• Liver metastases of intrahepatic cholangiocarcinoma: implications for an updated staging system

      Lamarca, Angela; Santos-Laso, Alvaro; Utpatel, K.; La Casta, Adelaida; Stock, Simone; Forner, Alejandro; Adeva, Jorge; Folseraas, Trine; Fabris, Luca; Macias, R. I. R.; et al. (2021-06)
      Background and aims: Intrahepatic cholangiocarcinoma (iCCA) with liver metastases is perceived to have a poor prognosis, but the American Joint Committee on Cancer (AJCC) classifies them as early stage in the absence of lymph nodes or extrahepatic spread. Approach and results: Patients with iCCA from the European Network for the Study of Cholangiocarcinoma (ENS-CCA) and Surveillance, Epidemiology, and End Results (SEER) registries with survival/staging (AJCC v.7) data were eligible. Modified staging was used (mAJCC v.7): group A: stages I-III (excluding T2bN0); group B: stage IVa (excluding T2bN1M0); group C: liver metastases (T2bN0/1); and group D: stage IVb (extrahepatic metastases). Survival analysis (Kaplan-Meier and Cox regression) was performed in an ENS-CCA training cohort (TC) and findings internally (ENS-CCA iVC) and externally (SEER) validated. The aim was to assess whether liver metastases (group C) had a shorter survival compared to other early stages (group A) to propose a modified version of AJCC v.8 (mAJCC v.8). A total of 574 and 4,171 patients from the ENS-CCA and SEER registries were included. Following the new classification, 19.86% and 17.31% of patients from the ENS-CCA and SEER registries were reclassified into group C, respectively. In the ENS-CCA TC, multivariable Cox regression was adjusted for obesity (p = 0.026) and performance status (P < 0.001); patients in group C (HR, 2.53; 95% CI, 1.18-5.42; P = 0.017) had a higher risk of death (vs. group A). Findings were validated in the ENS-CCA iVC (HR, 2.93; 95% CI, 2.04-4.19; P < 0.001) and in the SEER registry (HR, 1.88; 95% CI, 1.68-2.09; P < 0.001). Conclusions: iCCA with liver metastases has a worse outcome than other early stages of iCCA. Given that AJCC v.8 does not take this into consideration, a modification of AJCC v.8 (mAJCC v.8), including "liver metastases: multiple liver lesions, with or without vascular invasion" as an "M1a stage," is suggested.
    • Erratum to 'Longitudinal characterisation of haematological and biochemical parameters in cancer patients prior to and during COVID-19 reveals features associated with outcome'

      Lee, Rebecca J; Wysocki, O; Bhogal, T.; Shotton, Rohan; Tivey, Ann; Angelakas, Angelos; Aung, T.; Banfill, Kathryn; Baxter, M.; Boyce, H.; et al. (2021-04-01)
    • Brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine in patients with advanced-stage, classical Hodgkin lymphoma: A prespecified subgroup analysis of high-risk patients from the ECHELON-1 study

      Hutchings, Martin; Radford, John A; Ansell, S. M.; Illés, Árpád; Sureda, Anna; Connors, J. M.; Sýkorová, Alice; Shibayama, Hirohiko; Abramson, Jeremy S; Chua, Neil; et al. (2021-04)
      Approximately one-third of patients diagnosed with Hodgkin lymphoma presenting with Stage IV disease do not survive past 5 years. We present updated efficacy and safety analyses in high-risk patient subgroups, defined by Stage IV disease or International Prognostic Score (IPS) of 4-7, enrolled in the ECHELON-1 study that compared brentuximab vedotin plus doxorubicin, vinblastine, and dacarbazine (A + AVD) versus doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) as first-line therapy after a median follow-up of 37.1 months. Among patients treated with A + AVD (n = 664) or ABVD (n = 670), 64% had Stage IV disease and 26% had an IPS of 4-7. Patients with Stage IV disease treated with A + AVD showed consistent improvements in PFS at 3 years as assessed by investigator (hazard ratio [HR], 0.723; 95% confidence interval [CI], 0.537-0.973; p = 0.032). Similar improvements were seen in the subgroup of patients with IPS of 4-7 (HR, 0.588; 95% CI, 0.386-0.894; p = 0.012). The most common adverse events (AEs) in A + AVD-treated versus ABVD-treated patients with Stage IV disease were peripheral neuropathy (67% vs. 40%) and neutropenia (71% vs. 55%); in patients with IPS of 4-7, the most common AEs were peripheral neuropathy (69% vs. 45%), neutropenia (66% vs. 55%), and febrile neutropenia (23% vs. 9%), respectively. Patients in high-risk subgroups did not experience greater AE incidence or severity than patients in the total population. This updated analysis of ECHELON-1 shows a favorable benefit-risk balance in high-risk patients.
    • A prospective cohort study on the safety of checkpoint inhibitors in older cancer patients - the ELDERS study

