Feb 2016 cancer current awareness by Musgrove Park Hospital Library

Clinical Librarian Service Musgrove Park Academy

Current Awareness

Cancer Issue 3 February 2016

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This monthly Current Awareness Bulletin is produced by the Clinical Librarian, Musgrove Park Academy, to provide Hope Directorate staff with a range of cancer/haematology related resources to support practice. It includes recently published guidelines and research articles, news and policy items.

This guide provides a selection of resources relevant to the subject area and is not intended to be a comprehensive list. For further help or guidance, please contact a member of library staff.

This guide has been compiled by: Terry Harrison MLGS Clinical Librarian, HOPE Directorate Musgrove Park Hospital Library Service Terence.Harrison@tst.nhs.uk

Contents Click on a section title to navigate to contents

Page Recent journal articles

New books

Cochrane Reviews

Other evidence updates

Cancer in the News

Reports, publications and resources

Training & Networking Opportunities, Conferences, Events

Literature & Evidence search services

Training and Athens

Library contact details: Library Musgrove Park Academy Musgrove Park Hospital Taunton Somerset TA1 5DA Email: Library@tst.nhs.uk Tel: 01823 34 (2433) Fax: 01823 34 (2434) Clinical Librarian email: Terence.Harrison@tst.nhs.uk

RECENT JOURNAL ARTICLES BACK TO TOP

This is a list of recent journal articles on the topic of cancer (and haematology). Some articles are available in the library, or on-line via an Athens password, by following the link. If you would like an article that is not available as full text, please contact library staff: Library@tst.nhs.uk

Long-term toxic effects of proton radiotherapy for paediatric medulloblastoma: a phase 2 single-arm study Torunn I Yock, Beow Y Yeap, David H Ebb, et al. The Lancet, publ. online 29 January 2016 Compared with traditional photon radiotherapy, proton radiotherapy irradiates less normal tissue and might improve health outcomes associated with photon radiotherapy by reducing toxic effects to normal tissue. We did a trial to assess late complications, acute side-effects, and survival associated with proton radiotherapy in children with medulloblastoma.

Why cancer screening has never been shown to "save lives"—and what we can do about it Vinay Prasad, Jeanne Lenzer, David H Newman BMJ 2016; 352 doi: http://dx.doi.org/10.1136/bmj.h6080 (Published 06 January 2016) Despite growing appreciation of the harms of cancer screening, advocates still claim that it “saves lives.” This assertion rests, however, on reductions in disease specific mortality rather than overall mortality. Using disease specific mortality as a proxy for overall mortality deprives people of information about their chief concern: reducing their risk of dying. Although some people may have personal reasons for wanting to avoid a specific diagnosis, the burden falls on providers to provide clear information about both disease specific and overall mortality and to ensure that the overall goal of healthcare—to improve quantity and quality of life—is not undermined. In this article we argue that overall mortality should be the benchmark against which screening is judged and discuss how to improve the evidence upon which screening rests.

Prevalence of Nonrecommended Screening for Prostate Cancer and Breast Cancer in the United States Firas Abdollah, MD; Maxine Sun, MPH; Jesse D. Sammon, DO; et al. JAMA Oncol. Published online January 21, 2016 3

This survey study assesses the prevalence of nonrecommended screening for prostate cancer and breast cancer in the United States. Existing guidelines acknowledge the risks of overdiagnosis and overtreatment associated with early detection of prostate cancer and breast cancer and recommend against screening for these tumors in individuals with limited life expectancy. The cost to the US health care system related to overdiagnosis may be as high as $1.2 billion annually. That finding, combined with the aging population and an expected surge of older individuals with prostate cancer and breast cancer in upcoming years, indicates that a contemporary nationwide and state-by-state assessment of the prevalence of nonrecommended screening for prostate cancer and breast cancer is essential and timely.

A survey of patient expectations regarding sexual function following radical prostatectomy Serkan Deveci1, Geoffrey T. Gotto, Byron Alex, Keith O'Brien andJohn P. Mulhall DOI: 10.1111/bju.13398 336 consecutive patients (from 9 surgeons) with a mean age of 64Âą11 years had the survey instrument administered (216 underwent open and 120 underwent robotic RP). No significant differences existed in patient age or comorbidity profiles between the two groups. Only 38% of men had an accurate recollection of their nerve sparing status. The mean (SD) elapsed time post-RP at the time of postoperative assessment was 3 (2) months. Robotic RP patients expected shorter EF recovery time (6 vs 12 months, p=0.02), a higher likelihood of recovery back to baseline erectile function (75 vs. 50%, p=0.01), and lower potential need for ICI (4 vs. 20%, p=0.01). Almost half of all patients were unaware that they were rendered anejaculatory by their surgery. None of the robotic RP patients and only 10% of open RP patients recalled being informed of the potential for penile length loss (p<0.01) and none were aware of the association between RP and Peyronie's disease.

Failure-Free Survival and Radiotherapy in Nonmetastatic Prostate Cancer JAMA Oncol 2015 Nov 25;[EPub Ahead of Print], ND James, MR Spears, NW Clarke, et al A total of 721 men with newly diagnosed M0 disease were included: median age at entry, 66 (interquartile range [IQR], 61-72) years, median (IQR) prostate-specific antigen level of 43 (18-88) ng/mL. There were 40 deaths (31 owing to prostate cancer) with 17 months' median follow-up. Twoyear survival was 96% (95% CI, 93%-97%) and 2-year FFS, 77% (95% CI, 73%-81%). Median (IQR) FFS was 63 (26 to not reached) months. Time to FFS was worse in patients with N+ disease (HR, 2.02 [95% CI, 1.46-2.81]) than in those with N0 disease. Failure-free survival outcomes favored planned use of RT for patients with both N0M0 (HR, 0.33 [95% CI, 0.18-0.61]) and N+M0 disease (HR, 0.48 [95% CI, 0.29-0.79]).

Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL Graff JN, Baciarello G, Armstrong AJ, Ann Oncol. 2015 Nov 16. pii: mdv542. [Epub ahead of print] Among 609 elderly patients (35%) who participated in PREVAIL, median treatment duration was 16.6 and 5.0 months in the enzalutamide and placebo arms, respectively. In the elderly subgroup, OS was greater with enzalutamide than with placebo [32.4 months (95% confidence interval (CI) 27.7–not yet reached] versus 25.1 months (95% CI 22.6–28.0); hazard ratio (HR) = 0.61 (95% CI 0.47–0.79); P = 0.0001], as was rPFS [not yet reached (95% CI 12.3–not yet reached) versus 3.7 months (95% CI 3.6– 5.3); HR = 0.17 (95% CI 0.12–0.24); P < 0.0001]. Irrespective of treatment assignment, incidence of AEs was similar between the two age groups, except for an overall higher incidence of falls among elderly patients than younger patients [84/609 (13.8%) versus 62/1106 (5.6%)] and among elderly patients receiving enzalutamide than those receiving placebo [61/317 (19.2%) versus 23/292 (7.9%)].

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial The Lancet (published online), December 2015 Annual screening for ovarian cancer might lower cancer-related mortality, according to a large U.K. trial in the Lancet. The researchers caution that longer follow-up is needed "before firm conclusions can be reached." Over 200,000 postmenopausal women aged 50–74 without prior ovarian cancer or increased family risk were randomized to annual multimodal screening, annual transvaginal ultrasound screening, or no screening. Multimodal screening involved serum CA125 testing, with rising levels interpreted using an ovarian cancer algorithm and ultrasound performed as indicated. During a median 11 years' follow-up, the incidence of ovarian cancer mortality was not significantly lower in the multimodal and ultrasound groups (0.29% and 0.30%) than in the no-screening group (0.34%); however, the effect of multimodal screening became significant after 7 years. In addition, in a prespecified secondary analysis that excluded women with CA125 levels suggesting cancer at baseline, multimodal screening was associated with a 20% reduction in ovarian cancer mortality relative to no screening.

Targeting BCL2 With Venetoclax in Relapsed Chronic Lymphocytic Leukemia N. Engl. J. Med 2015 Dec 06;[EPub Ahead of Print], AW Roberts, MS Davids, JM Pagel, er al Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number,

Impact of Ipsilateral Blood Draws, Injections, Blood Pressure Measurements, and Air Travel on the Risk of Lymphedema for Patients Treated for Breast Cancer J. Clin. Oncol · December 17, 2015 Chantal M. Ferguson, Meyha N. Swaroop et al This study suggests that although cellulitis increases risk of lymphedema, ipsilateral blood draws, injections, blood pressure readings, and air travel may not be associated with arm volume increases. The results may help to educate clinicians and patients on posttreatment risk, prevention, and management of lymphedema.

