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Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The RMS2005 study included two phase III randomized trials for high-risk (HR) and observational trials for low (LR), standard (SR), and very high-risk (VHR) patients who have been partially reported. Herein, we present a comprehensive report of results achieved for the complete unselected nonmetastatic cohort and analyze the evolution of treatment in comparison with previous European protocols. After a median follow-up of 73.1 months, the 5-year event-free survival (EFS) and overall survival (OS) of the 1,733 patients enrolled were 70.7% (95% CI, 68.5 to 72.8) and 80.4% (95% CI, 78.4 to 82.3), respectively. The results by subgroup: LR (80 patients) EFS 93.7% (95% CI, 85.5 to 97.3), OS 96.7% (95% CI, 87.2 to 99.2); SR (652 patients) EFS 77.4% (95% CI, 73.9 to 80.5), OS 90.6% (95% CI, 87.9 to 92.7); HR (851 patients) EFS 67.3% (95% CI, 64.0 to 70.4), OS 76.7% (95% CI, 73.6 to 79.4); and VHR (150 patients) EFS 48.8% (95% CI, 40.4 to 56.7), OS 49.7% (95% CI, 40.8 to 57.9). The RMS2005 study demonstrated that 80% of children with localized rhabdomyosarcoma could be long-term survivors. The study has established the standard of care across the European pediatric Soft tissue sarcoma Study Group countries with the confirmation of a 22-week vincristine/actinomycin D regimen for LR patients, the reduction of the cumulative ifosfamide dose in the SR group, and for HR disease, the omission of doxorubicin and the addition of maintenance chemotherapy.

Rhabdomyosarcoma, although rare, is the most frequent soft tissue sarcoma in children and adolescents. It can present as a mass at nearly any site in the body, with most common presentations in the head and neck, genitourinary tract and extremities. The optimal diagnostic approach and management of rhabdomyosarcoma require a multidisciplinary team with multimodal treatment, including chemotherapy and local therapy. Survival has improved over the last decades; however, further improvement in management is essential with current 5-year overall survival ranging from 35% to 100%, depending on disease and patient characteristics. In the full patient journey, from diagnosis, staging, management to follow-up after therapy, the paediatric radiologist and nuclear physician are essential members of the multidisciplinary team. Recently, guidelines of the European paediatric Soft tissue sarcoma Study Group, the Cooperative Weichteilsarkom Studiengruppe and the Oncology Task Force of the European Society of Paediatric Radiology (ESPR), in an ongoing collaboration with the International Soft-Tissue Sarcoma Database Consortium, provided guidance for high-quality imaging. In this educational paper, given as a lecture during the 2022 postgraduate ESPR course, the multi-disciplinary team of our national paediatric oncology centre presents the journey of two patients with rhabdomyosarcoma and discusses the impact on and considerations for the clinical (paediatric) radiologist and nuclear physician. The key learning points of the guidelines and their implementation in clinical practice are highlighted and up-to-date insights provided for all aspects from clinical suspicion of rhabdomyosarcoma and its differential diagnosis, to biopsy, staging, risk stratification, treatment response assessment and follow-up.

Liver; Pediatrics; Sarcoma Fetge; Pediatria; Sarcoma Hígado; Pediatría; Sarcoma 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.

BACKGROUND AND PURPOSE The aim of this study was to determine the feasibility of hypofractionated schedules for metastatic bone/bone marrow lesions in children and to investigate dosimetric differences to the healthy surrounding tissues compared to conventional schedules. METHODS 27 paediatric patients (mean age, 7 years) with 50 metastatic bone/bone marrow lesions (n = 26 cranial, n = 24 extra-cranial) from solid primary tumours (neuroblastoma and sarcoma) were included. The PTV was a 2 mm expansion of the GTV. A prescription dose of 36 and 54 Gy EQD2α/β=10 was used for neuroblastoma and sarcoma lesions, respectively. VMAT plans were optimized for each single lesion using different fractionation schedules: conventional (30/20 fractions, V95% ≥ 99%, D0.1cm3 ≤ 107%) and hypofractionated (15/10/5/3 fractions, V100% ≥ 95%, D0.1cm3 ≤ 120%). Relative EQD2 differences in OARs Dmean between the different schedules were compared. RESULTS PTV coverage was met for all plans independently of the fractionation schedule and for all lesions (V95% range 95.5-100%, V100% range 95.1-100%), with exception of the vertebrae (V100% range 63.5-91.0%). For most OARs, relative mean reduction in the Dmean was seen for the hypofractionated plans compared to the conventional plans, with largest sparing in the 5 fractions (< 43%) followed by the 3 fractions schedule (< 40%). In case of PTV overlap with an OAR, a significant increase in dose for the OAR was observed with hypofractionation. CONCLUSIONS For the majority of the cases, iso-effective plans with hypofractionation were feasible with similar or less dose in the OARs. The most suitable fractionation schedule should be personalised depending on the spatial relationship between the PTV and OARs and the prescription dose.

