9 research outputs found
Impact of treatment planning target volumen (PTV) size on radiation induced diarrhoea following selenium supplementation in gynecologic radiation oncology - a subgroup analysis of a multicenter, phase III trial
No full textBackground: In a previous analysis (Int J Radiat Oncol Biol Phys 70:828-835,2010), we assessed whether an adjuvant supplementation with selenium (Se) improves Se status and reduces the radiation-induced side-effects of patients treated by adjuvant radiotherapy (RT) for cervical and uterine cancer. Now, a potential relation between the planning target volume (PTV) of the RT and the Se effect concerning radiation induced diarrhoea was evaluated in detail.
Methods: Whole blood Se concentrations had been measured in patients with cervical (n=11) and uterine cancer (n=70) after surgical treatment, during, and at the end of RT. Patients with initial Se concentrations of less than 84 μg/l were categorized as Se-deficient and randomized before RT to receive Se (as sodium selenite) per os on the days of RT, or to receive no supplement during RT. Diarrhoea was graded according to the Common Toxicity Criteria system (CTC, Version 2a). The evaluation of the PTV of the RT was ascertained with the help of a specialised computer-assisted treatment planning software used for radiation planning procedure.
Results: A total of 81 patients had been randomized for the initial supplementation study, 39 of which received Se [selenium group, SeG] and 42 serving as controls [control group, CG]. Mean Se levels did not differ between SeG and CG upon study initiation, but were significantly higher in the SeG compared to the CG at the end of RT. The actuarial incidence of at least CTC 2 radiation induced diarrhoea in the SeG was 20.5% compared to 44.5% in the CG (p=0.04). The median PTV in both groups was 1302 ml (916–4608). With a PTV of 1302 ml (n=40) the actuarial incidence of at least CTC 2 diarrhoea in the SeG was 19.1% (4 of 21 patients) versus 52.6% (10 of 19 patients) in the CG (p=0.046).
Conclusions: Se supplementation during RT was effective to improve blood Se status in Se-deficient cervical and uterine cancer patients, and reduces episodes and severity of RT-induced diarrhoea. This effect was most pronounced and significant in patients with large PTV (> 1302 ml)
Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries.
No full textBACKGROUND: In 2015, the second cycle of the CONCORD programme established global surveillance of cancer survival as a metric of the effectiveness of health systems and to inform global policy on cancer control. CONCORD-3 updates the worldwide surveillance of cancer survival to 2014. METHODS: CONCORD-3 includes individual records for 37·5 million patients diagnosed with cancer during the 15-year period 2000-14. Data were provided by 322 population-based cancer registries in 71 countries and territories, 47 of which provided data with 100% population coverage. The study includes 18 cancers or groups of cancers: oesophagus, stomach, colon, rectum, liver, pancreas, lung, breast (women), cervix, ovary, prostate, and melanoma of the skin in adults, and brain tumours, leukaemias, and lymphomas in both adults and children. Standardised quality control procedures were applied; errors were rectified by the registry concerned. We estimated 5-year net survival. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: For most cancers, 5-year net survival remains among the highest in the world in the USA and Canada, in Australia and New Zealand, and in Finland, Iceland, Norway, and Sweden. For many cancers, Denmark is closing the survival gap with the other Nordic countries. Survival trends are generally increasing, even for some of the more lethal cancers: in some countries, survival has increased by up to 5% for cancers of the liver, pancreas, and lung. For women diagnosed during 2010-14, 5-year survival for breast cancer is now 89·5% in Australia and 90·2% in the USA, but international differences remain very wide, with levels as low as 66·1% in India. For gastrointestinal cancers, the highest levels of 5-year survival are seen in southeast Asia: in South Korea for cancers of the stomach (68·9%), colon (71·8%), and rectum (71·1%); in Japan for oesophageal cancer (36·0%); and in Taiwan for liver cancer (27·9%). By contrast, in the same world region, survival is generally lower than elsewhere for melanoma of the skin (59·9% in South Korea, 52·1% in Taiwan, and 49·6% in China), and for both lymphoid malignancies (52·5%, 50·5%, and 38·3%) and myeloid malignancies (45·9%, 33·4%, and 24·8%). For children diagnosed during 2010-14, 5-year survival for acute lymphoblastic leukaemia ranged from 49·8% in Ecuador to 95·2% in Finland. 5-year survival from brain tumours in children is higher than for adults but the global range is very wide (from 28·9% in Brazil to nearly 80% in Sweden and Denmark). INTERPRETATION: The CONCORD programme enables timely comparisons of the overall effectiveness of health systems in providing care for 18 cancers that collectively represent 75% of all cancers diagnosed worldwide every year. It contributes to the evidence base for global policy on cancer control. Since 2017, the Organisation for Economic Co-operation and Development has used findings from the CONCORD programme as the official benchmark of cancer survival, among their indicators of the quality of health care in 48 countries worldwide. Governments must recognise population-based cancer registries as key policy tools that can be used to evaluate both the impact of cancer prevention strategies and the effectiveness of health systems for all patients diagnosed with cancer. FUNDING: American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation
Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412):a randomised, double-blind, phase 3 trial
No full textBackground: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC.Methods: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting.Findings: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1–52·3). Median event-free survival was not reached (95% CI 44·7 months–not reached) in the pembrolizumab group and 46·6 months (27·5–not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68–1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis).Interpretation: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches.Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.</p
The histology of brain tumors for 67 331 children and 671 085 adults diagnosed in 60 countries during 2000-2014: a global, population-based study (CONCORD-3).
No full textGlobal variations in survival for brain tumors are very wide when all histological types are considered together. Appraisal of international differences should be informed by the distribution of histology, but little is known beyond Europe and North America.
The source for the analysis was the CONCORD database, a program of global surveillance of cancer survival trends, which includes the tumor records of individual patients from more than 300 population-based cancer registries. We considered all patients aged 0-99 years who were diagnosed with a primary brain tumor during 2000-2014, whether malignant or nonmalignant. We presented the histology distribution of these tumors, for patients diagnosed during 2000-2004, 2005-2009, and 2010-2014.
Records were submitted from 60 countries on 5 continents, 67 331 for children and 671 085 for adults. After exclusion of irrelevant morphology codes, the final study population comprised 60 783 children and 602 112 adults. Only 59 of 60 countries covered in CONCORD-3 were included because none of the Mexican records were eligible. We defined 12 histology groups for children, and 11 for adults. In children (0-14 years), the proportion of low-grade astrocytomas ranged between 6% and 50%. Medulloblastoma was the most common subtype in countries where low-grade astrocytoma was less commonly reported. In adults (15-99 years), the proportion of glioblastomas varied between 9% and 69%. International comparisons were made difficult by wide differences in the proportion of tumors with unspecified histology, which accounted for up to 52% of diagnoses in children and up to 65% in adults.
To our knowledge, this is the first account of the global histology distribution of brain tumors, in children and adults. Our findings provide insights into the practices and the quality of cancer registration worldwide
The potential therapeutic role of selenium in diffuse large B-cell lymphoma
No full textPhDThe clinical background to this work confirms the very poor outcome of patients with recurrent diffuse large B-cell lymphoma (DLBCL) and highlights the need for better therapies. One such potential option would be to add selenium (Se) to conventional chemotherapy. Previous work has demonstrated the ability of non-toxic concentrations of Se to sensitise DLBCL cell lines to chemotherapy and to protect normal cells from chemotherapy-induced toxicity. The aims of this study were therefore to identify mechanisms of Se action and potential biomarkers of Se activity. The form of Se used was methylseleninic acid (MSA), a precursor of methylselenol, which is the metabolite thought to be responsible for the anti-tumour effects of organic Se compounds. DLBCL cell lines differed in their sensitivity to MSA, which may relate to differences in intracellular glutathione depletion by MSA. MSA sensitivity, however, was not related to the induction of DNA damage or to the p53 status of lymphoma cell lines. Although cytotoxic concentrations of MSA induced apoptosis, chemo-sensitising concentrations did not enhance apoptosis or alter pro-apoptotic pathways. MSA induced endoplasmic reticulum (ER) stress in a concentration-dependent manner, however, in an MSA-resistant cell line, this led to autophagy and cell survival. Thus, ER stress induction is not a mechanism of chemo-sensitisation. MSA inhibited HDAC activity in DLBCL cell lines but only in a cell-based assay, suggesting that a metabolite of MSA is responsible for this effect. In addition, MSA inhibited the hypoxia-induced induction of HIF-1α in DLBCL cell lines.