      Gomes, Fabio; Lorigan, Paul C; Woolley, Sharon; Foden, Philip; Burns, Katy; Yorke, Janelle; Blackhall, Fiona H; Medical Oncology Department, The Christie NHS Foundation Trust, Manchester (2021)
      Objective: Older cancer patients are underrepresented in the pivotal trials of checkpoint inhibitors (CPIs). This study aimed to investigate the impact of an ageing immune system on CPI-related toxicity and provide evidence for the role of geriatric assessments with CPI. Methods: The ELDERS study is a prospective observational study with two cohorts: older (70+ years of age) and younger (<70 years of age). Patients with advanced/metastatic non-small-cell lung cancer or melanoma starting single-agent CPI were eligible. The older cohort was assessed for frailty with Geriatric-8 (G8) screening, which when positive (<15 points) was followed by a holistic set of geriatric assessments. Primary endpoint was the incidence of grade 3-5 immune-related adverse events (irAEs). Results: One hundred and forty patients were enrolled with 43% being pretreated and pembrolizumab represented 92% of treatments on study. The older cohort had a significantly higher comorbidity burden (P < 0.001) and polypharmacy (P = 0.004). While 50% of older patients had a positive G8 screening, 60% on this frail subgroup had a performance status score of 0 or 1. There was no significant difference in the incidence of irAEs grade 3-5 between older and younger cohorts (18.6% versus 12.9%; odds ratio 1.55, confidence interval 95% 0.61-3.89; P = 0.353). Exposure to systemic steroids due to irAEs was numerically longer for older patients (22 versus 8 weeks; P = 0.208). A positive G8 screening predicted hospital admissions (P = 0.031) and risk of death (P = 0.01). Conclusions: The use of CPI in older patients was not associated with more high-grade toxicity. The G8 screening identified a subgroup with higher risk of AEs and its implementation should be considered in the context of CPI.
    • An international pragmatic randomized controlled trial to compare a single-use negative-pressure dressing versus the surgeon's preference of dressing to reduce the incidence of surgical site infection following emergency laparotomy: the SUNRRISE trial protocol

      Wilkin, R.; Coe, P.; Duarte, R.; Stott, M.; Pockney, P.; Egoroff, N.; Mehta, S.; Brown, J.; Magill, L.; Ives, N.; et al. (2021)
      Background: Surgical site infection (SSI) is a common complication following emergency laparotomy occurring in around 25% of patients in UK practice. The use of single use negative pressure dressings (SUNPDs) for these wounds has been proposed as a prophylactic method of reducing the rate of SSI. Method: The Single Use Negative pRessure dressing for Reduction In Surgical site infection following Emergency laparotomy (SUNRRISE) study is an international, multicentre, pragmatic, phase III randomised controlled trial (RCT) with internal feasibility phase. The primary aim is to determine if a single use negative pressure dressing (SUNPD) reduces surgical site infection (SSI) at 30 days post-operatively. Patients will be randomised in a 1:1 ratio to either a SUNPD or to receive a dressing of the surgeon's preference. Outcome assessors will be blinded to treatment allocation. The primary outcome measure is SSI within 30 days of surgery as defined by the Centers for Disease Control criteria. A total of 840 patients will be required to detect a relative reduction of 40% in SSI rates (from 25% to 15%) with 90% power accounting for 20% attrition rate. Discussion: SUNRRISE is an international, multicentre RCT evaluating the prophylactic use of SUNPD in primary closed emergency laparotomy wounds for the reduction of SSI. Our hypothesis is that a SUNPD is superior to the surgeon's preference of dressing in reducing surgical site infections at 30 days. These findings may influence dressing choice following emergency abdominal surgery in the future.
    • Ivosidenib: an investigational drug for the treatment of biliary tract cancers

      Angelakas, Angelos; Lamarca, Angela; Hubner, Richard A; McNamara, Mairead G; Valle, Juan W; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK (2021)
      Introduction: Biliary tract cancers (BTCs) [including cholangiocarcinoma and gallbladder cancer] are rare cancers associated with poor survival; most patients have advanced disease at diagnosis. Current chemotherapy reference regimens include cisplatin and gemcitabine as first-line and oxaliplatin and 5-fluorouracil (FOLFOX) in second-line. Molecular profiling has identified several actionable therapeutic targets including isocitrate dehydrogenase (IDH)1 mutations. Ivosidenib is a reversible inhibitor of mutant IDH1; it is currently approved for the treatment of acute myeloid leukaemia and has been studied in patients with advanced cholangiocarcinoma. Areas covered: This article introduces current treatments for BTC and sheds light on the mechanism of action, pharmacodynamics, pharmacokinetics, clinical efficacy and safety of ivosidenib in advanced cholangiocarcinoma. The authors conclude with insights on the changing treatment paradigm created by emerging drugs and precision approaches. Expert opinion: Ivosidenib is well-tolerated, with good oral exposure and long half-life as shown by phase I data. In a phase III study, ivosidenib has demonstrated improved progression-free survival compared to placebo (median 2.7 vs 1.4 months; hazard ratio 0.37; 95% confidence interval 0.25-0.54; one-sided p<0.0001); it has also demonstrated a trend towards increased overall survival in patients with cholangiocarcinoma and disease progression on prior chemotherapy. Final survival data from this study are pending presentation. Increased use of molecular profiling will continue to identify potential therapeutic targets and improve the prognosis of patients with these cancers.
    • Targeted therapies for extrahepatic cholangiocarcinoma: preclinical and clinical development and prospects for the clinic

      Cadamuro, M.; Lasagni, A.; Lamarca, Angela; Fouassier, L.; Guido, M.; Sarcognato, S.; Gringeri, E.; Cillo, U.; Strazzabosco, M.; Marin, J. J.; et al. (2021)
      Introduction: Until recently, cholangiocarcinoma (CCA) was a largely overlooked disease, and among CCAs, extrahepatic CCA (eCCA) was even more neglected. Despite the growing impact of molecularly targeted therapies and immunotherapy, prognosis of eCCA is dismal. Therefore, unraveling the complex molecular landscape of eCCA has become an urgent need. Deep phenotyping studies have revealed that eCCA is a heterogeneous tumor, harboring specific alterations categorizable into four classes, 'Mesenchymal', 'Proliferation', 'Immune', 'Metabolic'. Molecular alterations convey the activation of several pro-oncogenic pathways, where either actionable drivers or outcome predictors can be identified.Areas covered: We offer insights on perturbed pathways, molecular profiling, and actionable targets in eCCA and present a perspective on the potential stepping-stones to future progress. A systematic literature search in PubMed/ClinicalTrials.gov websites was performed by authors from different disciplines according to their specific topic knowledge to identify the newest and most relevant advances in precision medicine of eCCA.Expert opinion: eCCA is a distinct entity with unique features in terms of molecular classes, oncogenic drivers, and tumor microenvironment. Since more prevalent mutations are currently undruggable, and immunotherapy can be offered only to a minority of patients, international collaborations are instrumental to improve the understanding of the molecular underpins of this disease.
    • Developing tumor radiosensitivity signatures using LncRNAs

      Khan, Mairah T; Yang, Lingjian; More, Elisabet; Irlam-Jones, Joely J; Valentine, Helen R; Hoskin, Peter J; Choudhury, Ananya; West, Catharine M L; Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie NHS Foundation Trust Hospital, Manchester M20 4BX (2021)
      Long non-coding RNAs (lncRNAs) are involved in diverse biological processes, including DNA damage repair, and are of interest as potential biomarkers of radiosensitivity. We investigated whether lncRNA radiosensitivity signatures could be derived for use in cancer patients treated with radiotherapy. Signature development involved radiosensitivity measurements for cell lines and primary tumor samples, and patient outcome after radiotherapy. A 10-lncRNA signature trained on radiosensitivity measurements in bladder cell lines showed a trend towards independent validation. In multivariable analyses, patients with tumors classified as radioresistant by the lncRNA signature had poorer local relapse-free survival (P = 0.065) in 151 patients with muscle-invasive bladder cancer who underwent radiotherapy. An mRNA-based radiosensitivity index signature performed similarly to the lncRNA bladder signature for local relapse-free survival (P = 0.055). Pathway analysis showed the lncRNA signature associated with molecular processes involved in radiation responses. Knockdown of one of the lncRNAs in the signature showed a modest increase in radiosensitivity in one cell line. An alternative approach involved training on primary cervical tumor radiosensitivity or local control after radiotherapy. Both approaches failed to generate a cervix lncRNA radiosensitivity signature, which was attributed to the age of samples in our cohorts. Our work highlights challenges in validating lncRNA signatures as biomarkers in archival tissue from radiotherapy cohorts, but supports continued investigation of lncRNAs for a role in radiosensitivity.
    • Randomised controlled trial evidence questions the assumption that pulmonary metastasectomy benefits patients with colorectal cancer