Potential risks associated with traditional herbal medicine use in cancer care: A study of Middle Eastern oncology health care professionals Cancer 2015 Nov 24;[EPub Ahead of Print], E Ben-Arye, N Samuels, LH Goldstein Herbal medicine use, which is prevalent in Middle Eastern countries, has several potentially negative effects that include direct toxic effects, negative interactions with anticancer drugs, and increased chemosensitivity of cancer cells, requiring a reduction in dosedensity. Oncology HCPs working in countries in which herbal medicine use is prevalent need to better understand the implications of this practice. The presence of integrative physicians with training in complementary and traditional medicine can help patients and their HCPs reach an informed decision regarding the safety and effective use of these products.

Ibrutinib in Combination With Rituximab in Relapsed or Refractory Mantle Cell Lymphoma: A SingleCenter, Open-Label, Phase 2 Trial Lancet Oncol 2015 Nov 27;[EPub Ahead of Print], ML Wang, H Lee, H Chuang, et al Between July 15, 2013, and June 30, 2014, 50 patients were enrolled. Median age was 67 years (range 45–86), and the median number of previous regimens was three (range 1–9). At a median follow-up of 16·5 months (IQR 12·09–19·28), 44 (88%, 95% CI 75·7–95·5) patients achieved an objective response, with 22 (44%, 30·0–58·7) patients achieving a complete response, and 22 (44%, 30·0–58·7) a partial response. The only grade 3 adverse event in >=10% of patients was atrial fibrillation, which was noted in six (12%) patients. Grade 4 diarrhoea and neutropenia occurred in one patient each. Adverse events led to discontinuation of therapy in five (10%) patients (atrial fibrillation in three [6%] patients, liver infection in one [2%], and bleeding in one [2%]). Two patients died while on-study from cardiac arrest and septic shock; the latter was deemed possibly related to treatment

Does Gleason Score at Initial Diagnosis Predict Efficacy of Abiraterone Acetate Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer? An Analysis of Abiraterone Acetate Phase III Trials Ann. Oncol 2015 Nov 25;[EPub Ahead of Print], K Fizazi, TW Flaig, M Stöckle, et al 6

Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56-0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48-0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40-0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49-0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups

A Phase II Study of Cyclophosphamide, Etoposide, Vincristine and Prednisone (CEOP) Alternating With Pralatrexate (P) as Front Line Therapy for Patients With Peripheral T-Cell Lymphoma (PTCL): Final Results From the T- Cell Consortium Trial Br. J. Haematol 2015 Dec 02;[EPub Ahead of Print], RH Advani, SM Ansell, MJ Lechowicz, et al Peripheral T-cell lymphomas (PTCL) have suboptimal outcomes using conventional CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. The anti-folate pralatrexate, the first drug approved for patients with relapsed/refractory PTCL, provided a rationale to incorporate it into the front-line setting. This phase 2 study evaluated a novel front-line combination whereby cyclophosphamide, etoposide, vincristine and prednisone (CEOP) alternated with pralatrexate (CEOP-P) in PTCL. Patients achieving a complete or partial remission (CR/PR) were eligible for consolidative stem cell transplantation (SCT) after 4 cycles. Thirty-three stage II-IV PTCL patients were treated: 21 PTCL-not otherwise specified (64%), 8 angioimmunoblastic T cell lymphoma (24%) and 4 anaplastic large cell lymphoma (12%). The majority (61%) had stage IV disease and 46% were International Prognostic Index high/intermediate or high risk. Grade 3-4 toxicities included anaemia (27%), thrombocytopenia (12%), febrile neutropenia (18%), mucositis (18%), sepsis (15%), increased creatinine (12%) and liver transaminases (12%). Seventeen patients (52%) achieved a CR. The 2-year progression-free survival and overall survial, were 39% (95% confidence interval 21-57) and 60% (95% confidence interval 39-76), respectively. Fifteen patients (45%) (12 CR) received SCT and all remained in CR at a median follow-up of 21·5 months. CEOP-P did not improve outcomes compared to historical data using CHOP. Defining optimal front line therapy in PTCL continues to be a challenge and an unmet need.

Whole Pelvis Versus Prostate-Only Radiotherapy With or Without Short-Course Androgen Deprivation Therapy and Mortality Risk Clin Genitourin Cancer 2015 Dec 01;13(6)555-561, LZ Braunstein, MH Chen, DE Dosoretz, SA Salenius, MJ Katin, A Nanda, AV D'Amico Treatment with WPRT or short-course ADT is associated with a decreased risk of ACM, although a combination of the two does not yield greater benefit. This observation suggests a shared mechanism for this risk reduction, which we hypothesize to be via the treatment of micrometastatic disease within the pelvic lymph nodes.

When Are Breast Cancer Patients at Highest Risk of Venous Thromboembolism: A Cohort Study Using English Healthcare Data Blood 2015 Nov 16;[EPub Ahead of Print], 7

AJ Walker, J West, TR Card, C Crooks, et al Breast cancer patients are at increased risk of VTE, particularly in the peri-diagnosis period. However, no previous epidemiological studies have investigated the relative impact of breast cancer treatments in a time-dependent manner. We aimed to determine the impact of breast cancer stage, biology and treatment on the absolute and relative risks of VTE, using several recently linked data sources from England. Our cohort comprised 13,202 breast cancer patients from the Clinical Practice Research Datalink (linked to Hospital Episode Statistics and Cancer Registry data), diagnosed between 1997 and 2006 with follow-up continuing to the end of 2010. Cox regression analysis was performed to determine which demographic, treatment-related and biological factors independently affected VTE risk. Women had an annual VTE incidence of 6% whilst receiving chemotherapy which was 10.8-fold higher (95% CI, 8.2 to 14.4; absolute risk (AR) =59.6 per 1000 person-years) than women who did not receive chemotherapy. Following surgery the risk was significantly raised in the first month (HR=2.2; 95% CI 1.4 to 3.4; AR=23.5; reference group, no surgery), but it was not raised subsequent to this. Risk of VTE was noticeably higher in the 3-months following initiation of Tamoxifen compared with the risk before therapy (HR=5.5; 95% CI 2.3 to 12.7; AR=24.1), however commencement of aromatase inhibitors was not associated with VTE (HR=0.8; 95% CI 0.5 to 1.4; AR=28.3). In conclusion, women receiving chemotherapy for breast cancer have a clinically important risk of VTE, whilst an increased risk of VTE immediately following endocrine therapy is restricted to Tamoxifen.

The Benefit of HER2-Targeted Therapies on Overall Survival of Patients With Metastatic HER2Positive Breast Cancerâ&#x20AC;&#x201D;A Systematic Review Breast Cancer Res 2015 Nov 17;[EPub Ahead of Print], D Mendes, C Alves, N Afonso, Nineteen RCTs were eligible for inclusion, of which 12 assessed therapies targeting HER2+ mBC in the first-line setting. OS improved from 20.3 months in the first RCT (standard chemotherapy; Slamon et al. (N Engl J Med 344:783-92, 2001)) evaluating HER2-targeting therapies to 48 months in the study of Swain et al. (Lancet Oncol 14:461-71, 2013), with triple combination of pertuzumab, trastuzumab and docetaxel. Seven RCTs evaluated the OS of HER2-targeting therapies in the secondline setting and beyond. The OS in second-line setting improved from 15.3 months (capecitabine; Cameron et al. (Breast Cancer Res Treat 112:533-43, 2008)) to 30.7 months (trastuzumab emtansine; Verma et al. (N Engl J Med 367:1783-91, 2012)). In the third-line setting, the association of lapatinib and trastuzumab has demonstrated to improve OS to 4.5 months compared with lapatinib alone (14 months vs. 9.5 months; Blackwell et al. (J Clin Oncol 30:2585-92, 2012)).

Metastatic Melanoma Treatment: Combining Old and New Therapies Crit. Rev. Oncol. Hematol 2015 Nov 17;[EPub Ahead of Print], RJ Davey, A van der Westhuizen, NA Bowden Metastatic melanoma is an aggressive form of cancer characterised by poor prognosis and a complex etiology. Until 2010, the treatment options for metastatic melanoma were very limited. Largely ineffective dacarbazine, temozolamide or fotemustine were the only agents in use for 35 years. In recent years, the development of molecularly targeted inhibitors in parallel with the development of checkpoint inhibition immunotherapies has rapidly improved the outcomes for metastatic melanoma patients. Despite these new therapies showing initial promise; resistance and poor 8

duration of response have limited their effectiveness as monotherapies. Here we provide an overview of the history of melanoma treatment, as well as the current treatments in development. We also discuss the future of melanoma treatment as we go beyond monotherapies to a combinatorial approach. Combining older therapies with the new molecular and immunotherapies will be the most promising way forward for treatment of metastatic melanoma.

False-Positive Screening Mammograms Linked to Higher Risk for Breast Cancer By Kelly Young Women with false-positive results on screening mammography are more likely to be subsequently diagnosed with breast cancer than women with true-negative results, suggests a study from Cancer Epidemiology, Biomarkers & Prevention. Using data from U.S. breast cancer registries, researchers identified over 2.2 million screening mammograms that were false-positives or true-negatives among women without a history of breast cancer. After an average follow-up of 5.4 years, women with a false-positive result in which biopsy was recommended had the highest risk for subsequent breast cancer diagnosis (7.01 per 1000 person-years), followed by those with a false-positive result in which additional imaging was requested (5.51 per 1000) and those with true-negative mammograms (3.91 per 1000). The elevated risk persisted at 10 years after the false-positive results. NEJM Journal Watch Women's Health Editor-in-Chief Dr. Andrew Kaunitz comments: "I agree with the authors that their findings may facilitate better breast cancer prediction tools which in turn may inform future individualized screening and chemoprevention strategies."

Guidelines for the investigation and management of nodular lymphocyte predominant Hodgkin lymphoma British Journal of Haematology Volume 172, Issue 1, pages 32â&#x20AC;&#x201C;43, January 2016 The guideline group was selected to be representative of UK-based medical experts. Ovid MEDLINE, Ovid EMBASE and DYNAMED were searched systematically for publications in English from 1980 to 2014 using the key words Hodgkin disease, Hodgkin lymphoma and lymphocyte predominant Hodgkin lymphoma. References from relevant publications were also searched. Editorials, studies with <8 cases, letters and conference abstracts were excluded. The writing group produced the draft guideline, which was reviewed by the British Committee for Standards in Haematology (BCSH) Haemato-oncology Task Force. Further comments were invited from a sounding board of the British Society for Haematology (BSH) and patient representatives identified through the Lymphoma Association. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations (Atkins et al, 2004). The objective of this guideline is to provide healthcare professionals with guidance on the investigation and management of patients with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL). Individual patient circumstances may dictate an alternative approach.

Everolimus Improves Progression-Free Survival in Carcinoid Tumors 9

David H. Ilson, MD, PhD Reviewing Öberg K., Lancet 2015 Dec 15; Carcinoid tumors of the lung and gastrointestinal (GI) tract are rare. Despite an often indolent natural history, when these well-differentiated neuroendocrine tumors progress on somatostatin analogue therapy, there are limited treatment options. Investigators now report results of the RADIANT-4 trial, an industry-sponsored, international, randomized, double-blind, placebo-controlled trial of the mTOR inhibitor everolimus in patients with advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors of the lung or GI tract. Patients were randomized 2:1 to everolimus (10 mg orally daily) versus placebo. Most patients had GI primary tumors (55%–57%), were more than 18 months out from diagnosis (62%), had liver metastases (78%–80%), and had received prior somatostatin analogue therapy (53%–56%). Progression-free survival, the primary endpoint, was significantly improved with everolimus versus placebo (11.0 vs. 3.6 months; hazard ratio, 0.48; P<0.00001). Overall survival trended superior for everolimus (23.7 vs. 16.5 months). Limited responses were seen with everolimus, but disease control was higher compared with placebo. No new safety signals were seen. Expected drug-related grade 3 or 4 adverse events were seen, including stomatitis (9%), diarrhea (7%), fatigue (3%), and infection (7%).

Primary Tumor Resection and Overall Survival in Patients With Metastatic Colorectal Cancer Treated With Palliative Intent Clin Colorectal Cancer; 2015 Dec 29; SF Wong, HL Wong, KM Field, et al For de novo mCRC patients treated with palliative intent, PTR at diagnosis does not significantly improve overall survival when adjusting for known major prognostic factors. Outcomes of randomized trials examining the survival impact of PTR are awaited.

Long-Term Results of the HD2000 Trial: ABVD vs BEACOPP vs COPP-EBV-CAD in Advanced Hodgkin's J. Clin. Oncol; 2015 Dec 28; F Merli, S Luminari, PG Gobbi, et al With these mature results, we confirm that patients with advanced Hodgkin lymphoma have similar OS results when treated with ABVD, BEACOPP, or CEC. However, with longer follow-up, we were not able to confirm the superiority of BEACOPP over ABVD in terms of PFS, mainly because of higher mortality rates resulting from second malignancies observed after treatment with BEACOPP and CEC.

Targeting CD38 in Refractory Multiple Myeloma Michael E. Williams, MD, ScM Reviewing Rajkumar SV., Lancet 2016 Jan 6; To test the efficacy and safety of the anti-CD38 monoclonal antibody daratumumab in multiple myeloma, investigators conducted an industry-sponsored, multinational, randomized, phase II trial 10

involving 106 patients with relapsed disease that was refractory to both proteasome inhibitors and immunomodulatory agents. Most patients (80%) had received prior high-dose therapy and autologous stem cell transplantation, and 97% were resistant to their most recent treatment. Patients received a dose of 16 mg/kg weekly for 8 weeks, then biweekly for16 weeks, and then once every 4 weeks until disease progression or treatment intolerance.

Routine Molecular Profiling of Patients With Advanced Non–Small Cell Lung Cancer Lancet; 2016 Jan 14; EPub Ahead of Print; F Barlesi, J Mazieres, JP Merlio, et al 18 679 molecular analyses of 17 664 patients with NSCLC were done (of patients with known data, median age was 64·5 years [range 18–98], 65% were men, 81% were smokers or former smokers, and 76% had adenocarcinoma). The median interval between the initiation of analysis and provision of the written report was 11 days (IQR 7–16). A genetic alteration was recorded in about 50% of the analyses; EGFR mutations were reported in 1947 (11%) of 17 706 analyses for which data were available, HER2mutations in 98 (1%) of 11 723, KRAS mutations in 4894 (29%) of 17 001, BRAFmutations in 262 (2%) of 13 906, and PIK3CA mutations in 252 (2%) of 10 678; ALKrearrangements were reported in 388 (5%) of 8134 analyses. The median duration of follow-up at the time of analysis was 24·9 months (95% CI 24·8–25·0). The presence of a genetic alteration affected first-line treatment for 4176 (51%) of 8147 patients and was associated with a significant improvement in the proportion of patients achieving an overall response in first-line treatment (37% [95% CI 34·7–38·2] for presence of a genetic alteration vs 33% [29·5–35·6] for absence of a genetic alteration; p=0·03) and in second-line treatment (17% [15·0–18·8] vs 9% [6·7–11·9]; p<0·0001). Presence of a genetic alteration was also associated with improved first-line progression-free survival (10·0 months [95% CI 9·2–10·7] vs 7·1 months [6·1–7·9]; p<0·0001) and overall survival (16·5 months [15·0–18·3] vs 11·8 months [10·1–13·5]; p<0·0001) compared with absence of a genetic alteration.

Effect of Pretreatment Renal Function on Outcomes in the Adjuvant Treatment of Older Women With Breast Cancer J. Clin. Oncol; 2016 Jan 11; EPub Ahead of Print; SM Lichtman, CT Cirrincione, A Hurria, et al Excluding from clinical trials patients with renal insufficiency but good performance status on the basis of concern of excessive hematologic toxicity or poor outcomes may not be justified with appropriate dosing modifications. Results should be considered in the design of clinical trials for older patients.

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma 11

JAMA; 2015 Dec 15; 314 (23)2535-2543; R Stupp, S Taillibert, AA Kanner, et al In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival.

Prognostic Effect of BRAF and KRAS Mutations in Patients With Stage III Colon Cancer Treated FOLFOX Âą Cetuximab JAMA Oncol; 2016 Jan 14; EPub Ahead of Print; J Taieb, A Zaanan, K Le Malicot, et al BRAF V600E and KRAS mutations were significantly associated with shorter DFS and OS in patients with microsatellite-stable tumors but not in patients with MSI tumors. Future trials in the adjuvant setting will have to take into account mismatch repair, BRAF, and KRAS status for stratification.

Efficacy and Safety of Enzalutamide vs Bicalutamide for Patients With Metastatic Prostate Cancer Lancet Oncol; 2016 Jan 13; EPub Ahead of Print; ND Shore, S Chowdhury, A Villers, et al The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.

Volasertib vs Chemotherapy in Platinum-Resistant or -Refractory Ovarian Cancer J. Clin. Oncol; 2016 Jan 11; EPub Ahead of Print; E Pujade-Lauraine, F Selle, B Weber, et al Single-agent volasertib showed antitumor activity in patients with ovarian cancer. AEs in patients receiving volasertib were mainly hematologic and manageable.

A. Miscellaneous Nanoliposomal Irinotecan Effective for Pancreatic Cancer David H. Ilson, MD, PhD Reviewing Wang-Gillam A et al., Lancet 2015 Nov 20; Renal-Cell Cancer â&#x20AC;&#x201D; Targeting an Immune Checkpoint or Multiple Kinases D.I. Quinn and P.N. Lara 12

N Engl J Med 373:1872, November 5, 2015 Biology before Anatomy in Early Breast Cancer â&#x20AC;&#x201D; Precisely the Point C.A. Hudis N Engl J Med 373:2079, November 19, 2015 Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma R.J. Motzer and Others N Engl J Med 373:1803, November 5, 2015 Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia J.A. Burger and Others N Engl J Med, December 6, 2015 Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia A.W. Roberts and Others N Engl J Med, December 6, 2015

More articles (via BMJ): (IMPORTANT: you will need to logon to the BMJ to see the following items, or you can order items from the Library.)