Peripheral blood mononuclear cells (PBMCs) were relatively resistant to MSA and this was associated with increased expression of two pro-survival proteins, GRP78 and NF-κB. In addition, the metabolism of MSA differed between PBMCs and DLBCL cell lines, suggesting that methylselenol is formed more efficiently in the latter. In contrast, keratinocytes and fibroblasts were relatively sensitive to MSA, but MSA was unable to protect keratinocytes from the toxicity of chemotherapeutic agents. These results differ
3
from those obtained in DLBCL cell lines in which MSA enhances the activity of chemotherapeutic agents. Combining MSA and bortezomib in mantle cell lymphoma cell lines unexpectedly resulted in an antagonistic interaction. This was associated with the induction of ER stress and autophagy and increased expression of two pro-survival proteins, Bcl-2 and Mcl-1. A proteomics approach identified novel protein changes induced by chemo-sensitising concentrations of MSA in two DLBCL cell lines. Several potential biomarkers of Se activity were identified; GRP78, NF-κB, vascular endothelial growth factor and acetylated histone H3. In conclusion, Se in the form of MSA affects many intracellular pathways in DLBCL cell lines, such that it has not been possible to identify a single unifying mechanism of Se action. However, differences have been observed between PBMCs and DLBCL cell lines and this work has identified novel protein changes and mechanisms of Se actionKatherine Priestly Trust Fund
Medical reseach Counci
Selenium as a Modulator of Efficacy and Toxicity of Chemotherapy and Radiation
No full textSelenium (Se) is an essential trace mineral required in maintaining health in humans. Recent research has demonstrated that Se shows promise as an agent that can reduce the harmful side-effects of chemotherapy (CT) and radiotherapy (RT), while not compromising the effectiveness of treatment. Clinical evaluations using varying doses of Se have demonstrated a significant reduction in toxicity of CT and RT. Se supplementation appears to mediate its biological effects through four main mechanisms: Se treatment promotes the death of malignant cells, but not normal cells, through the differential effects on the endoplasmic reticulum stress response; it inhibits hypoxia-induced angiogenesis which is required by tumours for their blood supply; it enhances DNA repair in normal but not malignant cells; and it reverses cellular resistance to some cytotoxic drugs. The objectives of this thesis were to evaluate the biological characteristics of the differential impact of a Se compound, methylseleninic acid (MSA), on malignant and non-malignant human cells and how that modulates the effects of cisplatin chemotherapy and/or radiation. In parallel with this, similar evaluations were undertaken in patients receiving a Se compound or placebo in conjunction with cisplatin and radiation for head and neck squamous cell carcinoma (HNSCC). MSA induced differential effects in peripheral blood mononuclear cells (PBMC) obtained from healthy individuals compared to the monocytic leukaemia THP-1 cell-line. While MSA did not change PBMC viability, it reduced that of THP-1 cells in a concentration-dependent manner. Furthermore, MSA treatment enhanced the cytotoxicity of CT and RT toward THP-1 cells without compromising the survival of PBMC. This increased sensitivity in THP-1 cells is likely to be related to significantly reduced levels of intracellular glutathione (GSH) in response to MSA. In contrast, GSH levels in PBMC rose substantially in response to MSA. Assessment of ER stress response proteins revealed that pro-survival proteins (GRP78, phospho-eIF2α, and spliced XBP-1) were upregulated in PBMC in response to MSA treatment. The malignant THP-1 cells had high levels of