Deciphering the ways in which somatic mutations and germline susceptibility variants cooperate to promote cancer is challenging. Ewing sarcoma is characterized by fusions between EWSR1 and members of ...the ETS gene family, usually EWSR1-FLI1, leading to the generation of oncogenic transcription factors that bind DNA at GGAA motifs. A recent genome-wide association study identified susceptibility variants near EGR2. Here we found that EGR2 knockdown inhibited proliferation, clonogenicity and spheroidal growth in vitro and induced regression of Ewing sarcoma xenografts. Targeted germline deep sequencing of the EGR2 locus in affected subjects and controls identified 291 Ewing-associated SNPs. At rs79965208, the A risk allele connected adjacent GGAA repeats by converting an interspaced GGAT motif into a GGAA motif, thereby increasing the number of consecutive GGAA motifs and thus the EWSR1-FLI1-dependent enhancer activity of this sequence, with epigenetic characteristics of an active regulatory element. EWSR1-FLI1 preferentially bound to the A risk allele, which increased global and allele-specific EGR2 expression. Collectively, our findings establish cooperation between a dominant oncogene and a susceptibility variant that regulates a major driver of Ewing sarcomagenesis.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
In Euro‐EWING99‐R1 randomized trial, cyclophosphamide was shown to be noninferior to ifosfamide in the consolidation of standard‐risk Ewing sarcoma (SR‐EWS) after a common induction with VIDE ...(vincristine‐ifosfamide‐doxorubicin‐etoposide). We present the results of the late effects analysis of VAC (vincristine‐dactinomycin‐cyclophoshamide) vs VAI (vincristine‐dactinomycin‐ifosfamide) conducted in Euro‐EWING99‐R1 French cohort. Of 267 French randomized patients, 204 were alive and free‐of‐relapse at 5‐years including 172 with available long‐term follow‐up data concerning cardiac, renal and/or gonadal functions (sex‐ratio M/F = 1.3, median age at diagnosis = 14 years): 84 randomized in VAC (median cumulative doses: cyclophosphamide = 9.7 g/m2, ifosfamide = 59.4 g/m2) and 88 in VAI (ifosfamide = 97.1 g/m2). With a median follow‐up of 10 years (range = 5‐17), five late relapses and five second malignancies were recorded. The 10‐year event‐free survival among 5‐year free‐of‐relapse survivors was similar between VAC and VAI (93% vs 95%, P = .63). We estimated the 10‐year cumulative probabilities of cardiac and kidney toxicities at 4.4% (95% confidence interval 95% CI = 1.1%‐7.6%) and 34.8% (95% CI = 26.8%‐42.0%), respectively. Cardiac toxicity cumulative probability was similar in both arms, whereas kidney toxicity was higher in VAI (at 10 years, 43.0% vs 25.7%, P = .02), resulting from significant difference in glomerular toxicity (31.1% vs 13.1%, P < .01). At 10 years, gonadal toxicity was observed in 27% and 28% of pubertal men and women, respectively, without significant difference between VAC and VAI. Kidney and gonadal toxicities represent major issues in Euro‐EWING99‐R1, with significantly higher risk of kidney toxicities with VAI, without significant gonadal toxicity reduction. These results support the need to limit cumulative doses of both alkylating agents and to use mixed regimen as in VIDE‐VAC or VDC/IE (vincristine‐doxorubicin‐cyclophoshamide/ifosfamide‐etoposide).
What's new?
The Euro‐EWING99‐R1 trial compared the alkylating agents cyclophosphamide with ifosfamide in combination treatment for Ewing sarcoma. Here, the authors compare the late events between the two combination treatments using data from 172 patients enrolled in Euro‐EWING99‐R1. The combination containing ifosfamide carried a higher risk of kidney toxicity, but both regimens carried high rates of gonadal toxicity. Some of this toxicity could be avoided, they suggest, by using a mixed regimen to limit the dose of both alkylating agents.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The aim of this study is to evaluate the prevalence, determinants and prognostic value of pain at diagnosis in patients with desmoid‐type fibromatosis (DF). We selected patients from the ALTITUDES ...cohort (NCT02867033), managed by surgery, active surveillance or systemic treatments, with pain assessment at diagnosis. Patients were invited to fill QLQ‐C30 questionnaire and Hospital Anxiety Depression Scale. Determinants were identified using logistic models. Prognostic value on event‐free survival (EFS) was evaluated using the Cox model. Overall, 382 patients were included in the current study (median age: 40.2 years; 117 men). The prevalence of pain was 36%, without significant difference according to first‐line treatment (P = .18). In the multivariate analysis, pain was significantly associated with tumor size >50 mm (P = .013) and tumor site (P < .001); pain was more frequent in the neck and shoulder locations (odds ratio: 3.05 1.27‐7.29). Pain at baseline was significantly associated with poor quality of life (P < .001), depression (P = .02), lower performance status (P = .03) and functional impairment (P = .001); we also observed a nonsignificant association with anxiety (P = .10). In the univariate analysis, baseline pain was associated with poor EFS; the 3‐year EFS was 54% in patients with pain compared to 72% in those without pain. After adjustment for sex, age, size and line of treatment, pain was still associated with poor EFS (hazard ratio: 1.82 1.23‐2.68, P = .003). One third of recently diagnosed patients with DF experienced pain, especially those with larger tumors and neck/shoulder locations. Pain was associated with unfavorable EFS after adjustment for the confounders.
