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.     

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.     

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.     

Minimal residual disease predicts outcomes in KMT2A-rearranged but not KMT2A-germline infant acute lymphoblastic leukemia: Report from Children's Oncology Group study AALL0631

We measured minimal residual disease (MRD) by multiparameter flow cytometry at three time points (TP) in 117 infants with KMT2A (lysine [K]-specific methyltransferase 2A)-rearranged and 58 with KMT2A-germline acute lymphoblastic leukemia (ALL) on Children's Oncology Group AALL0631 study. For KMT2A-rearranged patients, 3-year event-free survival (EFS) by MRD-positive (≥0.01%) versus MRD-negative (<0.01%) was: TP1: 25% (±6%) versus 49% (±7%; p = .0009); TP2: 21% (±8%) versus 47% (±7%; p < .0001); and TP3: 22% (±14%) versus 51% (±6%; p = .0178). For KMT2A-germline patients, 3-year EFS was: TP1: 88% (±12%) versus 87% (±5%; p = .73); TP2: 100% versus 88% (±5%; p = .24); and TP3: 100% versus 87% (±5%; p = .53). MRD was a strong independent outcome predictor in KMT2A-rearranged, but not KMT2A-germline infant ALL.     

Extracranial germ cell tumours in children and adolescents: Results from the French TGM13 protocol

Background

Chemotherapy for non-seminomatous germ cell tumours (NSGCT) exposes to dose-dependent toxicities. The TGM13-NS protocol (EudraCT 2013-004039-60) aimed to decrease the chemotherapy burden compared to the previous TGM95 protocol while maintaining the 5-year event-free survival (EFS) at 80% or more.

Procedure

Patients less than 19 years of age with disseminated NSGCT were enrolled (May 2014 to May 2019) and stratified into four groups: two intermediate-risk (IR: localised tumour with low tumour markers [TM]) groups treated with VBP (vinblastine–bleomycin–cisplatin): three courses for IR1 (ovarian tumour any age/testis tumour less than or equal to 10 years) and four courses for IR2 (extragonadal tumour 10 years or less) groups, and two high-risk (HR: metastatic and/or high TM) groups treated with etoposide–cisplatin and either ifosfamide (VIP) or bleomycin (BEP): three courses for HR1 (ovarian tumour any age/testis tumour less than or equal to 10 years and low TM/testis tumour more than 10 years and very low TM) groups and four courses for HR2 (remainder) groups.

Results

One hundred fifteen patients were included: median age of 12.8 years (0.4–18.9); tumour sites: 44 ovaries, 37 testes and 34 extragonadal. The 5-year EFS and overall survival (OS) were 87% (95% CI: 80–92) and 95% (89–98), respectively (median follow-up: 3.5 years, range: 0.2–5.9), similar to those of the TGM95 protocol (5-year EFS 89% (84–93), 5-year OS 93% (89–95), p = .561). The 5-year EFS were 93% (95% CI: 80–98), 88% (71–95) and 79% (62–90) for ovarian, testicular and extragonadal tumours, respectively. The 5-year EFS varied (p = .02) according to the risk groups: 90% (66–97), 64% (30–85), 95% (72–99) and 87% (74–94) for IR1, IR2, HR1 and HR2, respectively. TM decline adjusted to tumour site, and alpha-fetoprotein (AFP) level revealed a prognostic impact of time to normalisation on EFS: HR = 1.03 (1.003–1.007).

Conclusion

Risk-adapted and globally decreased chemotherapy burden maintains excellent outcomes, exclusive of the IR2 group, which warrants more intensive chemotherapy.     

Feasibility of a tandem autologous peripheral blood stem cell transplant regimen for high risk neuroblastoma in a cooperative group setting: A Pediatric Oncology Group study: A Report from the Children's Oncology Group

Background

The Pediatric Oncology Group performed a pilot study to assess the feasibility of tandem high dose chemotherapy (HDC) with stem cell rescue (HDC/SCR). We report here the results of this single arm trial of induction chemotherapy, local control measures (surgery and local radiation), and tandem HDC/SCR.

Procedure

Patients with high risk neuroblastoma (NBL) underwent five cycles of induction chemotherapy and resection of primary tumors. Peripheral blood stem cells (PBSC) were collected after Course 3 without exvivo manipulation. Myeloablative chemotherapy was performed in rapid sequence after induction chemotherapy and surgery. The ability of patients to complete both cycles of HDC/SCR was a primary endpoint. Transplant‐related toxicity, progression‐free survival (PFS) and overall survival (OS) were recorded.

Results

A total of 33 patients were enrolled. Twenty‐two patients completed at least one HDC/SCR procedure and 17 patients completed both. Only one patient had insufficient stem cells collected for both transplants. There was one transplant‐related death; engraftment was rapid and toxicity was as expected. The PFS of the 33 patients treated on this study is 24.2% ± 7.5% and OS is 36.4% ± 8.4% at 5 years. For patients who received at least one transplant PFS is 36.4% ± 11.0% and OS is 45.5% ± 11.2% at 5 years.

Conclusions

The treatment of high risk NBL with tandem HDC/SCR is feasible in terms of transplant‐related mortality and the ability to collect adequate PBSC for two transplants. The outcomes from this intensified treatment have been used to design a Children's Oncology Group Phase III study testing the efficacy of tandem HDC/SCR. Pediatr Blood Cancer 2012; 59: 902–907. © 2012 Wiley Periodicals, Inc.     

Outcome of patients with undifferentiated embryonal sarcoma of the liver treated according to European soft tissue sarcoma protocols

Background

To assess the outcomes of pediatric patients with undifferentiated embryonal sarcoma of the liver (UESL) and treatment including at least surgery and systemic chemotherapy.

Methods

This study included patients aged up to 21 years with a pathological diagnosis of UESL prospectively enrolled from 1995 to 2016 in three European trials focusing on the effects of surgical margins, preoperative chemotherapy, use of radiotherapy (RT), and chemotherapy.

Results

Out of 65 patients with a median age at diagnosis of 8.7 years (0.6–20.8), 15 had T2 tumors, and one had lymph node spread, 14 were Intergroup Rhabdomyosarcoma Study (IRS) I, nine IRS II, 38 IRS III, and four IRS IV. Twenty-eight upfront surgeries resulted in five operative spillages and 11 infiltrated surgical margins, whereas 37 delayed surgeries resulted in no spillages (p = .0119) and three infiltrated margins (p = .0238). All patients received chemotherapy, including anthracyclines in 47. RT was administered in 15 patients. With a median follow-up of 78.6 months, 5-year overall and event-free survivals (EFS) were 90.1% (95% confidence interval [CI]: 79.2–95.5) and 89.1% (95% CI: 78.4–94.6), respectively. Two out four local relapses had previous infiltrated margins and two out of three patients with metastatic relapses received reduced doses of alkylating agents. Infiltrated margins (p = .1607), T2 stage (p = .3870), use of RT (p = .8731), and anthracycline-based chemotherapy (p = .1181) were not correlated with EFS.

Conclusions

Multimodal therapy improved the outcome of UESL. Neoadjuvant chemotherapy for pediatric patients increases the probability of complete surgical resection. The role of anthracyclines and RT for localized disease remains unclear.     

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.     

Improvement in the outcome of patients with antenatally diagnosed congenital diaphragmatic hernia using gentle ventilation and circulatory stabilization

Background/Objectives  No definitive treatment strategy has been established for patients with an antenatal diagnosed congenital diaphragmatic hernia (AD-CDH). From 1997 to 2003 in this department fetal stabilization (FS) was administered using both morphine and diazepam via the placenta just before delivery of the fetus by cesarean section. In contrast, from 2004 to the present, a combination of gentle ventilation (GV) and a delayed operation was selected, which was performed when the patient’s circulatory stabilization (CS) was achieved. Patients and methods  This study included 22 patients in the FS group and 16 patients in the GV + CS group, respectively. The outcomes in both groups were compared and the outcome in AD-CDH patients with a patch repaired operation, liver-up or lower lung-to-thorax transverse area ratio (L/T, <0.10) was further investigated in both groups. Results  The overall survival rate (SR) was 93.8% in the GV + CS group and 59.1% in the FS group, respectively (P = 0.04). For the patients with the lower L/T, the SR was 85.7% in GV + CS group and 53.8% in the FS group (P = 0.33). Regarding the patients using a patch and liver-up, the SR in GV + CS group was better than that in the FS group (patch: FS 44.4%, GV ± CS 87.5%, P = 0.18; liver-up: FS 57.8 and 87.5%, P = 0.30). Conclusion  Our strategy of using GV ± CS might thus be considered to be more effective than that using FS in the treatment of AD-CDH patients.     

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.     

Associations between neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio and prognosis in patients with neuroblastoma

Objectives

Recent studies have shown that the neutrophil-to-lymphocyte ratio (NLR) is a new inflammatory marker that is effective in determining the prognosis of many solid tumors, chemotherapy responses, survival, and their recurrence rate. Therefore, we performed a retrospective study to investigate the effect of neutrophil-to-lymphocyte and platelet-to-lymphocyte ratio (PLR) on risk factors and prognosis in these patients.

Materials and methods

In this study, 246 pediatric patients with neuroblastoma who were diagnosed, treated, and followed up during 2000–2021 in Division of Pediatric Oncology, Çukurova University Faculty of Medicine, were included. Required information of patients was obtained from archive files, Mergentech hospital program, and E-pulse system.