Major progress in recent decades has furthered our clinical and biological understanding of rhabdomyosarcoma (RMS) with improved stratification for treatment based on risk factors. Clinical risk factors alone were used to stratify patients for treatment in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 protocol. The current EpSSG overarching study for children and adults with frontline and relapsed rhabdomyosarcoma (FaR-RMS NCT04625907) includes FOXO1 fusion gene status in place of histology as a risk factor. Additional molecular features of significance have recently been recognized, including the MYOD1L122R gene mutation. Here, we review biological information showing that MYOD1L122R blocks cell differentiation and has a MYC-like activity that enhances tumorigenesis and is linked to an aggressive cellular phenotype. MYOD1L122R mutations can be found together with mutations in other genes, such as PIK3CA, as potentially cooperating events. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ten publications in the clinical literature involving 72 cases were reviewed. MYOD1L122R mutation in RMS can occur in both adults and children and is frequent in sclerosing/spindle cell histology, although it is also significantly reported in a subset of embryonal RMS. MYOD1L122R mutated tumors most frequently arise in the head and neck and extremities and are associated with poor outcome, raising the issue of how to use MYOD1L122R in risk stratification and how to treat these patients most effectively.

Rhabdomyosarcoma of the perianal/perineal region (PRMS) is rare, with poor survival and limited understanding of the functional consequences of treatment.International Society of Pediatric Oncology (SIOP) malignant mesenchymal tumor (MMT) 95, Italian RMS 96, and European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS 2005 studies were interrogated to identify factors that impact survival; in RMS 2005, functional outcomes were analyzed.Fifty patients (nonmetastatic) were identified, median age 6.4 years (range: 0.1-19.6): 29 male, 21 female. Tumors were5 cm in 33 patients. Histopathological subtype was alveolar in 35. Lymph nodes were involved in 23 patients. In RMS 2005, 16/21 (76%) tested alveolar tumors had positive FOXO1 fusion status. Diagnostic biopsy was performed in 37. Primary resection (13) was complete (R0) in one. Delayed primary excision (16) was complete in three. Radiotherapy (RT) in 34/50 patients included external beam (28), brachytherapy (3), and both (3). Nodal RT was given in 16/23 N1 patients (70%). Median follow-up of alive patients (29) was 84.1 months (range: 3.6-221.1). Relapse or progression occurred in 24 patients (48%), 87% were fatal and most events (63%) were locoregional. Five-year event-free survival (EFS) was 47.8 (95% CI: 32.8-61.3), and 5-year overall survival (OS) was 52.6 (95% CI: 36.7-66.2), with age ≥10 years and tumor size5 cm impacting 5-year EFS and OS (p .05). Functional outcome data showed bowel, genito-urinary, and psychological issues; fecal incontinence in four of 21 survivors, and urinary symptoms in two of 21.About 60% of patients with nonmetastatic PRMS survive; older patients and those with large tumors have the worst outcomes. Biopsy should be the initial procedure, and definitive local therapy individualized. Quality-of-life and functional studies are needed to better understand the consequences of treatment.

