‐year event‐free survival (EFS) rate for patients with localized tumors is 83% and overall survival (OS) is 92%. The 3‐year EFS rate for patients with distant metastases is 28% and OS rate is 42%. EWS‐FLI1 fusion genes were detected in 17 cases (74%) and EWS‐ERG in six cases (26%). Type 1 EWS‐FLI1 variant was present in 6/7 metastatic patients and 3/16 loco‐regional cases (P = 0.001). None of the patients experienced tumor progression before remission. All relapses occurred within 2 years from the end of treatment and local relapses (n = 3) happened in patients who did not receive radiation therapy. No secondary malignancies have been observed, median follow‐up of 4.3 years for surviving patients.

Conclusions

In this pilot study, the mP6 protocol produced a complete remission rate of 83% at 4 years in non‐metastatic ESFT reducing the risk of secondary malignancies. Pediatr Blood Cancer 2011;57:69–75. © 2011 Wiley‐Liss, Inc.     

Outcomes in childhood AML in the absence of transplantation in first remission--Children's Cancer Group (CCG) studies 2891 and CCG 213

Background

The majority of childhood acute myeloid leukemia (AML) patients lack a matched‐related bone marrow transplant (BMT) donor in first remission.

Procedure

Disease‐free survival (DFS), overall survival (OS), relapse‐free survival (RFS), and post‐relapse outcome were evaluated for children with de novo AML on CCG 213 and the standard timing (ST) and intensive timing (IT) induction arms of CCG 2891 who were randomized to (intent‐to‐treat, ITT) or who received (as‐treated, AT) only chemotherapy intensification.

Results

Outcomes at 8 years post‐induction in ITT analysis of chemotherapy intensification were as follows: 31% DFS, 43% OS on CCG 213; 34% DFS, 51% OS on CCG 2891 ST; 48% DFS, 56% OS on CCG 2891 IT. All toxic deaths during and following Capizzi II chemotherapy intensification on both protocols were in patients >3 years of age (P ≤ 0.001). Black race was a significant poor prognostic factor for OS (P = 0.008, hazard ratio: 1.74, 95% CI: 1.15–2.61). Overall 48% of patients on both trials relapsed and 19.1% of patients who relapsed on these trials survived. CR1 >12 months portends a much better OS for patients who relapse. Post‐relapse treatment included BMT in 47% of patients.

Conclusions

OS on CCG 2891 was superior to CCG 213 but equivalent between ST and IT arms due to better salvage rates post‐relapse in ST patients. Overall survival for childhood AML in the absence of BMT in CR1 is influenced by duration of CR1 and by race. Pediatr Blood Cancer 2008;50:9–16. © 2007 Wiley‐Liss, Inc.     

The utility of performing the initial lumbar puncture on day 8 in remission induction therapy for childhood acute lymphoblastic leukemia: TCCSG L99-15 study

Background

Traumatic lumbar puncture with leukemic blasts (TLP+), which has been reported to occur 5–10%, in the previous studies, adversely affects the outcome of children with acute lymphoblastic leukemia (ALL). Based on the results from our previous study, we deferred the initial lumbar puncture until day 8 in remission induction therapy in order to reduce the frequency of cases with TLP+.

Procedure

The study was conducted as a prospective cohort study within the Tokyo Children's Cancer Study Group (TCCSG) L99‐15 study. Between April 1999 and June 2003, 754 children with newly diagnosed ALL enrolled. The patients received the initial intrathecal chemotherapy after 7 days of prednisolone treatment. The incidence of central nervous system (CNS)‐positive (the presence of leukemic blasts in cerebrospinal fluid or cranial nerve palsy) including TLP+ cases and cumulative incidence of CNS relapse were examined.

Results

The incidence of CNS‐positive and TLP+ was 2.9% (n = 22) and 0.8% (n = 6), respectively. These incidences were much lower than those in the representative study groups employing the initial IT on day 1. Of 22 patients with CNS‐positive, only one patient relapsed in CNS, whereas 22 of the remaining CNS‐negative 723 patients suffered from CNS relapse. Overall, event‐free survival at 4 year was 78.2 ± 1.6%. Four‐year cumulative incidence of any CNS relapse was 3.3 ± 0.7%, which improved from our previous study in spite of limiting the use of cranial irradiation.

Conclusions

Our strategy reduced the frequency of CNS‐positive patients who required reinforcement of CNS‐directed therapy without compromising overall outcome. Pediatr Blood Cancer 2012; 58: 23–30. © 2011 Wiley Periodicals, Inc.     