Results

Median value for NLR was found to be 1.06, for PLR it was found as 92. The relationship of NLR values with age, stage, risk group, and Shimada was found to be statistically signifıcant with p < .001, vanillylmandelic acid (VMA) (p = .006) also depicted the signifıcant value. Likewise, the relationship of PLR values with age (p < .001), stage (p = .022), Shimada (p = .004), and N-Myc amplification (p = .039) was found to be statistically significant as well. Survival analysis showed that no statistically significant difference was observed among the higher and lower values of NLR. Survival rates were noticed to be higher in the lower values of NLR (10-year overall survival [OS] 55% vs. 49%, 10-year event-free survival (EFS) 54% vs. 43%), albeit nonsignificant.

Conclusion

Pretreatment evaluation of NLR and PLR values in patients with neuroblastoma may be instructive in respect of prognosis and risk group.     

The effect of montelukast on early‐life wheezing: A randomized,double‐blinded placebo‐controlled study

Background

Cysteinyl‐leukotrienes are increased in the airways of infants with virus‐associated wheezing. We aimed to determine the effects of a cysteinyl‐leukotriene‐1 receptor antagonist on symptoms during an early‐life wheezing illness and to investigate the factors that affect the response to this drug.

Method

This placebo‐controlled double‐blinded randomized controlled trial recruited children aged 3‐36 months with wheezing illness and randomized to active drug or placebo for 56 days. A symptom score diary (SSD) was kept by the children's caregivers.

Results

One‐hundred patients completed the study, and 62 (30 montelukast and 32 placebo) were analyzed. There were no significant differences in the percent of symptom‐free days, symptom scores, and the need for rescue salbutamol between the two groups. However, the percent of symptom‐free days within the first week was significantly higher for the montelukast than for the placebo group (13.8 ± 4.1% vs. 5.4 ± 3.4%; P = 0.028); wheezing score at 7th day was significantly lower for the montelukast than for the placebo group (0.5 ± 0.1 vs. 1.4 ± 0.2; P = 0.002). In addition, the number of inhaled ß₂‐agonist rescue episodes per day during the first week was significantly lower for the montelukast compared with the placebo group (12.7 ± 1.8 vs. 19.2 ± 1.6; P = 0.013).

Conclusions

Our results indicate that montelukast may be effective for reducing caregiver‐observed wheezing and the need for salbutamol during the first week of treatment for early‐life wheezing. The impact for caregivers and the optimal duration of treatment will need to be explored in studies of larger size.     

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.     

Phase II study of 131I-metaiodobenzylguanidine with 5 days of topotecan for refractory or relapsed neuroblastoma: Results of the French study MIITOP

Purpose

We report the results of the French multicentric phase II study MIITOP (NCT00960739), which evaluated tandem infusions of ¹³¹I-metaiodobenzylguanidine (mIBG) and topotecan in children with relapsed/refractory metastatic neuroblastoma (NBL).

Methods

Patients received ¹³¹I-mIBG on day 1, with intravenous topotecan daily on days 1–5. A second activity of ¹³¹I-mIBG was given on day 21 to deliver a whole-body radiation dose of 4 Gy, combined with a second course of topotecan on days 21–25. Peripheral blood stem cells were infused on day 31.

Results

Thirty patients were enrolled from November 2008 to June 2015. Median age at diagnosis was 5.5 years (2–20). Twenty-one had very high-risk NBL (VHR-NBL), that is, stage 4 NBL at diagnosis or at relapse, with insufficient response (i.e., less than a partial response of metastases and more than three mIBG spots) after induction chemotherapy; nine had progressive metastatic relapse. Median Curie score at inclusion was 6 (1–26). Median number of prior lines of treatment was 3 (1–7). Objective response rate was 13% (95% confidence interval [CI]: 4–31) for the whole population, 19% for VHR-NBL, and 0% for progressive relapses. Immediate tolerance was good, with nonhematologic toxicity limited to grade-2 nausea/vomiting in eight patients. Two-year event-free survival was 17% (95% CI: 6–32). Among the 16 patients with VHR-NBL who had not received prior myeloablative busulfan-melphalan consolidation, 13 had at least stable disease after MIITOP; 11 subsequently received busulfan-melphalan; four of them were alive (median follow-up: 7 years).

Conclusion

MIITOP showed acceptable tolerability in this heavily pretreated population and encouraging survival rates in VHR-NBL when followed by busulfan-melphalan.     

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.     

Worries and anxiety in parents of adult survivors of childhood cancer: A report from the Swiss Childhood Cancer Survivor Study-Parents

Objective

Having a child diagnosed with cancer is distressing for parents. We aimed to compare worries and anxiety in parents of adult childhood cancer survivors with parents of the Swiss general population (GP-parents), and to evaluate characteristics associated with worry in parents of survivors.