Simple Summary Hearing loss (HL) can be a side effect of paediatric cancer treatment and can be caused by chemotherapy but also local therapies such as radiotherapy and/or surgery of the head and neck region. In this study, the frequency and patterns of HL were assessed in survivors of head and neck rhabdomyosarcoma (HNRMS). Our secondary aim was to look into the dose-effect relationship between radiotherapy dose on the cochlea and the presence of HL. Forty-nine survivors of HNRMS were included in this study, forty-two of them underwent audiological evaluation. HL was found in up to 19% of the survivors. Four survivors had low frequencies HL with normal hearing or milder HL in the higher frequencies. In our series, HL (>= Muenster 2b) was significantly associated with the maximum cochlear irradiation dose (p = 0.047). More research is needed on HL patterns in HNRMS survivors and on the radiotherapy dose-effect relationship. Purpose: The frequency and patterns of HL in a HNRMS survivor cohort were investigated. A dose-effect relationship between the dose to the cochlea and HL was explored. Methods: Dutch survivors treated for HNRMS between 1993 and 2017 with no relapse and at least two years after the end of treatment were eligible for inclusion. The survivors were evaluated for HL with pure-tone audiometry. HL was graded according to the Muenster, Common Terminology Criteria for Adverse Events (CTCAE) v4.03 and International Society for Paediatric Oncology (SIOP) classification. We defined deleterious HL as Muenster >= 2b, CTCAE >= 2, and SIOP >= 2. Mixed-effects logistic regression was used to search for the dose-effect relationship between the irradiation dose to the cochlea and the occurrence of HL. Results: Forty-two HNRMS survivors underwent pure-tone audiometry. The Muenster, CTCAE and SIOP classification showed that 19.0% (n = 8), 14.2% (n = 6) and 11.9% (n = 5) of survivors suffered from HL, respectively. A low-frequency HL pattern with normal hearing or milder hearing loss in the higher frequencies was seen in four survivors. The maximum cochlear irradiation dose was significantly associated with HL (>= Muenster 2b) (p = 0.047). In our series, HL (>= Muenster 2b) was especially observed when the maximum dose to the cochlea exceeded 19 Gy. Conclusion: HL occurred in up to 19% of survivors of HNRMS. More research is needed on HL patterns in HNRMS survivors and on radiotherapy dose-effect relationships.

Background: Head and neck rhabdomyosarcoma (HNRMS) survivors are at risk to develop adverse events (AEs). The impact of these AEs on psychosocial well‐being is unclear. We aimed to assess psychosocial well‐being of HNRMS survivors and examine whether psychosocial outcomes were associated with burden of therapy.Procedure: Sixty‐five HNRMS survivors (median follow‐up: 11.5 years), treated in the Netherlands and the United Kingdom between 1990 and 2010 and alive ≥2 years after treatment visited the outpatient multidisciplinary follow‐up clinic once, in which AEs were scored based on a predefined list according to the Common Terminology Criteria for Adverse Events. Survivors were asked to complete questionnaires on health‐related quality of life (HRQoL; PedsQL and YQOL‐FD), self‐perception (KIDSCREEN), and satisfaction with appearances (SWA). HRQoL and self‐perception scores were compared with reference values, and the correlation between physician‐assessed AEs and psychosocial well‐being was assessed.Results: HNRMS survivors showed significantly lower scores on PedsQL school/work domain (P ≤ 0.01, P = 0.02, respectively), YQOL‐FD domains negative self‐image and positive consequences (P ≤ 0.01, P = 0.04, respectively) compared with norm data; scores on negative consequences domain were significantly higher (P = 0.03). Over 50% of survivors negatively rated their appearances on three or more items. Burden of AEs was not associated with generic HRQoL and self‐perception scores, but was associated with disease‐specific QoL (YQOL‐FD).Conclusion: In general, HRQoL in HNRMS survivors was comparable to reference groups; however, survivors did report disease‐specific consequences. We therefore recommend including specific questionnaires related to difficulties with facial appearance in a systematic monitoring program to determine the necessity for tailored care.

Background and purpose Survival after relapse of head and neck rhabdomyosarcoma (HNRMS) after prior external beam radiotherapy (EBRT) is poor, since options for adequate local treatment are often lacking. In this study we describe our experience with salvage AMORE in patients with relapsed HNRMS after prior EBRT. Materials and methods Patients with relapsed HNRMS after prior EBRT in which salvage AMORE treatment was considered feasible were analysed; this includes patients with parameningeal, head and neck non-parameningeal and orbital localization. AMORE treatment consisted of Ablative surgery, MOuld technique brachytherapy and surgical REconstruction. Results In total 18 patients received salvage AMORE treatment; nine patients had relapsed parameningeal (PM) RMS, two patients had relapsed head and neck non-parameningeal RMS (HN-nonPM) and seven patients had relapsed orbital RMS. Local control rate was 67% and 5-year overall survival was 54% (95% confidence interval: 31–78%); 3/9 patients with PM RMS, 0/2 patients with HN-nonPM RMS and 6/7 patients with orbital RMS were alive after a median follow-up of 8.6 years. One patient with PM RMS survived more than 5 years after which he died from a secondary cancer. Six patients developed a local relapse (of which one patient also developed a distant metastasis) and two patients developed distant metastases. Conclusions Salvage AMORE treatment is a feasible and effective local therapy approach even after prior EBRT. Since salvage AMORE treatment is sometimes the only curative option in patient with relapsed HNRMS, we encourage physicians to consider salvage AMORE treatment for patients with relapsed HNRMS after prior EBRT.

