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  • Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Study (PROCLIPI study)

    Quaglino, P.; Prince, H. M.; Cowan, Richard A; Vermeer, M.; Papadavid, L.; Bagot, M.; Servitjie, O.; Berti, E.; Guenova, E.; Stadler, R.; et al. (2020)
    BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) Study is a prospective analysis of an international database and here we examine front-line treatments and quality-of-life in patients with newly diagnosed Mycosis Fungoides (MF). OBJECTIVES: a) differences in first-line approach according to the TNMB staging; b) parameters related to a first-line systemic approach; c) response rates and quality of life (QoL) measures. PATIENTS AND METHODS: 395 newly diagnosed patients with early-stage MF (IA-IIA) were recruited from 41 centers in 17 countries between 1/1/2015-31/12/2018 following central clinicopathological review. RESULTS: First-line therapy was skin directed therapy (SDT) (81.6%) whilst a smaller percentage (44 cases;11.1%) received systemic therapy. Expectant observation was 7.3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA: 6%; IB: 14%; IIA:20%; IA-IB vs IIA: p<0.0001), presence of plaques (T1a+T2a: 5%; T1b+T2b: 17%; p<0.001), higher mSWAT (10: 15%; <=10: 7%; p=0.01) and folliculotropic MF (FMF) (24% vs 12%; p=0.001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs T1a/T2a: OR: 3.07) and FMF (OR: 2.82). The overall response rate (ORR) to first-line SDT was 73% whilst the ORR to first-line systemic treatments was lower (57%) (p=0.027). Health related QoL improved significantly in both patients with responsive and stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices and that SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently
  • Yttrium-90 radioembolization in intrahepatic cholangiocarcinoma: a multicenter retrospective analysis

    Buettner, S.; Braat, A.; Margonis, G. A.; Brown, D. B.; Taylor, K. B.; Borgmann, A. J.; Kappadath, S. C.; Mahvash, A.; JNM, I. J.; Weiss, M. J.; et al. (2020)
    PURPOSE: To report outcomes of yttrium-90 ((90)Y) radioembolization in patients with unresectable intrahepatic cholangiocarcinoma (ICC). MATERIALS AND METHODS: Retrospective review was performed of 115 patients at 6 tertiary care centers; 92 were treated with resin microspheres (80%), 22 were treated with glass microspheres (19%), and 1 was treated with both. Postintervention outcomes were compared between groups with chi(2) tests. Survival after diagnosis and after treatment was assessed by Kaplan-Meier method. RESULTS: Grade 3 laboratory toxicity was observed in 4 patients (4%); no difference in toxicity profile between resin and glass microspheres was observed (P = .350). Clinical toxicity per Society of Interventional Radiology criteria was noted in 29 patients (25%). Partial response per Response Evaluation Criteria In Solid Tumors 1.1 was noted in 25% of patients who underwent embolization with glass microspheres and 3% of patients who were treated with resin microspheres (P = .008). Median overall survival (OS) from first diagnosis was 29 months (95% confidence interval [CI], 21-37 mo) for all patients, and 1-, 3-, and 5-year OS rates were 85%, 31%, and 8%, respectively. Median OS after treatment was 11 months (95% CI, 8-13 mo), and 1- and 3-year OS rates were 44% and 4%, respectively. These estimates were not significantly different between resin and glass microspheres (P = .730 and P = .475, respectively). Five patients were able to undergo curative-intent resection after (90)Y radioembolization (4%). CONCLUSIONS: This study provides observational data of treatment outcomes after (90)Y radioembolization in patients with unresectable ICC.
  • Choice of second-line systemic therapy in stage IV small cell lung cancer (SCLC) - A decision-making analysis amongst European lung cancer experts