Methods

We conducted a nationwide, population-based study in parents of survivors (survivors aged ≥20 years at study, ≤16 years at diagnosis, >5 years post diagnosis) and GP-parents (≥1 child aged ≥20 years at study). We used the Worry and Anxiety Questionnaire (WAQ), and computed the WAQ total score (worries; possible range 0–80) and caseness for generalized anxiety disorder (anxiety), cognitive, somatic, and any criteria. We used multilevel, multivariable linear regression to identify characteristics associated with worries in parents of survivors.

Results

We included 787 parents of 513 survivors (41.0% fathers) and 478 GP-parents (42.3% fathers). Parents of survivors and GP-parents did not differ regarding worries (16.6 vs. 17.1, p = .977), anxiety (2.7% vs. 3.6%, p = .536), cognitive (p = .440), and somatic criteria (p = .067). Less parents of survivors met any criteria (17.7% vs. 24.0%, p = .039). Half of parents reported current cancer-related worries. Higher cancer-related worries were reported by mothers (β = 4.1; 95% CI: 2.0–6.2), parents with one child (β = 5.9; 95% CI: 2.0–9.7), currently experiencing disadvantages because of their child's former disease (β = 7.3; 95% CI: 4.0–10.6), or with support needs (β = 9.0; 95% CI: 3.9–14.2; p = .001).

Conclusions

It is encouraging that most parents of adult survivors report similar worries and anxiety as GP-parents, but cancer-related worries are still prevalent. Efforts should be made to empower parents to seek psycho-social support if required.     

Interdisciplinary care of pediatric oncology patients: A survey of clinicians in Central America and the Caribbean

Background

Quality cancer care depends on interdisciplinary communication. This study explored the communication practices of interdisciplinary clinicians, the types of healthcare services for which they engage in interdisciplinary collaboration, and the association between interdisciplinary care and perceived quality of care, as well as job satisfaction.

Methods

We conducted a survey of interdisciplinary clinicians from cancer centers in Guatemala, Honduras, Panama, El Salvador, and Haiti. The survey included 68 items including previously validated tools and novel questions.

Results

Total 174 interdisciplinary clinicians completed the survey: nurses (n = 60), medical subspecialists (n = 35), oncologists (n = 22), psychosocial providers (n = 20), surgeons (n = 12), pathologists (n = 9), radiologists (n = 9), and radiation oncologists (n = 5). Oncologists reported daily communication with nurses (95%) and other oncologists (91%). While 90% of nurses reported daily communication with other nurses, only 66% reported daily communication with oncologists, and more than 50% of nurses reported never talking to pathologists, radiologists, radiation oncologists, or surgeons. Most clinicians described interdisciplinary establishment of cancer treatment goals and prognosis (84%), patient preferences (81%), and determination of first treatment modality (80%). Clinicians who described more interdisciplinary collaboration had higher job satisfaction (p = .04) and perceived a higher level of overall quality of care (p = .004).

Conclusions

Clinicians in these limited resource settings describe strong interdisciplinary collaboration contributing to higher job satisfaction and perceived quality of care. However, nurses in these settings reported more limited interdisciplinary communication and care. Additional studies are necessary to further define clinical roles on interdisciplinary care teams and their associations with patient outcomes.     

Comparative study of preterm infants fed new and existing human milk fortifiers showed favourable markers of gastrointestinal status

Aim

This study examined the influence of different human milk fortifiers on biomarkers of gastrointestinal immaturity and inflammation in preterm infants.

Methods

We report secondary outcomes from a controlled, double-blind, randomised, parallel group study conducted from 2011 to 2014 in neonatal intensive care units at 11 metropolitan hospitals in France, Belgium, Germany, Switzerland and Italy. Preterm infants born at up to 32 weeks or weighing up to 1500 g were randomised to a new powdered human milk fortifier (n = 77) or a control fortifier (n = 76) for a minimum of 21 days. We analysed faecal markers of gut inflammation, namely alpha-1 antitrypsin and calprotectin, and maturity, namely elastase-1.

Results

Faecal alpha-1 antitrypsin was slightly lower in the new than control fortifier group after 21 days of full enteral feeding, with a geometric mean and standard deviation of 1.52 ± 1.32 vs 1.82 ± 1.44 mg/g stools (P = .01). There was no significant difference in faecal calprotectin (median [Q1-Q3] of 296 [136-565] μg/g stools in both groups combined at study day 21). Faecal elastase-1 was lower in the new fortifier than control fortifier group (202.5 ± 1.6 vs 257.7 ± 1.5 μg/g stools, P = .016).

Conclusion

Mean values for each parameter were within the ranges in healthy term infants, indicating favourable markers of gastrointestinal status in both groups. In addition, for faecal calprotectin, the relatively high concentration observed in preterm infants fed fortified human milk suggests that the threshold level for detecting necrotising enterocolitis should be revised.