      Batchelor, T.; Hasan, Jurjees; Macbeth, F.; Shackcloth, M.; Treasure, T.; Bristol Royal Infirmary, Bristol, UK. (2021)
      Pulmonary metastasectomy for sarcoma is surgery without proven benefit, and in the light of a randomized controlled trial examining pulmonary metastasectomy in colorectal cancer, it should be questioned.
    • Incidence of brain metastases (BMs) and outcomes in patients (pts) with extrapulmonary neuroendocrine neoplasms (EP-NENs)

      Kapacee, Zainul Abedin; Dawod, Mohammed; Allison, Jennifer; Frizziero, Melissa; Chakrabarty, Bipasha; Manoharan, Prakash; McBain, Catherine A; Mansoor, Was; Lamarca, Angela; Hubner, Richard A; et al. (2021)
      Introduction: The incidence, management and outcomes of pts with EP-NENs and BMs are unclear. Aim(s): To investigate outcomes in pts with EP-NENs ± BMs. Materials and methods: A retrospective study of consecutive pts with EP-NENs and BMs treated at a single ENETS CoE was performed. Median (med) overall survival (OS)/survival from BM diagnosis were estimated (Kaplan Meier). Results: Between Aug 04-Feb 20, 730 pts with an EP-NEN diagnosis were identified: med age 64 yrs (15-90); 56% male, 67% had advanced disease (ADVD). In pts with ADVD, the primary NEN site were: small bowel 42%, pancreas 22%, unknown 14%, large bowel 10%, other 5%, stomach 4% and appendix <1%; 37%, 30% and 30% pts had grade (G)1, 2 and 3 EP-NENs respectively (no grading 3%). Med OS for pts with ADVD G1, 2 and 3 EP-NENs without BMs were 95.8 (95% C.I 77.0-177.1), 61.7 (95% C.I 50.1-124.4) and 11.3 (95% C.I 9.3-14.4) months (mo) respectively. 17 pts (2.3%) developed BMs; 2 at initial diagnosis, 15 metachronously; 5 pts (29%) had a solitary BM, 12 (71%) had multiple BMs. The primary sites of origin were: unknown 41%, oesophagus 18%, pancreas 17%, small bowel 12%, cervix 6% and bladder 6%; 6%, 24% and 70% had G1, G2 and G3 EP-NENs respectively. Most common presenting symptoms of pts with BMs were limb weakness and cognitive impairment. Pts with BMs received high dose steroids and best supportive care (35%), whole brain radiotherapy with steroids (29%), surgery (18%) and localised radiotherapy (6%). Med OS for pts with G1+2 EP-NENs and BMs was not reached. Med OS in pts with G3 EP-NENs and BMs was 9.0 mo (95% CI 6.0-12.1); med survival from BM diagnosis was 2.0 mo (95% CI 0.0-4.4). Conclusion: BMs in pts with EP-NENs are rare, predominant in G3 NENs, and have a poor prognosis. Improved therapeutic options are needed.
    • Assessing the management of bone metastases in patients diagnosed with neuroendocrine neoplasms: Re-audit of clinical practice

      Garcia-Torralba, E; Lim, Kok Haw Jonathan; Barriuso, Jorge; McNamara, Mairead G; Hubner, Richard A; Mansoor, Was; Valle, Juan W; Lamarca, Angela; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, (2021)
      Introduction: There remains no global consensus on the optimal management of bone metastases in patients with neuroendocrine neoplasms (BM-NEN). Aim(s): To re-audit the clinical management of BM-NEN following the incorporation of institutional guidelines (TC-BM Guid) established in 2018 (PMID: 31639796). Materials and methods: Retrospective study of all patients with BM-NEN diagnosed from Jan-Dec 2019 following TC-BM Guid. Characteristics of BM-NEN and treatment received were evaluated against TC-BM Guid. Statistical analysis was performed using STATA v14. Results: Of 354 patients, 40 (11%) had BM (gastrointestinal: 53%, N=21; lung: 15%, N=6; unknown primary: 12%, N=5; other: 20%, N=8). BM were “widespread” in 80% (N=32). Compared to the cohort prior to TC-BM Guid implementation (2002-2018, N=85), incidence of symptoms (any), pain/hypercalcemia, and skeletal-related events were lower (45%, N=18 vs 78%, N=66; 40%, N=16 vs 64%, N=54; 13%, N=5 vs 20%, N=17, respectively). Use of analgesia for symptomatic BMs (80%, N=32 vs 44%, N=37) and use of bisphosphonates (33%, N=13 vs 22%, N=19) were higher. Use of radiotherapy and surgery were similar (23%, N=9 and 3%, N=1 respectively). The re-audit showed that management adhered to TC-BM Guid in the majority of patients (95%, N=38), including 4 patients who received best supportive care due to poor performance status (PS) and short prognosis (<3 months), which was not previously detailed in the guidelines. Conclusion: TC-BM Guid are deliverable, and current management of BM-NEN mostly adhered to these. Following this, TC-BM Guid were updated to reflect recommendations for symptomatic management only (best supportive care) for patients with poor PS/short life-expectancy.
    • Advanced small intestine well-differentiated neuroendocrine tumors (WD-SiNET): A survey of practice on 3rd line treatment

