Publications by authors named "Sarah Darby"

65 Publications

Grounded reality meets machine learning: A deep-narrative analysis framework for energy policy research.

Energy Res Soc Sci 2020 Nov;69:101704

Behaviour and Building Performance Group, The Martin Centre for Architectural and Urban Studies, Department of Architecture, University of Cambridge, Cambridge CB2 1PX, United Kingdom.

Text-based data sources like narratives and stories have become increasingly popular as critical insight generator in energy research and social science. However, their implications in policy application usually remain superficial and fail to fully exploit state-of-the-art resources which digital era holds for text analysis. This paper illustrates the potential of deep-narrative analysis in energy policy research using text analysis tools from the cutting-edge domain of computational social sciences, notably topic modelling. We argue that a nested application of topic modelling and grounded theory in narrative analysis promises advances in areas where manual-coding driven narrative analysis has traditionally struggled with directionality biases, scaling, systematisation and repeatability. The nested application of the topic model and the grounded theory goes beyond the frequentist approach of narrative analysis and introduces insight generation capabilities based on the probability distribution of words and topics in a text corpus. In this manner, our proposed methodology deconstructs the corpus and enables the analyst to answer research questions based on the foundational element of the text data structure. We verify theoretical compatibility through a meta-analysis of a state-of-the-art bibliographic database on energy policy, narratives and computational social science. Furthermore, we establish a proof-of-concept using a narrative-based case study on energy externalities in slum rehabilitation housing in Mumbai, India. We find that the nested application contributes to the literature gap on the need for multidisciplinary methodologies that can systematically include qualitative evidence into policymaking.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.erss.2020.101704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563684PMC
November 2020

Dose-response relationships for radiation-related heart disease: Impact of uncertainties in cardiac dose reconstruction.

Radiother Oncol 2020 Dec 3;153:155-162. Epub 2020 Sep 3.

Nuffield Department of Population Health, University of Oxford, Oxford, UK; Oxford Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Background And Purpose: Radiation-related heart disease (RRHD) can occur many decades after thoracic radiotherapy for Hodgkin lymphoma (HL) or childhood cancer (CC). To quantify the likely risk of RRHD for patients treated today, dose-response relationships derived from patients treated in previous decades are used. Publications presenting these dose-response relationships usually include estimates of uncertainties in the risks but ignore the effect of uncertainties in the reconstructed cardiac doses.

Materials/methods: We assessed the systematic and random uncertainties in the reconstructed doses for published dose-response relationships for RRHD risk in survivors of HL or CC. Using the same reconstruction methods as were used in the original publications, we reconstructed mean heart doses and, wherever possible, mean left-ventricular doses for an independent case-series of test patients. These patients had known, CT-based, cardiac doses which were compared with the reconstructed doses to estimate the magnitude of the uncertainties and their effect on the dose-response relationships.

Results: For all five reconstruction methods the relationship between reconstructed and CT-based doses was linear. For all but the simplest reconstruction method, the dose uncertainties were moderate, the effect of the systematic uncertainty on the dose-response relationships was less than 10%, and the effects of random uncertainty were small except at the highest doses.

Conclusions: These results increase confidence in the published dose-response relationships for the risk of RRHD in HL and CC survivors. This may encourage doctors to use these dose-response relationships when estimating individualised risks for patients-an important aspect of personalising radiotherapy treatments today.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2020.08.022DOI Listing
December 2020

Invasive breast cancer and breast cancer mortality after ductal carcinoma in situ in women attending for breast screening in England, 1988-2014: population based observational cohort study.

BMJ 2020 05 27;369:m1570. Epub 2020 May 27.

Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford OX3 7LF, UK.

Objective: To evaluate the long term risks of invasive breast cancer and death from breast cancer after ductal carcinoma in situ (DCIS) diagnosed through breast screening.

Design: Population based observational cohort study.

Setting: Data from the NHS Breast Screening Programme and the National Cancer Registration and Analysis Service.

Participants: All 35 024 women in England diagnosed as having DCIS by the NHS Breast Screening Programme from its start in 1988 until March 2014.

Main Outcome Measures: Incident invasive breast cancer and death from breast cancer.

Results: By December 2014, 13 606 women had been followed for up to five years, 10 998 for five to nine years, 6861 for 10-14 years, 2620 for 15-19 years, and 939 for at least 20 years. Among these women, 2076 developed invasive breast cancer, corresponding to an incidence rate of 8.82 (95% confidence interval 8.45 to 9.21) per 1000 women per year and more than double that expected from national cancer incidence rates (ratio of observed rate to expected rate 2.52, 95% confidence interval 2.41 to 2.63). The increase started in the second year after diagnosis of DCIS and continued until the end of follow-up. In the same group of women, 310 died from breast cancer, corresponding to a death rate of 1.26 (1.13 to 1.41) per 1000 women per year and 70% higher than that expected from national breast cancer mortality rates (observed:expected ratio 1.70, 1.52 to 1.90). During the first five years after diagnosis of DCIS, the breast cancer death rate was similar to that expected from national mortality rates (observed:expected ratio 0.87, 0.69 to 1.10), but it then increased, with values of 1.98 (1.65 to 2.37), 2.99 (2.41 to 3.70), and 2.77 (2.01 to 3.80) in years five to nine, 10-14, and 15 or more after DCIS diagnosis. Among 29 044 women with unilateral DCIS undergoing surgery, those who had more intensive treatment (mastectomy, radiotherapy for women who had breast conserving surgery, and endocrine treatment in oestrogen receptor positive disease) and those with larger final surgical margins had lower rates of invasive breast cancer.

Conclusions: To date, women with DCIS detected by screening have, on average, experienced higher long term risks of invasive breast cancer and death from breast cancer than women in the general population during a period of at least two decades after their diagnosis. More intensive treatment and larger final surgical margins were associated with lower risks of invasive breast cancer.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m1570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251423PMC
May 2020

Cardiac mortality after radiotherapy, chemotherapy and endocrine therapy for breast cancer: Cohort study of 2 million women from 57 cancer registries in 22 countries.

Int J Cancer 2020 Sep 4;147(5):1437-1449. Epub 2020 Mar 4.

National Cancer Registration and Analysis Service, Public Health England, London, United Kingdom.

