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.
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.
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.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, UILJ, UKNU, UL, UM, UPUK
High-throughput genomic analyses may improve outcomes in patients with advanced cancers. MOSCATO 01 is a prospective clinical trial evaluating the clinical benefit of this approach. Nucleic acids ...were extracted from fresh-frozen tumor biopsies and analyzed by array comparative genomic hybridization, next-generation sequencing, and RNA sequencing. The primary objective was to evaluate clinical benefit as measured by the percentage of patients presenting progression-free survival (PFS) on matched therapy (PFS2) 1.3-fold longer than the PFS on prior therapy (PFS1). A total of 1,035 adult patients were included, and a biopsy was performed in 948. An actionable molecular alteration was identified in 411 of 843 patients with a molecular portrait. A total of 199 patients were treated with a targeted therapy matched to a genomic alteration. The PFS2/PFS1 ratio was >1.3 in 33% of the patients (63/193). Objective responses were observed in 22 of 194 patients (11%; 95% CI, 7%-17%), and median overall survival was 11.9 months (95% CI, 9.5-14.3 months).
This study suggests that high-throughput genomics could improve outcomes in a subset of patients with hard-to-treat cancers. Although these results are encouraging, only 7% of the successfully screened patients benefited from this approach. Randomized trials are needed to validate this hypothesis and to quantify the magnitude of benefit. Expanding drug access could increase the percentage of patients who benefit.
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Young individuals, aged <40 years, represent 7% of all patients with early breast cancer (EBC), most of whom receive chemotherapy. Preserving future fertility in these patients has become a major ...concern. This prospective study assessed ovarian function during and after chemotherapy according to patient and tumor characteristics and evaluated the outcome of controlled ovarian hyperstimulation (COH). Ovarian reserve was evaluated in terms of amenorrhea duration and by longitudinal serum anti‐Müllerian hormone (AMH) level variations measured at study entry, during treatment and until 24 months thereafter. COH has been proposed for patients receiving adjuvant chemotherapy. We studied the association between clinical factors and ovarian function using Cox models and logistic regression. In this young population (age < 38 years, median = 32), 85 of 90 evaluable patients (94%) experienced chemo‐induced amenorrhea, including six persistent amenorrhea and one chemotherapy‐induced definitive ovarian failure. Overall, 33% of patients still had undetectable AMH values 12 months after the end of chemotherapy, although most had recovered spontaneous and regular menstrual function. No specific factor was associated with clinical or biological late ovarian dysfunction, except for age and baseline AMH value. Overall, 58 patients underwent COH. The mean number of total retrieved oocytes and metaphase II oocytes were of 11.7 and 6.9, respectively. Thus, our study confirms the importance of fertility preservation in young patients with EBC. Our findings indicate that sequential chemotherapy is associated with a higher risk of persistent amenorrhea. There was no significant association between tumor characteristics, fertility preservation or recovery of ovarian reserve.
What's new?
Serum anti‐Müllerian hormone (AMH) is a marker of ovarian follicular content and a real‐time indicator of both follicular depletion and ovarian recovery in patients with cancer. This prospective study describes the menstrual function and dynamics of serum AMH variations during and after chemotherapy in premenopausal patients treated for breast cancer. The findings indicate that sequential chemotherapy is associated with a higher risk of persistent amenorrhea. There was no significant association between tumor characteristics, fertility preservation with controlled ovarian hyperstimulation or recovery of the ovarian reserve. The study underlines the necessity of fertility preservation before commencing chemotherapy.
With the aim of describing the long-term follow-up and to define the prognostic role of the clinical/pathological/molecular characteristics at diagnosis for childhood, adolescent and young adults ...affected by anaplastic large cell lymphoma (ALCL), we analyzed 420 patients aged up to 22 years homogeneously treated within the international ALCL99 trial. The 10-year progression free survival (PFS) was 70% and overall survival was 90%, rare late relapses occurred but no secondary malignancies were reported. Among clinical/pathological characteristics, only patients presenting a small cell/lymphohistiocytic (SC/LH) pattern were independently associated with risk of failure (hazard ratio = 2.49). Analysis of minimal disseminated disease (MDD), available for 162 patients, showed that both SC/LH pattern (hazard ratio = 2.4) and MDD positivity (hazard ratio = 2.15) were significantly associated with risk of failure in multivariate analysis. Considering MDD and SC/LH results, patients were separated into three biological/pathological (bp) risk groups: a high-risk group (bpHR) including MDD-positive patients with SC/LH pattern; a low-risk group (bpLR) including MDD-negative patients without SC/LH pattern; and an intermediate-risk group (bpIR) including remaining patients. The 10-year PFS was 40%, 75% and 86% for bpHR, bpIR and bpLR, respectively (p < 0.0001). These results should be considered in the design of future ALCL trials to tailor individual treatments.