Background and purpose: To quantify renal and diaphragmatic interfractional motion in order to estimate systematic and random errors, and to investigate the correlation between interfractional motion and patient-specific factors.Material and methods: We used 527 retrospective abdominal-thoracic cone beam CT scans of 39 childhood cancer patients (

Background. In radiotherapy, the magnitude of respiratory-induced tumor motion is often measured using a single four-dimensional computed tomography (4DCT). This magnitude is required to determine the internal target volume. The aim of this study was to compare the magnitude of respiratory-induced motion of pancreatic tumors on a single 4DCT with the motion on daily cone beam CT (CBCT) scans during a 3–5-week fractionated radiotherapy scheme. In addition, we investigated changes in the respiratory motion during the treatment course.Material and methods. The mean peak-to-peak motion (i.e. magnitude of motion) of pancreatic tumors was measured for 18 patients using intratumoral gold fiducials visible on CBCT scans made prior to each treatment fraction (10–27 CBCTs per patient; 401 CBCTs in total). For each patient, these magnitudes were compared to the magnitude measured on 4DCT. Possible time trends were investigated by applying linear fits to the tumor motion determined from daily CBCTs as a function of treatment day.Results. We found a significant (p ≤ 0.01) difference between motion magnitude on 4DCT and on CBCT in superior-inferior, anterior-posterior and left-right direction, in 13, 9 and 12 of 18 patients, respectively. In the anterior- posterior and left-right direction no fractions had a difference ≥ 5 mm. In the superior-inferior direction the difference was ≥ 5 mm for 17% of the 401 fractions. In this direction, a significant (p ≤ 0.05) time trend in tumor motion was observed in 4 of 18 patients, but all trends were small (− 0.17–0.10 mm/day) and did not explain the large differences in motion magnitude between 4DCT and CBCT.Conclusion. A single measurement of the respiratory-induced motion magnitude of pancreatic tumors using 4DCT is often not representative for the magnitude during daily treatment over a 3–5-week radiotherapy scheme. For this patient group it may be beneficial to introduce breath-hold to eliminate respiratory-induced tumor motion.

BackgroundRadiotherapy is a well-known cause of adverse events (AEs). To reduce AEs, an innovative local treatment was developed in Amsterdam: Ablative surgery, MOuld brachytherapy and surgical REconstruction (AMORE).Aims: (1) to determine the prevalence of AEs in HNRMS survivors and (2) to compare AEs between survivors treated with the international standard: external beam radiotherapy (EBRT-based: London) and survivors treated with AMORE if feasible, otherwise EBRT (AMORE-based: Amsterdam).MethodsAll HNRMS survivors, treated in London or Amsterdam between January 1990 and December 2010 (n = 153), and alive ⩾2 years post-treatment were eligible (n = 113). A predefined list of AEs was assessed in a multidisciplinary clinic and graded according to the Common Terminology Criteria for Adverse Events.ResultsEighty HNRMS survivors attended the clinic (median follow-up 10.5 years); 63% experienced ⩾1 severe or disabling event, and 76% had ⩾5 AEs (any grade). Survivors with EBRT-based treatment were, after adjustment for site, age at diagnosis, and follow-up duration, at increased risk to develop any grade 3/4 event or ⩾5 AEs (any grade) compared with survivors with AMORE-based treatments (p = 0.032 and 0.01, respectively). Five year overall survival (source population) after EBRT-based treatment was 75.0%, after AMORE-based treatment 76.9%, p = 0.56.ConclusionThis study may serve as a baseline inventory and can be used in future studies for prospective assessments of AEs following the introduction of novel local treatment modalities. AMORE-based local treatment resulted in similar overall survival and a reduction of AEs secondary to local treatment.