Comparisons of patients receiving different cancer treatments reflect the effects of both treatment and patient selection. In breast cancer, however, if radiotherapy decisions are unrelated to laterality, comparisons of left-sided and right-sided cancers can demonstrate the causal effects of higher-versus-lower cardiac radiation dose. Cardiac mortality was analysed using individual patient data for 1,934,248 women with breast cancer in 22 countries. The median date of diagnosis was 1996 and the interquartile range was 1987-2002. A total of 1,018,505 women were recorded as irradiated, 223,077 as receiving chemotherapy, 317,619 as receiving endocrine therapy and 55,264 died of cardiac disease. Analyses were stratified by time since breast cancer diagnosis, age at diagnosis, calendar year of diagnosis and country. Patient-selection effects were evident for all three treatments. For radiotherapy, there was also evidence of selection according to laterality in women irradiated 1990 or later. In patients irradiated before 1990, there was no such selection and cardiac mortality was higher in left-sided than right-sided cancer (rate ratio [RR]: 1.13, 95% confidence interval 1.09-1.17). Left-versus-right cardiac mortality RRs were greater among younger women (1.46, 1.19, 1.20, 1.09 and 1.08 after cancer diagnoses at ages <40, 40-49, 50-59, 60-69 and 70+ years, 2p =0.003). Left-versus-right RRs also increased with time since cancer diagnosis (1.03, 1.11, 1.19 and 1.21 during 0-4, 5-14, 15-24 and 25+ years, 2p =0.002) while for women who also received chemotherapy, the left-versus-right RR was 1.42 (95% confidence interval 1.13-1.77), compared to 1.10 (1.05-1.16) for women who did not (2p = 0.03). These results show that the relative increase in cardiac mortality from cardiac exposure during breast cancer radiotherapy given in the past was greater in younger women, lasted into the third decade after exposure and was greater when chemotherapy was also given.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.32908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7496256PMC
September 2020

Heart failure after treatment for breast cancer.

Eur J Heart Fail 2020 02 12;22(2):366-374. Epub 2019 Nov 12.

Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

Background: We aimed to develop dose-response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies.

Methods And Results: A case-control study was performed within a cohort of breast cancer survivors treated during 1980-2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9-13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) -2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7-21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m (IQR 240-319). A dose-dependent increase was observed after anthracycline without trastuzumab (ERR = 1.5% per mg/m , 95% CI 0.5-4.1). After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1-110.1) compared to no chemotherapy.

Conclusions: In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ejhf.1620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137787PMC
February 2020

Reliability of preoperative breast biopsies showing ductal carcinoma in situ and implications for non-operative treatment: a cohort study.

Breast Cancer Res Treat 2019 Nov 6;178(2):409-418. Epub 2019 Aug 6.

Antoni van Leeuwenhoek - Netherlands Cancer Institute, Amsterdam, The Netherlands.

Purpose: The future of non-operative management of DCIS relies on distinguishing lesions requiring treatment from those needing only active surveillance. More accurate preoperative staging and grading of DCIS would be helpful. We identified determinants of upstaging preoperative breast biopsies showing ductal carcinoma in situ (DCIS) to invasive breast cancer (IBC), or of upgrading them to higher-grade DCIS, following examination of the surgically excised specimen.

Methods: We studied all women with DCIS at preoperative biopsy in a large specialist cancer centre during 2000-2014. Information from clinical records, mammography, and pathology specimens from both preoperative biopsy and excised specimen were abstracted. Women suspected of having IBC during biopsy were excluded.

Results: Among 606 preoperative biopsies showing DCIS, 15.0% (95% confidence interval 12.3-18.1) were upstaged to IBC and a further 14.6% (11.3-18.4) upgraded to higher-grade DCIS. The risk of upstaging increased with presence of a palpable lump (21.1% vs 13.0%, p = 0.04), while the risk of upgrading increased with presence of necrosis on biopsy (33.0% vs 9.5%, p < 0.001) and with use of 14G core-needle rather than 9G vacuum-assisted biopsy (22.8% vs 7.0%, p < 0.001). Larger mammographic size increased the risk of both upgrading (p = 0.01) and upstaging (p = 0.004).

Conclusions: The risk of upstaging of DCIS in preoperative biopsies is lower than previously estimated and justifies conducting randomized clinical trials testing the safety of active surveillance for lower grade DCIS. Selection of women with low grade DCIS for such trials, or for active surveillance, may be improved by consideration of the additional factors identified in this study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10549-019-05362-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797705PMC
November 2019

Endocrine therapy in the years following a diagnosis of breast cancer: A proof of concept study using the primary care prescription database linked to cancer registration data.

Cancer Epidemiol 2019 08 22;61:185-189. Epub 2019 May 22.

Nuffield Department of Population Health, University of Oxford, Richard Doll Building, Old Road Campus, Oxford, OX3 7LF, United Kingdom.

Introduction: National cancer registration data were linked to the Primary Care Prescription Database (PCPD) in England. The level of endocrine therapy (ET) prescribed in women after a diagnosis of breast cancer was studied.

Materials And Methods: Cancer registrations for women diagnosed with breast cancer during 1995-2015, who survived to 31st March 2015, were linked to ET prescriptions issued during April-July 2015.

Results: Among 369 277 survivors of breast cancer diagnosed during 1995-2015, 37% were prescribed ET during April-July 2015. Among women whose breast cancer diagnosis was after 31st July 2010, 81% of those recorded with oestrogen receptor positive (ER+ve) disease were prescribed ET compared with only 6% of those with ER-ve disease. Younger women usually received tamoxifen and older women usually received aromatase inhibitors.

Discussion: The pattern of ET use observed in these data corresponds to that expected. This provides confidence in the potential of the PCPD for epidemiological research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.canep.2019.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859491PMC
August 2019

Clinical Intensity Modulated Proton Therapy for Hodgkin Lymphoma: Which Patients Benefit the Most?

Pract Radiat Oncol 2019 May 29;9(3):179-187. Epub 2019 Jan 29.

Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom; Oxford Cancer Centre, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

Purpose: Radiation therapy (RT) improves control of Hodgkin lymphoma (HL), but patients who undergo RT are at risk for late effects, including cardiovascular disease and second cancers, because of radiation doses to organs at risk (OARs). Proton therapy (PT) can reduce OAR doses compared with conventional photon RT. However, access to PT is currently limited, so referrals must be appropriately selective. We aimed to identify subgroups of patients with HL who could benefit the most dosimetrically from RT with PT based on the prechemotherapy disease characteristics.

