ICON8 investigated the safety and efficacy of weekly dose dense chemotherapy (q1w) in patients with epithelial ovarian cancer (EOC) compared to standard three weekly chemotherapy (q3w). ICON8 had co-primary outcomes of progression free (PFS) and overall survival (OS). Mature OS and updated PFS results are reported here.

Etoposide (E) at 100 mg/m2 combined with Cisplatin (P) at 20 mg/m2 represents an induction 2-day regimen embedded in our clinical practice for patients with advanced GCT or TN at high risk of early death. We evaluated 24/7 Em-EP administration to a combined GCT-TN cohort at our Emergency Cancer Treatment Centre (ECTC) to determine its efficacy within the acute setting. Patients who received Em-EP during a five-year interval were identified from electronic databases at Imperial College Healthcare NHS Trust. Data collected included demographics, treatment details and clinical outcome. Em-EP was administered in the emergency setting to 104 patients, predominantly young adults (median age 35, range 17–71). Half the cases were GCT (n = 52): 22 male (6 seminomas, 13 non-seminomas); 30 female (2 dysgerminomas, 28 non-dysgerminomas). The other 50% were treated for TN (n = 52): 45 gestational (GTN) and 7 non-gestational. Most patients received Em-EP for a new cancer diagnosis (n = 100, 96%), within 24 h (n = 93, 89%) and out-of-hours (n = 74, 70%). Indications for Em-EP included symptomatic disease (n = 66, 63%), high-burden disease, (n = 51, 49%) and organ failure requiring Intensive Care Unit support (n = 9, 9%). Neutropenic sepsis was observed in 5%. Four-week overall survival after Em-EP administration was 98%. Despite the potentially fatal complications encountered in the acute setting, early mortality with Em-EP is low at our ECTC. Specialist units that treat unwell patients with advanced GCT or TN should consider making Em-EP available 24/7 for emergency administration. Its efficacy within a prospective cohort and in other platinum-sensitive malignancies requires evaluation.

Background Carboplatin and paclitaxel administered every 3 weeks is standard-of-care first-line chemotherapy for epithelial ovarian cancer. The Japanese JGOG3016 trial showed a significant improvement in progression-free and overall survival with dose-dense weekly paclitaxel and 3-weekly carboplatin. In this study, we aimed to compare efficacy and safety of two dose-dense weekly regimens to standard 3-weekly chemotherapy in a predominantly European population with epithelial ovarian cancer. Methods In this phase 3 trial, women with newly diagnosed International Federation of Gynecology and Obstetrics stage IC-IV epithelial ovarian cancer were randomly assigned to group 1 (carboplatin area under the curve [AUC]5 or AUC6 and 175 mg/m(2) paclitaxel every 3 weeks), group 2 (carboplatin AUC5 or AUC6 every 3 weeks and 80 mg/m(2) paclitaxel weekly), or group 3 (carboplatin AUC2 and 80 mg/m(2) paclitaxel weekly). Written informed consent was provided by all women who entered the trial. The protocol had the appropriate national research ethics committee approval for the countries where the study was conducted. Patients entered the trial after immediate primary surgery, or before neoadjuvant chemotherapy with subsequent planned delayed primary surgery. The trial coprimary outcomes were progression-free survival and overall survival. Data analyses were done on an intention-to-treat basis, and were powered to detect a hazard ratio of 0 .75 in progression-free survival. The main comparisons were between the control group (group 1) and each of the weekly research groups (groups 2 and 3). Findings Between June 6, 2011, and Nov 28, 2014, 1566 women were randomly assigned to treatment. 72% (365), completed six protocol-defined treatment cycles in group 1, 60% (305) in group 2, and 63% (322) in group 3, although 90% (454), 89% (454), and 85% (437) completed six platinum-based chemotherapy cycles, respectively. Paclitaxel dose intensification was achieved with weekly treatment (median total paclitaxel dose 1010 mg/m(2) in group 1; 1233 mg/m(2) in group 2; 1274 mg/m(2) in group 3). By February, 2017, 1018 (65%) patients had experienced disease progression. No significant progression-free survival increase was observed with either weekly regimen (restricted mean survival time 24.4 months [97.5% CI 23.0-26.0] in group 1, 24.9 months [24.0-25.9] in group 2, 25.3 months [23.9-26.9] in group 3; median progression-free survival 17.7 months [IQR 10.6-not reached] in group 1, 20.8 months [11.9-59.0] in group 2, 21.0 months [12.0-54.0] in group 3; log-rank p=0.35 for group 2 vs group 1; group 3 vs 1 p=0.51). Although grade 3 or 4 toxic effects increased with weekly treatment, these effects were predominantly uncomplicated. Febrile neutropenia and sensory neuropathy incidences were similar across groups. Interpretation Weekly dose-dense chemotherapy can be delivered successfully as first-line treatment for epithelial ovarian cancer but does not significantly improve progression-free survival compared with standard 3-weekly chemotherapy in predominantly European populations. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.

Background: For several decades, standard first-line chemotherapy for EOC has been carboplatin (C) and paclitaxel (T), administered 3-weekly (q3w). The JGOG3016 trial reported clinically significant lengthening of PFS and overall survival in Japanese women using dose-dense weekly (q1w) T but with increased toxicity. ICON8 is a 3-arm trial, comparing standard q3w CT with dose-dense q1w regimens in a predominantly European patient group. Methods: Eligible women with FIGO stage IcG3- IV EOC were randomised 1:1:1 to Arm 1 (standard) - q3w C AUC5/6 + q3w T 175mg/m2; Arm 2 - q3w C AUC5/6 + q1w T 80mg/m2; Arm 3 - q1w C AUC2 + q1w T 80 mg/m2. Patients entered ICON8 after immediate primary surgery (IPS), or received neo-adjuvant chemotherapy with planned delayed primary surgery (DPS). Primary intention to treat analysis compared arm 2v1 and arm 3v1 using methods for data with non-proportional hazards. Results: 1566 women were randomised Jun 2011-Nov 2014. Median age- 62 years, 72% serous histology, 93% ECOG performance status 0/1. 48% had IPS, 50% planned DPS, 2% inoperable. 72%, 60%, 63% completed 6 cycles protocol-defined treatment in arms 1, 2, 3. Completion rate for 6 cycles platinum was 88% (90%; 89%; 85%). Paclitaxel dose-intensification was achieved (median total dose T (mg/m2)-1011; 1234; 1274). Grade (G) 3/4 toxicity (predominantly uncomplicated low neutrophils) was seen in 42%; 63%; 53% patients. Incidence of G3/4 febrile neutropenia (4%; 6%; 3%) and ≥G2 sensory neuropathy (28%; 25%; 23%) were similar across arms. At Feb 2017, 64% patients had experienced disease progression. No significant increase in PFS was observed with either weekly treatment (log-rank arm 2v1 p = 0.45; arm 3v1 p = 0.56, non-proportionality p = 0.02, restricted mean survival time=24.4; 24.9; 25.3 months in arms 1, 2, 3, median PFS- 17.9; 20.6; 21.1months, HR = 0.92 arm 2v1, HR = 0.94 arm 3v1). Conclusions: Although weekly dose-dense chemotherapy can be delivered successfully as first-line EOC treatment without substantial toxicity increase, it does not significantly improve PFS compared to standard 3-weekly CT. Clinical trial identification: ISRCTN: ISRCTN10356387 EUDRACT: 2010-022209-16 CTA: 2010-022209-16 ENGOT: OV-13 MREC: 11/LO/0043 Legal entity responsible for the study: Medical Research Council Clinical Trials Unit at University College London Funding: Cancer Research UK; Medical Research Council Disclosure: All authors have declared no conflicts of interest.