What's new?
The natural course of desmoid‐type fibromatosis (DF) is unpredictable, ranging from spontaneous regression to life‐threatening disease progression. Pain, which is a major concern in patients with DF, could be a revealing symptom. This prospective cohort study of newly diagnosed cases is the first study to analyze the frequency of pain in a large number of DF patients, as well as the determinants and consequences of pain. One third of recently diagnosed patients experienced pain, especially those with larger tumors and neck/shoulder locations. Pain severely impacted quality of life and was associated with unfavorable event‐free survival after adjustment for confounders.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Ewing sarcoma (ES) is an aggressive sarcoma of bone and soft tissue occurring at any age with a peak incidence in adolescents and young adults. The treatment of ES relies on a multidisciplinary ...approach, coupling risk-adapted intensive neoadjuvant and adjuvant chemotherapies with surgery and/or radiotherapy for control of the primary site and possible metastatic disease. The optimization of ES multimodality therapeutic strategies has resulted from the efforts of several national and international groups in Europe and North America and from cooperation between pediatric and medical oncologists. Successive first-line trials addressed the efficacy of various cyclic combinations of drugs incorporating doxorubicin, vincristine, cyclophosphamide, ifosfamide, etoposide, and dactinomycin and identified prognostic factors now used to tailor therapies. The role of high-dose chemotherapy is still debated. Current 5-year overall survival for patients with localized disease is 65% to 75%. Patients with metastases have a 5-year overall survival < 30%, except for those with isolated pulmonary metastasis (approximately 50%). Patients with recurrence have a dismal prognosis. The many insights into the biology of the EWS-FLI1 protein in the initiation and progression of ES remain to be translated into novel therapeutic strategies. Current options and future approaches will be discussed.
Summary
Relapses involving the central nervous system (CNS) are rare in children and adolescents with ALK+ anaplastic large cell lymphoma (ALCL) treated with regimens including CNS prophylaxis. Early ...identification of patients at high‐risk for CNS relapse would enable stratification and better adaptation of initial treatment especially in the light of the upcoming targeted therapies with limited CNS penetration. We analyzed clinical and histological data of all ALK+ALCL patients with CNS relapse registered in ALCL99‐database with the aim to describe risk factors and outcome. Characteristics of patients with no relapse, relapse without CNS involvement and CNS relapse were compared. At a median follow‐up of 8 years (0.05–18 years), a CNS involvement was reported at first or subsequent relapse in 26/618 patients. Median interval between initial diagnosis and first CNS relapse was 8 months (IQR 5.55–10.61/range 1.31–130.69). The 5‐year cumulative risk of CNS relapse was 4% (95% CI 2.9–5.5). Bone marrow involvement, peripheral blasts and CNS involvement at diagnosis were more frequent in patients with CNS relapse than in patients with no relapse or with relapse with no CNS involvement. The treatment of CNS relapse was heterogeneous. The median survival after CNS relapse was 23.7 months. Eleven patients were alive at last follow‐up. Three‐year overall survival after CNS relapse was 48.70% (95% CI 30.52–67.23).
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress ...has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse.
Childhood cancer survivors are at increased risk for second primary leukemia (SPL), but there is little consensus on the magnitude of some risk factors because of the small size of previous studies. ...We performed a pooled analysis of all published studies with detailed treatment data, including estimated active bone marrow (ABM) dose received during radiation therapy and doses of specific chemotherapeutic agents for childhood cancer diagnosed from 1930 through 2000, in order to more thoroughly investigate treatment‐related risks of SPL. A total of 147 SPL cases (of which 69% were acute myeloid leukemia AML) were individually matched to 522 controls, all from four case‐control studies including patients from six countries (France, United Kingdom, United States, Canada, Italy and Netherlands). Odds ratios (OR) and corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression, and the excess OR per Gray (EOR/Gy) was also calculated. After accounting for the other therapies received, topoisomerase II inhibitor was associated with an increased SPL risk (highest tertile vs none: OR = 10.0, 95% CI: 3.7‐27.3). Radiation dose to the ABM was also associated with increased SPL risk among those not receiving chemotherapy (EOR/Gy = 1.6, 95% CI: 0.1‐14.3), but not among those who received chemotherapy (CT). SPL were most likely to occur in the first decade following cancer treatment. Results were similar when analyses were restricted to AML. The evidence of interaction between radiation and CT has implications for leukemogenic mechanism. The results for topoisomerase II inhibitors are particularly important given their increasing use to treat childhood cancer.