Methods And Materials: Normal tissue radiation doses were calculated for 21 patients with HL who were treated with deep-inspiration breath-hold pencil-beam scanning (PBS) PT and compared with doses from 3-dimensional conformal (3D-CRT) and partial arc volumetric modulated (PartArc) photon RT. Prechemotherapy disease characteristics associated with significant dosimetric benefits from PBS compared with photon RT were identified.

Results: Treatment with PBS was well tolerated and provided with good local control. PBS provided dosimetric advantages for patients whose clinical treatment volume extended below the seventh thoracic level and for female patients with axillary disease. In addition, an increasing dosimetric benefit for some OARs was observed for increasing target volume. PBS significantly reduced the mean dose to the heart, breast, lungs, spinal cord, and esophagus. Dose homogeneity and conformity within the target volume were also superior with PBS, but some high-dose measures and hot spots were increased with PBS compared with partial arc volumetric modulated photon RT.

Conclusions: PBS gives good target coverage and local control while providing reductions in radiation dose to OARs for individuals who receive RT for HL compared with advanced photon RT. Our findings highlight groups of patients who would be expected to gain more dosimetric benefit from PBS. These findings facilitate the selection of patients who should be considered a priority for PT.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prro.2019.01.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493042PMC
May 2019

Cardiac Structure Doses in Women Irradiated for Breast Cancer in the Past and Their Use in Epidemiological Studies.

Pract Radiat Oncol 2019 May 26;9(3):158-171. Epub 2019 Jan 26.

Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom.

Purpose: Incidental cardiac exposure during radiation therapy may cause heart disease. Dose-response relationships for cardiac structures (segments) may show which ones are most sensitive to radiation. Radiation-related cardiac injury can take years to develop; thus, studies need to involve women treated using 2-dimensional planning, with segment doses estimated using a typical computed tomography (CT) scan. We assessed whether such segment doses are accurate enough to use in dose-response relationships using the radiation therapy charts of women with known segment injury. We estimated interregimen and interpatient segment dose variability and segment dose correlations.

Methods And Materials: The radiation therapy charts of 470 women with cardiac segment injury after breast cancer radiation therapy were examined, and 41 regimens were identified. Regimens were reconstructed on a typical CT scan. Doses were estimated for 5 left ventricle (LV) and 10 coronary artery segments. Correlations between cardiac segments were estimated. Interpatient dose variation was assessed in 10 randomly selected CT scans for left regimens and in 5 for right regimens.

Results: For the typical CT scan, interregimen segment dose variation was substantial (range, LV segments <1-39 Gy; coronary artery segments <1-48 Gy). In 10 CT scans, interpatient segment dose variation was higher for segments near field borders (range, 3-47 Gy) than other segments (range, <2 Gy). Doses to different left-anterior descending coronary artery (LADCA) segments were highly correlated with each other, as were doses to different LV segments. Also, LADCA segment doses were highly correlated with doses to LV segments usually supplied by the LADCA. For individual regimens there was consistency in hotspot location and segment ranking of higher-versus-lower dose.

Conclusions: The scope for developing quantitative cardiac segment dose-response relationships in patients who had 2-dimensional planning is limited because different segment doses are often highly correlated, and segment-specific dose uncertainties are not independent of each other. However, segment-specific doses may be reliably used to rank segments according to higher-versus-lower doses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.prro.2019.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493043PMC
May 2019

Radiation Dose-Response for Risk of Myocardial Infarction in Breast Cancer Survivors.

Int J Radiat Oncol Biol Phys 2019 03 29;103(3):595-604. Epub 2018 Oct 29.

Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Purpose: Previous reports suggest that radiation therapy for breast cancer (BC) can cause ischemic heart disease, with the radiation-related risk increasing linearly with mean whole heart dose (MWHD). This study aimed to validate these findings in younger BC patients and to investigate additional risk factors for radiation-related myocardial infarction (MI).

Methods And Materials: A nested case-control study was conducted within a cohort of BC survivors treated during 1970 to 2009. Cases were 183 patients with MI as their first heart disease after BC. One control per case was selected and matched on age and BC diagnosis date. Information on treatment and cardiovascular risk factors was abstracted from medical and radiation charts. Cardiac doses were estimated for each woman by reconstructing her regimen using modern 3-dimensional computed tomography planning on a typical patient computed tomography scan.

Results: Median age at BC of cases and controls was 50.2 years (interquartile range, 45.7-54.7). Median time to MI was 13.6 years (interquartile range, 9.9-18.1). Median MWHD was 8.9 Gy (range, 0.3-35.2 Gy). MI rate increased linearly with increasing MWHD (excess rate ratio [ERR] per Gy, 6.4%; 95% confidence interval, 1.3%-16.0%). Patients receiving ≥20 Gy MWHD had a 3.4-fold (95% confidence interval, 1.5-7.6) higher MI rate than unirradiated patients. ERRs were higher for younger women, with borderline significance (ERR, 24.2%/Gy; ERR, 2.5%/Gy; P = .054). Whole heart dose-volume parameters did not modify the dose-response relationship significantly.

Conclusions: MI rate after radiation for BC increases linearly with MWHD. Reductions in MWHD are expected to contribute to better cardiovascular health of BC survivors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2018.10.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361769PMC
March 2019

Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer.

Br J Cancer 2018 08 1;119(4):408-418. Epub 2018 Aug 1.

Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.

Background: Improved breast cancer (BC) survival and evidence showing beneficial effects of internal mammary chain (IMC) irradiation underscore the importance of studying late cardiovascular effects of BC treatment.

Methods: We assessed cardiovascular disease (CVD) incidence in 14,645 Dutch BC patients aged <62 years, treated during 1970-2009. Analyses included proportional hazards models and general population comparisons.