Opportunities to enter patients into more than one clinical trial are not routinely considered in cancer research and experiences with co-enrolment are rarely reported. Potential benefits of allowing appropriate co-enrolment have been identified in other settings but there is a lack of evidence base or guidance to inform these decisions in oncology. Here, we discuss the benefits and challenges associated with co-enrolment based on experiences in the Add-Aspirin trial – a large, multicentre trial recruiting across a number of tumour types, where opportunities to co-enrol patients have been proactively explored and managed. The potential benefits of co-enrolment include: improving recruitment feasibility; increased opportunities for patients to participate in trials; and collection of robust data on combinations of interventions, which will ensure the ongoing relevance of individual trials and provide more cohesive evidence to guide the management of future patients. There are a number of perceived barriers to co-enrolment in terms of scientific, safety and ethical issues, which warrant consideration on a trial-by-trial basis. In many cases, any potential effect on the results of the trials will be negligible – limited by a number of factors, including the overlap in trial cohorts. Participant representatives stress the importance of autonomy to decide about trial enrolment, providing a compelling argument for offering co-enrolment where there are multiple trials that are relevant to a patient and no concerns regarding safety or the integrity of the trials. A number of measures are proposed for managing and monitoring co-enrolment. Ensuring acceptability to (potential) participants is paramount. Opportunities to enter patients into more than one cancer trial should be considered more routinely. Where planned and managed appropriately, co-enrolment can offer a number of benefits in terms of both scientific value and efficiency of study conduct, and will increase the opportunities for patients to participate in, and benefit from, clinical research.

OBJECTIVE:To quantify the risk of developing post-molar gestational trophoblastic neoplasia (pGTN) beyond the first normal human chorionic gonadotrophin (hCG) in women who have had a complete (CHM) or partial molar pregnancy (PHM) and to re-evaluate the current UK Hydatidiform mole hCG surveillance guidelines.METHODS:The Charing Cross Hospital Trophoblast Disease Centre database was screened to identify all registered cases of hydatidiform mole (HM) between 1980 and 2009.RESULTS:We identified 20,144 cases of HM, comprising 8400 CHM, 9586 PHM, and 2158 cases of unclassified hydatidiform mole (UHM). Twenty-nine cases (20 CHM, 3 PHM and 6 UHM) developed pGTN after the first normal hCG. For CHM the risk of pGTN at the point of hCG normalisation was 1 in 406, and fell rapidly in the first six months of monitoring. For PHM the risk of pGTN at the point of hCG normalisation was 1 in 3195. Women with CHM where hCG normalisation occurred beyond 56days after uterine evacuation of molar tissue were found to have a 3.8-fold higher risk of pGTN.CONCLUSIONS:Our results show that pGTN can occur after hCG normalisation following PHM but the risk is extremely low. Women with CHM have a comparatively higher risk of pGTN after hCG normalisation. Those with CHM where hCG normalises within 56days have a lower risk of pGTN. We have revised the current UK hCG surveillance protocol for PHM to a single additional confirmatory normal urine hCG measurement one month after first normalisation. The protocol for CHM remains unchanged.

There is now a considerable body of data supporting the hypothesis that aspirin could be effective in the prevention and treatment of colorectal cancer, and a number of phase III randomised controlled trials designed to evaluate the role of aspirin in the treatment of colorectal cancer are ongoing. Although generally well tolerated, aspirin can have adverse effects, including dyspepsia and, infrequently, bleeding. To ensure a favourable balance of benefits and risks from aspirin, a more personalised assessment of the advantages and disadvantages is required. Emerging data suggest that tumour PIK3CA mutation status, expression of cyclo-oxygenase-2 and human leukocyte antigen class I, along with certain germline polymorphisms, might all help to identify individuals who stand to gain most. We review both the underpinning evidence and current data, on clinical, molecular and genetic biomarkers for aspirin use in the prevention and treatment of colorectal cancer, and discuss the opportunities for further biomarker research provided by ongoing trials.

ICON8 is a randomised GCIG phase III 3-arm trial comparing 6 cycles of standard 3-weekly (q3w) carboplatin/paclitaxel with weekly (q1w) dose-dense treatment. Patients had immediate primary surgery (IPS) or neo-adjuvant chemotherapy and delayed primary surgery (DPS) after 3 cycles. Two interim analyses were planned: 1A, first 50 patients (pts) in each arm; 1B, first 50 DPS pts in each arm, ICON8 being the first trial of dose-dense treatment with DPS. 1566 women were randomised between Jun 2011 and Nov 2014 to: Arm 1 - q3w carboplatin AUC5/6 + paclitaxel 175mg/m2; Arm 2 - q3w carboplatin AUC5/6 + q1w paclitaxel 80mg/m2; Arm 3 - q1w carboplatin AUC2 + paclitaxel 80 mg/m2. The interim safety analyses included 237 patients. Feasibility was measured by completion of protocol treatment, safety by the rate of any G3+ toxicity experienced per patient. Stage 1A analysis included 85 IPS and 65 DPS pts, median age 59 years and 64% stage IIIC/IV disease. Stage 1B included 87 further DPS pts (total DPS = 152), median age 62 years, 92% stage IIIC/IV. Protocol treatment completion was lower than expected but >80% 1A and >75% 1B pts received 6 cycles of platinum chemotherapy. Increased paclitaxel dose intensity was achieved (see table). Most common reason for not completing protocol treatment was toxicity. G3+ toxicity was more frequent in arms 2 and 3, mainly due to uncomplicated neutropenia.Tabled 1Stage 1AStage 1AStage 1AStage 1BStage 1BStage 1BArm 1 n = 50Arm 2 n = 50Arm 3 n = 50Arm 1 n = 50Arm 2 n = 52Arm 3 n = 50FeasibilityProtocol treatment completion, N(%) P-value (compared to arm 1)39 (78%) -29 (58%) 0.0329 (58%) 0.0329 (58%) -34 (65%) 0.4725 (50%) 0.426 cycles platinum chemotherapy, N(%) P-value (compared to arm 1)44 (88%) -46 (92%) 0.5140 (80%) 0.2340 (80%) -46 (88%) 0.2739 (78%) 0.81Carboplatin dose intensity (AUC/week) median1.791.861.831.821.781.77Paclitaxel dose intensity (mg/m2/weed) median53.564.167.851.365.567.9ToxicityG3/4+ Toxicity, N(%)17 (35%)29 (58%)24 (48%)24 (50%)33 (63%)23 (46%)G3/4+ Uncomplicated neutropenia, N(%)4 (8%)16 (32%)11 (22%)5 (10%)19 (37%)13 (26%)G3/4+ Febrile neutropenia, N(%)2 (4%)1 (2%)1 (2%)1 (2%)3 (6%)0G3/4+ Thrombocytopenia, N(%)2 (4%)2 (4%)1 (2%)2 (4%)3 (6%)1 (2%)G2+ Sensory neuropathy, N(%)12 (25%)15 (30%)9 (18%)16 (33%)6 (12%)5 (10%) Open table in a new tab Completion of 6 cycles of platinum chemotherapy was high; however, protocol-defined q1w regimens were frequently modified. Protocol treatment completion differed significantly between arms in stage 1A, but not 1B, perhaps reflecting q3w paclitaxel toxicity in DPS patients. Rates of clinically relevant toxicity were acceptable, and despite aggressive dosing thresholds febrile neutropenia was rare. No dose modifications were implemented following stage 1A/1B analyses, but early use of G-CSF was recommended. PFS results are expected in Q2 2017, OS in 2018.

