Evidence for a delay in diagnosis of Wilms' tumour in the UK compared with Germany: implications for primary care for children

The UK has a longstanding system of general practice which provides the vast majority of primary care, including that for children. It acts as a 'gatekeeper' to more specialist care. Parents may also use accident and emergency departments as their first point of medical contact for their children. Outcomes in the UK for many conditions in children appear to be worse than in comparable European countries where there is direct access to care by paediatricians. We have therefore looked at pathways to diagnosis and compared outcomes in the childhood kidney cancer, Wilms' tumour, which has been treated in the UK and Germany within the same clinical trial for over a decade. We find that Wilms' tumours are significantly larger in volume and have a more advanced tumour stage at diagnosis in the UK compared to Germany. There is a small (∼3%) difference in event free and overall survival between the two countries. Our data suggest that the system of primary care for children in the UK is less likely to result in the incidental finding of an abdominal mass in a child with no or vague symptoms. This may be a reason for the poorer outcome

Clinical benefit of systemic therapies for recurrent ovarian cancer-ESMO-MCBS scores

BACKGROUND: Licensed systemic treatment options for platinum-sensitive recurrent ovarian cancer are platinum-based chemotherapy and maintenance treatment with bevacizumab and poly (ADP-ribose) polymerase inhibitors. For platinum-resistant disease, several non-platinum options are available. We aimed to assess the clinical benefit of these treatments according to the European Society of Medical Oncology (ESMO)-Magnitude of Clinical Benefit Scale (MCBS). MATERIALS AND METHODS: A PubMed search was carried out including all studies evaluating systemic treatment of recurrent epithelial ovarian cancer, from 1990 onwards. Randomised trials with an adequate comparator and design showing a statistically significant benefit of the study arm were independently scored by two blinded observers using the ESMO-MCBS. RESULTS: A total of 1127 papers were identified, out of which 61 reported results of randomised trials of sufficient quality. Nineteen trials showed statistically significant results and the studied treatments were graded according to ESMO-MCBS. Only three treatments showed substantial benefit (score of 4 on a scale of 1-5) according to the ESMO-MCBS: platinum-based chemotherapy with paclitaxel in the platinum-sensitive setting and the addition of bevacizumab to chemotherapy in the platinum-resistant setting. The WEE1 inhibitor adavosertib (not licensed) also scores a 4, based on a recent small phase II study. Assessment of quality-of-life data and toxicity using the ESMO-MCBS showed to be complex, which should be taken into account in using this score for clinical decision making. CONCLUSION: Only a few licensed systemic therapies for recurrent ovarian cancer show substantial clinical benefit based on ESMO-MCBS scores. Trials demonstrating overall survival benefit are sparse

Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921

Pediatric patients; Intolerant; Chronic myeloid leukemiaPacientes pediátricos; Intolerantes; Leucemia mieloide crónicaPacients pediàtrics; Intolerants; Leucèmia mieloide crònicaPurpose Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients. Patients and Methods In the phase I part of this international, open-label trial (ClinicalTrials.gov identifier: NCT04258943), children age 1-18 years with R/I (per European LeukemiaNet 2013) Ph+ CML were enrolled using a 6 + 4 design, testing 300, 350, and 400 mg/m2 once daily with food. The RP2D was the dose resulting in 0/6 or 1/10 dose-limiting toxicities (DLTs) during the first cycle and achieving adult target AUC levels for the respective indication. As ND participants were only enrolled in phase II, the ND RP2D was selected based on data from R/I patients. Results Thirty patients were enrolled; 27 were evaluable for DLT: six at 300 mg/m2, 11 at 350 mg/m2 (one DLT), and 10 at 400 mg/m2 (one DLT). The mean AUCs at 300 mg/m2, 350 mg/m2, and 400 mg/m2 were 2.20 μg h/mL, 2.52 μg h/mL, and 2.66 μg h/mL, respectively. The most common adverse event was diarrhea (93%; ≥grade 3: 11%). Seven patients stopped because of intolerance and eight because of insufficient response. Complete cytogenetic and major molecular response to bosutinib appeared comparable with other published phase I/II trials with second-generation TKIs in children. Conclusion Bosutinib was safe and effective. The pediatric RP2D was 400 mg/m2 once daily (max 600 mg/d) with food in R/I patients and 300 mg/m2 once daily (max 500 mg/d) with food in ND patients, which achieved targeted exposures as per adult experience.Sponsorship for the study was provided by Erasmus MC/Sophia Children's Hospital, Department of Pediatrics, Rotterdam, the Netherlands