What's new?
Childhood cancer survivors are at increased risk for second primary leukemia (SPL), but which treatments confer the greatest risk? In this study, the authors found that topoisomerase II inhibitors increased the risk of SPL by as much as 10‐fold, which was far higher than for other chemotherapies. Radiation therapy also increased the subsequent risk of SPL, but only in patients who didn't also receive chemotherapy. Given the poor prognosis of SPL, these results should help inform surveillance guidelines for childhood cancer survivors, and guide assessment of leukemia risks for specific treatment protocols.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Aim
To assess objective response after two cycles of temozolomide and topotecan (TOTEM) in children with refractory or relapsed miscellaneous extracranial solid and central nervous system (CNS) ...tumors, including medulloblastoma and primitive neuroectodermal tumors (PNET).
Procedure
Multicenter, nonrandomized, phase 2 basket trial including children with solid tumors, completed by a one‐stage design confirmatory cohort for medulloblastoma, and an exploratory cohort for PNET. Main eligibility criteria were refractory/relapsed measurable disease and no more than two prior treatment lines. Temozolomide was administered orally at 150 mg/m2/day followed by topotecan at 0.75 mg/m2/day intravenously for five consecutive days every 28 days. Tumor response was assessed every two cycles according to WHO criteria and reviewed independently.
Results
Thirty‐two patients were enrolled and treated in the miscellaneous solid tumor and 33 in the CNS strata; 20 patients with medulloblastoma and six with PNET were included in the expansion cohorts. The median age at inclusion was 10.0 years (range, 0.9‐20.9). In the basket cohorts, confirmed complete and partial responses were observed in one glioma, four medulloblastoma, and one PNET, leading to the extension. The overall objective response rate (ORR) in medulloblastoma was 28% (95% CI, 12.7‐47.2) with 1/29 complete and 7/29 partial responses, those for PNET 10% (95% CI, 0.3‐44.5). Post hoc Bayesian analysis estimates that the true ORR in medulloblastoma is probably between 20% and 30% and below 20% in PNET. The most common treatment‐related toxicities of the combination therapy were hematologic.
Conclusions
Temozolomide‐topotecan results in significant ORR in children with recurrent and refractory medulloblastoma with a favorable toxicity profile.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
In the OS2006 study, patients younger than 18 years were treated with a methotrexate‐based regimen (MTX), patients older than 25 years with a doxorubicin–cisplatin–ifosfamide‐based regimen (API–AI), ...whereas patients aged 18–25 years received either API–AI or MTX. We herein report the prespecified subgroup analysis of the outcome of 106 patients treated with API–AI. Preoperative chemotherapy combined three doxorubicin–ifosfamide–cisplatin (API) and two doxorubicin–ifosfamide (AI) courses. Postoperative chemotherapy was assigned by risk group: localised patients with a good histological response (<10% viable cells) received two AI and two cisplatin–ifosfamide (PI) courses; patients with synchronous metastases, poor histological response or unresectable primary received five cycles of etoposide–ifosfamide (EI). Of the 106 patients, 61 were randomised to receive or not zoledronate. Median age was 30 years (range 18–67), 66 (62%) patients were >25 years. The primary tumours were axial in 28 patients (26%), and 28 (26%) presented with metastases. Ninety‐six patients (91%) had surgery, conservative in 82 (85%); 36 patients (38%, 95% CI 28–48%) were good responders. Toxicity was manageable, with no significant difference in severe acute toxicity between patients aged >25 years and those younger. With a median follow‐up of 4.8 years, the 5‐year event‐free survival and overall survival rates were 46% (95% CI 36–56) and 57% (95% CI 47–67), respectively. The primary tumour size and initial metastases correlated with a higher risk of event. In these 106 osteosarcoma adult patients, API–AI proved feasible with no excess of toxicity, and favourable activity despite poor‐prognosis factors.
What's new?
Osteosarcoma paediatric patients are commonly treated with high‐dose methotrexate combined to other active agents. Methotrexate pharmacokinetics varies considerably with age, however, with few prospective studies dedicated to adult patients and currently no consensus concerning the optimal chemotherapy regimen in these patients. This paper describes the population of 106 adult osteosarcoma patients enrolled in the OS 2006 phase III study, their treatment and their outcomes using a chemotherapy backbone without methotrexate that combines doxorubicin, cisplatin, and ifosfamide. This study confirms prior findings that the API‐AI regimen has acceptable toxicity and yields favourable activity in adult osteosarcoma patients with poor prognosis factors.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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