Background: Metformin use has been associated with a reduced risk of developing cancer and an improvement in overall cancer survival rates in meta-analyses, but, to date, evidence to support the use of metformin as an adjuvant therapy in individual cancer types has not been presented.Patients and methods: We systematically searched research databases, conference abstracts and trial registries for any studies reporting cancer outcomes for individual tumour types in metformin users compared with non-users, and extracted data on patients with early-stage cancer. Studies were assessed for design and quality, and a meta-analysis was conducted to quantify the adjuvant effect of metformin on recurrence-free survival (RFS), overall survival (OS) and cancer-specific survival (CSS), to inform future trial design.Results: Of 7670 articles screened, 27 eligible studies were identified comprising 24 178 participants, all enrolled in observational studies. In those with early-stage colorectal cancer, metformin use was associated with a significant benefit in all outcomes [RFS hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.47-0.85; OS HR 0.69, CI 0.58-0.83; CSS HR 0.58, CI 0.39-0.86]. For men with early-stage prostate cancer, metformin was associated with significant, or borderline significant, benefits in all outcomes (RFS HR 0.83, CI 0.69-1.00; OS HR 0.82, CI 0.73-0.93; CSS HR 0.58, CI 0.37-0.93); however, there was significant heterogeneity between studies. The data suggest that prostate cancer patients treated with radical radiotherapy may benefit more from metformin (RFS HR 0.45, CI 0.29-0.70). In breast and urothelial cancer, no significant benefits were identified. Sufficient data were not available to conduct analyses on the impact of metformin dose and duration.Conclusions: Our findings suggest that metformin could be a useful adjuvant agent, with the greatest benefits seen in colorectal and prostate cancer, particularly in those receiving radical radiotherapy, and randomised, controlled trials which investigate dose and duration, alongside efficacy, are advocated.

BackgroundThere is a considerable body of pre-clinical, epidemiological and randomised data to support the hypothesis that aspirin has the potential to be an effective adjuvant cancer therapy.MethodsAdd-Aspirin is a phase III, multi-centre, double-blind, placebo-controlled randomised trial with four parallel cohorts. Patients who have undergone potentially curative treatment for breast (n=3100), colorectal (n=2600), gastro-oesophageal (n=2100) or prostate cancer (n=2120) are registered into four tumour specific cohorts. All cohorts recruit in the United Kingdom, with the breast and gastro-oesophageal cohort also recruiting in India. Eligible participants first undertake an active run-in period where 100mg aspirin is taken daily for approximately eight weeks. Participants who are able to adhere and tolerate aspirin then undergo a double-blind randomisation and are allocated in a 1:1:1 ratio to either 100mg aspirin, 300mg aspirin or a matched placebo to be taken daily for at least five years. Those participants ≥75years old are only randomised to 100mg aspirin or placebo due to increased toxicity risk.ResultsThe primary outcome measures are invasive disease-free survival for the breast cohort, disease-free survival for the colorectal cohort, overall survival for the gastro-oesophageal cohort, and biochemical recurrence-free survival for the prostate cohort, with a co-primary outcome of overall survival across all cohorts. Secondary outcomes include adherence, toxicity including serious haemorrhage, cardiovascular events and some cohort specific measures.ConclusionsThe Add-Aspirin trial investigates whether regular aspirin use after standard therapy prevents recurrence and prolongs survival in participants with four non-metastatic common solid tumours.