    Fruh, M.; Panje, C. M.; Reck, M.; Blackhall, Fiona H; Califano, Raffaele; Cappuzzo, F.; Besse, B.; Novello, S.; Garrido, P.; Felip, E.; et al. (2020)
    OBJECTIVES: Stage IV small cell lung cancer (SCLC) is associated with short survival and progression after first-line systemic therapy frequently occurs within months. Although topotecan is approved for second-line treatment, its efficacy is limited, and treatment heterogeneity exists. MATERIAL AND METHODS: The decision-making patterns for second line treatment of 13 European medical oncologists with expertise in SCLC were analyzed. RESULTS: The two criteria most relevant to decision-making were the performance status and the interval of recurrence since first-line treatment. With an interval of less than 3 months since the end of first-line chemotherapy, 62 % of the experts recommended cyclophosphamide, doxorubicin and vincristine (CAV) for fit patients and 54 % recommended topotecan for unfit patients. For an interval of more than 6 months, a clear consensus for a re-challenge with a platinum doublet was achieved (92 %). However, there was no consensus on the second-line therapy with an interval of 3-6 months since the end of first-line therapy. CONCLUSION: Real world practice may differ from recommendations in general guidelines and cannot always be directly derived from trial results as other factor such as habits, patient's preference, convenience or costs have to be factored in.
  • Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia

    Joseph, N.; Kirkby, Norman; Hoskin, Peter J; West, Catharine ML; Choudhury, Ananya; Dale, R. G.; Ministry of Health, Colombo, Sri Lanka. (2020)
    OBJECTIVE: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3-4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. METHODS: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity.40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration)30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution)The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. RESULTS: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5-8 Gy when delivered in 2 Gy fractions. CONCLUSION: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. ADVANCES IN KNOWLEDGE: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.
  • An investigation into dose optimisation for imaging root canal anatomy using cone beam CT

    McGuigan, M.; Theodorakou, Chrysoula; Duncan, H. F.; Jonathan, D.; Sengupta, A.; Keith, H.; Dublin Dental University Hospital, Trinity College Dublin, Dublin, Ireland. (2020)
    OBJECTIVES: To identify a dose as low as diagnostically acceptable and a threshold level of image quality for CBCT imaging root canals, using maxillary first molar (M1M) second mesio-buccal (MB2) canals of varying complexity for two CBCT scanners. METHODS: Dose-area product (DAP) and contrast-to-noise ratio (CNR) were measured for two scanners at a range of exposure parameters. Subjective-image-quality assessment (SIQA) at the same exposures was performed for 3 M1M's of varying MB2 complexity, positioned in a anthropomorphic phantom. Nine raters (three endodontists, three dental radiologists and three junior staff) assessed canal visibility, using a five-point confidence scale rating (CSR). RESULTS: Identification of simple-moderate MB2 canal complexity was achieved at a range of protocols, with DAP values of /=209.3 mGy cm(2) and "/=203.2 mGy cm(2) and CNRs of 3 and 7.6 for Promax((R))3D and Accuitomo-F170((R)) respectively. For complex canal anatomy
  • Systemic anti-cancer therapy delivery in the home: a service model

    Burns, Victoria; Misra, Vivek; Paton, Nina; SACT Outreach Manager, The Christie NHS Foundation Trust, Manchester. (2020)
    The Christie NHS Foundation Trust is a leader in adapting patient care in response to treatment advances and new patient-centred care/efficiency initiatives. Due to extended waiting times in cancer clinics, The Christie developed an at-home treatment service to help reduce the pressure on clinics and improve patient experience. This article provides a detailed examination of the requirements necessary to successfully develop a home service for the delivery of systemic anticancer treatment. The authors discuss the criteria used to identify suitable at-home treatments, as well as necessary resources and equipment. The success of the Christie at Home service was examined using a patient survey to assess the standard of this care. Details are given regarding the challenges of implementing a homecare service and potential future challenges. As an example, systemic treatment with eribulin as a 'Christie at Home' therapy demonstrates the practicalities of introduction of new therapies in a homecare service.
  • Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB Trial