Results: CVD rate-ratio for left-versus-right breast irradiation without IMC was 1.11 (95% CI 0.93-1.32). Compared to right-sided breast irradiation only, IMC irradiation (interquartile range mean heart doses 9-17 Gy) was associated with increases in CVD rate overall, ischaemic heart disease (IHD), heart failure (HF) and valvular heart disease (hazard ratios (HRs): 1.6-2.4). IHD risk remained increased until at least 20 years after treatment. Anthracycline-based chemotherapy was associated with an increased HF rate (HR = 4.18, 95% CI 3.07-5.69), emerging <5 years and remaining increased at least 10-15 years after treatment. IMC irradiation combined with anthracycline-based chemotherapy was associated with substantially increased HF rate (HR = 9.23 95% CI 6.01-14.18), compared to neither IMC irradiation nor anthracycline-based chemotherapy.

Conclusions: Women treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41416-018-0159-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6133926PMC
August 2018

Cardiac Structure Injury After Radiotherapy for Breast Cancer: Cross-Sectional Study With Individual Patient Data.

J Clin Oncol 2018 08 23;36(22):2288-2296. Epub 2018 May 23.

Carolyn Taylor, Paul McGale, David Cutter, Frances K. Duane, Zhe Wang, and Sarah C. Darby, Nuffield Department of Population Health, University of Oxford; Kazem Rahimi, George Institute for Global Health, University of Oxford, Oxford, United Kingdom; Dorthe Brønnum, North Denmark Regional Hospital, Hjoerring; Maj-Britt Jensen, Danish Breast Cancer Cooperative Group, Rigshospitalet, Copenhagen; Ebbe Lorenzen and Marianne Ewertz, Odense University Hospital, Odense, Denmark; Candace Correa, Community Cancer Center, Normal, IL; Bruna Gigante and Per Hall, Karolinska Institutet; Bruna Gigante, Danderyd Hospital; and Per Hall, South General Hospital, Stockholm, Sweden.

Purpose Incidental cardiac irradiation can cause cardiac injury, but little is known about the effect of radiation on specific cardiac segments. Methods For 456 women who received breast cancer radiotherapy between 1958 and 2001 and then later experienced a major coronary event, information was obtained on the radiotherapy regimen they received and on the location of their cardiac injury. For 414 women, all with documented location of left ventricular (LV) injury, doses to five LV segments were estimated. For 133 women, all with documented location of coronary artery disease with ≥ 70% stenosis, doses to six coronary artery segments were estimated. For each segment, numbers of women with left-sided and right-sided breast cancer were compared. Results Of women with LV injury, 243 had left-sided breast cancer and 171 had right-sided breast cancer (ratio of left v right, 1.42; 95% CI, 1.17 to 1.73), reflecting the higher typical LV radiation doses in left-sided cancer (average dose left-sided, 8.3 Gy; average dose right-sided, 0.6 Gy; left minus right dose difference, 7.7 Gy). For individual LV segments, the ratios of women with left- versus right-sided radiotherapy were as follows: inferior, 0.94 (95% CI, 0.70 to 1.25); lateral, 1.42 (95% CI, 1.04 to 1.95); septal, 2.09 (95% CI, 1.37 to 3.19); anterior, 1.85 (95% CI, 1.39 to 2.46); and apex, 4.64 (95% CI, 2.42 to 8.90); corresponding left-minus-right dose differences for these segments were 2.7, 4.9, 7.2, 10.4, and 21.6 Gy, respectively ( P < .001). For women with coronary artery disease, the ratios of women with left- versus right-radiotherapy for individual coronary artery segments were as follows: right coronary artery proximal, 0.48 (95% CI, 0.26 to 0.91); right coronary artery mid or distal, 1.69 (95% CI, 0.85 to 3.36); circumflex proximal, 1.46 (95% CI, 0.72 to 2.96); circumflex distal, 1.11 (95% CI, 0.45 to 2.73); left anterior descending proximal, 1.89 (95% CI, 1.07 to 3.34); and left anterior descending mid or distal, 2.33 (95% CI, 1.19 to 4.59); corresponding left-minus-right dose differences for these segements were -5.0, -2.5, 1.6, 3.5, 9.5, and 38.8 Gy ( P = .002). Conclusion For individual LV and coronary artery segments, higher radiation doses were strongly associated with more frequent injury, suggesting that all segments are sensitive to radiation and that doses to all segments should be minimized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2017.77.6351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6067799PMC
August 2018

Case Report of Wernicke's Encephalopathy After Sleeve Gastrectomy.

Nutr Clin Pract 2018 Aug 14;33(4):510-514. Epub 2017 Dec 14.

Department of Anesthesiology, Graduate School of Medicine, University of Tennessee Medical Center, Knoxville, Tennessee, USA.

Background: We report a case of a patient who was 3 months post-sleeve gastrectomy and presented with acute stroke symptoms ultimately due to Wernicke's encephalopathy (WE) after bariatric surgery. A 20-year-old white female presented to an outside hospital 3 months after sleeve gastrectomy complaining of nausea and vomiting. She initially underwent a cholecystectomy and later became less responsive and required intubation. Magnetic resonance imaging changes, presumed to be an acute stroke, prompted her transfer to our facility. Intravenous (IV) thiamin was administered, and the patient's symptoms improved over the course of her hospital stay.

Results: Thiamin levels were markedly low, and the patient rapidly improved with the administration of IV thiamin. The patient was discharged to inpatient rehabilitation.

Conclusion: Bariatric surgery is a less common cause of WE but can lead to acute WE due to malabsorption of thiamin. In patients undergoing bariatric surgery, clinicians should be vigilant about the potential for WE to occur. In addition, based on history, WE should be considered in the differential diagnosis for symptoms of acute ischemic stroke.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/0884533617722758DOI Listing
August 2018

Reaching a 1.5°C target: socio-technical challenges for a rapid transition to low-carbon electricity systems.

Philos Trans A Math Phys Eng Sci 2018 May;376(2119)

Environmental Change Institute, School of Geography and the Environment, University of Oxford, Oxford OX1 3QY, UK.