Repurposing drugs as anticancer therapeutics could shorten the conventional investigational pathway and open multiple new avenues of investigation [[1]Scannell J.W. Blanckley A. Boldon H. Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency.Nat Rev Drug Discov. 2012; 11: 191-200Crossref PubMed Scopus (1211) Google Scholar]. Evidence of potential anticancer effects can be collated from in vitro and in vivo models, taking into account whether biologically/clinically relevant concentrations or doses of the drug have been evaluated. With drugs already in widespread use for an alternative indication, data on cancer incidence and mortality may be available from epidemiological studies or preferably randomised controlled trials (RCTs) investigating the drug in the alternate situation. Anticancer effects of the candidate drug may be subtle, requiring prolonged use, as major short-term effects should have been previously identified. To show an effect in a prospective trial requires a population with a low cancer burden but high event rate who can receive the therapy for sufficient time to see a therapeutic benefit. For these reasons adjuvant trials are attractive. Aspirin, developed for its analgesic/anti-inflammatory properties was repurposed once as a cardiovascular drug and is now under investigation as an anticancer agent [[2]Langley R.E. Burdett S. Tierney J.F. Cafferty F. Parmar M.K. Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy?.Br J Cancer. 2011; 105: 1107-1113Crossref PubMed Scopus (119) Google Scholar] after meta-analyses of cardio/cerebrovascular trials showed a reduction in cancer incidence, cancers presenting with metastases and cancer deaths in patients on aspirin [3Rothwell P.M. Fowkes F.G. Belch J.F. Ogawa H. Warlow C.P. Meade T.W. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.Lancet. 2011; 377: 31-41Abstract Full Text Full Text PDF PubMed Scopus (1184) Google Scholar, 4Rothwell P.M. Wilson M. Price J.F. Belch J.F. Meade T.W. Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials.Lancet. 2012; 379: 1591-1601Abstract Full Text Full Text PDF PubMed Scopus (743) Google Scholar]. Add-Aspirin is an RCT designed to assess the potential benefits of aspirin after primary curative therapy for non-metastatic cancer [[5]Phillips I. Langley R. Gilbert D. Ring A. Aspirin as a treatment for cancer.Clin Oncol. 2013; 25: 333-335Abstract Full Text Full Text PDF Scopus (22) Google Scholar]. Attention has now turned to further opportunities for repurposing agents in the adjuvant setting.Vitamin D: Mode of Action and Biological HypothesesVitamin D refers to a group of fat soluble molecules, of which 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) is the active form. Vitamin D can be attained from the diet but mainly derives from the action of UVB on 7-dehydrocholesterol in skin. This is hydroxylated in the liver and then again in the proximal tubules of the kidneys to produce 1,25(OH)2D3 (Figure 1a) and acts via the nuclear vitamin D receptor. Vitamin D has a well-characterised role in the maintenance of skeletal calcium balance but the vitamin D receptor has been found in almost every tissue, including cancer cells [[6]Nagpal S. Na S. Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands.Endocr Rev. 2005; 26: 662-687Crossref PubMed Scopus (770) Google Scholar]. In vitro at least, 1,25(OH)2D3 shows a range of potentially beneficial effects (Figure 1b) against many of the hallmarks of cancer [[7]Feldman D. Krishnan A.V. Swami S. Giovannucci E. Feldman B.J. The role of vitamin D in reducing cancer risk and progression.Nat Rev. 2014; 14: 342-357Crossref Scopus (857) Google Scholar]. Anti-proliferative effects are observed (via pRB-E2F, β-catenin/E-Cadherin, Wnt, epidermal growth factor receptor and IGFR signalling and repression of C-myc). Vitamin D can induce apoptosis in vitro at biologically relevant concentrations in colonic, breast and prostate cancer cell lines [[8]Leyssens C. Verlinden L. Verstuyf A. Antineoplastic effects of 1,25(OH)2D3 and its analogs in breast, prostate and colorectal cancer.Endocr Relat Cancer. 2013 Mar 22; 20: R31-R47Crossref PubMed Scopus (86) Google Scholar]. Vitamin D suppresses angiogenesis and modulates tumour invasion and diminishes inflammatory pathways associated with cancer, decreasing cyclooxygenase-2 and increasing 15-PGDH. These anticancer effects seem to translate in vivo in mouse models at least [[7]Feldman D. Krishnan A.V. Swami S. Giovannucci E. Feldman B.J. The role of vitamin D in reducing cancer risk and progression.Nat Rev. 2014; 14: 342-357Crossref Scopus (857) Google Scholar]. It has also been hypothesised that vitamin D might modulate antibody-dependent cellular cytotoxicity, specifically in the therapeutic use of rituximab against CD20+ lymphomas [[9]Bittenbring J.T. Neumann F. Altmann B. et al.Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large B-cell lymphoma treated with but not without rituximab.J Clin Oncol. 2014; 32: 3242-3248Crossref PubMed Scopus (110) Google Scholar]. The converse argument is that low levels of vitamin D may identify ill health [[10]Autier P. Boniol M. Pizot C. Mullie P. Vitamin D status and ill health: a systematic review.Lancet. 2014; 2: 76-89PubMed Scopus (801) Google Scholar]. Inflammatory processes involved with ill health depress vitamin D levels and would therefore be more likely to be associated with, for example, more advanced disease at presentation.Vitamin D and Primary Prevention of CancerThe hypothesis that vitamin D offers a protective effect against cancer was based initially on geographical observations, where increasing latitude (implying decreased exposure to UVB) was associated with increased incidence and mortality from cancer [11Garland C.F. Garland F.C. Do sunlight and vitamin D reduce the likelihood of colon cancer?.Int J Epidemiol. 1980; 9: 227-231Crossref PubMed Scopus (750) Google Scholar, 12International Agency for Research on Cancer IARC Working groups Report: Vitamin D and Cancer.2008Google Scholar], leading to observational studies and analysis of RCTs (summarised in Table 1). Observational studies [13Feskanich D. Ma J. Fuchs C.S. et al.Plasma vitamin D metabolites and risk of colorectal cancer in women.Cancer Epidemiol Biomarkers Prev. 2004; 13: 1502-1508PubMed Google Scholar, 14Wactawski-Wende J. Kotchen J.M. Anderson G.L. et al.Calcium plus vitamin D supplementation and the risk of colorectal cancer.New Engl J Med. 2006; 354: 684-696Crossref PubMed Scopus (845) Google Scholar, 15Jenab M. Bueno-de-Mesquita H.B. Ferrari P. et al.Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study.Br Med J. 2010; 340: b5500Crossref PubMed Scopus (331) Google Scholar] support an association between reduced colorectal cancer incidence and higher serum levels of 25-hydroxyvitamin D. A meta-analysis [[25]Ma Y. Zhang P. Wang F. Yang J. Liu Z. Qin H. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies.J Clin Oncol. 2011; 29: 3775-3782Crossref PubMed Scopus (310) Google Scholar] also showed this reduction in risk (relative risk 0.67, 95% confidence interval = 0.54–0.80) when comparing highest to lowest serum levels. By contrast, data from two RCTs that studied the effect of vitamin D supplementation or placebo [20Trivedi D.P. Doll R. Khaw K.T. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.Br Med J. 2003; 326: 469Crossref PubMed Google Scholar, 21Chlebowski R.T. Johnson K.C. Kooperberg C. et al.Calcium plus vitamin D supplementation and the risk of breast cancer.J Natl Cancer Inst. 2008; 100: 1581-1591Crossref PubMed Scopus (355) Google Scholar] and looked specifically at cancer outcomes found no significant effect of supplementation on the incidence of colorectal cancer (Table 2). Possible explanations for this include inadequate doses of vitamin D administered and short follow-up (the effect of aspirin on colorectal cancer incidence in randomised trials took over 10 years to become apparent [[26]Cook N.R. Lee I.M. Zhang S.M. Moorthy M.V. Buring J.E. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial.Ann Intern Med. 2013; 159: 77-85Crossref PubMed Scopus (245) Google Scholar]). In breast cancer, observational evidence is less conclusive. Although some studies [[16]Bertone-Johnson E.R. Chen W.Y. Holick M.F. et al.Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer.Cancer Epidemiol Biomarkers Prev. 2005; 14: 1991-1997Crossref PubMed Scopus (323) Google Scholar] have shown an inverse relationship between serum 25-hydroxyvitamin D levels and breast cancer risk, this has not been reproduced elsewhere [[18]Amir E. Cecchini R.S. Ganz P.A. et al.25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1.Breast Cancer Res Treat. 2012; 133: 1077-1088Crossref PubMed Scopus (48) Google Scholar]. Similarly, the only RCT to have specifically reported the incidence of invasive breast cancer showed no difference between the women receiving vitamin D supplementation compared with those receiving placebo [[21]Chlebowski R.T. Johnson K.C. Kooperberg C. et al.Calcium plus vitamin D supplementation and the risk of breast cancer.J Natl Cancer Inst. 2008; 100: 1581-1591Crossref PubMed Scopus (355) Google Scholar] (Table 1). For prostate cancer, the evidence is even more variable, with only a few smaller studies showing a weak association [[19]Tuohimaa P. Vitamin D, aging, and cancer.Nutr Rev. 2008; 66: S147-S152Crossref PubMed Scopus (29) Google Scholar]. No RCTs have looked specifically at the effect of vitamin D supplementation on the incidence of prostate cancer. A recent Cochrane review [[27]Bjelakovic G. Gluud L.L. Nikolova D. et al.Vitamin D supplementation for prevention of cancer in adults.Cochrane Database Syst Rev. 2014; 6: CD007469Crossref PubMed Scopus (113) Google Scholar] concluded that there is currently no firm evidence that vitamin D supplementation affects cancer incidence based on 14 trials and almost 50 000 participants (relative risk = 1.00, 95% confidence interval 0.94–1.06, P = 0.88). Notably this also included trials reporting cancer as a specific adverse event as opposed to a defined outcome.Table 1Observational studies and randomised controlled trials (RCTs) reporting the effect of vitamin D levels and cancer incidenceReferenceStudy designPopulationParticipants (n)Cancer incidenceObservational studies[13]Feskanich D. Ma J. Fuchs C.S. et al.Plasma vitamin D metabolites and risk of colorectal cancer in women.Cancer Epidemiol Biomarkers Prev. 2004; 13: 1502-1508PubMed Google ScholarCase control study within cohort studyWomen aged 30–55 years (USA)Nurses' Health Study193 cases of colorectal cancer, matched with 2 controls per caseDecreased colorectal cancer risk (OR = 0.53, 95% CI 0.27–1.04)With higher levels of serum[14]Wactawski-Wende J. Kotchen J.M. Anderson G.L. et al.Calcium plus vitamin D supplementation and the risk of colorectal cancer.New Engl J Med. 2006; 354: 684-696Crossref PubMed Scopus (845) Google ScholarCase control study within RCTPostmenopausal women aged 50–79 years (USA)Women's Health Initiative study (RCT)317 cases of colorectal cancer.306 had adequate serum dataHigher colorectal cancer risk (OR = 0.75, 95% CI 0.39–1.48) with lower baseline serum level (trend P = 0.02)[15]Jenab M. Bueno-de-Mesquita H.B. Ferrari P. et al.Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study.Br Med J. 2010; 340: b5500Crossref PubMed Scopus (331) Google ScholarCase control study within cohort studyMen and women (Europe)EPIC Study1248 cases of colorectal cancer.Lower risk of colorectal cancer (incident rate ratio = 0.77, 95% CI 0.56–1.06) for highest concentration of circulating 25–(OH)D (trend P < 0.001)[16]Bertone-Johnson E.R. Chen W.Y. Holick M.F. et al.Plasma 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D and risk of breast cancer.Cancer Epidemiol Biomarkers Prev. 2005; 14: 1991-1997Crossref PubMed Scopus (323) Google ScholarCase control study within cohort studyWomen aged 30–55 years (USA)Nurses' Health Study701 cases of breast cancer 724 case controlsLower risk of breast cancer with higher serum levels of vitamin D metabolites (patients in highest quintile RR = 0.73 (95% CI 0.49–1.07, P = 0.06)[17]Freedman D.M. Chang S.C. Falk R.T. et al.Serum levels of vitamin D metabolites and breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial.Cancer Epidemiol Biomarkers Prev. 2008; 17: 889-894Crossref PubMed Scopus (133) Google ScholarCase control study within RCTMen and women (USA)(Women aged 55–74 years)Prostate, lung colorectal, and ovarian cancer screening trial1005 breast cancer cases, matched (1:1) with controlsNo association with decreasing serum levels and increased breast cancer cases (RR = 1.04 95% CI 0.75–1.45), trend P = 0.81[18]Amir E. Cecchini R.S. Ganz P.A. et al.25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1.Breast Cancer Res Treat. 2012; 133: 1077-1088Crossref PubMed Scopus (48) Google ScholarCase control study within RCTWomen aged ≥35 years at increased risk of breast cancer (USA, Canada).NSABP-P1231 cases of invasive breast cancer, 856 controlsNo association of increased breast cancer with suboptimal serum levels (<72 nmol/l); univariate analysis OR = 1.25 95% CI 0.88–1.77, P = 0.21[19]Tuohimaa P. Vitamin D, aging, and cancer.Nutr Rev. 2008; 66: S147-S152Crossref PubMed Scopus (29) Google ScholarCase control study on Nordic serum bank of 200 000 samplesMen (Norway)622 cases of prostate cancer matched with controlsLow and high levels of calcidiol serum associated with higher risk of prostate cancer, average levels posed lowest riskRCTs[20]Trivedi D.P. Doll R. Khaw K.T. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.Br Med J. 2003; 326: 469Crossref PubMed Google ScholarVitamin D supplementation versus placeboMen and women living in the community (UK)Aged ≥65 years2686Total cancer: RR = 1.09, 95% CI 0.86–1.36, P = 0.47(colorectal cancer: RR = 1.02 95% CI 0.60–1.74, P = 0.94)(respiratory cancer: RR = 1.12 95% CI 0.56–2.25, P = 0.75)14Wactawski-Wende J. Kotchen J.M. Anderson G.L. et al.Calcium plus vitamin D supplementation and the risk of colorectal cancer.New Engl J Med. 2006; 354: 684-696Crossref PubMed Scopus (845) Google Scholar, 21Chlebowski R.T. Johnson K.C. Kooperberg C. et al.Calcium plus vitamin D supplementation and the risk of breast cancer.J Natl Cancer Inst. 2008; 100: 1581-1591Crossref PubMed Scopus (355) Google ScholarDaily vitamin D plus calcium versus placeboPostmenopausal women36 282Total cancer incidence RR = 0.76 (95% CI = 0.38–1.55)(invasive colorectal cancer HR = 1.08, 95% CI = 0.86–1.34)(invasive breast cancer HR = 0.96, 95% CI = 0.85–1.09)[22]Lappe J.M. Travers-Gustafson D. Davies K.M. Recker R.R. Heaney R.P. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial.Am J Clin Nutr. 2007; 85: 1586-1591PubMed Google ScholarCa only or Ca plus vitamin D3 or placeboHealthy postmenopausal women aged >55 years (USA)1179Total cancer incidence: RR = 0.76 (95% CI 0.38–1.55)∗Calculated by Keum et al. [24] for the meta-analysis by comparing the Ca + vitamin D versus Ca only arms.[23]Avenell A. MacLennan G.S. Jenkinson D.J. et al.Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial).J Clin Endocrinol Metab. 2012; 97: 614-622Crossref PubMed Scopus (194) Google ScholarVitamin D3 or calcium or both or placeboPeople over 70 years (85% women) with previous low trauma fracture5292Total cancer incidence: HR = 1.07 (95% CI = 0.92–1.25)HR, hazard ratio; OR, odds ratio; RR, relative risk; Ca, Calcium; CI, confidence interval.∗ Calculated by Keum et al. [24]Keum N. Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis.Br J Cancer. 2014; 111: 976-980Crossref PubMed Scopus (101) Google Scholar for the meta-analysis by comparing the Ca + vitamin D versus Ca only arms. Open table in a new tab Table 2Randomised controlled trials of vitamin D supplementation and reported cancer outcomes. No individual study showed a significant effect on cancer mortality, although a meta-analysis of these trials [24]Keum N. Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis.Br J Cancer. 2014; 111: 976-980Crossref PubMed Scopus (101) Google Scholar did find that supplementation significantly reduced total cancer mortality (relative risk [RR] = 0.88, 95% confidence interval [CI] = 0.78–0.98)ReferencePopulationParticipants (n)InterventionControlVitamin D doseFollow-up durationCancer outcomes[20]Trivedi D.P. Doll R. Khaw K.T. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.Br Med J. 2003; 326: 469Crossref PubMed Google ScholarMen and women aged ≥65 years living in the community (UK)2686Vitamin D supplementationPlacebo100 000 IU (∼833 IU/day) given 4 monthly5 yearsOverall cancer mortality: RR = 0.86 95% CI 0.61–1.20, P = 0.37Colon cancer: RR = 0.62 95% CI 0.24–1.60, P = 0.33Respiratory cancer: RR = 0.89 95% CI 0.38–2.09, P = 0.7814Wactawski-Wende J. Kotchen J.M. Anderson G.L. et al.Calcium plus vitamin D supplementation and the risk of colorectal cancer.New Engl J Med. 2006; 354: 684-696Crossref PubMed Scopus (845) Google Scholar, 21Chlebowski R.T. Johnson K.C. Kooperberg C. et al.Calcium plus vitamin D supplementation and the risk of breast cancer.J Natl Cancer Inst. 2008; 100: 1581-1591Crossref PubMed Scopus (355) Google ScholarPostmenopausal women36 282Daily vitamin D plus calciumPlacebo400 IU/day vitamin D plus 1500 mg/day calcium7 yearsOverall cancer mortality: HR = 0.90, 95% CI 0.77 to 1.05[23]Avenell A. MacLennan G.S. Jenkinson D.J. et al.Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial).J Clin Endocrinol Metab. 2012; 97: 614-622Crossref PubMed Scopus (194) Google ScholarPeople over 70 years (85% women) with previous low trauma fracture5292Vitamin D3 or calcium or bothPlaceboDaily oral vitamin D3 (800 IU per day); calcium (1000 mg per day)3 yearsOverall cancer mortality: HR = 0.85 95% CI 0.68–1.06HR, hazard ratio. Open table in a new tab Vitamin D: Evidence of Effect on Cancer Mortality (Secondary Prevention)An inverse relationship between serum vitamin D levels and cancer death has also been reported in observational studies [28Chowdhury R. Kunutsor S. Vitezova A. et al.Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies.Br Med J. 2014; 348: g1903Crossref PubMed Scopus (451) Google Scholar, 29Yin L. Ordonez-Mena J.M. Chen T. Schottker B. Arndt V. Brenner H. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: a systematic review and meta-analysis.Prevent Med. 2013; 57: 753-764Crossref PubMed Scopus (87) Google Scholar] and a meta-analysis of observational data [[30]Schottker B. Jorde R. Peasey A. et al.Vitamin D and mortality: meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States.Br Med J. 2014; 348: g3656Crossref PubMed Scopus (297) Google Scholar] found an association between serum concentrations of 25-hydroxyvitamin D and cancer mortality in patients with a history of cancer (relative risk = 1.70, 95% confidence interval 1.00–2.88). Studies have reported similar findings specifically in breast [[31]Mohr S.B. Gorham E.D. Kim J. Hofflich H. Garland C.F. Meta-analysis of vitamin D sufficiency for improving survival of patients with breast cancer.Anticancer Res. 2014; 34: 1163-1166PubMed Google Scholar], prostate [[32]Shui I.M. Mucci L.A. Kraft P. et al.Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study.J Natl Cancer Inst. 2012; 104: 690-699Crossref PubMed Scopus (141) Google Scholar] and colorectal cancer, with a meta-analysis [[33]Maalmi H. Ordonez-Mena J.M. Schottker B. Brenner H. Serum 25-hydroxyvitamin D levels and survival in colorectal and breast cancer patients: systematic review and meta-analysis of prospective cohort studies.Eur J Cancer. 2014; 50: 1510-1521Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar] and subsequent data from Scotland [[34]Zgaga L. Theodoratou E. Farrington S.M. et al.Plasma vitamin D concentration influences survival outcome after a diagnosis of colorectal cancer.J Clin Oncol. 2014; 32: 2430-2439Crossref PubMed Scopus (111) Google Scholar] that also included evidence of interaction between vitamin D and sequence variation at the vitamin D receptor gene locus, giving further support to the importance of the vitamin D pathway.Three RCTs [14Wactawski-Wende J. Kotchen J.M. Anderson G.L. et al.Calcium plus vitamin D supplementation and the risk of colorectal cancer.New Engl J Med. 2006; 354: 684-696Crossref PubMed Scopus (845) Google Scholar, 20Trivedi D.P. Doll R. Khaw K.T. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.Br Med J. 2003; 326: 469Crossref PubMed Google Scholar, 23Avenell A. MacLennan G.S. Jenkinson D.J. et al.Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial).J Clin Endocrinol Metab. 2012; 97: 614-622Crossref PubMed Scopus (194) Google Scholar] testing vitamin D versus placebo for non-cancer primary end points reported overall cancer mortality. Although the results for each trial suggested a benefit of supplementation, none individually reached significance (Table 2). However, a recent meta-analysis of these [[24]Keum N. Giovannucci E. Vitamin D supplements and cancer incidence and mortality: a meta-analysis.Br J Cancer. 2014; 111: 976-980Crossref PubMed Scopus (101) Google Scholar] did conclude that supplementation significantly reduced total cancer mortality (relative risk = 0.88, 95% confidence interval = 0.78–0.98).Randomised Trials of Vitamin D for the Prevention of CancerFour large randomised trials are underway or have recently completed recruitment across the US, Europe and Australia investigating high doses of oral vitamin D versus placebo in the general population for 5 years with pre-specified end points including cancer and total mortality. VITAL (Vitamin D and omega-3 Trial) recruited 25 874 patients in the US, using 2000 IU/day oral vitamin D [[35]Pradhan A.D. Manson J.E. Update on the Vitamin D and OmegA-3 trial (VITAL).J Steroid Biochem Mol Biol. 2015 Apr 9; (pii: S0960-0760(15)00103-X. http://dx.doi.org/10.1016/j.jsbmb.2015.04.006. [Epub ahead of print])Crossref PubMed Scopus (62) Google Scholar]. The Finnish Vitamin D trial (FIND) will recruit 18 000 patients, randomising between 1600 IU/day or 3200 IU/day. D-Health (Australia) plans to recruit 20 000 patients, randomised to 60 000 IU/month having first completed a pilot phase showing an appropriate increase in vitamin D levels [[36]Tran B. Armstrong B.K. Carlin J.B. et al.Recruitment and results of a pilot trial of vitamin D supplementation in the general population of Australia.J Clin Endocrinol Metab. 2012; 97: 4473-4480Crossref PubMed Scopus (18) Google Scholar]. VIDAL (Vitamin D and Longevity) is a UK trial also currently in pilot, randomising patients to 100 000 IU/month oral vitamin D. Key aspects of the pilot phases included the assessment of both compliance and contamination with off-trial supplementation through patient questionnaire and direct measurement of vitamin D levels.A Randomised Trial of Vitamin D in the Adjuvant Setting?Compared with aspirin, the evidence pertaining to vitamin D is less consistent. For primary prevention there is observational evidence to support an association between low levels of vitamin D and increased incidence of colorectal cancer in particular, but this is not corroborated by current RCTs. With secondary prevention the association between low levels of vitamin D and poorer cancer outcomes seems to be relatively robust, but the efficacy of vitamin D supplementation is only suggested by the RCTs (noting issues around suboptimal dosing and follow-up). Although RCTs are underway to address the efficacy of vitamin D supplementation in the primary setting, i.e. cancer prevention, further evaluation may be required in the adjuvant setting, raising a number of important issues.The mechanism of action required for anti-neoplastic activity of a repurposed drug may require different pharmacodynamics to the previous indication or might only be effective under certain conditions, for example whether a patient has low basal vitamin D levels or a PIK3CA mutation (as has been postulated in some aspirin studies). Trials that test the same dose and administration of a drug for indication A in novel situation B (discussed in the context of repurposing metformin [[37]Pollak M. Overcoming drug development bottlenecks with repurposing: repurposing biguanides to target energy metabolism for cancer treatment.Nat Med. 2014; 20: 591-593Crossref PubMed Scopus (76) Google Scholar]) risk false negative results and an opportunity lost. Considering an adjuvant trial of vitamin D there are two approaches with different challenges. First, one could test whether vitamin D supplementation in patients who are deficient improves outcomes (accepting that identification of these patients is itself controversial [[38]Maxmen A. Nutrition advice: the vitamin D-lemma.Nature. 2011; 475: 23-25Crossref PubMed Scopus (57) Google Scholar]) or alternatively whether supplementation over and above basal levels reduces relapse and death. The former requires proper selection of patients with the low basal vitamin D, randomised to receive adequate supplementation [[39]Heaney R.P. Guidelines for optimizing design and analysis of clinical studies of nutrient effects.Nutr Rev. 2014; 72: 48-54Crossref PubMed Scopus (212) Google Scholar] but raises significant ethical questions if patients at low levels are to be left without supplementation. The latter risks enrolling a heterogeneous population with variable vitamin D metabolism, diluting treatment effects and losing any demonstrable benefit. In the sole adjuvant study thus far, patients with high-risk malignant melanoma are randomised to receive a loading dose of 500 000 IU vitamin D and then 50 000 IU monthly [[40]Saw R.P. Armstrong B.K. Mason R.S. et al.Adjuvant therapy with high dose vitamin D following primary treatment of melanoma at high risk of recurrence: a placebo controlled randomised phase II trial (ANZMTG 02.09 Mel-D).BMC Cancer. 2014; 14: 780Crossref PubMed Scopus (29) Google Scholar], testing whether this approach could maintain vitamin D concentrations and adherence during 2 years of treatment. Importantly the trial also aims to show no clinically significant difference in the incidence of hypercalcaemia or renal calculi and no clinically significant difference in renal function between the active and placebo groups.How these issues might be addressed represents a challenge to the oncology and clinical trial community, where vitamin D tends to polarise opinion. Further data on cancer outcomes will emerge over the next few years as results from the large randomised vitamin D prevention trials mature. In the meantime, alternative agents for repurposing as adjuvant anticancer drugs might take priority. Repurposing drugs as anticancer therapeutics could shorten the conventional investigational pathway and open multiple new avenues of investigation [[1]Scannell J.W. Blanckley A. Boldon H. Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency.Nat Rev Drug Discov. 2012; 11: 191-200Crossref PubMed Scopus (1211) Google Scholar]. Evidence of potential anticancer effects can be collated from in vitro and in vivo models, taking into account whether biologically/clinically relevant concentrations or doses of the drug have been evaluated. With drugs already in widespread use for an alternative indication, data on cancer incidence and mortality may be available from epidemiological studies or preferably randomised controlled trials (RCTs) investigating the drug in the alternate situation. Anticancer effects of the candidate drug may be subtle, requiring prolonged use, as major short-term effects should have been previously identified. To show an effect in a prospective trial requires a population with a low cancer burden but high event rate who can receive the therapy for sufficient time to see a therapeutic benefit. For these reasons adjuvant trials are attractive. Aspirin, developed for its analgesic/anti-inflammatory properties was repurposed once as a cardiovascular drug and is now under investigation as an anticancer agent [[2]Langley R.E. Burdett S. Tiern