Concurrent chemotherapy (carboplatin, paclitaxel, etoposide) and involved-field radiotherapy in limited stage small cell lung cancer: a Dutch multicenter phase II study

To improve the prognosis of limited stage small cell lung cancer (LS-SCLC) the addition of concurrent thoracic radiotherapy to a platinum-containing regimen is important. In the Netherlands, we initiated a multicenter, phase II study, of the combination of four cycles of carboplatin (AUC 5), paclitaxel (200 mg m−2) and etoposide (2 × 50 mg orally for 5 days) combined with 45 Gy (daily fractions of 1.8 Gy). The radiation was given to the involved field and concurrently with the second and third chemotherapy cycle. Patients with a partial or complete response received prophylactic cranial irradiation to a dose of 30 Gy. From January 1999 to December 2001, 37 of the 38 patients with LS-SCLC entered were eligible for toxicity analysis and response. Grade 3 and 4 haematological toxicity occurred in 57% (21/37) with febrile neutropenia in 24% (9/37). There were no treatment-related deaths or other grade 4 toxicity. Grade 3 toxicities were oesophagitis (27%), radiation pneumonitis (6%), anorexia (14%), nausea (16%), dyspnea (19%) and lethargy (22%). The objective response rate was 92% (95% confidence interval (CI) 80–98%) with a median survival time of 19.5 months (95% CI 12.8–29.2). The 1-, 2- and 5-year survival rate was 70, 47 and 27%, respectively. In field local recurrences occurred in six patients. Distant metastases were observed in 19 patients of which 13 in the brain. This study indicates that combination chemotherapy with concurrent involved-field radiation therapy is an effective treatment for LS-SCLC. Despite PCI, the brain remained the most important site of recurrence

Adjuvant treatment in colorectal cancer

British Journal of Cancer (2002) 86, 1525–1526. DOI: 10.1038/sj/bjc/6600280 www.bjcancer.co

99mTc Hynic-rh-Annexin V scintigraphy for in vivo imaging of apoptosis in patients with head and neck cancer treated with chemoradiotherapy

PURPOSE: The purpose of this study was to determine the value of (99m)Tc Hynic-rh-Annexin-V-Scintigraphy (TAVS), a non-invasive in vivo technique to demonstrate apoptosis in patients with head and neck squamous cell carcinoma. METHODS: TAVS were performed before and within 48 h after the first course of cisplatin-based chemoradiation. Radiation dose given to the tumour at the time of post-treatment TAVS was 6-8 Gy. Single-photon emission tomography data were co-registered to planning CT scan. Complete sets of these data were available for 13 patients. The radiation dose at post-treatment TAVS was calculated for several regions of interest (ROI): primary tumour, involved lymph nodes and salivary glands. Annexin uptake was determined in each ROI, and the difference between post-treatment and baseline TAVS represented the absolute Annexin uptake: Delta uptake (DeltaU). RESULTS: In 24 of 26 parotid glands, treatment-induced Annexin uptake was observed. Mean DeltaU was significantly correlated with the mean radiation dose given to the parotid glands (r = 0.59, p = 0.002): Glands that received higher doses showed more Annexin uptake. DeltaU in primary tumour and pathological lymph nodes showed large inter-patient differences. A high correlation was observed on an inter-patient level (r = 0.71, p = 0.006) between the maximum DeltaU in primary tumour and in the lymph nodes. CONCLUSIONS: Within the dose range of 0-8 Gy, Annexin-V-scintigraphy showed a radiation-dose-dependent uptake in parotid glands, indicative of early apoptosis during treatment. The inter-individual spread in Annexin uptake in primary tumours could not be related to differences in dose or tumour volume, but the Annexin uptake in tumour and lymph nodes were closely correlated. This effect might represent a tumour-specific apoptotic respons