A 1.5°C global average target implies that we should no longer focus on merely incremental emissions reductions from the electricity system, but rather on fundamentally re-envisaging a system that, sooner rather than later, becomes carbon free. Many low-carbon technologies are surpassing mainstream predictions for both uptake and cost reduction. Their deployment is beginning to be disruptive within established systems. 'Smart technologies' are being developed to address emerging challenges of system integration, but their rates of future deployment remain uncertain. We argue that transition towards a system that can fully displace carbon generation sources will require expanding the focus of our efforts beyond technical solutions. Recognizing that change has social and technical dimensions, and that these interact strongly, we set out a socio-technical review that covers electricity infrastructure, citizens, business models and governance. It describes some of the socio-technical challenges that need to be addressed for the successful transition of the existing electricity systems. We conclude that a socio-technical understanding of electricity system transitions offers new and better insights into the potential and challenges for rapid decarbonization.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5°C above pre-industrial levels'.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1098/rsta.2016.0462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897831PMC
May 2018

Exposure of the lungs in breast cancer radiotherapy: A systematic review of lung doses published 2010-2015.

Radiother Oncol 2018 01 12;126(1):148-154. Epub 2017 Dec 12.

Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, UK.

Background And Purpose: We report a systematic review of lung radiation doses from breast cancer radiotherapy.

Methods And Materials: Studies describing breast cancer radiotherapy regimens published during 2010-2015 and reporting lung dose were included. Doses were compared between different countries, anatomical regions irradiated, techniques and use of breathing adaptation.

Results: 471 regimens from 32 countries were identified. The average mean ipsilateral lung dose (MLD) was 9.0 Gy. MLD for supine radiotherapy with no breathing adaption was 8.4 Gy for whole breast/chest wall (WB/CW) radiotherapy, 11.2 Gy when the axilla/supraclavicular fossa was irradiated, and 14.0 Gy with the addition of internal mammary chain irradiation; breathing adaptation reduced MLD by 1 Gy, 2 Gy and 3 Gy respectively (p < 0.005). For WB/CW radiotherapy, MLD was lowest for tangents in prone (1.2 Gy) or lateral decubitus (0.8 Gy) positions. The highest MLD was for IMRT in supine position (9.4 Gy). The average mean contralateral lung dose (MLD) for WB/CW radiotherapy was higher for IMRT (3.0 Gy) than for tangents (0.8 Gy).

Conclusions: Lung doses from breast cancer radiotherapy varied substantially worldwide, even between studies describing similar regimens. Lymph node inclusion and IMRT use increased exposure, while breathing adaptation and prone/lateral decubitus positioning reduced it.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2017.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5807032PMC
January 2018

Risk of heart disease in relation to radiotherapy and chemotherapy with anthracyclines among 19,464 breast cancer patients in Denmark, 1977-2005.

Radiother Oncol 2017 05 30;123(2):299-305. Epub 2017 Mar 30.

Department of Oncology, Odense University Hospital, Denmark; Institute of Clinical Research, University of Southern Denmark, Denmark. Electronic address:

Background And Purpose: The risk of heart disease subsequent to breast cancer radiotherapy was examined with particular focus on women receiving anthracycline-containing chemotherapy.

Material And Methods: Women diagnosed with early-stage breast cancer in Denmark, 1977-2005, were identified from the register of the Danish Breast Cancer Cooperative Group, as was information on cancer-directed treatment. Information on heart disease was sought from the Danish National Patient and Cause of Death Registries. Incidence rate ratios were estimated comparing left-sided with right-sided cancer (IRR, LvR), stratified by calendar year, age, and time since breast cancer radiotherapy.

Results: Among 19,464 women receiving radiotherapy, the IRR, LvR, was 1.11 (95% CI 1.03-1.20, p=0.005) for all heart disease and among those also receiving anthracyclines the IRR, LvR, was 1.32 (95% CI 1.02-1.70, p=0.03). This risk was highest if the treatment was given before the age of 50years (IRR, LvR, 1.44, (95% CI 1.04-2.01) but there was no significant trend with age or time since treatment.

Conclusions: Radiotherapy for left-sided breast cancer is associated with a higher risk of heart disease than for right-sided with the largest increases seen in women who also received anthracycline-containing chemotherapy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2017.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446317PMC
May 2017

A cardiac contouring atlas for radiotherapy.

Radiother Oncol 2017 03 21;122(3):416-422. Epub 2017 Feb 21.

Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, UK.

Background And Purpose: The heart is a complex anatomical organ and contouring the cardiac substructures is challenging. This study presents a reproducible method for contouring left ventricular and coronary arterial segments on radiotherapy CT-planning scans.

Material And Methods: Segments were defined from cardiology models and agreed by two cardiologists. Reference atlas contours were delineated and written guidelines prepared. Six radiation oncologists tested the atlas. Spatial variation was assessed using the DICE similarity coefficient (DSC) and the directed Hausdorff average distance (d→). The effect of spatial variation on doses was assessed using six different breast cancer regimens.

Results: The atlas enabled contouring of 15 cardiac segments. Inter-observer contour overlap (mean DSC) was 0.60-0.73 for five left ventricular segments and 0.10-0.53 for ten coronary arterial segments. Inter-observer contour separation (mean d→) was 1.5-2.2mm for left ventricular segments and 1.3-5.1mm for coronary artery segments. This spatial variation resulted in <1Gy dose variation for most regimens and segments, but 1.2-21.8Gy variation for segments close to a field edge.

Conclusions: This cardiac atlas enables reproducible contouring of segments of the left ventricle and main coronary arteries to facilitate future studies relating cardiac radiation doses to clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2017.01.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356506PMC
March 2017

Long-term hospitalisation rates among 5-year survivors of Hodgkin lymphoma in adolescence or young adulthood: A nationwide cohort study.

Int J Cancer 2017 May 14;140(10):2232-2245. Epub 2017 Mar 14.

Danish Cancer Society Research Center, Strandboulevarden 49, Copenhagen, 2100, Denmark.