Colon cancer Practice Pointer: Explaining laboratory test results to patients: what the clinician needs to know Maurice John Oâ&#x20AC;&#x2122;Kane, Berenice Lopez Charity says NHS must deal with "woeful lack of support" for colorectal cancer survivors Zosia Kmietowicz Case Review: A cutaneous presentation of a common condition Adam Daunton, Gerald Langman, J M R Goulding Survival rates after bowel cancer surgery rise in England and Wales Jacqui Wise Operating to remove recurrent colorectal cancer: have we got it right? 13

Tom Treasure, Kathryn Monson, Francesca Fiorentino, Christopher Russell New bowel cancer screening test is recommended for England Jacqui Wise

Cancer: dermatological Sentinel lymph node biopsy in melanoma Michael Bigby, Catalin Popescu Cancer drugs can be four times more costly in some wealthy countries than in others Zosia Kmietowicz

Urological cancer Orchiectomy has fewer adverse effects than chemical castration for metastatic prostate cancer Jacqui Wise

Chemotherapy Study links negative news stories about statins to patientsâ&#x20AC;&#x2122; likelihood of giving them up Nigel Hawkes NICE rejects trastuzumab emtansine for use on NHS Zosia Kmietowicz Fate of new cancer drug is uncertain in Netherlands, as institute deems it too costly Pieter van Eijsden Cancer drugs can be four times more costly in some wealthy countries than in others Zosia Kmietowicz Rheumatic diseases should be actively treated in pregnancy, new guidelines say Jacqui Wise

Radiotherapy Nausea and vomiting in palliative care Emily Collis, Harriet Mather Adult survivors of childhood cancer are at high risk of cardiac abnormalities, study finds 14

Jacqui Wise

Screening (oncology) Sentinel lymph node biopsy in melanoma Michael Bigby, Catalin Popescu Breast surgeon faces 21 charges of unlawfully wounding 11 patients Clare Dyer What Your Patient is Thinking: I chose reconstruction, but not to "look good" Stella Duffy New bowel cancer screening test is recommended for England Jacqui Wise Statistics Notes: Inverse probability weighting Mohammad Ali Mansournia, Douglas G Altman Women aged 50 to 74 should have mammogram every two years, say US guidelines Jacqui Wise Retinoblastoma survivors face raised risk of serious health problems, study finds Zosia Kmietowicz Organ transplantation may link to deaths from cancer, study finds Jacqui Wise Ultrasound is similar to mammography in detecting breast cancer, study shows Susan Mayor Whether screening for ovarian cancer saves lives is still unclear despite large trial Zosia Kmietowicz NICE rejects trastuzumab emtansine for use on NHS Zosia Kmietowicz Survival rates after bowel cancer surgery rise in England and Wales Jacqui Wise Five in six women reject drugs that could reduce their risk of breast cancer 15

Zosia Kmietowicz Continuous HRT with oestrogen plus progestogen is linked to reduced risk of endometrial cancer Susan Mayor Screening for early breast cancer reduces invasive cancer, study finds Susan Mayor Operating to remove recurrent colorectal cancer: have we got it right? Tom Treasure, Kathryn Monson, Francesca Fiorentino, Christopher Russell Sugar tax and screening: listen to the evidence Fiona Godlee Full disclosure about cancer screening Gerd Gigerenzer

Haematology (incl blood transfusion) Hospitalsâ&#x20AC;&#x2122; probes into avoidable deaths are "not consistent, reliable, or transparent," ombudsman finds Clare Dyer

Breast cancer NICE rejects trastuzumab emtansine for use on NHS Zosia Kmietowicz Hormone treatment may help prevent premature menopause in cancer patients Jacqui Wise Ultrasound is similar to mammography in detecting breast cancer, study shows Susan Mayor Christmas 2015: Cancerâ&#x20AC;&#x2122;s Darwinian dilemma: an evolutionary tale in three acts Mel Greaves Five in six women reject drugs that could reduce their risk of breast cancer Zosia Kmietowicz Screening for early breast cancer reduces invasive cancer, study finds 16

Susan Mayor NICE guidance on menopause: cognitive behavioural therapy is an effective non-hormonal intervention for managing vasomotor symptoms Myra S Hunter, Amanda Griffiths, Eleanor Mann, Rona Moss-Morris, Melanie Smith, Pauline Slade Full disclosure about cancer screening Gerd Gigerenzer Women aged 50 to 74 should have mammogram every two years, say US guidelines Jacqui Wise Cut drinking to reduce risk of cancer, says new guidance Jacqui Wise Breast surgeon faces 21 charges of unlawfully wounding 11 patients Clare Dyer NICE guidelines on the menopause Martha Hickey, Emily Banks

Gynecological cancer Obesity is one of biggest risks to womenâ&#x20AC;&#x2122;s health, says Englandâ&#x20AC;&#x2122;s chief medical officer Gareth Iacobucci Continuous HRT with oestrogen plus progestogen is linked to reduced risk of endometrial cancer Susan Mayor Cancer drugs can be four times more costly in some wealthy countries than in others Zosia Kmietowicz Whether screening for ovarian cancer saves lives is still unclear despite large trial Zosia Kmietowicz Investigative Journalism: Attacking the devil: the thalidomide story Rebecca Coombes NICE guidelines on the menopause Martha Hickey, Emily Banks 17

Head and neck cancer Obesity is one of biggest risks to women’s health, says England’s chief medical officer Gareth Iacobucci

Lung cancer (oncology) Fate of new cancer drug is uncertain in Netherlands, as institute deems it too costly Pieter van Eijsden Doctors and Research: "It’s the duty of every doctor to get involved with research" Anne Gulland

Prevention Five in six women reject drugs that could reduce their risk of breast cancer Zosia Kmietowicz

In brief: Ibrutinib vs Temsirolimus for Relapsed Mantle Cell Lymphoma Lancet; 2015 Dec 07; EPub Ahead of Print; M Dreyling, W Jurczak, M Jerkeman, et al Individualized Risk Prediction for 24-Month Event-Free Survival in DLBCL Am. J. Hematol; 2015 Nov 26; EPub Ahead of Print; MJ Maurer, JP Jais, H Ghesquières, et al Ibrutinib in Combination With Rituximab in Relapsed or Refractory Mantle Cell Lymphoma Lancet Oncol; 2015 Nov 27; EPub Ahead of Print; ML Wang, H Lee, H Chuang, et al Cyclophosphamide, Etoposide, Vincristine, and Prednisone Alternating With Pralatrexate for Peripheral T-Cell Lymphoma Br. J. Haematol; 2015 Dec 02; EPub Ahead of Print; RH Advani, SM Ansell, MJ Lechowicz, et al Bendamustine Plus Rituximab vs Fludarabine Plus Rituximab for Relapsed Indolent and Mantle Cell Lymphomas Lancet Oncol; 2015 Dec 04; EPub Ahead of Print; M Rummel, U Kaiser, C Balser Combining Old and New Therapies for Metastatic Melanoma Crit. Rev. Oncol. Hematol; 2015 Nov 17; EPub Ahead of Print; RJ Davey, A van der Westhuizen, NA Bowden Ipilimumab For Melanoma With Preexisting Autoimmune Disorders JAMA Oncol; 2015 Dec 03; EPub Ahead of Print; DB Johnson, RJ Sullivan, PA Ott, et al 18

Immunologic Approaches to Cancer Prevention Semin. Oncol; 2015 Nov 13; EPub Ahead of Print; ME Wojtowicz, BK Dunn, A Umar Immunotherapy Combinations With Checkpoint Inhibitors in Metastatic Melanoma Semin. Oncol; 2015 Oct 15; EPub Ahead of Print; M Atkins Carfilzomib and Dexamethasone vs Bortezomib and Dexamethasone for Patients With Relapsed or Refractory Multiple Myeloma Lancet Oncol; 2015 Dec 05; EPub Ahead of Print; MA Dimopoulos, P Moreau, A Palumbo, et al Panobinostat Plus Bortezomib and Dexamethasone in Relapsed and Refractory Myeloma Blood; 2015 Dec 02; EPub Ahead of Print; PG Richardson, VT Hungria, SS Yoon, et al Home Administration of Bortezomib Is Cost-Effective and Preferred by Patients Ann. Oncol; 2015 Nov 16; EPub Ahead of Print; A Lassalle, P ThomarĂŠ, C Fronteau, et al t(11;14) Correlates With Worse Survival in Multiple Myeloma After Early High-Dose Therapy Leukemia; 2015 Oct 21; EPub Ahead of Print; GP Kaufman, MA Gertz, A Dispenzieri, et al Survival and Functional Stability in Chronic Kidney Disease Due to Surgical Removal of Nephrons Eur Urol; 2015 Dec 01; 68 (6)996-1003; BR Lane, S Demirjian, IH Derweesh, et al Nivolumab + Ipilimumab Shows Promise in Metastatic Renal Cell Carcinoma PracticeUpdate Editorial Team; 2015 Nov 07 Clinical Benefit of Everolimus Second-Line After Sunitinib Is Confirmed in Metastatic Renal Cell Carcinoma PracticeUpdate Editorial Team; 2015 Nov 07 High-Dose lnterleukin-2 Remains Effective as First-Line Therapy for Metastatic Renal Cell Carcinoma PracticeUpdate Editorial Team; 2015 Nov 07 Circulating Tumor DNA Detected in One in Four Patients with Advanced Renal Cell Carcinoma PracticeUpdate Editorial Team; 2015 Nov 07 CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer P. Dalerba and Others | N Engl J Med 2016;374:211-22

For automated tables of contents: Oncology â&#x20AC;&#x201C; click here Haematology â&#x20AC;&#x201C; click here.