Pretransplant functional imaging and outcome in pediatric patients with relapsed/refractory Hodgkin lymphoma undergoing autologous transplantation

1 Background

Pretransplant functional imaging (FI), particularly a negative positron emission tomography (PET), is a strong predictor of outcome in adults with relapsed or refractory Hodgkin lymphoma (HL), but data in pediatrics are limited.

2 Methods

The medical records of 49 consecutive pediatric patients, who received autologous transplant at a single institution, were retrospectively analyzed. All patients had either gallium or PET scan before transplant and were conditioned with carmustine, etoposide, cytarabine, and melphalan (BEAM). Deauville scores were retrospectively assigned for patients with PET (score ≥ 4 positive).

3 Results

Of the 49 patients (median age, 16.2 years), 41 (84%) were pretransplant FI negative and eight (16%) were pretransplant FI positive, after first‐ to fourth‐line salvage therapy, and a median of two salvage cycles. Eighteen patients (37%) received posttransplant radiation. At a median follow up of 46 months, 45 patients (92%) were alive and disease free, and there were three nonrelapse deaths and only one relapse death (Deauville score of 5). The 4‐year progression‐free survival (PFS) for the entire cohort was 92% (95% confidence interval [CI]: 78–97), and PFS based on pretransplant disease status was 95% (95% CI: 82–99%) in the negative FI group versus 75% (95% CI: 31–93) if positive FI (P = 0.057).

4 Conclusion

Our analysis revealed outstanding outcomes for children and adolescents with relapsed/refractory HL. There were too few relapses to identify the predictive value of pretransplant metabolic status, but pediatric patients with relapsed/refractory HL and a negative pretransplant FI had excellent survival.     

Identification of Discrete Prognostic Groups in Ewing Sarcoma

Background

Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification.

Procedure

We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5‐year overall survival for each group using Kaplan–Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials.

Results

A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age <18 years, non‐pelvic primary; (ii) localized, age <18, pelvic primary or localized, age ≥18, white, non‐Hispanic; (iii) localized, age ≥18, all races/ethnicities other than white, non‐Hispanic; (iv) metastatic, age <18; and (v) metastatic, age ≥18. These five groups were applied to the COG dataset and showed significantly different overall and event‐free survival based upon this classification system (P < 0.0001). A sub‐analysis of COG patients treated with ifosfamide and etoposide as a component of therapy evaluated these findings in patients receiving contemporary therapy.

Conclusions

Recursive partitioning analysis yields discrete prognostic groups in EWS that provide valuable information for patients and clinicians in determining an individual patient's risk of death. These groups may enable future clinical trials to adjust EWS treatment according to individualized risk. Pediatr Blood Cancer © 2015 Wiley Periodicals, Inc.     

High-dosage chemotherapy in primary metastasized and relapsed Ewing's sarcoma. (EI)CESS]

BACKGROUND: Patients (pts) with primary metastatic Ewing tumours (ET) have a poor prognosis for event free survival (EFS) compared to pts with localised disease. Following relapse the prognosis is extremely poor. Therefore these primary metastatic and relapsed pts were piloted for high dose therapy (HDT) for the last years. PATIENTS AND METHODS: Between April 1984 and May 1997, 131 ET pts who underwent HDT were registered in the German CESS/EICESS office: 79 pts with primary metastases and 52 pts with relapsed tumours. After induction therapy, consisting of chemotherapy and local therapy, pts received high dose regimens, mainly based on melphalan and/or etoposide (92%). Stem cell rescue was applied from allogeneic bone marrow (n = 13), autologous bone marrow (n = 17), or peripheral blood stem cells (n = 95). The date of analysis was September 1st, 1998. Outcome was calculated by Kaplan-Meier-analyses. RESULTS: The median time under study since high dose therapy was 3.7 years. 35/131 pts (26.7%) were in continuous complete remission, 80/131 pts (61.1%) had relapsed or progressed, 11/131 pts (8.4%) died of complications and 5/131 pts (3.8%) presented with secondary malignancies. For the total group of primary metastatic pts, EFS five years after diagnosis was 19% for pts with HDT and 27% for those without (p = 0.9209). The subgroup of pts with primary lung and bone metastases seemed to benefit from HDT (EFS five years after diagnosis: 34% versus 5%, p = 0.0001). Outcome of pts with an early ET relapse (< 2 years) was also improved by HDT (EFS four years after relapse: 17% versus 2%, p = 0.0001). CONCLUSIONS: The total group of primary metastatic ET pts showed no obvious benefit from HDT, based on melphalan and/or etoposide. Pts with metastases to multiple organ systems, and early relapse seemed to benefit from HDT. The value of HDT should be assessed in prospective clinical trials.     

Early lymphocyte recovery as a prognostic indicator for high-risk Ewing sarcoma

BACKGROUND: Increasing evidence suggests that lymphocyte recovery plays a major part in tumor control. Facilitating immune reconstitution might be a novel direction of cancer therapy. The purpose of this study was to determine if early lymphocyte recovery is an independent prognostic indicator for high-risk Ewing sarcoma outcome. RESULTS: Data of 24 Ewing sarcoma patients were analyzed (age, 3 to 50 y; median, 16.5; male to female, 16:8). The 5-year overall survival (OS) of the total population was 47.9% [10.6 standard error (SE)]. Patients were separated into 2 groups: prolonged lymphopenia versus early lymphocyte recovery, using a threshold absolute lymphocyte count (ALC) of > or =500 cells/microL on day 15. The majority (67%; n=16) of the patients had an ALC > or =500 cells/microL, and of these 10/16 are alive with a 5-year OS of 58.7% (13.2 SE). In contrast, 33% (n=8) of patients had an ALC <500 cells/microL on day 15 and only 2/8 are alive with a 5-year OS of 25% (15.3 SE). This difference was significant (P=0.007 using the log rank test). When comparing patients with metastatic disease, patients with an ALC-15 < 500 cells/microL had a median survival of 13 months, whereas patients with an ALC-15 > or =500 cells/microL had a median survival of 29.5 months. All patients had an ALC before chemotherapy of >1000 cells/microL. The difference was significant (P value=0.001 using the log rank test). Univariate analysis of platelet counts, age, sex, and absolute neutrophil count showed no statistically significant association with OS. CONCLUSIONS: The data demonstrate that an ALC > or =500 cells/microL on day 15 of the first course of chemotherapy is an independent prognostic factor associated with superior OS in high-risk Ewing sarcoma.     

Metastatic Ewing sarcoma/PNET of bone at diagnosis: prognostic factors--a report from Saudi Arabia

BACKGROUND: To evaluate outcome and prognostic factors in Saudi Arabian patients with metastatic Ewing sarcoma and PNET of bone (PMES) at diagnosis. PROCEDURE: Ninety-nine of 304 (33%) consecutive patients with Ewing sarcoma and PNET of bone registered at our centre from 1975 to 1998, had metastatic disease at registration and 93 were available for analysis. The maximum x-axis diameter of the primary tumor was used as the measure of primary tumor size. Usually a trial of systemic treatment was undertaken before a decision was made on local treatment. Standard chemotherapy regimens were used in all treated patients. Forty-one (44%) patients did not receive radical local treatment due to an inadequate response to chemotherapy, or a decision not to undertake more than palliative treatment. Radical treatment of the primary site was radiation alone 41 (79%), resection alone 7 (13%), and resection and radiation 4 (8%). RESULTS: The 5-year survival rates were 9% for all 93 evaluable patients, 16% for 52 patients who received chemotherapy and radical local treatment, 0% for 41 patients who received lesser treatment, 19% for 43 patients with lung metastases alone, and 0% (P = 0.002) for 50 patients with other sites involved. For 60 patients with imaging data, 5-year survivals were 34 and 0% when the maximum transverse diameter of the primary tumor was < 10 cm (N = 20) and > or = 10 cm (N = 40), respectively. CONCLUSIONS: Small primary tumor size and the presence of lung metastases alone were the only significant favorable prognostic factors. Earlier diagnosis will be the basis for better results.     

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.     

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.     

Dose response and local control using radiotherapy in non-metastatic Ewing sarcoma

BACKGROUND: To determine prognostic factors for local control in the radiotherapeutic management of non-metastatic Ewing sarcoma. PROCEDURE: Forty patients with localized Ewing sarcoma (ES) were treated with primary site RT at one institution. Median RT dose was 55.8 Gy (range, 25.5-76 Gy). Chemotherapy was given to 34 patients (85%) with the most common regimen being vincristine, dactinomycin, cyclophosphamide, doxorubicin alternating with ifosfamide and etoposide (VACA + IE) in 10. Median follow-up for surviving patients was 12.3 years (range, 1.7-26.4 years). RESULTS: The 5- and 10-year local control rate was 78.2%. On multivariate analysis, RT dose was the only prognostic factor to impact on local control. The 5- and 10-year local control rate was 88.7% for RT dose >or=49 Gy and was 37.5% for <49 Gy (P = 0.0002, log-rank test). For tumors or=49 Gy and 50.0% for RT dose <49 Gy (P = 0.01, log-rank test). For tumors >8 cm, the 5- and 10-year local control rate was 85.7% for RT dose >or=54 Gy and 26.7% for RT dose <54 Gy (P = 0.006, log-rank test). CONCLUSIONS: Radiotherapy dose was found to influence local control in ES. In particular, patients who received RT doses >or=49 Gy for tumor size or=54 Gy for tumor size >8 cm had improved local control.     

VIncristine,irinotecan, and temozolomide in children and adolescents with relapsed rhabdomyosarcoma

1 Background

The combination of vincristine, irinotecan, and temozolomide (VIT) is often used to treat children and adolescents with relapsed rhabdomyosarcoma (RMS); however, the outcome of these patients has not been previously described.

2 Procedures

We sought to determine the response rate (RR) and progression‐free survival (PFS) for patients with relapsed RMS treated with VIT by retrospective review of patients treated at five tertiary care hospitals. Prior treatment with irinotecan was permitted.

3 Results

Among 19 patients with a median age of 8 years (range 2–17 years), 12 (63%) were males and 12 (63%) had embryonal histology. Median time to relapse from initial diagnosis was 16 months (range 2.8‐45 months). VIT was used as first, second, third, or fourth line of therapy in four (21%), seven (37%), six (32%), and two (10%) patients, respectively. Four patients received VIT as adjuvant therapy following radiation and/or surgery. Therefore, among 15 evaluable patients, the best response to VIT was 0 (complete response, CR), 0 (partial response, PR), 4 (stable disease, SD), and 11 (progressive disease, PD) for an overall clinical benefit rate (CR + PR + SD) of 26.7% (95% CI: 7.8–55.1%). After a median follow‐up of 8 months, 2 (10%) patients were alive without disease, 3 (16%) were alive with disease, and 14 (74%) patients died of PD. PFS at 3 months was 23% (95% CI: 5.7–46.7%).

4 Conclusions

VIT therapy in combination with adequate local control is associated with some disease control in patients with first relapse RMS and may be another reasonable option to offer patients as salvage therapy.     

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.     

Second-line treatment of pediatric patients with relapsed rhabdomyosarcoma adapted to initial risk stratification: Data of the European Soft Tissue Sarcoma Registry (SoTiSaR)

Background

Outcome of relapsed disease of localized rhabdomyosarcoma remains poor. An individual treatment approach considering the initial systemic treatment and risk group was included in the Cooperative Weichteilsarkom Studiengruppe (CWS) Guidance.

Methods

Second-line chemotherapy (sCHT) ACCTTIVE based on anthracyclines (adriamycin, carboplatin, cyclophosphamide, topotecan, vincristine, etoposide) was recommended for patients with initial low- (LR), standard- (SR), and high-risk (HR) group after initial treatment without anthracyclines. TECC (topotecan, etoposide, carboplatin, cyclophosphamide) was recommended after initial anthracycline-based regimen in the very high-risk (VHR) group. Data of patients with relapse (n = 68) registered in the European Soft Tissue Sarcoma Registry SoTiSaR (2009–2018) were retrospectively analyzed.

Results

Patients of initial LR (n = 2), SR (n = 16), HR (n = 41), and VHR (n = 9) group relapsed. sCHT consisted of ACCTTIVE (n = 36), TECC (n = 12), or other (n = 15). Resection was performed in 40/68 (59%) patients and/or radiotherapy in 47/68 (69%). Initial risk stratification, pattern/time to relapse, and achievement of second complete remission were significant prognostic factors. Microscopically incomplete resection with additional radiotherapy was not inferior to microscopically complete resection (p = .17). The 5-year event-free survival (EFS) and overall survival (OS) were 26% (±12%) and 31% (±14%). The 5-year OS of patients with relapse of SR, HR, and VHR groups was 80% (±21%), 20% (±16%), and 13% (±23%, p = .008), respectively.

Conclusion

Adapted systemic treatment of relapsed disease considering the initial risk group and initial treatment is reasonable. New treatment options are needed for patients of initial HR and VHR groups.