pro-survival proteins at baseline, which increased to a variable degree, especially caspase-8, in response to MSA. Putative pharmacodynamic markers of biological activity of Se were evaluated in plasma samples and PBMC from HNSCC patients in a randomised, placebo-controlled, double-blind phase II trial. Patients were treated with a 7-week radical course of concurrent cisplatin and RT (CRT) and were randomised to receive either selenomethionine (SLM) or matching placebo for 11 weeks, starting a week prior to CRT treatment. Because the trial is not yet complete, treatment allocation remains blinded and thus the pharmacodynamic results according to treatment with SLM or placebo cannot be made at the time of writing this thesis. However, markers of angiogenesis and the selenoprotein glutathione peroxidise 3 were measured and shown to significantly change during the course of treatment in a patient-specific manner. Lastly, ER stress markers were shown to be detected in PBMC obtained from patients during treatment. Se compounds differentially affect non-malignant and malignant cells. This results in increased therapeutic efficacy of cisplatin and RT targeting malignant cells. These effects appear to be mediated, at least in part, by modulation of intracellular GSH and ER stress response protein
The histology of brain tumors for 67 331 children and 671 085 adults diagnosed in 60 countries during 2000-2014: a global, population-based study (CONCORD-3)
No full textAuteurs : The CONCORD Working GroupInternational audienceBackground: Global variations in survival for brain tumors are very wide when all histological types are considered together. Appraisal of international differences should be informed by the distribution of histology, but little is known beyond Europe and North America.Methods: The source for the analysis was the CONCORD database, a program of global surveillance of cancer survival trends, which includes the tumor records of individual patients from more than 300 population-based cancer registries. We considered all patients aged 0-99 years who were diagnosed with a primary brain tumor during 2000-2014, whether malignant or nonmalignant. We presented the histology distribution of these tumors, for patients diagnosed during 2000-2004, 2005-2009, and 2010-2014.Results: Records were submitted from 60 countries on 5 continents, 67 331 for children and 671 085 for adults. After exclusion of irrelevant morphology codes, the final study population comprised 60 783 children and 602 112 adults. Only 59 of 60 countries covered in CONCORD-3 were included because none of the Mexican records were eligible. We defined 12 histology groups for children, and 11 for adults. In children (0-14 years), the proportion of low-grade astrocytomas ranged between 6% and 50%. Medulloblastoma was the most common subtype in countries where low-grade astrocytoma was less commonly reported. In adults (15-99 years), the proportion of glioblastomas varied between 9% and 69%. International comparisons were made difficult by wide differences in the proportion of tumors with unspecified histology, which accounted for up to 52% of diagnoses in children and up to 65% in adults.Conclusions: To our knowledge, this is the first account of the global histology distribution of brain tumors, in children and adults. Our findings provide insights into the practices and the quality of cancer registration worldwide
Discovery of novel molecular and biochemical predictors of response and outcome in diffuse large B-cell lymphoma
No full textPhDDiscovery of Novel Molecular and Biochemical Predictors
of Response and Outcome in Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the commonest form of non-Hodgkin
lymphoma and responds to treatment with a 5-year overall survival (OS) of 40-50%.