Introduction Erythema nodosum is often associated with a distressing symptomatology, including painful subcutaneous nodules, polyarthropathy, and significant fatigue. Whilst it is a well-documented side-effect of estrogen therapy in females, we describe what we believe to be the first report in the literature of erythema nodosum as a result of estrogen therapy in a male. Case presentation A 64-year-old Afro-Caribbean man with locally advanced carcinoma of the prostate agreed to participate in a randomized controlled trial comparing estrogen patches with luteinizing hormone-releasing hormone analogs to achieve androgen deprivation, and was allocated to the group receiving estrogen patches. One month later he presented with tender lesions on his shins and painful swelling of his ankles, wrists, and left shoulder. This was followed by progressive severe fatigue that required hospital admission, where he was diagnosed with erythema nodosum by a rheumatologist. Two months after discontinuing the estrogen patches the erythema nodosum, and associated symptoms, had fully resolved, and to date he remains well with no further recurrence. Conclusion Trial results may establish transdermal estrogen as an alternative to luteinizing hormone-releasing hormone analogs in the management of prostate cancer, and has already been established as a therapy for male to female transsexuals. It is essential to record the toxicity profile of transdermal estrogen in men to ensure accurate safety information. This case report highlights a previously undocumented toxicity of estrogen therapy in men, of which oncologists, urologists, and endocrinologists need to be aware. Rheumatologists and dermatologists should add estrogen therapy to their differential diagnosis of men presenting with erythema nodosum.

To the Editors: The diagnosis of HIV-associated plasmablastic multicentric Castleman disease (MCD) is based on the presence of histopathological features. However, MCD is a relapsing and remitting disease, and so, clinical correlates should also be present to confirm active disease.1 Although there are no evidence-based gold standard criteria for establishing a diagnosis of active MCD, both the French ANRS (Agence Nationale de Recherche sur le SIDA) 117 CastlemaB trial group and the National Cancer Institute (NCI) have described criteria to define an attack of MCD.2,3 The French ANRS definition requires raised serum C-reactive protein (CRP) (in the absence of any other cause), pyrexia, and at least 3 of 12 clinical features.2 The NCI scheme requires raised serum CRP, at least 1 clinical symptom, and 1 laboratory abnormality probably or definitely attributed to MCD.3 The serum CRP cutoff is higher in the French (>20 mg/L) than in the US (>3 mg/L) scheme. Neither system has been validated on an independent data series of patients. We applied the 2 diagnostic schemes to our cohort of 75 newly diagnosed patients treated for MCD (including 61 previously described cases4). All patients had histologically confirmed MCD with IgM lambda restricted plasmablasts with positive immunostaining for Kaposi's sarcoma herpes virus (KSHV). Central histopathological review was completed for 64 cases by a single pathologist (K.N.). Full clinical and treatment details were prospectively collected since 2000 and retrospectively collated for 3 cases diagnosed before 2000. The publication of the ARNS definition of an attack of MCD in 20072 included 2 features not previously recorded (xerostomia and nasal obstruction); these were added to the prospective data collection in late 2007. Laboratory measurements were recorded at the time that the diagnosis was established. The median duration of symptoms at the time that the diagnosis was established was 3 months (maximum, 48 months). The median age at MCD of the 75 patients (89% male) was 42 years (range, 23–69 years). The median CD4 cell count was 233 cells per cubic millimeter (range, 24–1429 cells/mm3), and the median interval between HIV diagnosis and MCD diagnosis was 2.5 years (range, 0–28 years). Two were diagnosed before 1996 (the date of routine use of combination antiretroviral therapy in our cohort) and 26 (35%) had an AIDS defining illness before MCD. Thirty-two (43%) were established on highly active antiretroviral therapy for at least 3 months at MCD diagnosis, of whom 18 (56%) had an undetectable plasma HIV viral load (<400 to <50 copies/mm3 depending on assay used) and a further 11 (34%) had low level HIV viremia <500 copies per cubic millimeter. The median duration of symptoms before the diagnosis of MCD was 3 months (range, 0.5–48 months). The median follow-up is 5.6 years (maximum, 19 years), and the overall 5-year survival for this cohort is 78% (95% confidence interval, 67% to 88%). At MCD diagnosis, 4 (5%) had histological evidence of “frank” plasmablastic lymphoma (n = 1) or “microlymphoma” (n = 3) coexisting with MCD.5,6 The ANRS scheme requires patients to fulfill all of the 3 criteria: 74/75 (99%) had a fever and 71/75 (95%) had at least 3 of the 12 clinical criteria; however, CRP measurement at the initial MCD diagnosis was only available for 68 patients, and only 55 (81%) had levels above 20 mg/L. Overall, 13 of the 68 patients with full data available failed to achieve compliance with all 3 criteria, giving a specificity of 81% for the ANRS scale (Table 1). Of the 13 patients who did not meet the 3 standards, only 9 failed because their serum CRP measurement was below 20 mg/L, whereas the remaining 4 patients had in addition the absence of fever (n = 1) or fewer than 3 clinical features (n = 3). The NCI criteria similarly requires fulfillment of all 3 categories, and 75/75 (100%) had at least 1 clinical criteria; 68/72 (94%) had at least 1 laboratory abnormality meeting the criteria, and 66/68 (97%) with serum CRP measurements available at diagnosis had levels above 3 mg/L. Overall, 6 of the 68 patients with full data available failed to achieve compliance with all 3 criteria, giving a specificity of 92% for the NCI scale (Table 1). Four of the 6 patients who did not meet the NCI criteria did not have the necessary abnormal laboratory levels, whereas 2 other patients had serum CRP values below 3 mg/L.TABLE 1: Frequency of ANRS and NCI Clinical Criteria Defining Active MCD in the Cohort of 75 Patients, Including 4 Patients With MCD With Concomitantly Diagnosed LymphomaAlthough both systems categorize the majority of our patients as having active MCD, the looser criteria in the NCI scheme identified more of our cohort as having active MCD. The false-negative rates are 19% for ANRS and 8% for NCI. Both classification models were cumbersome and included redundancy; for example, every patient with jaundice, ascites, or edema already had more than 2 of the other clinical criteria in the ARNS classification, whereas every patient with fatigue and weight loss also had fevers or night sweats in the NCI scheme. Moreover, the systems allow interpretation that may introduce confusion. For example, many patients may have gastrointestinal symptoms that relate to antiretroviral therapy rather than MCD, and jaundice may be a consequence of atazanavir rather than MCD. This study has not attempted to establish the capacity of either scheme to correctly exclude patients without MCD, and so, the specificity and power of the 2 schemes cannot be established. The combination of histopathological features, detectable plasma KSHV DNA, and B symptoms could provide a simpler system that could be widely applied without ambiguity. In our cohort, all 75 patients had fever, night sweats, or weight loss, and all had histopathological features of MCD, including IgM lambda–restricted KSHV LANA-positive plasmablasts. Plasma levels of KSHV were measured at diagnosis in 60 of the 75 patients and were detected in 58 (median, 237,000 copies/mL; range, 0–554,000,000 copies/mL). In 2006, a new assay for measuring plasma levels of KSHV was introduced, and since that time, all 47 new patients have had detectable levels. The importance of diagnostic clinics criteria that complement histological findings remain for KSHV-negative idiopathic MCD, where the histological diagnosis is often less than straight forward and no serological markers for disease exist. However, in people living with HIV and KSHV associated MCD, the histological diagnosis has been made considerably easier by the emergence of immunostaining for KSHV and the presence of IgM lambda restriction analyses. Moreover, the detection of elevated KSHV DNA in the blood greatly assists the diagnosis. Under these circumstances, the value of clinical criteria is more limited, and the imprecision further limits their worth. The triad of histopathological findings, detectable plasma KSHV, and B symptoms should suffice.