In most countries, reference chemotherapy for osteosarcoma is MAP regimen (M = high-dose methotrexate, AP = doxorubicin-cisplatinum). In France, the standard preoperative chemotherapy for ...children/adolescents combines M and etoposide-ifosfamide (EI), based on the OS94-trial. We report the safety and efficacy results of patients ≤25 years treated with preoperative M-EI regimen enroled in the French OS2006-study, between 2007 and 2014.
Treatment comprised preoperative chemotherapy with the 7 M-courses and 2 EI-courses, then surgery and postoperative chemotherapy assigned by risk's groups: standard-risk (good histological response without metastases) received 12 M-courses, 3 EI-courses; high-risk (poor histologic response, initial metastases or unresectable primary) received 5 M-courses alternated with 5 AP-courses. 253 patients were randomised to receive (n = 128) or not (n = 125) zoledronate.
409/522 patients enroled in the OS2006 study who received preoperative M-EI were analysed. Median age was 14.3 years (4.7–24.5), with 55 patients aged 18–25 years. Primary tumour location was limb in 383 patients (94%) and 85 (21%) presented metastases. Median chemotherapy duration was 37.4 weeks. 381 (96%) patients underwent surgery, 258 patients (65%) had a good histologic response. 187/324 patients (58%) with localised disease did not receive doxorubicin nor cisplatinum. Toxicity was evaluated in the randomised study: most patients experienced ≥1 severe toxicity (grade IV haematological or grade III/IV extra-haematological). Median follow-up was 4.8 years, and 168 patients had events. Five-year event-free survival was 56% (95% CI, 51–62%) and overall survival 71% (66–76%).
M-EI regimen/strategy was feasible for patient aged ≤25 years with survival rates are comparable to those obtained with MAP regimen.
•Paediatric and young adult methotrexate-based chemotherapy regimen of OS2006 protocol.•Event-free survival and overall survival rates were similar to those with standard Methotrexate-Doxorubicin-Cisplatinum (MAP) regimen used worldwide.•First-line treatment with doxorubicin and cisplatinum was avoided in 58% patients with localised tumours.
Abstract Background The most appropriate design of Phase-II trials evaluating new therapies in osteosarcoma remains poorly defined. Objective To study consistency in phase-II clinical trials ...evaluating new therapies for osteosarcoma recurrences with respect to eligibility criteria, response assessment, end-points, statistical design and reported results. Methods Systematic review of clinical trials registered on clinicaltrials.gov , clinicaltrialsregister.eu and French National Cancer Institute website or referenced in PubMed and American Society of Clinical Oncology websites, between 2003 and 2016, using the following criteria: (osteosarcoma OR bone sarcoma) AND (Phase-II). Results Among the 99 trials identified, 80 were Phase-II, 17 I/II and 2 II/III, evaluating mostly targeted therapy (n = 40), and chemotherapy alone (n = 26). Results were fully (n = 28) or partially (abstract, n = 6) published. Twenty-four trials were dedicated to osteosarcoma, 22 had an osteosarcoma stratum. Twenty-eight out of 99 trials refer to the age range observed at recurrence (28%). Overall, 65 trials were run in multicentre settings, including 17 international trials. Only 9 trials were randomised. The primary end-point was tumour response in 71 trials (response rate, n = 40 or best response, n = 31), with various definitions (complete + partial ± minor response and stable disease), mainly evaluated with RECIST criteria (n = 69); it was progression-free survival in 24 trials and OS in 3. In single-arm trials evaluating response rate, the null hypothesis tested (when available, n = 12) varied from 5% to 25%. Conclusion No robust historical data can currently be derived from past efficacy Phase-II trials. There is an urgent need to develop international randomised Phase-II trials across all age ranges with standardised primary end-point.
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