In the present study, we report on the full range of physical diseases acquired by survivors of Hodgkin lymphoma diagnosed in adolescence or young adulthood. In a Danish nationwide population-based cohort study, 1,768 five-year survivors of Hodgkin lymphoma diagnosed at ages 15-39 years during 1943-2004 and 228,447 comparison subjects matched to survivors on age and year of birth were included. Hospital discharge diagnoses and bed-days during 1977-2010 were obtained from the Danish Patient Register for 145 specific disease categories gathered in 14 main diagnostic groups. The analysis was conducted separately on three subcohorts of survivors, that is, survivors diagnosed 1943-1976 for whom we had no information on rehospitalisation for Hodgkin lymphoma and survivors diagnosed 1977-2004, split into a subcohort with no expected relapses and a subcohort for whom a rehospitalisation for Hodgkin lymphoma indicated a relapse. The overall standardised hospitalisation rate ratios (RRs) were 2.0 [95% confidence interval (CI), 1.9-2.1], 1.5 (1.4-1.6) and 2.9 (2.6-3.1) respectively, and the corresponding RRs for bed-days were 3.5 (3.4-3.5), 1.8 (1.8-1.9) and 10.4 (10.3-10.6). Highest RRs were seen for nonmalignant haematological conditions (RR: 2.6; 3.1 and 9.7), malignant neoplasms (RR: 3.2; 2.5 and 4.7) and all infections combined (RR: 2.5; 2.2 and 5.3). Survivors of Hodgkin lymphoma in adolescence or young adulthood are at increased risk for a wide range of diseases that require hospitalisation. The risk depends on calendar period of treatment and on whether the survivors were rehospitalised for Hodgkin lymphoma, and thus likely had a relapse.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ijc.30655DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5396317PMC
May 2017

Risk of heart failure in survivors of Hodgkin lymphoma: effects of cardiac exposure to radiation and anthracyclines.

Blood 2017 04 31;129(16):2257-2265. Epub 2017 Jan 31.

Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Hodgkin lymphoma (HL) survivors treated with radiotherapy and/or chemotherapy are known to have increased risks of heart failure (HF), but a radiation dose-response relationship has not previously been derived. A case-control study, nested in a cohort of 2617 five-year survivors of HL diagnosed before age 51 years during 1965 to 1995, was conducted. Cases (n = 91) had moderate or severe HF as their first cardiovascular diagnosis. Controls (n = 278) were matched to cases on age, sex, and HL diagnosis date. Treatment and follow-up information were abstracted from medical records. Mean heart doses and mean left ventricular doses (MLVD) were estimated by reconstruction of individual treatments on representative computed tomography datasets. Average MLVD was 16.7 Gy for cases and 13.8 Gy for controls ( = .003). HF rate increased with MLVD: relative to 0 Gy, HF rates following MVLD of 1-15, 16-20, 21-25, and ≥26 Gy were 1.27, 1.65, 3.84, and 4.39, respectively ( < .001). Anthracycline-containing chemotherapy increased HF rate by a factor of 2.83 (95% CI: 1.43-5.59), and there was no significant interaction with MLVD ( = .09). Twenty-five-year cumulative risks of HF following MLVDs of 0-15 Gy, 16-20 Gy, and ≥21 Gy were 4.4%, 6.2%, and 13.3%, respectively, in patients treated without anthracycline-containing chemotherapy, and 11.2%, 15.9%, and 32.9%, respectively, in patients treated with anthracyclines. We have derived quantitative estimates of HF risk in patients treated for HL following radiotherapy with or without anthracycline-containing chemotherapy. Our results enable estimation of HF risk for patients before treatment, during radiotherapy planning, and during follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1182/blood-2016-09-740332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418626PMC
April 2017

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study.

Circulation 2016 Nov 7;134(20):1519-1531. Epub 2016 Nov 7.

From Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom (K.E.H., D.J.C., S.C.D.); Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Edgbaston, United Kingdom (K.E.H., R.C.R., D.L.W., C.J.B., M.M.F., C.F., J.G., K.F.W., J.K., M.M.H.); Department of Paediatric Haematology and Oncology, Royal Hospital for Sick Children, University of Edinburgh, United Kingdom (A.B.E.); Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre (M.C.M.); National Institute for Health Research University College London Hospitals Biomedical Research Centre, United Kingdom (J.W.); and British Heart Foundation Centre for Research Excellence (D.J.C, S.C.D).

Background: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used.

Methods: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated.

Results: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4-5.2) decreasing to 1.2 (95% confidence interval, 1.1-1.3) for individuals aged 35 to 39 years (2P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease.

Conclusions: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022514DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5106083PMC
November 2016

Dose and Fractionation in Radiation Therapy of Curative Intent for Non-Small Cell Lung Cancer: Meta-Analysis of Randomized Trials.

Int J Radiat Oncol Biol Phys 2016 11 25;96(4):736-747. Epub 2016 Jul 25.

Nuffield Department of Population Health, University of Oxford, Oxford, Oxfordshire, UK. Electronic address:

Purpose: The optimum dose and fractionation in radiation therapy of curative intent for non-small cell lung cancer remains uncertain. We undertook a published data meta-analysis of randomized trials to examine whether radiation therapy regimens with higher time-corrected biologically equivalent doses resulted in longer survival, either when given alone or when given with chemotherapy.

Methods And Materials: Eligible studies were randomized comparisons of 2 or more radiation therapy regimens, with other treatments identical. Median survival ratios were calculated for each comparison and pooled.

Results: 3795 patients in 25 randomized comparisons of radiation therapy dose were studied. The median survival ratio, higher versus lower corrected dose, was 1.13 (95% confidence interval [CI] 1.04-1.22) when radiation therapy was given alone and 0.83 (95% CI 0.71-0.97) when it was given with concurrent chemotherapy (P for difference=.001). In comparisons of radiation therapy given alone, the survival benefit increased with increasing dose difference between randomized treatment arms (P for trend=.004). The benefit increased with increasing dose in the lower-dose arm (P for trend=.01) without reaching a level beyond which no further survival benefit was achieved. The survival benefit did not differ significantly between randomized comparisons where the higher-dose arm was hyperfractionated and those where it was not. There was heterogeneity in the median survival ratio by geographic region (P<.001), average age at randomization (P<.001), and year trial started (P for trend=.004), but not for proportion of patients with squamous cell carcinoma (P=.2).

Conclusions: In trials with concurrent chemotherapy, higher radiation therapy doses resulted in poorer survival, possibly caused, at least in part, by high levels of toxicity. Where radiation therapy was given without chemotherapy, progressively higher radiation therapy doses resulted in progressively longer survival, and no upper dose level was found above which there was no further benefit. These findings support the consideration of further radiation therapy dose escalation trials, making use of modern treatment methods to reduce toxicity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2016.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5082441PMC
November 2016

Cumulative burden of disease: a relevant measure of the late side-effects of cancer treatment.

Lancet Oncol 2016 09 25;17(9):1189-90. Epub 2016 Jul 25.

Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK; Department of Oncology, Oxford Cancer and Haematology Centre, University of Oxford, Oxford, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/S1470-2045(16)30283-2DOI Listing
September 2016

Can Observational Data Replace Randomized Trials?

J Clin Oncol 2016 09 25;34(27):3355-7. Epub 2016 Jul 25.

University of Oxford, Oxford, United Kingdom

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2016.68.8879DOI Listing
September 2016

Reply to D. Vordermark and T. Pelz and R. Mazzola et al.

J Clin Oncol 2016 08 2;34(24):2941-2. Epub 2016 May 2.

The Netherlands Cancer Institute, Amsterdam, Netherlands

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2016.67.4358DOI Listing
August 2016

Uncertainties in estimating heart doses from 2D-tangential breast cancer radiotherapy.

Radiother Oncol 2016 04 27;119(1):71-6. Epub 2016 Feb 27.

Institute of Clinical Research, University of Southern Denmark, Odense, Denmark; Department of Oncology, Odense University Hospital, Denmark.

Background And Purpose: We evaluated the accuracy of three methods of estimating radiation dose to the heart from two-dimensional tangential radiotherapy for breast cancer, as used in Denmark during 1982-2002.

Material And Methods: Three tangential radiotherapy regimens were reconstructed using CT-based planning scans for 40 patients with left-sided and 10 with right-sided breast cancer. Setup errors and organ motion were simulated using estimated uncertainties. For left-sided patients, mean heart dose was related to maximum heart distance in the medial field.

Results: For left-sided breast cancer, mean heart dose estimated from individual CT-scans varied from <1Gy to >8Gy, and maximum dose from 5 to 50Gy for all three regimens, so that estimates based only on regimen had substantial uncertainty. When maximum heart distance was taken into account, the uncertainty was reduced and was comparable to the uncertainty of estimates based on individual CT-scans. For right-sided breast cancer patients, mean heart dose based on individual CT-scans was always <1Gy and maximum dose always <5Gy for all three regimens.

Conclusions: The use of stored individual simulator films provides a method for estimating heart doses in left-tangential radiotherapy for breast cancer that is almost as accurate as estimates based on individual CT-scans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.radonc.2016.02.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4871929PMC
April 2016

Inferring the Effects of Cancer Treatment: Divergent Results From Early Breast Cancer Trialists' Collaborative Group Meta-Analyses of Randomized Trials and Observational Data From SEER Registries.

J Clin Oncol 2016 Mar 19;34(8):803-9. Epub 2016 Jan 19.

Katherine E. Henson, David Cutter, Paul McGale, Carolyn Taylor, and Sarah C. Darby, University of Oxford, Oxford, United Kingdom; and Reshma Jagsi, University of Michigan, Ann Arbor, MI

Purpose: To compare the effect of breast cancer radiotherapy as estimated from observational data with findings from randomized trials.

Materials And Methods: Rate ratios were obtained for selected end points among 13,932 women randomly assigned to receive radiotherapy or not in trials contributing to recent meta-analyses by the Early Breast Cancer Trialists' Collaborative Group. Estimates of the same quantities were derived for 393,840 women registered with breast cancer in the US SEER registries between 1973 and 2008.

Results: In the randomized trials, radiotherapy after breast-conserving surgery reduced mortality from both breast cancer (rate ratio, 0.82; 95% CI, 0.75 to 0.90) and all causes (rate ratio, 0.92; 95% CI, 0.86 to 0.99). Reductions of similar magnitude were seen in the trials of radiotherapy after mastectomy in node-positive disease (rate ratios, breast cancer 0.84; 95% CI, 0.76 to 0.94; all causes, 0.89; 95% CI, 0.81 to 0.97). In the observational data, radiotherapy after breast-conserving surgery was associated with much larger mortality reductions (rate ratios, breast cancer, 0.64; 95% CI, 0.62 to 0.66; all causes, 0.63; 95% CI, 0.62 to 0.65), whereas radiotherapy after mastectomy in node-positive disease was associated with substantial increases in mortality (rate ratios, breast cancer, 1.34; 95% CI, 1.31 to 1.37; all causes, 1.23; 95% CI, 1.22 to 1.25). Detailed adjustment of the observational data for potential confounders did not reduce the divergence from the randomized data.

Conclusion: This study of mortality after radiotherapy for breast cancer found strikingly divergent results between the Early Breast Cancer Trialists' Collaborative Group meta-analyses of randomized data and the SEER observational data, even when efforts had been made to remove confounding and selection biases. Nonrandomized comparisons are liable to provide misleading estimates of treatment effects. Therefore, they need careful justification every time they are used.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2015.62.0294DOI Listing
March 2016

Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma.

J Clin Oncol 2016 Jan 16;34(3):235-43. Epub 2015 Nov 16.

Frederika A. van Nimwegen, Michael Schaapveld, Michael Hauptmann, Karen Kooijman, Berthe M.P. Aleman, and Flora E. van Leeuwen, Netherlands Cancer Institute, Amsterdam; Michael Schaapveld, Netherlands Comprehensive Cancer Organization; Judith Roesink, University Medical Center Utrecht, Utrecht; Cècile P.M. Janus, Erasmus MC Cancer Institute, Rotterdam; Augustinus D.G. Krol, Leiden University Medical Center, Leiden; Richard van der Maazen, Radboud University Medical Center, Nijmegen, Netherlands; David J. Cutter, and Sarah C. Darby, University of Oxford; and David J. Cutter, Oxford University Hospitals NHS Trust, Oxford, United Kingdom.

Purpose: Cardiovascular diseases are increasingly recognized as late effects of Hodgkin lymphoma (HL) treatment. The purpose of this study was to identify the risk factors for coronary heart disease (CHD) and to quantify the effects of radiation dose to the heart, chemotherapy, and other cardiovascular risk factors.

Patients And Methods: We conducted a nested case-control study in a cohort of 2,617 5-year HL survivors, treated between 1965 and 1995. Cases were patients diagnosed with CHD as their first cardiovascular event after HL. Detailed treatment information was collected from medical records of 325 cases and 1,204 matched controls. Radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose (MHD). A risk factor questionnaire was sent to patients still alive.