    Lin, N. U.; Borges, V.; Anders, C.; Murthy, R. K.; Paplomata, E.; Hamilton, E.; Hurvitz, S.; Loi, S.; Okines, A.; Abramson, V.; et al. (2020)
    PURPOSE: In the HER2CLIMB study, patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer with brain metastases (BMs) showed statistically significant improvement in progression-free survival (PFS) with tucatinib. We describe exploratory analyses of intracranial efficacy and survival in participants with BMs. PATIENTS AND METHODS: Patients were randomly assigned 2:1 to tucatinib or placebo, in combination with trastuzumab and capecitabine. All patients underwent baseline brain magnetic resonance imaging; those with BMs were classified as active or stable. Efficacy analyses were performed by applying RECIST 1.1 criteria to CNS target lesions by investigator assessment. CNS-PFS (intracranial progression or death) and overall survival (OS) were evaluated in all patients with BMs. Confirmed intracranial objective response rate (ORR-IC) was evaluated in patients with measurable intracranial disease. RESULTS: There were 291 patients with BMs: 198 (48%) in the tucatinib arm and 93 (46%) in the control arm. The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (hazard ratio [HR], 0.32; 95% CI, 0.22 to 0.48; P < .0001). Median CNS-PFS was 9.9 months in the tucatinib arm versus 4.2 months in the control arm. Risk of death was reduced by 42% in the tucatinib arm (OS HR, 0.58; 95% CI, 0.40 to 0.85; P = .005). Median OS was 18.1 versus 12.0 months. ORR-IC was higher in the tucatinib arm (47.3%; 95% CI, 33.7% to 61.2%) versus the control arm (20.0%; 95% CI, 5.7% to 43.7%; P = .03). CONCLUSION: In patients with HER2-positive breast cancer with BMs, the addition of tucatinib to trastuzumab and capecitabine doubled ORR-IC, reduced risk of intracranial progression or death by two thirds, and reduced risk of death by nearly half. To our knowledge, this is the first regimen to demonstrate improved antitumor activity against BMs in patients with HER2-positive breast cancer in a randomized, controlled trial.
  • Assessing full benefit of rivaroxaban prophylaxis in high-risk ambulatory patients with cancer: thromboembolic events in the randomized CASSINI Trial

    Khorana, A. A.; McNamara, Mairead G; Kakkar, A. K.; Streiff, M. B.; Riess, H.; Vijapurkar, U.; Kaul, S.; Wildgoose, P.; Soff, G. A.; Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, Ohio, (2020)
    Introduction In the CASSINI study, rivaroxaban thromboprophylaxis significantly reduced primary venous thromboembolism (VTE) endpoints during the intervention period, but several thromboembolic events designated as secondary efficacy endpoints were not included in the primary analysis. This study was aimed to evaluate the full impact of rivaroxaban thromboprophylaxis on all prespecified thromboembolic endpoints occurring on study. Methods CASSINI was a double-blind, randomized, placebo-controlled study in adult ambulatory patients with cancer at risk for VTE (Khorana score /=2). Patients were screened at baseline for deep-vein thrombosis (DVT) and randomized if none was found. The primary efficacy endpoint was a composite of lower extremity proximal DVT
  • Multi-institutional dosimetric delivery assessment of intracranial stereotactic radiosurgery on different treatment platforms

    Dimitriadis, A.; Tsang, Y.; Thomas, R. A. S.; Palmer, A. L.; Eaton, D.; Lee, J.; Patel, R.; Silvestre Patallo, I.; Gouldstone, C.; Snaith, J. A. D.; et al. (2020)
    BACKGROUND AND PURPOSE: Assessment of dosimetric accuracy of radiosurgery on different treatment platforms. MATERIAL AND METHODS: Thirty-three single fraction treatment plans were assessed at thirty centres using an anthropomorphic head phantom with target and brainstem structures. The target being a single irregular shaped target, ~8 cc, 10 mm from the brainstem. The phantom was 'immobilised', scanned, planned and treated following the local protocols. EBT-XD films and alanine pellets were used to measure absolute dose, inside both the target and the brainstem, and compared with TPS predicted dose distributions. RESULTS: PTV alanine measurements from gantry-based linacs showed a median percentage difference to the TPS of 0.65%. Cyberknife (CK) had the highest median difference of 2.3% in comparison to the other platforms. GammaKnife (GK) showed the smallest median of 0.3%. Similar trends were observed in the OAR with alanine measurements showing median percentage differences of1.1%, 2.0% and 0.4%, for gantry-based linacs, CK and GK respectively. All platforms showed comparable gamma passing rates between axial and sagittal films. CONCLUSIONS: This comparison has highlighted the dosimetric variation between measured and TPS calculated dose for each delivery platform. The results suggest that clinically acceptable agreement with the predicted dose distributions is achievable by all treatment delivery systems.
  • Landmark survival analysis and impact of anatomic origin in prospective clinical trials of biliary tract cancer

    McNamara, Mairead G; Lopes, A.; Wasan, H.; Malka, D.; Goldstein, D.; Shannon, J.; Okusaka, T.; Knox, J. J.; Wagner, A. D.; Andre, T.; et al. (2020)
    BACKGROUND: Inclusion of all patients with advanced biliary tract cancer (aBTC), irrespective of anatomic location, in prospective trials, is debated. Survival rates from landmark analysis offer more relevant information once patients have survived for some time. AIM: assess survival impact of BTC anatomic site origin and landmark survival (LS). PATIENTS AND METHODS: Patients enrolled into prospective first-line aBTC clinical trials were included. OS was analysed using Cox-proportional-hazard-regression; LS and 95% confidence intervals (CIs) were calculated. RESULTS: Overall: 1333 patients included (Jan 97-Dec 15); median age 63-years (range 23-85); 46%-male; 84%-ECOG-PS0/1; 25%-locally-advanced (LA), 72%-metastatic, 3%-not reported (NR); gallbladder-(GBC): 385 (29%), cholangiocarcinoma not-specified-(CCA-NS): 363 (27%), extrahepatic-(EHC): 247 (19%), intrahepatic-(IHC): 209 (16%), ampulla: 53 (4%), 76 (6%) NR. Treatment was mono-chemotherapy: 310-(23%), cisplatin/gemcitabine: 482-(36%), other combination: 520-(39%), NR: 21-(2%). Median OS: 10.2-months (95%-CI 9.6-10.9). All sites (treatment-adjusted) had decreased risk of death vs GBC: EHC-(P<.001), IHC-(P<.002), CCA-NS-(P<.003), ampulla-(P=.003). This reduced risk vs GBC was maintained in those receiving cisplatin/gemcitabine in EHC-(P<.001) and IHC-(P<.001), but not in CCA-NS-(P=.82) or ampulla-(P=.96). Probabilities of surviving an additional year given survival to 1, 2, 3, and 4 years post-trial registration were 37%, 45%, 61%, and 63% respectively. For patients who survived 1 year; those receiving combination therapy vs mono (P=.008) (acknowledging potential selection bias), and those with IHC and CCA-NS vs GBC had better LS (both P<.05). Metastatic stage vs LA was associated with shorter LS (P=.002). ECOG-PS and gender had no evidence of effect on LS (P.05
  • Once daily versus twice-daily radiotherapy in the management of limited disease small cell lung cancer - Decision criteria in routine practice

    Glatzer, M.; Faivre-Finn, Corinne; De Ruysscher, D.; Widder, J.; Van Houtte, P.; Troost, E. G. C.; Dahele, M. R.; Slotman, B. J.; Ramella, S.; Pottgen, C.; et al. (2020)
    BACKGROUND: In limited disease small cell lung cancer (LD-SCLC), the CONVERT trial has not demonstrated superiority of once-daily (QD) radiotherapy (66 Gy) over twice-daily (BID) radiotherapy (45 Gy). We explored the factors influencing the selection between QD and BID regimens. METHODS: Thirteen experienced European thoracic radiation oncologists as selected by the European Society for Therapeutic Radiation Oncology (ESTRO) were asked to describe their strategies in the management of LD-SCLC. Treatment strategies were subsequently converted into decision trees and analysed for agreement and discrepancies. RESULTS: Logistic reasons, patients performance status and radiotherapy dose constraints were the three major decision criteria used by most experts in decision making. The use of QD and BID regimens was balanced among European experts, but there was a trend towards the BID regimen for fit patients able to travel twice a day to the radiotherapy site. CONCLUSION: BID and QD radiotherapy are both accepted regimens among experts and the decision is influenced by pragmatic factors such as availability of transportation.
  • Prognostic indices in diffuse large B-cell lymphoma in the rituximab era: an analysis of the UK National Cancer Research Institute R-CHOP 14 versus 21 phase 3 trial

    Gleeson, M.; Counsell, N.; Cunningham, D.; Lawrie, A.; Clifton-Hadley, L.; Hawkes, E.; McMillan, A.; Ardeshna, K. M.; Burton, C.; Chadwick, N.; et al. (2020)
    We compared the International Prognostic Index (IPI), Revised (R)-IPI and age-adjusted (aa)-IPI as prognostic indices for patients with diffuse large B-cell lymphoma (DLBCL) in the UK National Cancer Research Institute (NCRI) R-CHOP 14 versus 21 trial (N = 1080). The R-IPI and aa-IPI showed no marked improvement compared to the IPI for overall and progression-free survival, in terms of model fit or discrimination. Similar results were observed in exploratory analyses incorporating the Grupo Espanol de Linfomas/Transplante de Medula Osea (GELTAMO)-IPI, where baseline beta2-microglobulin data were available (N = 655). Although our findings support current use of the IPI, a novel prognostic tool to better delineate a high-risk DLBCL group in the rituximab era is needed.
  • Second-line treatment in patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma: a systematic review and meta-analysis

    McNamara, Mairead G; Frizziero, Melissa; Jacobs, Timothy; Lamarca, Angela; Hubner, Richard A; Valle, Juan W; Amir, E.; Department of Medical Oncology, The Christie NHS Foundation Trust/Division of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. (2020)
    Background: There is no standard second-line treatment for patients with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma (EP-PD-NEC). This study explored data evaluating second-line treatment in these patients. Methods: A search of MEDLINE and EMBASE identified studies reporting survival and/or response data for patients with EP-PD-NEC receiving second-line therapy. Association between various factors (age, gender, ECOG performance status, primary tumour location, morphology, Ki-67, treatment and grade 3/4 haematological toxicity) and response rate (RR), progression-free (PFS) and overall survival (OS) were assessed with a mixed effects meta-regression weighted by individual study sample size. Due to a small sample size, associations were reported quantitatively, based on magnitude of beta coefficient rather than statistical significance. Results: Of 83 identified studies, 19 were eligible, including 4 prospective and 15 retrospective studies. Analysis comprised 582 patients, with a median number of 19 patients in each study (range 5-100). Median age was 59 years (range 53-66). Median RR was 18% (range 0-50; 0% for single-agent everolimus, temozolomide, topotecan; 50% with amrubicin), median PFS was 2.5 months (range 1.15-6.0) and median OS was 7.64 months (range 3.2-22.0). Studies with a higher proportion of patients with a Ki-6755% had lower RR (beta = -0.73) and shorter OS (beta = -0.82). Conclusion: Second-line therapy for patients with advanced EP-PD-NEC has limited efficacy and the variety of regimens used is diverse. Ki-67"55% is associated with worse outcomes. Prospective randomised studies are warranted to enable exploration of new treatment strategies."
  • Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses

    Zhang, H.; Ahearn, T. U.; Lecarpentier, J.; Barnes, D.; Beesley, J.; Qi, G.; Jiang, X.; O'Mara, T. A.; Zhao, N.; Bolla, M. K.; et al. (2020)
    Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.
  • Adjuvant chemotherapy in biliary tract cancer: state of the art and future perspectives

    Sanoyan, D. A.; McNamara, Mairead G; Lamarca, Angela; Valle, Juan W; Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland. (2020)
    PURPOSE OF REVIEW: Biliary tract cancers (BTCs) have a poor prognosis; most patients present with advanced disease and, even after surgical resection for early-stage disease local and distant relapses are frequent. Involved resection margins and lymph node involvement are the most relevant known adverse prognostic factors. Historically clinicians have made clinical decisions based on data from institutional series and uncontrolled studies, with their inherent limitations. In this review, data from recently-reported prospective randomized trials are reviewed and clinical implications discussed. RECENT FINDINGS: Results from prospective randomized phase III trials (namely BILCAP, PRODIGE-12, and BCAT) are reviewed: none of the studies met their primary endpoint by intention-to-treat analysis. However, following a per-protocol sensitivity analysis of the BILCAP study, adjuvant capecitabine (for 6 months) showed a clinically-relevant improvement in overall survival and provides reference data for future clinical trials. SUMMARY: Adjuvant chemotherapy with capecitabine should be considered following curative resection of BTC. Identification of benefit in anatomical subgroups is ongoing and future trials should also consider the implication of molecular subtypes of BTC (for prognostic impact and on-target therapeutic options).
  • Ivosidenib in IDH1-mutant, chemotherapy-refractory cholangiocarcinoma (ClarIDHy): a multicentre, randomised, double-blind, placebo-controlled, phase 3 study

    Abou-Alfa, G. K.; Macarulla, T.; Javle, M. M.; Kelley, R. K.; Lubner, S. J.; Adeva, J.; Cleary, J. M.; Catenacci, D. V.; Borad, M. J.; Bridgewater, J.; et al. (2020)
    BACKGROUND: Isocitrate dehydrogenase 1 (IDH1) mutations occur in approximately 13% of patients with intrahepatic cholangiocarcinoma, a relatively uncommon cancer with a poor clinical outcome. The aim of this international phase 3 study was to assess the efficacy and safety of ivosidenib (AG-120)-a small-molecule targeted inhibitor of mutated IDH1-in patients with previously treated IDH1-mutant cholangiocarcinoma. METHODS: This multicentre, randomised, double-blind, placebo-controlled, phase 3 study included patients from 49 hospitals in six countries aged at least 18 years with histologically confirmed, advanced, IDH1-mutant cholangiocarcinoma who had progressed on previous therapy, and had up to two previous treatment regimens for advanced disease, an Eastern Cooperative Oncology Group performance status score of 0 or 1, and a measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (2:1) with a block size of 6 and stratified by number of previous systemic treatment regimens for advanced disease to oral ivosidenib 500 mg or matched placebo once daily in continuous 28-day cycles, by means of an interactive web-based response system. Placebo to ivosidenib crossover was permitted on radiological progression per investigator assessment. The primary endpoint was progression-free survival by independent central review. The intention-to-treat population was used for the primary efficacy analyses. Safety was assessed in all patients who had received at least one dose of ivosidenib or placebo. Enrolment is complete; this study is registered with, NCT02989857. FINDINGS: Between Feb 20, 2017, and Jan 31, 2019, 230 patients were assessed for eligibility, and as of the Jan 31, 2019 data cutoff date, 185 patients were randomly assigned to ivosidenib (n=124) or placebo (n=61). Median follow-up for progression-free survival was 6.9 months (IQR 2.8-10.9). Progression-free survival was significantly improved with ivosidenib compared with placebo (median 2.7 months [95% CI 1.6-4.2] vs 1.4 months [1.4-1.6]; hazard ratio 0.37; 95% CI 0.25-0.54; one-sided p<0.0001). The most common grade 3 or worse adverse event in both treatment groups was ascites (four [7%] of 59 patients receiving placebo and nine [7%] of 121 patients receiving ivosidenib). Serious adverse events were reported in 36 (30%) of 121 patients receiving ivosidenib and 13 (22%) of 59 patients receiving placebo. There were no treatment-related deaths. INTERPRETATION: Progression-free survival was significantly improved with ivosidenib compared with placebo, and ivosidenib was well tolerated. This study shows the clinical benefit of targeting IDH1 mutations in advanced, IDH1-mutant cholangiocarcinoma. FUNDING: Agios Pharmaceuticals.
  • Radiotherapy and systemic treatment for non-melanoma skin cancer in the COVID-19 pandemic

    Rembielak, Agata; Sykes, Andrew J; Fife, K.; Challapalli, A.; Nobes, J. P.; The Christie NHS Foundation Trust, Manchester, UK; The University of Manchester, Manchester, UK (2020)
  • NUC-1031/cisplatin versus gemcitabine/cisplatin in untreated locally advanced/metastatic biliary tract cancer (NuTide:121)

    McNamara, Mairead G; Goyal, L.; Doherty, M.; Springfeld, C.; Cosgrove, D.; Sjoquist, K. M.; Park, J. O.; Verdaguer, H.; Braconi, C.; Ross, P. J.; et al. (2020)
    Gemcitabine/cisplatin is standard of care for first-line treatment of patients with advanced biliary tract cancer (aBTC); new treatments are needed. NUC-1031 is designed to overcome key cancer resistance mechanisms associated with gemcitabine. The tolerability/efficacy signal of NUC-1031/cisplatin in the Phase Ib ABC-08 study suggested that this combination may represent a more efficacious therapy than gemcitabine/cisplatin for patients with aBTC, leading to initiation of the global NuTide:121 study which will include 828 patients /=18 years with untreated histologically/cytologically-confirmed aBTC (including cholangiocarcinoma
  • Histological phenotypic subtypes predict recurrence risk and response to adjuvant chemotherapy in patients with stage III colorectal cancer