Pulsed dose rate (PDR) brachytherapy is a treatment modality that combines physical advantages of high dose rate (HDR) brachytherapy with the radiobiological advantages of low dose rate brachytherapy. The aim of this review was to describe the effective clinical use of PDR brachytherapy worldwide in different tumour locations. We found 66 articles reporting on clinical PDR brachytherapy including the treatment procedure and outcome. Moreover, PDR brachytherapy has been applied in almost all tumour sites for which brachytherapy is indicated and with good local control and low toxicity. The main advantage of PDR is, because of the small pulse sizes used, the ability to spare normal tissue. In certain cases, HDR resembles PDR brachytherapy by the use of multifractionated low-fraction dose.

Objective. The aim of this study is to investigate the impact of treatment policy changes in cervical cancer patients treated with adjuvant (chemo) radiotherapy.Methods. Between 1970 and 2007, 292 patients received adjuvant radiotherapy after a radical hysterectomy with pelvic lymphadenectomy for early stage cervical carcinoma. All patients received pelvic radiotherapy (40 Gy-46 Gy in 1.8 Gy-2 Gy/fraction). Vaginal vault brachytherapy boost (10-14 Gy) was increasingly used for patients with high-risk factors, and since 1993 systematically applied in patients with at least 2 of the 3 risk factors: adenocarcinoma, nodal involvement and parametrial invasion. Cisplatin-based chemotherapy was introduced in this group of patients from 2000.Results. The 5-year cumulative risk of local recurrence (CRLR) was 13% (95%CI 9%-17%), resulting in an overall 5-year survival (OS) of 78% (95%CI 83%-73%). Since 1970, the OR for the 5-year locoregional recurrence risk (LRR) decreased from 2.5 to 1.15 (linear-OR = -0.02/year). The OR for the 5-year mortality risk reduced from 2.2 in 1970 to 1.0 in 2007 (linear-OR = -0.03/year). The largest risk reductions were observed before 1990 with a minor rise after 2002. The risk of severe late toxicity reduced from 1.8% to 1.5% (linear-OR = -0.03/year). The addition of concomitant adjuvant chemotherapy since 2000 may have benefited a subgroup of patients with squamous cell carcinoma, but not the patients with adenocarcinoma, and after introduction of chemotherapy the risk of severe late toxicity tripled from 2% to 7%.Conclusion. Since 1970, tumour recurrence risk and mortality have decreased, as radiation dose increased. The potential benefit of concomitant adjuvant chemotherapy could not be demonstrated in this nonrandomized study. (C) 2014 Elsevier Inc. All rights reserved.

DISCLOSURE: The following authors disclosed financial relationships relevant to this publication: Dr Fockens is a consultant to Olympus, Fujifilm, Boston Scientific, and Cook. Dr Bel collaborates on projects for Elekta. Dr van Hooft is a consultant to Cook Ireland Ltd and Boston Scientific. All other authors disclosed no financial relationships relevant to this publication. Dr van der Horst and Eelco Lens were supported by the Foundation Bergh in het Zadel through the Dutch Cancer Society (KWF Kankerbestrijding) project no. UVA 2011-5271.

The aim of this study was to quantify interfractional pancreatic position variation using fiducial markers visible on daily cone beam computed tomography (CBCT) scans. In addition, we analyzed possible migration of the markers to investigate their suitability for tumor localization. For 13 pancreatic cancer patients with implanted Visicoil markers, CBCT scans were obtained before 17 to 25 fractions (300 CBCTs in total). Image registration with the reference CT was used to determine the displacement of the 2 to 3 markers relative to bony anatomy and to each other. We analyzed the distance between marker pairs as a function of time to identify marker registration error (SD of linear fit residuals) and possible marker migration. For each patient, we determined the mean displacement of markers relative to the reference CT (systematic position error) and the spread in displacements (random position error). From this, we calculated the group systematic error, Σ, and group random error, σ. Marker pair distances showed slight trends with time (range, -0.14 to 0.14 mm/day), possibly due to tissue deformation, but no shifts that would indicate marker migration. The mean SD of the fit residuals was 0.8 mm. We found large interfractional position variations, with for 116 of 300 (39%) fractions a 3-dimensional vector displacement of >10 mm. The spread in displacement varied significantly (P