NEW BOOKS BACK TO TOP

If you are unable to find a book, or require a book that is not on this list, please ask library staff who will be able to locate the book for you using interlibrary loan.

Hoffbrand's essential haematology (7th ed.) A. Victor Hoffbrand, Paul A. H. Moss Hoffbrand's Essential Haematology has built a reputation as the flagship haematology textbook for both students and junior doctors, providing an authoritative introduction to the subject. Now in its 7th edition, this classic text provides up-to-date knowledge of the pathogenesis, clinical and laboratory features, treatment of blood and bone marrow disorders, in its concise and user-friendly style.

Clinical radiation oncology (4th ed.) Leonard L. Gunderson, Joel E. Tepper Perfect for radiation oncology physicians and residents needing a multidisciplinary, treatment-focused resource, this updated edition continues to provide the latest knowledge in this consistently growing field. Not only will you broaden your understanding of the basic biology of disease processes, you'll also access updated treatment algorithms, information on techniques, and state-of-the-art modalities.

COCHRANE REVIEWS/UPDATES BACK TO TOP

Interventions for the treatment of oral and oropharyngeal cancers: targeted therapy and immunotherapy Chan Kelvin KW, Glenny Anne-Marie, Weldon Jo C, et al Cochrane Database of Systematic Reviews; 2015, NO: 12 We found some evidence that adding EGFR mAb to standard therapy may increase overall survival, progression-free survival and locoregional control, while resulting in an increase in skin toxicity for some mAb (cetuximab).There is insufficient evidence to determine whether adding TKIs to standard therapies changes any of our primary outcomes.Very low quality evidence from a single study suggests that rIL-2 combined with surgery may increase overall survival compared with surgery alone.

Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen Dominick Sally, Hickey Martha, Chin Jason, Su H Irene Cochrane Database of Systematic Reviews, 2015, 12 The LNG-IUS reduces the incidence of benign endometrial polyps and endometrial hyperplasia in women with breast cancer taking tamoxifen. At 12 and 24 months of follow-up, the LNG-IUS increased abnormal vaginal bleeding or spotting among women in the treatment group compared to those in the control. There is no clear evidence from the available randomised controlled trials that the LNG-IUS prevents endometrial cancer in these women. There is no clear evidence from the available randomised controlled trials that the LNG-IUS affects the risk of breast cancer recurrence or breast cancer-related deaths. Larger studies are necessary to assess the effects of the LNG-IUS on the incidence of endometrial cancer, and to determine whether the LNG-IUS might have an impact on the risk of secondary breast cancer events. 22

Adjuvant (post-surgery) chemotherapy for early stage epithelial ovarian cancer Cochrane Database of Systematic Reviews, 2015, 12 Lawrie Theresa A, Winter-Roach Brett A, Heus Pauline, Kitchener Henry C High-quality evidence indicates that adjuvant platinum-based chemotherapy is effective in prolonging survival in women with early stage (FIGO stage I/IIa) epithelial ovarian cancer. It remains uncertain whether women with low- and intermediate-risk early stage disease will benefit as much from adjuvant chemotherapy as women with high-risk disease. Decisions to use adjuvant chemotherapy (AC) in these women should be mindful of this uncertainty, and the uncertainty regarding adverse events. Treatment of women with lower risk disease should be individualised to take into account individual factors.

Screening for nasopharyngeal cancer Yang Shujuan, Wu Siying, Zhou Jing, Chen Xiao Y Cochrane Database of Systematic Reviews, 2015, 11 We identified no trials that met the review inclusion criteria. We retrieved 31 full-text studies for further investigation following the search. However, none met the eligibility criteria for a RCT or CCT investigation on the efficacy of screening for nasopharyngeal cancer.Authors' conclusions: No data from RCTs or CCTs are available to allow us to determine the efficacy of screening for nasopharyngeal cancer, or the cost-effectiveness and cost-benefit of a screening strategy. Highquality studies with long-term follow-up of mortality and cost-effectiveness are needed.

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy Cochrane Database of Systematic Reviews, 2015, 12 Skoetz Nicole, Bohlius Julia, Engert Andreas As we only found two small trials with 195 patients altogether, no conclusion for clinical practice is possible. More trials are necessary to assess the benefits and harms of G(M)-CSF compared to antibiotics for infection prevention in cancer patients receiving chemotherapy.

Blood CEA levels for detecting recurrent colorectal cancer Nicholson Brian D, Shinkins Bethany, Pathiraja Indika, Roberts Nia W 23

Cochrane Database of Systematic Reviews, 2015, 12 CEA is insufficiently sensitive to be used alone, even with a low threshold. It is therefore essential to augment CEA monitoring with another diagnostic modality in order to avoid missed cases. Trying to improve sensitivity by adopting a low threshold is a poor strategy because of the high numbers of false alarms generated. We therefore recommend monitoring for colorectal cancer recurrence with more than one diagnostic modality but applying the highest CEA cut-off assessed (10 Âľg/L).

Symptoms, ultrasound imaging and biochemical markers alone or in combination for the diagnosis of ovarian cancer in women with symptoms suspicious of ovarian cancer Rai Nirmala, Champaneria Rita, Snell Kym, et al Cochrane Database of Systematic Reviews, 2015, 12 This is the protocol for a review and there is no abstract. The objectives are as follows:To establish the accuracy of symptoms, ultrasound and biomarkers alone or in combination for the diagnosis of ovarian cancer in pre- and postmenopausal women.To compare the accuracy of different tests or test combinations.We will investigate the following sources of heterogeneity:Population: Clinical setting (generalist/primary care/community/family practice) versus specialist setting (cancer unit/cancer centre/gynaecological oncology) Menopausal status Index tests: Test positivity threshold Experience of the ultrasound test operator (general sonographers versus specialist interest) Target condition: Histological subtype Study quality: Case-control versus other study designs Study quality: for study participants not receiving surgery initially following a negative index test result: 12 months follow-up versus less than 12 months follow-up

Haloperidol for the treatment of nausea and vomiting in palliative care patients Murray-Brown Fay, Dorman Saskie Cochrane Database of Systematic Reviews, 2015, 11 Since the last version of this review, we found one new study for inclusion but the conclusion remains unchanged. There is incomplete evidence from published RCTs to determine the effectiveness of haloperidol for nausea and vomiting in palliative care. Other than the trial of ABH gel vs placebo, we did not identify any fully published RCTs exploring the effectiveness of haloperidol for nausea and vomiting in palliative care patients for this update, but two trials are underway.

Interleukin-2 as maintenance therapy for children and adults with acute myeloid leukaemia in first complete remission Mao Chen, Fu Xiao-Hong, Yuan Jin-Qiu et al Cochrane Database of Systematic Reviews, 2015, 11 There is no evidence for a difference between IL-2 maintenance therapy and no treatment with respect to disease-free survival or overall survival of people with AML in first CR; however, the quality of the evidence is moderate or low, and further research is likely or very likely to have an important impact on the estimate or our confidence in the estimate. Adverse events seem to be more frequent in participants treated with IL-2, but the quality of the evidence is very low and our confidence in the estimates is very uncertain. Thus, further prospective randomised trials are needed before definitive conclusions can be drawn on these issues.

Leukoreduction for the prevention of adverse reactions from allogeneic blood transfusion Simancas-Racines Daniel, Osorio Dimelza, Martí-Carvajal Arturo J, Arevalo-Rodriguez Ingrid Cochrane Database of Systematic Reviews, 2015, 12 There is no clear evidence for supporting or rejecting the routine use of leukoreduction in all patients requiring PRBC transfusion for preventing TRALI, death, infection, non-infectious complications and other adverse events. As the quality of evidence is very low to low, more evidence is needed before a definitive conclusion can be drawn.

