High-dose chemoradiotherapy followed by surgery versus surgery alone in esophageal cancer: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>We aimed to assess whether high-dose preoperative chemoradiotherapy (CRT) improves outcome in esophageal cancer patients compared to surgery alone and to define possible prognostic factors for overall survival.</p> <p>Methods</p> <p>Hundred-and-seven patients with disease stage IIA - III were treated with either surgery alone (n = 45) or high-dose preoperative CRT (n = 62). The data were collected retrospectively. Sixty-seven patients had adenocarcinomas, 39 squamous cell carcinomas and one undifferentiated carcinoma. CRT was given as three intensive chemotherapy courses by cisplatin 100 mg/m²on day 1 and 5-fluorouracil 1000 mg/m²/day, from day 1 through day 5 as continuous infusion. One course was given every 21 days. The last two courses were given concurrent with high-dose radiotherapy, 2 Gy/fraction and a median dose of 66 Gy. Kaplan-Meier survival analysis with log rank test was used to obtain survival data and Cox Regression multivariate analysis was used to define prognostic factors for overall survival.</p> <p>Results</p> <p>Toxicity grade 3 of CRT occurred in 30 (48.4%) patients and grade 4 in 24 (38.7%) patients of 62 patients. One patient died of neutropenic infection (grade 5). Fifty percent (31 patients) in the CRT group did undergo the planned surgery. Postoperative mortality rate was 9% and 10% in the surgery alone and CRT+ surgery groups, respectively (p = 1.0). Median overall survival was 11.1 and 31.4 months in the surgery alone and CRT+ surgery groups, respectively (log rank test, p = 0.042). In the surgery alone group one, 3 and 5 year survival rates were 44%, 24% and 16%, respectively and in the CRT+ surgery group they were 68%, 44% and 29%, respectively. By multivariate analysis we found that age of patient, performance status, alcoholism and > = 4 pathological positive lymph nodes in resected specimen were significantly associated with overall survival, whereas high-dose preoperative CRT was not.</p> <p>Conclusion</p> <p>We found no significant survival advantage in esophageal cancer stage IIA-III following preoperative high-dose CRT compared to surgery alone. Patient's age, performance status, alcohol abuse and number of positive lymph nodes were prognostic factors for overall survival.</p

Phase II trial of docetaxel, cisplatin and fluorouracil followed by carboplatin and radiotherapy in locally advanced oesophageal cancer

This study was performed to assess the efficacy and safety of docetaxel, cisplatin and fluorouracil combination in patients with unresectable locally advanced oesophageal squamous cell carcinoma. Treatment consisted of docetaxel 60 mg m−2, cisplatin 75 mg m−2 on day 1 and fluorouracil 750 mg m−2 day−1 on days 2–5, repeated every 3 weeks for three cycles, followed by carboplatin 100 mg m−2 week−1 for 5 weeks and concurrent radiotherapy (45 Gy in 25 fractions, 5 days week−1). After radiotherapy, eligible patients either underwent an oesophagectomy or received high dose rate endoluminal brachytherapy (HDR-EBT). Thirty-one out of 37 enrolled patients completed the planned chemotherapy and 30 completed chemoradiation. After completion of chemotherapy, 49% (95% CI: 32.2–66.2) had a clinical response. Twelve patients (32%) underwent a resection, which was radical in 60% (postoperative mortality: 0%). A pathological complete response was documented in four patients (11% of enrolled, 30% of resected). The median survival was 10.8 months (95% CI: 8.1–12.4), and the 1- and 2-year survival rates were 35.1 and 18.9%, respectively. Grade 3–4 toxicities were neutropoenia 32%, anaemia 11%, non-neutropoenic infections 18%, diarrhoea 6% and oesophagitis 5%. Nine patients (24%) developed a tracheo-oesophageal fistula during treatment. Even if the addition of docetaxel to cisplatin and 5-fluorouracil (5-FU) seems to be more active than the cisplatin and 5-FU combination, an incremental improvement in survival is not seen, and the toxicity observed in this study population is of concern. In order to improve the prognosis of these patients, new drugs, combinations and strategies with a better therapeutic index need to be identified

Neoadjuvant chemotherapy prior to preoperative chemoradiation or radiation in rectal cancer: should we be more cautious?

Neoadjuvant chemotherapy (NACT) is a term originally used to describe the administration of chemotherapy preoperatively before surgery. The original rationale for administering NACT or so-called induction chemotherapy to shrink or downstage a locally advanced tumour, and thereby facilitate more effective local treatment with surgery or radiotherapy, has been extended with the introduction of more effective combinations of chemotherapy to include reducing the risks of metastatic disease. It seems logical that survival could be lengthened, or organ preservation rates increased in resectable tumours by NACT. In rectal cancer NACT is being increasingly used in locally advanced and nonmetastatic unresectable tumours. Randomised studies in advanced colorectal cancer show high response rates to combination cytotoxic therapy. This evidence of efficacy coupled with the introduction of novel molecular targeted therapies (such as Bevacizumab and Cetuximab), and long waiting times for radiotherapy have rekindled an interest in delivering NACT in locally advanced rectal cancer. In contrast, this enthusiasm is currently waning in other sites such as head and neck and nasopharynx cancer where traditionally NACT has been used. So, is NACT in rectal cancer a real advance or just history repeating itself? In this review, we aimed to explore the advantages and disadvantages of the separate approaches of neoadjuvant, concurrent and consolidation chemotherapy in locally advanced rectal cancer, drawing on theoretical principles, preclinical studies and clinical experience both in rectal cancer and other disease sites. Neoadjuvant chemotherapy may improve outcome in terms of disease-free or overall survival in selected groups in some disease sites, but this strategy has not been shown to be associated with better outcomes than postoperative adjuvant chemotherapy. In particular, there is insufficient data in rectal cancer. The evidence for benefit is strongest when NACT is administered before surgical resection. In contrast, the data in favour of NACT before radiation or chemoradiation (CRT) is inconclusive, despite the suggestion that response to induction chemotherapy can predict response to subsequent radiotherapy. The observation that spectacular responses to chemotherapy before radical radiotherapy did not result in improved survival, was noted 25 years ago. However, multiple trials in head and neck cancer, nasopharyngeal cancer, non-small-cell lung cancer, small-cell lung cancer and cervical cancer do not support the routine use of NACT either as an alternative, or as additional benefit to CRT. The addition of NACT does not appear to enhance local control over concurrent CRT or radiotherapy alone. Neoadjuvant chemotherapy before CRT or radiation should be used with caution, and only in the context of clinical trials. The evidence base suggests that concurrent CRT with early positioning of radiotherapy appears the best option for patients with locally advanced rectal cancer and in all disease sites where radiation is the primary local therapy

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron

Multiplicity of cerebrospinal fluid functions: New challenges in health and disease

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces