Outcome for patients with metastatic rhabdomyosarcoma (RMS) is poor. This study presents the results of the MTS 2008 study with a pooled analysis including patients from the concurrent BERNIE study.
...In MTS 2008, patients with metastatic RMS received four cycles of ifosfamide, vincristine, and actinomycin D (IVA) plus doxorubicin, five cycles of IVA, and 12 cycles of maintenance chemotherapy (low-dose cyclophosphamide and vinorelbine). The BERNIE study randomly assigned patients to the addition or not of bevacizumab to the same chemotherapy. Local therapy (surgery/radiotherapy) was given to the primary tumor and all metastatic sites when feasible.
MTS 2008 included 270 patients (median age, 9.6 years; range, 0.07-20.8 years). With a median follow-up of 50.3 months, 3-year event-free survival (EFS) and overall survival (OS) were 34.9% (95% CI, 29.1 to 40.8) and 47.9% (95% CI, 41.6 to 53.9), respectively. In pooled analyses on 372 patients with a median follow-up of 55.2 months, 3-year EFS and OS were 35.5% (95% CI, 30.4 to 40.6) and 49.3% (95% CI, 43.9 to 54.5), respectively. Patients with ≤ 2 Oberlin risk factors (ORFs) had better outcome than those with ≥ 3 ORFs: 3-year EFS was 46.1% versus 12.5% (
< .0001) and 3-year OS 60.0% versus 26.0% (
< .0001). Induction chemotherapy and maintenance appeared tolerable; however, about two third of patients needed dose adjustments during maintenance.
Outcome remains poor for patients with metastatic RMS and multiple ORFs. Because of the design of the studies, it was not possible to determine whether the intensive induction regimen and/or the addition of maintenance treatment resulted in apparent improvement of outcome compared with historical cohorts. Further studies, with novel treatment approaches are urgently needed, to improve outcome for the group of patients with adverse prognostic factors.
Desmoplastic small round cell tumor (DSRCT) is a devastating disease which most commonly affects adolescents, with a male predominance. Despite the best multimodality treatment efforts, most patients ...will ultimately not survive more than 3-5 years after diagnosis. Some research trials in soft-tissue sarcoma and Ewing sarcoma include DSRCT patients but few studies have been tailored to the specific clinical needs and underlying cytogenetic abnormalities characterizing this disease such as the typical EWSR1-WT1 gene fusion. Downstream activation of EWSR1-WT1 gene fusion includes signaling pathways of platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and insulin growth factor (IGF)-1. Other biological pathways that are activated and expressed in DSRCT cells include endothelial growth factor receptor (EGFR), androgen receptor pathway, c-KIT, MET, and transforming growth factor (TGF) beta. Investigation of somatic mutations, copy number alterations (CNA), and chromosomes in DSRCT samples suggests that deregulation of mesenchymal-epithelial reverse transition (MErT)/epithelial-mesenchymal transition (EMT) and DNA damage repair (DDR) may be important in DSRCT. This mini review looks at known druggable targets in DSRCT and existing clinical evidence for targeted treatments, particularly multityrosine kinase inhibitors such as pazopanib, imatinib, and sorafenib alone or in combination with other agents such as mTOR (mammalian target of rapamycin) inhibitors. The aim is to increase shared knowledge about current available treatments and identify gaps in research to further efforts toward clinical development of targeted agents.
Tumour-agnostic drugs in paediatric cancers Chisholm, Julia C; Carceller, Fernando; Marshall, Lynley V
British journal of cancer,
05/2020, Letnik:
122, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The recognition that new cancer drugs can be truly tumour-agnostic based on mechanism-of-action is important for paediatric cancers, where access to novel targeted therapies developed for adult ...indications has sometimes been problematic. The recently approved drug larotrectinib is an excellent case study of the development of a tumour-agnostic drug relevant to children.
nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients ...with recurrent/refractory solid tumours treated with nab-paclitaxel are reported.
Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D).
Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1–2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases high-grade, malignant and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST.
nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma.
NCT01962103.
2013-000144-26.
•This phase 1 study determined the maximum tolerated dose/recommended phase II dose (RP2D) of nab-paclitaxel in paediatric patients.•The paediatric RP2D is 240 mg/m2 given days 1, 8 and 15 every 4 weeks.•This dose demonstrated preliminary signs of activity and manageable toxicity.•Results warrant the phase II study of nab-paclitaxel in this population.
The VIT-0910 trial was conducted to evaluate efficacy and safety of the vincristine-irinotecan combination with and without temozolomide (VIT and VI, respectively) in relapsed or refractory ...rhabdomyosarcoma (RMS).
In this randomized European phase II trial, patients age 0.5-50 years received 21-day cycles combining vincristine (1.5 mg/m
once a day on day 1 and day 8) and irinotecan (50 mg/m
once a day from day 1 to day 5) with and without temozolomide (125 mg/m
once a day from day 1 to day 5 and 150 mg/m
once a day from cycle 2), until progression or unacceptable toxicity. The primary end point was objective response rate after two cycles. Secondary end points included best response, progression-free survival, overall survival, and adverse events. A Simon 2-stage design was initially planned to separately analyze 40 patients/arm. After amendment, the trial sample size was increased to 120 and a comparison between arms, adjusted for confounding factors, was added to the statistical plan (ClinicalTrials.gov, NCT01355445).
Overall, 120 patients (60 per arm) were recruited in 37 European centers. The median age was 11 years (range, 0.75-45); 89% of patients had a relapsed RMS. The objective response rate was 44% (24 of 55 evaluable patients) for VIT versus 31% (18 of 58) for VI (adjusted odds ratio, 0.50; 95% CI, 0.22 to 1.12;
= .09). The VIT arm achieved significantly better overall survival (adjusted hazard ratio, 0.55; 95% CI, 0.35 to 0.84;
= .006) compared with VI, with consistent progression-free survival results (adj-hazard ratio, 0.68; 95% CI, 0.46 to 1.01;
= .059). Overall, patients experienced adverse events ≥ grade 3 more frequently with VIT than VI (98%
78%, respectively;
= .009), including a significant excess of hematologic toxicity (81%
61%;
= .025).
The addition of temozolomide to VI improved chemotherapy efficacy for patients with relapsed RMS, with manageable increase in toxicity. VIT is considered the new standard treatment in these patients in the European paediatric Soft Tissue Sarcoma Group and will be the control arm in the next randomized trial.
In tumours, hypoxia-a condition in which the demand for oxygen is higher than its availability-is well known to be associated with reduced sensitivity to radiotherapy and chemotherapy, and with ...immunosuppression. The consequences of hypoxia on tumour biology and patient outcomes have therefore led to the investigation of strategies that can alleviate hypoxia in cancer cells, with the aim of sensitising cells to treatments. An alternative therapeutic approach involves the design of prodrugs that are activated by hypoxic cells. Increasing evidence indicates that hypoxia is not just clinically significant in adult cancers but also in paediatric cancers. We evaluate relevant methods to assess the levels and extent of hypoxia in childhood cancers, including novel imaging strategies such as oxygen-enhanced magnetic resonance imaging (MRI). Preclinical and clinical evidence largely supports the use of hypoxia-targeting drugs in children, and we describe the critical need to identify robust predictive biomarkers for the use of such drugs in future paediatric clinical trials. Ultimately, a more personalised approach to treatment that includes targeting hypoxic tumour cells might improve outcomes in subgroups of paediatric cancer patients.
The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory ...solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study.
Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m2 of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response CR + partial response PR). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease SD), progression-free survival, 1-year overall survival, safety and pharmacokinetics.
Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia 50% and anaemia 48%), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive.
In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed.
NCT01962103 and EudraCT 2013-000144-26.
•The phase II study confirmed nab-paclitaxel safety/tolerability in pediatric patients.•No response was observed in patients with Ewing sarcoma or neuroblastoma.•One patient with rhabdomyosarcoma achieved a confirmed partial response.•The most common grade III/IV toxicities were neutropenia (50%) and anaemia (48%).