    Roseweir, A. K.; Park, J. H.; Hoorn, S. T.; Powell, A. G.; Aherne, S.; Roxburgh, C. S.; McMillan, D. C.; Horgan, P. G.; Ryan, E.; Sheahan, K.; et al. (2020)
    Histological 'phenotypic subtypes' that classify patients into four groups (immune, canonical, latent and stromal) have previously been demonstrated to stratify survival in a stage I-III colorectal cancer (CRC) pilot cohort. However, clinical utility has not yet been validated. Therefore, this study assessed prognostic value of these subtypes in additional patient cohorts along with associations with risk of recurrence and response to chemotherapy. Two independent stage I-III CRC patient cohorts (internal and external cohort) were utilised to investigate phenotypic subtypes. The primary endpoint was disease-free survival (DFS) and the secondary endpoint was recurrence risk (RR). Stage II-III patients, from the SCOT adjuvant chemotherapy trial, were utilised to further validate prognostic value and for exploratory analysis assessing associations with adjuvant chemotherapy. In an 893-patient internal cohort, phenotypic subtype independently associated with DFS (p = 0.025) and this was attenuated in stage III patients (p = 0.020). Phenotypic subtype also independently associated with RR (p < 0.001) in these patients. In a 146-patient external cohort, phenotypic subtype independently stratified patients by DFS (p = 0.028), validating their prognostic value. In 1343 SCOT trial patients, the effect of treatment type significantly depended on phenotypic subtype (pinteraction = 0.011). Phenotypic subtype independently associated with DFS in stage III patients receiving FOLFOX (p = 0.028). Furthermore, the immune subtype significantly associated with better response to FOLFOX compared to CAPOX adjuvant chemotherapy in stage III patients (p = 0.013). In conclusion, histological phenotypic subtypes are an effective prognostic classification in patients with stage III CRC that associates with risk of recurrence and response to FOLFOX adjuvant chemotherapy.
  • Pulmonary metastasectomy in colorectal cancer (PulMiCC): Updated analysis of 93 randomised patients - control survival is much better than previously assumed

    Milosevic, M.; Edwards, J.; Tsang, D.; Dunning, J.; Shackcloth, M.; Batchelor, T.; Coonar, A.; Hasan, Jurjees; Davidson, B.; Marchbank, A.; et al. (2020)
    AIMS: Lung metastases from colorectal cancer are resected in selected patients in the belief that this confers a significant survival advantage. It is generally assumed that the five-year survival of these patients would be near zero without metastasectomy. We have tested the clinical effectiveness of this practice in PulMiCC, a randomised controlled non-inferiority trial. METHODS: Multidisciplinary teams in 14 hospitals recruited patients with resectable lung metastases into a two-arm trial. Randomisation was remote and stratified by site with minimisation for age, sex, primary cancer stage, interval since primary resection, prior liver involvement, number of metastases, and carcinoembryonic antigen. The trial management group were blind to patient allocation until after intention to treat analysis. RESULTS: From 2010 to 2016, 93 participants were randomised, aged 35 to 86 years, with 1-6 lung metastases at a median of 2.7 years after colorectal cancer resection. 29% had prior liver metastasectomy. Characteristics were well-matched and similar to observational studies. The median survival after metastasectomy was 3.5 years (95%CI:3.1,6.6) compared with 3.8 years (95%CI:3.1,4.6) for controls. The estimated unadjusted hazard ratio for death within five years, comparing metastasectomy to control, was 0.93 (95%CI:0.56,1.56). Use of chemotherapy or local ablation was infrequent and similar in each group. CONCLUSIONS: The control group patients who do not have lung metastasectomy have better survival than is assumed. Survival in the metastasectomy group are comparable with the many single arm follow-up studies. The groups were well matched with features similar to reported case series.

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