Intravesical bacillus Calmette-Guérin versus mitomycin C for Ta and T1 bladder cancer Schmidt Stefanie, Kunath Frank, Coles Bernadette, et al Cochrane Database of Systematic Reviews, 2015, 11 This is the protocol for a review and there is no abstract. The objectives are as follows:To assess the effects of bacillus Calmette-Guérin (BCG) intravesical therapy compared to mitomycin C (MMC) intravesical therapy for treating Ta and T1 bladder cancer in adults.

Interventions for preventing oral mucositis in patients with cancer receiving treatment: cytokines and growth factors Riley Philip, Glenny Anne-Marie, Worthington Helen V, et al Cochrane Database of Systematic Reviews, 2015, 12

This is the protocol for a review and there is no abstract. The objectives are as follows:To assess the effects of cytokines and growth factors for preventing oral mucositis in patients with cancer who are receiving treatment.

Corticosteroids for adult patients with advanced cancer who have nausea and vomiting (not related to chemo- or radiotherapy, or surgery) Vayne-Bossert Petra, Haywood Alison, Good Phillip, et al Cochrane Database of Systematic Reviews, 2015, 12 This is the protocol for a review and there is no abstract. The objectives are as follows:To assess the effects of corticosteroids on nausea and vomiting not related to chemotherapy, radiotherapy, or surgery in adult cancer patients.

Acellular dermal matrices for breast reconstruction surgery Rolph Rachel, Duffy James MN, Mehta Saahil N, et al Cochrane Database of Systematic Reviews, 2015,12 This is the protocol for a review and there is no abstract. The objectives are as follows:To assess the effects of acellular dermal matrices in prosthetic breast reconstructions following cancer and prophylactic breast surgery.

OTHER EVIDENCE UPDATES BACK TO TOP

Note: you may need to logon via Athens when clicking on links in this section.

Up-to-date latest: click here (you may need to logon via Athens)

Dynamed updates (you may need to logon via Athens): click here

More from Dynamed: Bisphosphonates in Women with Early Breast Cancer 

In postmenopausal women with early breast cancer, bisphosphonates may reduce breast cancer mortality and bone recurrence.

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In premenopausal women with early breast cancer, bisphosphonates do not appear to reduce breast cancer mortality or bone recurrence

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Overall, bisphosphonates may reduce risk of fracture

For women with breast cancer, bisphosphonates are recommended for the treatment of metastatic disease with evidence of bone destruction (J Clin Oncol 2011 Mar 20;29(9):1221, NCCN website). However, the American Society of Clinical Oncology does not currently recommend bone-modifying agents in women without evidence of bone metastasis, even if other extraskeletal metastases are present. While previous randomized trials have suggested that bisphosphonates may reduce recurrence and increase survival women with early breast cancer (N Engl J Med 2011 Oct 13;365(15):1396, N Engl J Med 2009 Feb 12;360(7):679, Lancet Oncol 2012 Jul;13(7):734), two systematic reviews have found no significant association (Cochrane Database Syst Rev 2012 Feb 15;(2):CD003474, J Natl Compr Canc Netw 2010 Mar;8(3):279). To further investigate the impact of bisphosphonates on breast cancer outcomes, 27

the Early Breast Cancer Trialistsâ&#x20AC;&#x2122; Collaborative Group performed an individual patient data metaanalysis including 18,766 women with early breast cancer from 26 randomized trials comparing adjuvant bisphosphonates vs. control. The mean treatment duration was 3.4 years and 97% of women were treated for 2-5 years. During the median follow-up of 5.6 years, 3,453 women experienced a first recurrence and 2,106 died. Estimated 10-year event rates for recurrence, distant recurrence, bone recurrence, and breast cancer-specific mortality were calculated. Overall, women taking bisphosphonates had a significantly lower risk of a bone recurrence and also had a small, but statistically significant, reduction in breast cancer-specific mortality. However, in subgroup analyses examining demographic, disease-related, and treatment-related factors, bisphosphonate response was influenced by age and menopausal status. For the analysis by menopausal status, there were 11,767 postmenopausal women and 6,171 premenopausal women. Comparing bisphosphonates vs. control in analyses of postmenopausal women, the 10-year breast cancer-specific mortality (14.7% vs. 18%, p = 0.002) and risk of bone recurrence (6.6% vs. 8.8%, p = 0.0002) were significantly lower with adjuvant bisphosphonate therapy. In premenopausal women, there were no significant differences in 10year risk of breast cancer-specific mortality (20.6% vs. 20.7%) or bone recurrence (10.3% vs. 10.3%) comparing bisphosphonates vs. controls. Bisphosphonates were also associated with a reduced risk of fracture in an analysis of 13,341 women from studies reporting this outcome. The results of this meta-analysis contradict two previous systematic reviews finding no significant associations between bisphosphonate treatment and breast cancer recurrence or bone metastases (Cochrane Database Syst Rev 2012 Feb 15;(2):CD003474, J Natl Compr Canc Netw 2010 Mar;8(3):279). These systematic reviews were limited by their inclusion of both early and advance breast cancer patients and more importantly, they did not take into account menopausal status. The current meta-analysis, which used individual patient data rather than trial-level data, found menopausal status significantly influences the effect of bisphosphonates on women with early breast cancer, with positive effects in postmenopausal women only. These results are consistent with one prior systematic review finding no significant difference overall comparing bisphosphonates vs. placebo in women with early breast cancer, but a significant increase in survival in a subgroup analysis of menopausal women (PLoS One 2013;8(8):e70044). Altogether, these results suggest bisphosphonates may be an appropriate adjuvant treatment to help increase survival in postmenopausal women with early breast cancer. For more information, see the Bone-modifying agents in breast cancer topic in DynaMed Plus. DynaMed users click here.

Initial Treatment with Ibrutinib Increases Survival Compared to Chlorambucil in Older Patients with Chronic Lymphocytic Leukemia Reference - RESONATE-2 trial (N Engl J Med 2015 Dec 17;373(25):2425) (level 1 [likely reliable] evidence) 

Ibrutinib is currently recommended for the initial management of chronic lymphocytic leukemia (CLL) only in patients with chromosome 17p deletions.

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Compared to chlorambucil, ibrutinib increased overall survival, progression-free survival, and overall response rates in older patients with previously untreated CLL or small lymphocytic lymphoma without chromosome 17p deletions.

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Although the median treatment duration was longer with ibrutinib, it did not appear to increase adverse events and was associated with a lower rate of discontinuation due to adverse events.

Recommendations for the initial management of chronic lymphocytic leukemia (CLL) vary based on age, fitness, comorbidities, and chromosomal deletions (NCCN 2015 Mar). In patients without chromosome 11 or 17 deletions, chlorambucil alone is currently recommended for patients ≥ 70 years old and younger patients with comorbidities (NCCN 2015 Mar, Ann Oncol 2011 Sep;22 Suppl 6:vi50). Ibrutinib, a covalent inhibitor of Bruton tyrosine kinase, is recommended for initial management of patients with CLL and chromosome 17p deletions. In patients without 17p deletions, ibrutinib is currently approved only as a second-line therapy. To further assess the safety and efficacy of ibrutinib, a recent randomized trial compared ibrutinib 420 mg orally once daily vs. chlorambucil 0.5 mg/kg IV on days 1 and 15 of each 28 day cycle in 269 patients ≥ 65 years old with untreated CLL or small lymphocytic lymphoma without chromosome 17p deletions. Treatment continued until disease progression or the development of unacceptable toxic effects, and patients randomized to chlorambucil could receive a maximum of 12 cycles. The median treatment duration was 17.4 months with ibrutinib vs. 7.1 months with chlorambucil and patients were followed for a median of 18.4 months. Comparing ibrutinib vs. chlorambucil, 24 month overall survival was 98% vs. 85% (p = 0.001) and 18-month progression free survival was 90% vs. 52% (p < 0.001). The overall response rate was 86% in the ibrutinib group vs. 35% in the chlorambucil group (p < 0.001, NNT 2). Ibrutinib was also associated with a lower rate of discontinuation due to adverse events and a significantly greater sustained improvement in hematological parameters. These results were consistent across subgroup analyses by age, sex, disease stage, performance status, chromosome 11q deletion, IGHV mutation, and presence of bulky disease. The most common adverse events associated 29

with ibrutinib were diarrhea, fatigue, nausea, and cough, while nausea, fatigue, neutropenia, anemia, and vomiting were the most commonly reported with chlorambucil. The results of this trial found that ibrutinib was not only more effective than chlorambucil, with higher survival and response rates in the ibrutinib group, but it was also better tolerated. The median treatment duration was much longer with ibrutinib and few patients discontinued treatment due to adverse events. In fact, at the time of the analysis 87% of patients randomized to ibrutinib were still receiving treatment, but only 40% of patients completed the maximum 12 cycles of chlorambucil. Even with the longer exposure time, ibrutinib did not appear to have a higher rate of adverse events. This study also raises a few additional considerations for the treatment of CLL. First, new therapies including obinutuzumab plus chlorambucil and bendamustine plus rituximab are now available. A trial is currently underway comparing bendamustine plus rituximab vs. rituximab plus ibrutinib vs. ibrutinib alone (NCT01886872), and the results of that trial should provide further information on the comparative efficacy of ibrutinib in patients with untreated CLL. Second, longer follow-up is necessary to fully evaluate ibrutinib therapy. However, the overall results of this trial suggest that ibrutinib should be considered for the initial management of all older patients with CLL or small lymphocytic lymphoma, not just patients with chromosome 17p deletions. For more information, see the Initial management of chronic lymphocytic leukemia (CLL) topic in DynaMed Plus. DynaMed users click here.