Predicting outcome using the best available method, the International Prognostic Index
(IPI), is inaccurate and unsatisfactory. This thesis describes research undertaken to
discover, explore and validate new molecular and biochemical predictors of response
and long-term outcome with the aims of improving on the inaccurate IPI and of
suggesting novel therapeutic approaches. Two strategies were adopted: a rational and
an empirical approach. The rational strategy used gene expression profiling to identify
transcriptional signatures that correlated with outcome to treatment and from which a
model of 13-genes accurately predict long-term OS. Two components of the 13-gene
model, PKC and PDE4B, were studied using inhibitors in lymphoma cell-lines and
primary cell cultures. PKC inhibition using SC-236 proved to be cytostatic and
cytotoxic in the cell-lines examined and to a lesser extent in primary tumours. PDE4
inhibition using piclamilast and rolipram had no effect either alone or in combination
with chemotherapy. The empirical approach investigated the trace element selenium in
presentation serum and found that it was a biochemical predictor of response and
outcome to treatment. In an attempt to provide evidence of a causal relationship as an
explanation for the associations between presentation serum selenium, response and
outcome, two selenium compounds, methylseleninic acid (MSA) and
selenodiglutathione (SDG) were studied in vitro in the same lymphoma cell-lines and
primary cell cultures. Both MSA and SDG exhibited cytostatic and cytotoxic activity
and caspase-8 and caspase-9 driven apoptosis. For SDG reactive oxygen species
generation was important for its activity in three of the four cell-lines. In conclusion,
molecular and biochemical predictors of response and survival were discovered in
DLBCL that led to viable targets for drug intervention being validated in vitro
Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus concurrent chemoradiotherapy in patients with locally advanced squamous cell carcinoma of the head and neck (KEYNOTE-412): a randomised, double-blind, phase 3 trial
No full textBackground: Despite multimodal therapy, 5-year overall survival for locally advanced head and neck squamous cell carcinoma (HNSCC) is about 50%. We assessed the addition of pembrolizumab to concurrent chemoradiotherapy for locally advanced HNSCC. Methods: In the randomised, double-blind, phase 3 KEYNOTE-412 trial, participants with newly diagnosed, high-risk, unresected locally advanced HNSCC from 130 medical centres globally were randomly assigned (1:1) to pembrolizumab (200 mg) plus chemoradiotherapy or placebo plus chemoradiotherapy. Randomisation was done using an interactive response technology system and was stratified by investigator's choice of radiotherapy regimen, tumour site and p16 status, and disease stage, with participants randomly assigned in blocks of four per stratum. Participants, investigators, and sponsor personnel were masked to treatment assignments. Local pharmacists were aware of assignments to support treatment preparation. Pembrolizumab and placebo were administered intravenously once every 3 weeks for up to 17 doses (one before chemoradiotherapy, two during chemoradiotherapy, 14 as maintenance therapy). Chemoradiotherapy included cisplatin (100 mg/m2) administered intravenously once every 3 weeks for two or three doses and accelerated or standard fractionation radiotherapy (70 Gy delivered in 35 fractions). The primary endpoint was event-free survival analysed in all randomly assigned participants. Safety was analysed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03040999, and is active but not recruiting. Findings: Between April 19, 2017, and May 2, 2019, 804 participants were randomly assigned to the pembrolizumab group (n=402) or the placebo group (n=402). 660 (82%) of 804 participants were male, 144 (18%) were female, and 622 (77%) were White. Median study follow-up was 47·7 months (IQR 42·1–52·3). Median event-free survival was not reached (95% CI 44·7 months–not reached) in the pembrolizumab group and 46·6 months (27·5–not reached) in the placebo group (hazard ratio 0·83 [95% CI 0·68–1·03]; log-rank p=0·043 [significance threshold, p≤0·024]). 367 (92%) of 398 participants treated in the pembrolizumab group and 352 (88%) of 398 participants treated in the placebo group had grade 3 or worse adverse events. The most common grade 3 or worse adverse events were decreased neutrophil count (108 [27%] of 398 participants in the pembrolizumab group vs 100 [25%] of 398 participants in the placebo group), stomatitis (80 [20%] vs 69 [17%]), anaemia (80 [20%] vs 61 [15%]), dysphagia (76 [19%] vs 62 [16%]), and decreased lymphocyte count (76 [19%] vs 81 [20%]). Serious adverse events occurred in 245 (62%) participants in the pembrolizumab group versus 197 (49%) participants in the placebo group, most commonly pneumonia (43 [11%] vs 25 [6%]), acute kidney injury (33 [8%] vs 30 [8%]), and febrile neutropenia (24 [6%] vs seven [2%]). Treatment-related adverse events led to death in four (1%) participants in the pembrolizumab group (one participant each from aspiration pneumonia, end-stage renal disease, pneumonia, and sclerosing cholangitis) and six (2%) participants in the placebo group (three participants from pharyngeal haemorrhage and one participant each from mouth haemorrhage, post-procedural haemorrhage, and sepsis). Interpretation: Pembrolizumab plus chemoradiotherapy did not significantly improve event-free survival compared with chemoradiotherapy alone in a molecularly unselected, locally advanced HNSCC population. No new safety signals were seen. Locally advanced HNSCC remains a challenging disease that requires better treatment approaches. Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA
