Isolated late testicular relapse of B‐cell acute lymphoblastic leukemia treated with intensive systemic chemotherapy and response‐based testicular radiation: A Children's Oncology Group study

1 Background

The incidence of isolated testicular relapse (ITR) of acute lymphoblastic leukemia (ALL) has decreased with contemporary treatment strategies, but outcomes are suboptimal with a 58% 5‐year overall survival (OS). This study aimed to improve outcome in patients with ITR of B‐cell ALL (B‐ALL) occurring after 18 months of first clinical remission using intensive systemic chemotherapy and to decrease long‐term sequelae by limiting use of testicular radiation.

2 Procedure

Forty patients in first ITR of B‐ALL were enrolled. Induction (dexamethasone, vincristine, daunorubicin, and intrathecal triple therapy) was preceded by one dose of high‐dose methotrexate (MTX, 5 g/m²). Following induction, 25 of 26 patients who had persistent testicular enlargement underwent testicular biopsy. Eleven had biopsy‐proven disease and received bilateral testicular radiation (24 Gy), whereas twenty‐nine did not.

3 Results

Overall 5‐year event‐free survival (EFS)/OS was 65.0 ± 8.8%/73.1 ± 8.3%, with 5‐year EFS 62.1 ± 11.0% vs. 72.7 ± 14.4% for patients who did not receive radiation therapy (XRT) (n = 29) compared with those who did (n = 11), respectively (P = 0.64). There were six second bone marrow relapses and six second ITRs. The proportion of second relapses was similar in the patients that received testicular radiation and those who did not. However, the 5‐year OS was similar for patients who did not receive XRT (72.6 ± 10.2%) compared with those who did (72.7 ± 14.4%) (P = 0.85).

4 Conclusions

A 5‐year OS rate of 73.1 ± 8.3% was obtained in children with first ITR of B‐ALL occurring after 18 months of CR1 (length of first clinical remission) using intensive chemotherapy and limiting testicular radiation.     

Clinical significance of pulmonary nodules detected by CT and Not CXR in patients treated for favorable histology Wilms tumor on national Wilms tumor studies-4 and -5: a report from the Children's Oncology Group

Background

Metastatic lung disease in Wilms tumor (WT) patients was traditionally identified by chest radiograph (CXR). It is unclear whether patients with small lesions, detectable only by computed tomography (“CT‐only” lesions), require the more intensive therapy, including doxorubicin and lung irradiation, given to patients with metastases detectable by CXR.

Procedures

This study involved 417 patients with favorable histology WT and isolated lung metastases (detected by CXR or CT) who were registered on National Wilms tumor Study (NWTS)‐4 or ‐5. Outcomes by method of detection (CXR vs. CT‐only), use of lung radiation, and 2‐ or 3‐drug chemotherapy (dactinomycin and vincristine ± doxorubicin) were determined and compared using the log‐rank test.

Results

There were 231 patients with lung lesions detected by CXR and 186 by CT‐only. Of the patients with CT‐only nodules, 37 received only 2 drugs and 101 did not receive lung radiation. Five‐year event‐free survival (EFS) was greater for patients receiving three drugs (including doxorubicin) with or without lung radiation than for those receiving two drugs (80% vs. 56%; P = 0.004). There was no difference seen in 5‐year overall survival (OS) between the 3‐ and 2‐drug subsets (87% vs. 86%; P = 0.91). There were no significant differences in EFS (82% vs. 72%; P = 0.13) or OS (91% vs. 83%; P = 0.46) for patients with CT‐only nodules whether they received lung radiation or not.

Conclusions

Our results suggest that patients with CT‐only lung lesions may have improved EFS but not OS from the addition of doxorubicin but do not appear to benefit from pulmonary radiation. Pediatr Blood Cancer 2012;59:631–635. © 2012 Wiley Periodicals, Inc.     

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.     

Outcome of high-risk stage 3 neuroblastoma with myeloablative therapy and 13-cis-retinoic acid: a report from the Children's Oncology Group

Background

The components of therapy required for patients with INSS Stage 3 neuroblastoma and high‐risk features remain controversial.

Procedure

A retrospective cohort design was used to determine if intensive chemoradiotherapy with purged autologous bone marrow rescue (ABMT) and/or 13‐cis‐retinoic acid (13‐cis‐RA) improved outcome for patients with high‐risk neuroblastoma that was not metastatic to distant sites. We identified 72 patients with INSS Stage 3 neuroblastoma enrolled between 1991 and 1996 on the Phase 3 CCG‐3891 randomized trial. Patients were analyzed on an intent‐to‐treat basis using a log‐rank test.

Results

The 5‐year event‐free survival (EFS) and overall survival (OS) rates for patients with Stage 3 neuroblastoma were 55 ± 6% and 59 ± 6%, respectively (n = 72). Patients randomized to ABMT (n = 20) had 5‐year EFS of 65 ± 11% and OS of 65 ± 11% compared to 41 ± 11 (P = 0.21) and 46 ± 11% (P = 0.23) for patients randomized to CC (n = 23), respectively. Patients randomized to 13‐cis‐RA (n = 23) had 5‐year EFS of 70 ± 10% and OS of 78 ± 9% compared to 63 ± 12% (P = 0.67) and 67 ± 12% (P = 0.55) for those receiving no further therapy (n = 16), respectively. Patients randomized to both ABMT and 13‐cis‐RA (n = 6) had a 5‐year EFS of 80 ± 11% and OS of 100%.

Conclusion

Patients with high‐risk Stage 3 neuroblastoma have an overall poor prognosis despite aggressive chemoradiotherapy. Further studies are warranted to determine if myeloablative consolidation followed by 13‐cis‐RA maintenance therapy statistically significantly improves outcome. Pediatr Blood Cancer 2009;52:44–50. © 2008 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.     

Localized vaginal/uterine rhabdomyosarcoma—results of a pooled analysis from four international cooperative groups

1 Background

Vaginal/uterine rhabdomyosarcoma (VU RMS) is one of the most favorable RMS sites. To determine the optimal therapy, the experience of four cooperative groups (Children's Oncology Group [COG], International Society of Pediatric Oncology (SIOP) Malignant Mesenchymal Tumor Group [MMT], Italian Cooperative Soft Tissue Sarcoma Group [ICG], and European pediatric Soft tissue sarcoma Study Group [EpSSG]) was analyzed.

2 Procedure

From 1981 to 2009, 237 patients were identified. Median age (years) at diagnosis differed by tumor location; it was 1.9 for vagina (n = 160), 2.7 for uterus corpus (n = 26), and 13.5 for uterus cervix (n = 51). Twenty‐eight percent of patients received radiation therapy (RT) as part of primary therapy (23% COG, 27% MMT, 46% ICG, and 42% EpSSG), with significant differences in the use of brachytherapy between the cooperative groups (23% COG, 76% MMT, 64% ICG, and 88% EpSSG).

3 Results

Ten‐year event‐free (EFS) and overall survival (OS) were 74% (95% CI, 67–79%) and 92% (95% CI, 88–96%), respectively. In univariate analysis, OS was inferior for patients with uterine RMS and for those with regional lymph node involvement. Although EFS was slightly lower in patients without initial RT (71% without RT vs. 81% with RT; P = 0.08), there was no difference in OS (94% without RT vs. 89% with RT; P = 0.18). Local control using brachytherapy was excellent (93%). Fifty‐one (51.5%) of the 99 survivors with known primary therapy and treatment for relapse were cured with chemotherapy with or without conservative surgery.

4 Conclusions

About half of all patients with VU RMS can be cured without systematic RT or radical surgery. When RT is indicated, modalities that limit sequelae should be considered, such as brachytherapy.     

Primary lung metastases in pediatric malignant non-Wilms renal tumors: data from SIOP 93-01/GPOH and SIOP 2001/GPOH

Malignant non-Wilms renal tumors (NWRT) are a small but relevant subgroup of renal neoplasms in children. In this study we analyzed corresponding data from the trials SIOP 93-01/GPOH and SIOP 2001/GPOH of the Society of Pediatric Oncology and Hematology.Data of 22 patients with NWRT and primary lung metastases were retrospectively reviewed. Analyses included epidemiology, tumor characteristics, chemotherapy, local treatment, and outcome.The following diagnoses were registered: Malignant Rhabdoid tumor of the kidney (MRTK, n=15), Renal-cell carcinoma (RCC, n=3), Clear-cell sarcoma of the kidney (CCSK, n=3), and primitive neuro ectodermal tumor (PNET, n=1). Median age of patients at diagnosis was 14 months. Overall survival was 36.36% (8/22). Of the 15 children with MRTK 3 survived, 3/3 patients with RCC, 1/3 patients with CCSK, and 1/1 patient with PNET survived. Lung metastases disappeared in 6 patients after initial chemotherapy, 6/8 patients undergoing local treatment of lung metastases (surgery, irradiation, or both) achieved complete remission. Only patients with complete clearance of lung lesions, either through neoadjuvant chemotherapy or subsequent local treatment, survived. Mean Follow up was 31 months (1-137).Survival of patients with stage IV NWRT is dismal. Complete removal of lung metastases seems mandatory for survival. An aggressive diagnostic and therapeutic approach seems justified in affected children.     

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.     

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.

     

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.     

Evolving of therapeutic strategies for CNS‐PNET

Background

A protocol for the intensive treatment of non‐cerebellar PNET (CNS‐PNET) combining chemotherapy and radiotherapy was launched in 2000. Efforts were subsequently made to improve the prognosis and to de‐escalate the treatment for selected patient groups.

Procedure

Twenty‐eight consecutive patients were enrolled for a high‐dose drug schedule (methotrexate, etoposide, cyclophosphamide, and carboplatin ± vincristine), followed by hyperfractionated accelerated CSI (HART‐CSI) at total doses of 31–39 Gy, depending on the patient's age, with two high‐dose thiotepa courses following CSI. After the first 15 patients had been treated, craniospinal irradiation (CSI) was replaced with focal radiotherapy (RT) for selected cases (non‐metastatic and not progressing during induction chemotherapy). Eight of the 28 children received the same chemotherapy but conventionally fractionated focal RT at 54 Gy.

Results

The 5‐year progression‐free survival (PFS), event‐free survival (EFS), and overall survival (OS) rates were 62%, 53%, and 52%, respectively, for the whole series, and 70%, 70%, and 87% for the eight focally irradiated children. Residual disease and metastases were not prognostically significant. In children with residual disease, response to RT was significant (5‐year PFS 59% vs. 20%, P = 0.01), while the total dose of CSI was not. There were three treatment‐related toxic events. Relapses were local in seven cases (including two of the eight focally irradiated patients), and both local and disseminated in 2.

Conclusions

This intensive schedule enabled treatment stratification for the purposes of radiation, thereby sparing some children full‐dose CSI. Local control is the main goal of treatment for CNS‐PNET. Pediatr Blood Cancer 2013;60:2031–2035. © 2013 Wiley Periodicals, Inc.     

A Clinical Perspective of Bilateral Renal Tumors - Data from Three Consecutive German Cooperative Trials

PurposeThe therapeutic approach for bilateral renal masses is different to unilateral renal masses. This is due to biological facts such as a remarkably higher number with nephroblastomatosis, but also to the fact that clinicians must keep drug doses as low as possible to prevent side effects.Material and MethodsWe analysed the prospectively collected data of 138 patients with bilateral renal masses registered in the consecutive German national trials SIOP9/GPO, SIOP93-01/GPOH and SIOP2001/GPOH from January 1989 to May 2005.ResultsThe median follow up was 6.2 years. All but one patient already had bilateral masses at diagnosis. Median age at diagnosis was 1.9 years with a female/male distribution of 1.5/1. 18 (13%) patients had distant metastases at diagnosis. 25% of all registered patients had a concomitant syndrome. Aiming to reduce the tumor mass as much as possible, 132 patients received preoperative chemotherapy according to the trial protocols for stage V, 6 patients underwent initial surgery. Preoperative treatment duration in the nephroblastoma group ranged from 1 to 12 weeks, leading to an average volume reduction of 44%. 11 patients with bilateral nephroblastomatosis suffered from progression, 3 eventually died from nephroblastoma. 2y/5y EFS and OS for the nephroblastoma group were 82.7/71.5% and 89/85.7%, respectively. Metastases at diagnosis, local stage III and anaplasia in histology had a negative impact on outcome.ConclusionsFive treatment-associated deaths including one acute renal failure underline the importance of a cautious approach in the complex treatment of bilateral renal tumours, including nephron-sparing surgery. This aim often can be facilitated by multimodal preoperative treatment (e.g. 1, 2 or 3 four-weeks courses of actinomycin, vincristine and doxorubicin) tailored to the individual tumor status defined by imaging after each cycle.     

Prognostic factors for event‐free survival in liver transplantation for hepatoblastoma: A single‐center experience

Hepatoblastoma (HB) is the most common malignant liver tumor in children. Twenty percent of the cases may remain unresectable after neoadjuvant chemotherapy and, for these patients, liver transplant (LT) is an accepted therapeutic option. To analyze the risk factors to event‐free survival (EFS) that influence the clinical outcome of patients with HB receiving LT, we retrospectively analyzed 21 patients with HB who underwent LT between January 1, 2005, and May 1, 2018. Overall survival (OS) was 90%. The univariate analysis shows that the AFP level at the time of LT was associated with a higher risk of EFS. With a ROC curve analysis, we established a cutoff point value of AFP levels at 16 000 ng/dL, with a sensitivity of 71.43% and a specificity of 85.71%. Multivariate analysis showed that patients with higher values of pretransplant AFP (>16 000 ng/dL) had a significantly higher risk of EFS than those transplanted with lower levels (HR: 10.180; 95% CI: 1.54‐66.97; P = .02). Efforts should be made to improve the selection of candidates for LT for unresectable HB, aiming at a better definition of chemoresistance as a risk factor of poor outcomes.     

Long‐term survival after autologous peripheral blood stem cell transplantation in two patients with malignant rhabdoid tumor of the kidney

A 5‐month‐old male with stage II malignant rhabdoid tumor of the kidney (MRTK) and a 24‐month‐old male with stage III MRTK were treated with surgical resection of tumors and chemotherapy of alternating ICE (ifosfamide, carboplatin, and etoposide) and VDC (vincristine, doxorubicin, and cyclophosphamide), followed by high‐dose chemotherapy using etoposide, carboplatin, and melphalan with autologous hematopoietic stem cell transplantation (SCT). Two patients have been alive without any evidence of disease for 30 and 37 months after diagnosis, respectively, and require no medication. Consolidation with SCT should be further studies for selected patients with high‐risk MRTK. Pediatr Blood Cancer 2009;52:888–890. © 2009 Wiley‐Liss, Inc.     

Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children's Oncology Group

Background

Diagnostic mIBG (meta-iodobenzylguanidine) scans are an integral component of response assessment in children with high-risk neuroblastoma. The role of end-of-induction (EOI) Curie scores (CS) was previously described in patients undergoing a single course of high-dose chemotherapy (HDC) and autologous hematopoietic cell transplant (AHCT) as consolidation therapy.

Objective

We now examine the prognostic significance of CS in patients randomized to tandem HDC and AHCT on the Children's Oncology Group (COG) trial ANBL0532.

Study design

A retrospective analysis of mIBG scans obtained from patients enrolled in COG ANBL0532 was performed. Evaluable patients had mIBG-avid, International Neuroblastoma Staging System (INSS) stage 4 disease, did not progress during induction therapy, consented to consolidation randomization, and received either single or tandem HDC (n = 80). Optimal CS cut points maximized the outcome difference (≤CS vs. >CS cut-off) according to the Youden index.

Results

For recipients of tandem HDC, the optimal cut point at diagnosis was CS = 12, with superior event-free survival (EFS) from study enrollment for patients with CS ≤ 12 (3-year EFS 74.2% ± 7.9%) versus CS > 12 (59.2% ± 7.1%) (p = .002). At EOI, the optimal cut point was CS = 0, with superior EOI EFS for patients with CS = 0 (72.9% ± 6.4%) versus CS > 0 (46.5% ± 9.1%) (p = .002).

Conclusion

In the setting of tandem transplantation for children with high-risk neuroblastoma, CS at diagnosis and EOI may identify a more favorable patient group. Patients treated with tandem HDC who exhibited a CS ≤ 12 at diagnosis or CS = 0 at EOI had superior EFS compared to those with CS above these cut points.     

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.     

Influence of image‐defined risk factors on the outcome of patients with localised neuroblastoma. A report from the LNESG1 study of the European International Society of Paediatric Oncology Neuroblastoma Group

Background

The European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image‐defined risk factors (IDRF) on operative complications and survival (EFS and OS).

Procedure

534 patients with localised, non‐MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo‐adjuvant chemotherapy.

Results

In L1 patients (Group 1) 5‐year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients.

Conclusions

In localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning. Pediatr Blood Cancer 2015;62:1536–1542. © 2015 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.     

A medication diary‐book for pediatric patients with acute lymphoblastic leukemia in Indonesia

Background

Event‐free survival of pediatric patients with acute lymphoblastic leukemia (ALL) in Yogyakarta, Indonesia was low (20%). The aim of the study was to evaluate the effectiveness of using a medication diary‐book on the treatment outcome of childhood ALL.

Procedure

A randomized study was conducted with 109 pediatric patients with ALL in a pediatric oncology center in Yogyakarta, Indonesia. Both intervention and control groups received a structured parental education program and donated chemotherapy. The intervention group received a medication diary‐book to remind parents and families to take oral chemotherapy and present for scheduled appointments or admissions. Event‐free survival estimate (EFS) at 3 years was assessed.

Results

Among pediatric patients with ALL with highly educated mothers (senior high school or higher), the EFS‐estimate at 3 years of the intervention group was significantly higher than the EFS‐estimate at 3 years of the control group (62% vs. 29%, P = 0.04). Among pediatric patients with ALL with low‐educated mothers, no significant difference was found in the EFS‐estimates at 3 years between the intervention and control group (26% vs. 18%, P = 0.86).

Conclusions

We conclude that a medication diary‐book might be useful to improve the survival of pediatric patients with ALL in resource‐limited settings, particularly in patients with highly educated mothers. Pediatr Blood Cancer 2013;60:1593–1597. © 2013 Wiley Periodicals, Inc.     

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.