PURPOSE:Combination antiretroviral therapy (cART) is standard of care for patients with HIV diagnosed with Kaposi's sarcoma (KS), but the current role of systemic chemotherapy is undefined.PATIENTS AND METHODS:Since 1998, a prospective stage-stratified approach has been adopted for 469 patients with HIV with KS. Patients with early-stage (T0) KS are treated with cART alone; patients with advanced-stage (T1) KS receive cART plus liposomal anthracycline chemotherapy. Clinical characteristics, overall survival, and KS progression-free survival were analyzed according to stage at presentation and treatment received.RESULTS:A total of 303 patients presented with T0 stage KS, including 237 who were not receiving cART, and 166 patients had T1 stage KS. Patients with T0 KS had higher CD4 cell counts (P < .001); 90% of patients with T0 KS who were not receiving cART and 84% of those with T1 KS were treated in accordance with the stage-stratified approach. Median follow-up was 4.6 years, and 5-year overall survival was 89%; 54 patients have died, 15 as a result of KS. Overall 5-year survival was 92% for T0 KS and 83% to T1 KS (P = .0024). On-treatment analysis of 213 cART-naive patients with T0 KS treated with cART alone revealed 5-year overall survival of 95% and progression-free survival of 77%. For 140 patients with T1 disease treated with cART and liposomal anthracycline chemotherapy, 5-year overall survival was 85%.CONCLUSION:This stage-stratified approach to the management of KS achieves high survival in patients with advanced KS and reduces exposure to chemotherapy in patients with early-stage KS.