BMJ Evidence Updates: Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial. Lancet Oncol

Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VRCAP) or vincristine (R-CHOP) for non-GCB DLBCL. Blood

Non-pharmacological nurse-led interventions to manage anxiety in patients with advanced cancer: A systematic literature review. Int J Nurs Stud

Levonorgestrel intrauterine system for endometrial protection in women with breast cancer on adjuvant tamoxifen. Cochrane Database Syst Rev

Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol

Intermittent High-Dose Intravenous Interferon Alfa-2b for Adjuvant Treatment of Stage III Melanoma: Final Analysis of a Randomized Phase III Dermatologic Cooperative Oncology Group Trial. J Clin Oncol

Leukoreduction for the prevention of adverse reactions from allogeneic blood transfusion. Cochrane Database Syst Rev Patient-reported outcomes with anastrozole versus tamoxifen for postmenopausal patients with ductal carcinoma in situ treated with lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet. 2015 Dec 10.

Adjuvant Imatinib for High-Risk GI Stromal Tumor: Analysis of a Randomized Trial J Clin Oncol. 2015 Nov 2 Nedaplatin plus docetaxel versus cisplatin plus docetaxel for advanced or relapsed squamous cell carcinoma of the lung (WJOG5208L): a randomised, open-label, phase 3 trial. Lancet Oncol. 2015 Oct 27.

Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After

Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE). J Clin Oncol. 2015 Dec 10;33(35):4194-201. Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study. Lancet. 2015 Dec 4.

Acute Toxicity and Quality of Life After Dose-Intensified Salvage Radiation Therapy for Biochemically Recurrent Prostate Cancer After Prostatectomy: First Results of the Randomized Trial SAKK 09/10. J Clin Oncol

Effect of Opioids vs NSAIDs and Larger vs Smaller Chest Tube Size on Pain Control and Pleurodesis Efficacy Among Patients With Malignant Pleural Effusion: The TIME1 Randomized Clinical Trial. JAMA

Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study. Lancet

Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas. J Clin Oncol

Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial. Lancet 32

Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host Disease. N Engl J Med

Standard first-line chemotherapy with or without nintedanib for advanced ovarian cancer (AGO-OVAR 12): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol

Interval debulking surgery for advanced epithelial ovarian cancer. Cochrane Database Syst Rev

Exercise for Men with Prostate Cancer: A Systematic Review and Meta-analysis. Eur Urol

Implementation and validation of a risk stratification method at The Ottawa Hospital to guide thromboprophylaxis in ambulatory cancer patients at intermediate-high risk for venous thrombosis. Thromb Res

Randomized Double-Blind Trial of Pregabalin Versus Placebo in Conjunction With Palliative Radiotherapy for Cancer-Induced Bone Pain. J Clin Oncol

Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial. Lancet Oncol

Surgery for the resolution of symptoms in malignant bowel obstruction in advanced gynaecological and gastrointestinal cancer. Cochrane Database Syst Rev

S-1 plus leucovorin versus S-1 plus leucovorin and oxaliplatin versus S-1 plus cisplatin in patients with advanced gastric cancer: a randomised, multicentre, open-label, phase 2 trial. Lancet Oncol

Ovarian Suppression With Triptorelin During Adjuvant Breast Cancer Chemotherapy and Long-term Ovarian Function, Pregnancies, and Disease-Free Survival: A Randomized Clinical Trial. JAMA

Bevacizumab for newly diagnosed pleural mesothelioma in the Mesothelioma Avastin Cisplatin Pemetrexed Study (MAPS): a randomised, controlled, open-label, phase 3 trial. Lancet

Ovarian cancer screening and mortality in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial. Lancet

Prophylactic antibiotics or G(M)-CSF for the prevention of infections and improvement of survival in cancer patients receiving myelotoxic chemotherapy. Cochrane Database Syst Rev

Anastrozole versus tamoxifen for the prevention of locoregional and contralateral breast cancer in postmenopausal women with locally excised ductal carcinoma in situ (IBIS-II DCIS): a double-blind, randomised controlled trial. Lancet

NICE guidance: ď&#x201A;ˇ

VivaScope 1500 and 3000 imaging systems for detecting skin cancer lesions - guidance (DG19) NICE has assessed the VivaScope 1500 and 3000 (MAVIG) imaging systems for skin cancer lesions to help the NHS decide whether to use these products

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Pembrolizumab for advanced melanoma not previously treated with ipilimumab: www.nice.org.uk/guidance/ta366

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Erlotinib and gefitinib for treating non-small-cell lung cancer that has progressed after prior chemotherapy: http://www.nice.org.uk/guidance/ta374

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Bortezomib for previously untreated mantle cell lymphoma http://www.nice.org.uk/guidance/ta370

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New End of Life Care guidance (NICE): End-of-life care in England must be tailored to the needs of dying patients rather than a "tick-box approach", the health watchdog NICE says. Patients must be treated with respect and compassion, it said, and doctors should avoid making "snap decisions" about whether someone was dying. The guidance is designed to address misuse of the previous system, the Liverpool Care Pathway.

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CANCER IN THE NEWS BACK TO TOP

B. NHS Behind the Headlines Blood test could help improve prostate cancer outcomes "A blood test can determine whether prostate cancer patients are likely to respond to drugs," BBC News reports. The test assesses whether men with prostate cancer have a good chance, or not, of responding well to a drug called abiraterone…

More Early Breast Cancers Detected on Screening, Fewer Invasive Cancers Later? By Amy Orciari Herman Detection of ductal carcinoma in situ (DCIS) during mammographic screening is associated with lower risk for invasive breast cancer in the following 3 years, according to a retrospective study in the Lancet Oncology. Researchers examined data on over 5.2 million women aged 50–64 who underwent mammography at 84 U.K. screening units between 2003 and 2007. Across the units, risk for invasive cancer within 3 years after screening appeared to decrease as the rate of screendetected DCIS increased. The researchers estimate that when DCIS is detected in up to 1.5 per 1000 women screened, two invasive interval cancers are avoided for every three DCIS cases. When it's detected in 1.5–2.5 per 1000 women, one interval cancer is avoided for every five DCIS cases (with this higher detection rate, some DCIS cases could be less aggressive lesions, the authors note). Commenting on the DCIS cases that did not appear to lead to invasive cancer, the lead author told the Wall Street Journal: "We can't be sure they would not have progressed. It may have taken longer than three years." A Lancet Oncology commentator notes that the findings "do not mitigate the harms due to overdiagnosis caused by the detection of low-grade DCIS, which represents about 15% of screen-detected DCIS." And Dr. Andrew Kaunitz of NEJM Journal Watch Women's Health says: "For me ... the short 3-year follow-up makes the clinical implications of this report hard to interpret." Lancet Oncology article (Free PDF)

Melanoma at Arm's Length Hensin Tsao, MD, PhD Reviewing Ribero S et al., Br J Dermatol 2015 Dec 14; For predicting total body nevi count, it appears that the arm is the window to the whole…In terms of moles, it appears that the arm is the window to the whole. An arm mole count of 11 or more strongly correlates with a total mole count greater than 100, indicating elevated melanoma risk. Arm nevi count could be an easy marker of risk considered alongside other features such as complexion, hair color, and personal and family history of skin cancer.

Melanoma Meets Microbiome Kenneth Y. Tsai, MD, PhD Reviewing Vétizou M et al., Science 2015 Nov 27; 350:1079 Two groundbreaking studies implicate specific bacterial species in regulating gut immunity and response to immunotherapy in physically distant tumors — an entirely new angle in cancer therapy…These technically difficult and groundbreaking studies implicate specific bacterial species in regulating gut immunity and responses to immunotherapies in physically distant tumors. This approach presents an entirely new angle in cancer therapy. How important the gut microbiome is as a determinant of response to therapy is not yet known, but immunotherapies may be optimized by manipulation of the GI microbiome in the future.

Other items of interest 

Pregnancy Doesn't Heighten Risk for Hodgkin Lymphoma Relapse (CME/CE)

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CardioBreak: FDA Looks at Ezetimibe, VTE Tx in Cancer

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Breast cancer preventive therapy ignored

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Prostate cancer found earlier, treated less aggressively

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5 unmet concerns of brain tumour patients

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Enzyme Drives Mutation in Breast Cancer (CME/CE)

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High-risk women reject breast cancer prevention

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Carboplatin Role in Triple-Negative Breast Cancer Unresolved (CME/CE)

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Slippery Slope: Is Afinitor for Breast Cancer Avastin Redux?