The primary aim of this study was to analyse and evaluate the impact of different local treatments on the pattern of relapse in children with primary head and neck non-parameningeal (HNnPM) ...rhabdomyosarcoma (RMS), treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 study. The secondary aim was to assess whether current risk stratification is valid for this specific site.
This study includes all patients with localised HNnPM RMS enrolled in the RMS2005 study between 2005 and 2016. Treatment comprised chemotherapy adapted to risk group, with local surgery and/or radiation therapy. The main outcome measures were event-free survival (EFS) and overall survival (OS).
A total of 165 patients were identified; the median age was 6.4 years (range, 0.1–25). The most common tumour sites were cheek/chin (22%) and nasal ala/nasolabial fold (20%). Histology was unfavourable for 40%, and regional nodal involvement present in 26%. Local therapy included surgery (58%) and/or radiotherapy (72%) to primary tumour and/or regional lymph nodes. After a median follow-up of 66 months (range, 6–158), 42 patients experienced an event, and 17 are still alive. Tumour events were frequent in oral primary (36%), parotid site (26%), cheek/chin (24%), and nasal ala/nasolabial fold (24%) and included locoregional failure in 84% of cases. The 5-year EFS and OS were 75% (95% confidence interval CI: 67.3–81.2) and 84.9% (95% CI: 77.5–89.7), respectively. Favourable histology was associated with a better EFS (82.3% versus 64.6%; p = 0.02) and nodal spread with a worse OS (88.6% versus 76.1%; p = 0.04). Different sublocations within the HNnPM primary did not have significant impact on outcome.
Locoregional relapse/progression is the main tumour failure event in this site. Despite frequent unfavourable risk factors, HNnPM RMS remains a favourable location in the context of a risk-adapted strategy.
•Large prospective analysis of children with head and neck rhabdomyosarcoma.•Adapted strategy according to risk factors allows favourable outcome.•Unfavourable histology and cervical lymph node involvement is frequent in this site.•Locoregional relapse/progression is the main tumour failure event.
We evaluated the role of bevacizumab as part of the multi-modality treatment of children and adolescents with metastatic rhabdomyosarcoma (RMS) or non-rhabdomyosarcoma soft tissue sarcoma (NRSTS).
...Eligible patients aged ≥6 months to <18 years were randomised to receive induction chemotherapy (four cycles of IVADo + five cycles of IVA, ±bevacizumab), surgery and/or radiotherapy, followed by maintenance chemotherapy (12 cycles of low-dose cyclophosphamide + vinorelbine, ±bevacizumab). The primary objective was event-free survival (EFS) evaluated by an independent radiological review committee.
One hundred and fifty-four patients were randomised to receive chemotherapy alone (n = 80) or with bevacizumab (n = 74). At the data cut-off for the primary efficacy analysis, median EFS was 14.9 months (95% confidence interval CI: 10.8–35.9) with chemotherapy and 20.6 months (95% CI: 15.2–24.9) with bevacizumab plus chemotherapy (stratified hazard ratio HR = 0.93; 95% CI: 0.61–1.41; P = 0.72). The HR for EFS in patients with RMS (n = 103) was 1.24 (95% CI: 0.73–2.09) versus 0.64 (95% CI: 0.32–1.26) for those with NRSTS (n = 49). Objective response rate was 36.0% (95% CI: 25.2–47.9) with chemotherapy and 54.0% (95% CI: 40.9–66.6) with bevacizumab plus chemotherapy (difference of 18.0%; 95% CI: 0.6–35.3). There were no treatment-related deaths and no increased incidence of grade 3/4 toxicities with bevacizumab.
The addition of bevacizumab to chemotherapy appeared tolerable in children and adolescents with metastatic RMS/NRSTS, but the primary end-point of EFS did not show statistically significant improvement.
Trial registration: ClinicalTrials.gov, NCT00643565.
•BERNIE evaluated the role of bevacizumab in childhood/adolescent metastatic soft tissue sarcoma.•The addition of bevacizumab to the chemotherapy backbone appeared tolerable.•The primary end-point of event-free survival did not show statistically significant improvement.•These data do not support the use of bevacizumab in metastatic RMS.
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