Results: The median interval between HL and CHD was 19.0 years. Risk of CHD increased linearly with increasing MHD (excess relative risk [ERR]) per Gray, 7.4%; 95% CI, 3.3% to 14.8%). This results in a 2.5-fold increased risk of CHD for patients receiving a MHD of 20 Gy from mediastinal radiotherapy, compared with patients not treated with mediastinal radiotherapy. ERRs seemed to decrease with each tertile of age at treatment (ERR/Gy(<27.5years), 20.0%; ERR/Gy(27.5-36.4years), 8.8%; ERR/Gy(36.5-50.9years), 4.2%; P(interaction) = .149). Having ≥ 1 classic CHD risk factor (diabetes mellitus, hypertension, or hypercholesterolemia) independently increased CHD risk (rate ratio, 1.5; 95% CI, 1.1 to 2.1). A high level of physical activity was associated with decreased CHD risk (rate ratio, 0.5; 95% CI, 0.3 to 0.8).

Conclusion: The linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors. Appropriate early management of CHD risk factors and stimulation of physical activity may reduce CHD risk in HL survivors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1200/JCO.2015.63.4444DOI Listing
January 2016

Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013.

Int J Radiat Oncol Biol Phys 2015 Nov 3;93(4):845-53. Epub 2015 Aug 3.

Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.

Purpose: Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013.

Methods And Materials: Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this "mean heart dose."

Results: In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies.

Conclusions: Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijrobp.2015.07.2292DOI Listing
November 2015

Cardiovascular disease after cancer therapy.

EJC Suppl 2014 Jun 29;12(1):18-28. Epub 2014 May 29.

Clinical Trial Service Unit, University of Oxford, Oxford, United Kingdom.

Improvements in treatment and earlier diagnosis have both contributed to increased survival for many cancer patients. Unfortunately, many treatments carry a risk of late effects including cardiovascular diseases (CVDs), possibly leading to significant morbidity and mortality. In this paper we describe current knowledge of the cardiotoxicity arising from cancer treatments, outline gaps in knowledge, and indicate directions for future research and guideline development, as discussed during the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer (EORTC). Better knowledge is needed of the late effects of modern systemic treatments and of radiotherapy to critical structures of the heart, including the effect of both radiation dose and volume of the heart exposed. Research elucidating the extent to which treatments interact in causing CVD, and the mechanisms involved, as well as the extent to which treatments may increase CVD indirectly by increasing cardiovascular risk factors is also important. Systematic collection of data relating treatment details to late effects is needed, and great care is needed to obtain valid and generalisable results. Better knowledge of these cardiac effects will contribute to both primary and secondary prevention of late complications where exposure to cardiotoxic treatment is unavoidable. Also surrogate markers would help to identify patients at increased risk of cardiotoxicity. Evidence-based screening guidelines for CVD following cancer are also needed. Finally, risk prediction models should be developed to guide primary treatment choice and appropriate follow up after cancer treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejcsup.2014.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250533PMC
June 2014

International Expert Consensus on Primary Systemic Therapy in the Management of Early Breast Cancer: Highlights of the Fifth Symposium on Primary Systemic Therapy in the Management of Operable Breast Cancer, Cremona, Italy (2013).

J Natl Cancer Inst Monogr 2015 May;2015(51):90-6

Medical Oncology Unit (VA, ABe), University of Brescia, and Breast Unit (RP, LV, ELS) Spedali Civili Hospital, Brescia, Italy; U.O. Multidisciplinare di Patologia Mammaria, S.S. Terapia Molecolare e Farmacogenomica, AZ. Istituti Ospitalieri di Cremona, Cremona, Italy (DG, AR, MRC, LD, ABo); Departments of Radiation Oncology (TB) and Pathology (FS), University of Texas MD Anderson Cancer Center, Houston, TX; Department of Medical Oncology and Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA (MC); Division of Experimental Therapeutics, Breast Cancer Program, Istituto Europeo di Oncologia, Milan, Italy (GC); Biomarkers Unit, Department of Experimental Oncology and Molecular Medicine (MGD), and Medical Oncology Unit (SDC), Fondazione IRCCS - Istituto Nazionale Tumori, Milan, Italy (MGD); Academic Department of Biochemistry, Biochemical Endocrinology (MD), Department of Surgery, Breast Unit (PB), and The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research and Breast Unit (MD, GS), Royal Marsden Hospital, London, UK; Department of Pathology, Melbourne University, Parkville, Australia (SF); Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK (ALH); Mount Vernon Cancer Centre, London, UK (AM); Section of Medical Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT (CH); Memorial Sloan Kettering Cancer Center, New York, NY (CAH); Division of Medical Oncology, Department of Hemato-oncology, IRCCS Policlinico 'San Matteo' Foundation, Pavia, Italy (PP); Dipartimento Medicina di Laboratorio, SC Anatomia ed Istocitopatologia Diagnostica e di Screening, A.O.U. Città della Salute e della Scienza di Torino, Università di Torino, Turin, Italy (AS); N. N. Petrov Research Institute of Oncology, St. Petersburg, Russia (VS); German Breast Group & University of Frankfurt, Neu-Isenburg, Germany (GvM); The Russell H. Morgan Department of Radiology

Expert consensus-based recommendations regarding key issues in the use of primary (or neoadjuvant) systemic treatment (PST) in patients with early breast cancer are a valuable resource for practising oncologists. PST remains a valuable therapeutic approach for the assessment of biological antitumor activity and clinical efficacy of new treatments in clinical trials. Neoadjuvant trials provide endpoints, such as pathological complete response (pCR) to treatment, that potentially translate into meaningful improvements in overall survival and disease-free survival. Neoadjuvant trials need fewer patients and are less expensive than adjuvant trial, and the endpoint of pCR is achieved in months, rather than years. For these reasons, the neoadjuvant setting is ideal for testing emerging targeted therapies in early breast cancer. Although pCR is an early clinical endpoint, its role as a surrogate for long-term outcomes is the key issue. New and better predictors of treatment efficacy are needed to improve treatment and outcomes. After PST, accurate management of post-treatment residual disease is mandatory. The surgery of the sentinel lymph-node could be an acceptable option to spare the axillary dissection in case of clinical negativity (N0) of the axilla at the diagnosis and/or after PST. No data exists yet to support the modulation of the extent of locoregional radiation therapy on the basis of the response attained after PST although trials are underway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jncimonographs/lgv023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5009414PMC
May 2015