Introduction: Evidence has recently emerged to suggest that mutations in the PIK3CA gene in colorectal cancer might identify patients that receive greater benefit from aspirin in the adjuvant setting. Add-Aspirin is a planned and funded, double blind, placebo-controlled, randomised trial assessing the potential benefits of aspirin after primary curative therapy for non-metastatic cancer (colorectal, gastro-oesophageal, breast and prostate cancer). Participants (n = 9920 which includes 2600 with colorectal cancer) will receive aspirin 100mg daily, aspirin 300mg daily or matching placebo for at least 5 years. Each tumour specific cohort is individually powered and has a separate co-primary outcome measure. Methods: We assessed current data on the association between PIK3CA mutation status and benefit from aspirin after a colorectal diagnosis, as well as other genetic mutations associated with benefit from aspirin to assess how this should be addressed within the setting of a planned randomised adjuvant trial. Results: Long-term follow-up of randomised trials designed to assess vascular benefits of aspirin, show that taking daily low-dose aspirin for 5 years reduces the incidence of cancer, particularly those that arise from the gastrointestinal tract (1). Observational data suggest aspirin is associated with a lower risk of developing BRAF-wild type colorectal tumours (2). Recent data on the association between PIK3CA mutation status, aspirin use and survival outcomes involve small numbers of patients with mutations, and include stage I-IV patients where the biological effects may be different and are not consistent (see table1). Conclusion: The potential benefits of aspirin include effects on both the development of primary tumours, as well as the development and spread of metastases which may involve different signaling pathways. To date the data suggest that patients with both mutated and wild type PIK3CA colorectal tumours may benefit from aspirin after a diagnosis of colorectal cancer. Add-Aspirin incorporates an active run-in period which can be utilised to ascertain PIK3CA mutation status in the colorectal cohort prior to randomisation and used as a stratification factor, providing a framework to investigate this important clinical question efficiently and reliably. Subgroup analyses by PIK3CA status are planned and accumulating data will be reviewed by an Independent Data Monitoring Committee ensuring the full potential benefits of aspirin are realised. References: 1. Rothwell, P.M., et al., Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet, 2011. 377(9759): p.31-41. 2. Nishihara, R., et al., Aspirin use and risk of colorectal cancer according to BRAF mutation status. JAMA, 2013. 309(24): p.2563-71. 3. Liao, X., et al., Aspirin Use, Tumor PIK3CA Mutation, and Colorectal-Cancer Survival. NEJM, 2012. 367(17): p.1596-1606. 4. Domingo, E., et al., Evaluation of PIK3CA Mutation As a Predictor of Benefit From Nonsteroidal Anti-Inflammatory Drug Therapy in Colorectal Cancer. J Clin Oncol, 2013. 31(34): p.4297-305. 5. Kothari, N., et al., Regular aspirin (ASA) use and survival in patients with PIK3CA-mutated metastatic colorectal cancer (CRC). J Clin Oncol, 2014. 32 (suppl3; abstr386). 6. Reimers, M.S., et al., Low dose aspirin use after diagnosis, HLA class I tumour expression and colon cancer survival. JAMA Internal Medicine (in press), 2014.

TPS1617 Background: Pre-clinical data demonstrate that aspirin inhibits tumour growth and prevents metastases. Meta-analyses of individual patient data from randomized trials evaluating cardiovascular (CV) effects of aspirin show reduced metastases and cancer deaths for those on aspirin. Toxicity concerns have limited aspirin use as a primary anti-cancer prevention agent. In the adjuvant setting, the risk:benefit ratio differs, with higher morbidity and mortality from recurrence potentially outweighing risks. Aspirin, an inexpensive drug with a potential therapeutic role in several common cancers, could have a large impact on the global cancer burden. The Add-Aspirin trial investigates if aspirin use after curative treatment for non-metastatic solid tumours prevents recurrence and prolongs survival. Methods: Add-Aspirin is a double blind, placebo-controlled, multicentre, international trial. Eligible participants (n=9,920) from the UK and India will have had potentially curative treatment for non-metastatic cancer. There are 4 separate tumour cohorts – breast (BC), colorectal (CRC), gastro-oesophageal (GOC) and prostate cancer (PC). Following an 8 week active run-in period of aspirin 100mg daily to assess adherence and tolerability, participants are randomised to aspirin 100mg, 300mg or placebo daily for > 5 years. Each tumour specific cohort is individually powered and has a separate disease-specific primary outcome measure: BC (n = 3,100) invasive disease-free survival (DFS); CRC (n = 2,600) DFS; GOC (n = 2,100) overall survival (OS); and PC (n = 2,120) biochemical recurrence-free survival. Secondary outcome measures include adherence, toxicity and CV events. OS across the 4 cohorts is a co-primary outcome measure. Sub-studies include assessment of thromboxane B2 for compliance and methodological work to assess the utility of long-term passive follow up. Blood/tissue specimens collected at enrolment will allow tumour-specific mutations to be used as stratification factors. Recruitment will commence by May 2014. Funder CRUK; Sponsor University College UK. Clinical trial information: 2013-004398-28.

BACKGROUND:The population in developed countries is ageing. Cancer is a disease of ageing, and this is likely to lead to an increase in the number of older patients diagnosed with cancer with significant implications for resource allocation and research priorities. Breast Cancer in older women presents a number of challenges.AIMS:This paper describes the trends in number of new breast cancer registrations in older patients over the last 38 years.MATERIALS AND METHODS:Data were extracted from the Office for National Statistics describing new registrations of breast cancer for patients aged 65 or over, from 1971 to 2009.RESULTS:The number of diagnoses of breast cancer across all age groups increased from 17,694 in 1971 to 40,260 in 2009. The proportion of diagnoses of breast cancer made in women aged 65 and over increased from 42% in 1971 to 45% in 2009. The proportion of diagnoses of breast cancer made in women aged 70 and over increased from 30% in 1971 to 33% in 2009. The number of cases of breast cancer registered in patients aged 65 and over has increased from 7376 in 1971 to 17,934 in 2009.DISCUSSION:The reasons for the large increases in the number of older women diagnosed with breast cancer, and older women represent an increasing proportion of those diagnosed are multi-factorial. These include the ageing of the population, obesity, alcohol consumption, use of hormone replacement therapy and reproductive factors, improved breast cancer awareness and the UK National Screening Programme. Clinician attitudes and behaviours and also cancer registries striving to increase their levels are other causes. The effective management of these women will present constraints to service delivery and should therefore influence research priorities.CONCLUSION:This short communication reports on the increasing registration of breast cancer in the older age group which will present a number of challenges for the future.

Purpose of the study: The population in developed countries is ageing. Cancer is a disease of ageing, and this will lead to an increase in the number of older patients diagnosed with cancer. The magnitude of the increase will have significant implications for service provision, resource allocation and research planning because to date older patients have been under-represented in clinical trials. This analysis describes the trends in the number of new cancer registrations in older patients over the last 38 years.

a large number of these smaller components to form sensible combinations or patterns.This process of breaking down sound waveforms and reformulating into combination of nerve signals, allows the brain to distinguish the different frequencies of sound which form the individual notes, different pitches in music, music combinations (harmonics) or noise.