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Alecensa Approved for Lung Cancer Tied to Gene Mutation

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Vistogard Approved for Chemotherapy Overdose

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Early Chemo Less Likely to Help Black Breast Cancer Patients

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'Liquid Biopsy' Finds Estrogen Receptor Mutations (CME/CE)

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Little Activity With PD-L1 Drug in Breast Cancer (CME/CE)

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Could a Scan Someday Replace Lymph Node Biopsy?

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Depression May Be Tied to Lower Breast Cancer Survival

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Timing May Be Key to Success of Surgery, Chemo for Early Breast Cancer

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Some Breast Cancer Patients Can Skip Chemo (CME/CE)

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New Model for Prostate Cancer Screening Reduces Biopsies

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Breast surgeon faces 21 charges of unlawfully wounding 11 patients

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Validation of First-Line Pazopanib in Metastatic Renal Carcinoma 37

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Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma

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Androgen Receptor Expression Signals Beneficial Tamoxifen Response in Estrogen Receptor– Negative Breast Cancer

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Incidence of Radiation-Induced Breast Cancer Examined

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One-Third of Invasive Penile Cancers Contain HPV DNA

REPORTS, PUBLICATIONS AND RESOURCES

Guidelines/guidance: High-quality primary palliative care delivery in medical oncology A new guidance statement has been developed by the American Society of Clinical Oncology (ASCO) and the American Academy of Hospice and Palliative Medicine (AAHPM). The two organizations have partnered to develop these recommendations to help medical oncology practices identify essential palliative care services and deliver high-quality primary palliative care to patients with cancer.

Guidelines Issued on Caring for Breast Cancer Survivors By Kristin J. Kelley The American Cancer Society and the American Society of Clinical Oncology have released guidelines for primary care clinicians and other providers on how to best care for adult women after breast cancer treatment. The guidelines, published in the Journal of Clinical Oncology, provide recommendations for five key areas of survivorship, and include the following: 

Surveillance for Recurrence: Survivors should have physical exams every 3–6 months for 3 years after primary therapy, every 6–12 months for the next 2 years, and then annually.

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Screening for Other Primary Cancers: Patients should be screened just like patients in the general population are.

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Management of Late Effects of Cancer and Its Treatment: Providers should assess patients for body image concerns and for symptoms including fatigue, depression, and pain after treatment, as well as counsel them on how to prevent lymphedema.

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Health Promotion: Clinicians should counsel patients on maintaining good health (e.g., exercise, nutrition, smoking cessation).

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Care Coordination: Providers should work with the patient's oncologists and caregivers to implement a survivorship care plan.

Journal of Clinical Oncology article (Free)

Quality of Death Index The Economist Intelligence Unit’s Quality of Death Index, commissioned by the Lien Foundation, highlights advances as well as the remaining challenges and gaps in policy and infrastructure. This second edition of the Index, updated and expanding upon the first iteration published in 2010, found rich nations, including the UK, tend to rank highest. As in 2010 the UK ranks first thanks to

comprehensive national policies, the extensive integration of palliative care into its National Health Service, and a strong hospice movement. It also earns the top score in quality of care. Australia and New Zealand come second and third overall, and four other comparatively rich Asia-Pacific countries achieve rankings in the top 20. Otherwise, European countries dominate the top 20, with the addition of the US and Canada at positions 9 and 11, respectively.

NEW free online education in cancer genetics Colleagues at Plymouth University have used an educational grant to develop four modules on genetic testing in familial breast and ovarian cancer, mainly aimed at health professionals working in cancer care. The four modules are now ready for use, with pre and post module quizzes for each. These are interactive online modules, offered free of charge for any health professional. They are designed to be completed as continuing professional education and we will issue a certificate for those who achieve a satisfactory score after finishing each module. Students need to register on the course page HERE and can then access all modules free of charge.

USPSTF Updates Screening Mammography Guidance for Average-Risk Women By Andrew M. Kaunitz, MD The U.S. Preventive Services Task Force has updated its screening mammography guidance, with particular attention given to individualized screening for women in their 40s, tomosynthesis, and adjunctive imaging for women with radiologically dense breast tissue. The new guidance — published in the Annals of Internal Medicine — doesn't apply to women at substantially increased risk for breast cancer. Key statements are as follows: 

Biennial screening is recommended for women aged 50 to 74 (B recommendation).

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Initiation of screening before age 50 should be individualized depending on patient preferences (C recommendation).

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For women aged ≥75, current evidence is insufficient to assess the benefits and harms of screening (I statement).

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Current evidence is insufficient to assess the benefits and harms of adding tomosynthesis to conventional screening mammography (I statement).

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For women with radiologically dense breasts, current evidence is insufficient to assess the benefits and harms of adjunctive ultrasound, magnetic resonance imaging (MRI), or tomosynthesis (I statement).

Although I plan to continue recommending screening based on USPSTF guidance, I will also continue to support the preferences of my patients who prefer to initiate screening before age 50, to undergo screening annually, and to continue screening after age 74. Click here for UPPSTF recommendation: statement

TRAINING & NETWORKING OPPORTUNITIES, CONFERENCES, EVENTS BACK TO TOP

British Psychosocial Oncology Society Conference â&#x20AC;&#x201C; Cambridge, March 2016 Psychosocial Oncology is the field of study concerned with psychological, social and behavioural aspects of cancer. The British Psychosocial Oncology Society (BPOS) work not only with those who have been diagnosed with cancer, but also their families, friends and the professionals who care for them, and work across the cancer spectrum, from thinking about prevention, screening before cancer is diagnosed, through treatment, and into survivorship and end of life care. The BPOS annual conference Promoting the advancement of education, clinical practice, and research in psychosocial oncology and AGM will be held on Thursday 3 to Friday 4 March 2016 at Madingley Hall, Cambridge. The conference has a dual theme: integrated care and patient experiences.

14th International Congress in Targeted Anticancer Therapies (TAT2016) The congress will be held in Washington, DC, March 23-26. Deadline for the submission of abstracts is Jan. 15. Contact Congress By Design, P.O. Box 77, 3480 DB Harmelen, the Netherlands; or call (31) 88 089 8101; or fax (31) 88 089 8109; or e-mail tat@congressbydesign.com ; or see.

OTHER SERVICES BACK TO TOP A. Literature & Evidence searches 

Are you looking for the latest evidence-based research, but haven’t got time to trawl the databases?

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Do you need a literature search carried out?

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Do you need to find evidence to support an improvement?

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Do you want to know how something has been done elsewhere and whether it worked?

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Library staff provide a literature and evidence search service for busy clinicians who are pressed for time.

To request a search, please complete and return this form, providing as much information as possible. Alternatively if you would like an assisted search training session, where we will sit down with you and go through the steps of a literature search, then please contact the library. B. Journal clubs Do you have a journal club or are thinking of starting one up? If so, please contact the Library. We will be happy to attend any new or existing journal club in a contributory or facilitating role.

TRAINING AND ATHENS BACK TO TOP

Most electronic resources are available via an Athens password. You can register for this via the Library intranet page, or from home at http://www.swice.nhs.uk/ and following the link for Athens self-registration. Please note that registering from home will take longer as it will need to be verified that you are NHS staff/student on placement. Library staff are available to train individual staff or small groups. Training can take place in the library or at your work place if you have access to appropriate IT facilities. COURSES INCLUDE: Library Induction You will be given a detailed overview of all library information systems and resources and how to use them. Library registration and obtaining an OpenAthens password are included. Accessing NHS eResources You will be introduced to all the electronic information resources available to NHS staff including eJournals, eBooks, healthcare databases and useful websites.

Searching for Evidence (beginners) You will be introduced to the 8 leading healthcare databases and shown how to plan your literature search, how to execute it effectively and how to save and print your results. Searching for Evidence (advanced) You will be shown how to search across multiple databases, how to use the thesaurus, the subject headings and the full range of limit options. Introduction to Critical Appraisal This course introduces the basics of critical appraisal and its role in evidence-based practice. Pre-Course Skills Parts 1 & 2 These 2 sessions are designed for staff about to start a course who need a thorough update on information gathering skills. Attendance at both sessions is required. Library Mini-Breaks 30 minute sessions tailored to meet your needs e.g. Cochrane Library, how to find clinical guidelines, using eBooks, library electronic A-Z website, RSS feeds, journal contents pages using Outlook. Rapid Evidence Searching NEW Using tried and tested techniques, rapid searching of the evidence base for when quick solutions are needed. Reflective Practice NEW How to read and comment upon a paper Writing for publication NEW Everything you need to know about writing a paper for publication Collaborative "Living Evidence" Searching/Appraisal NEW Group searching/appraisal of evidence in computer labs (suitable for MDTs and similar).

TO BOOK A COURSE, click here