      Lamarca, Angela; Cives, M.; de Mestier, L.; Crona, J.; Spada, F.; Oberg, K.; Pavel, M.; Alonso-Gordoa, T.; The Christie NHS Foundation Trust, Manchester, (2021)
      Introduction: Selection of third-line treatment after somatostatin analogues (SSA) and Peptide Receptor Radionuclide Therapy (PRRT) for WD-SiNETs remains challenging. Aim(s): Understand current practice and rationale for decision-making in the 3rd-line setting after SSA and PRRT. Materials and methods: An online survey (replies collected between 5/8/2020 and 21/9/2020) was built. Weighted average (WA) of likelihood of usage between responders (1 very unlikely; 4 very likely) was used to reflect the relevance of factors explored. Results: A total of 28 replies; medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from ENETS CoE (57.1%), who followed ENETS guidelines (82.1%). Overall, 3rd-line treatment for WD-SiNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%) or personal experience (22.2%). EVE was likely used if Ki-67 < 10% (WA 3.27/4) or age < 70 years (WA 3.23/4), in the 3rd-line setting (WA 3.23/4); irrespective of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was chosen if rapid progression (within 6 months) (WA 3.35/4), Ki-67 10-20% (WA 2.77/4), negative SSTR2 imaging (WA 2.65/4) or high tumor burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-FU (57.7%), FOLFOX (23.1%). LE was selected if presence of CS (WA 3.24/4) or Ki-67 < 10% (WA 2.8/4), after progression to other treatments (WA 2.8/4). IFN was rarely used (WA 1.3/4). Conclusion: Selection of 3rd line therapy is based on multiple factors mainly Ki-67, rate of progression, CS and tumor burden; decisions should be made within a multidisciplinary setting
    • Empowerment survey for patients with neuroendocrine tumors - A pilot study in Spanish population

      Hernando, J.; Sampedro-Nunez, M.; de Nova, J. L. M.; Trivino, E. M.; Vazquez, G.; Hernandez, X.; Fernandez, E.; Cusido, E.; Guaras, B.; Olmo-Garcia, M.; et al. (2021)
      Introduction: Quality of life is very important in patients with neuroendocrine tumors (NET), but other aspects such as satisfaction and empowerment of patients have been less studied. In Spain, there is a lack of validated cancer empowerment questionnaires. Aim(s): The aim of the present study is to conduct a pilot test with an online survey of patient’s empowerment in NET in the Spanish population. Materials and methods: The Spanish survey was designed with previous general health empowerment questionnaires (Health Education Impact Questionnaire, Maunsell 2014), internal hospital satisfaction scores, and direct feedback from NET-España Patient Advocacy group. The final survey was approved by GETNE Academy taskforce. Anonymous online survey was conducted between August and November 2020 in NET patients from NET-España association in Spain. Results: 67 NET patients answered (95.5% completed all questions). Scale internal consistency was good. Most patients had medium or high levels of general empowerment-related to NET. We identified two main areas where most patients had a low level of empowerment, including psychological support and patient's self-management groups. Specific questions related to NET characteristics and NET-specific treatments reflect the situation of NET management in Spain and reveals a high knowledge about the biology of the disease and current available therapies. Conclusion: This NET empowerment survey is understandable, easy to answer, and useful to measure the empowerment of the Spanish population with NET. After this initial pilot experience, a larger study in an unselected population is necessary for the validation of this questionnaire.
    • To determine the true incidence of brain metastases in atypical lung neuroendocrine tumors and explore factors that increase the risk of intracranial disease

      Jones, J; Spurgeon, Laura; Shaheen, Fadhel; Lewis, Alexandra R; Mansoor, Was; Khan, Adeel; The Christie NHS Foundation Trust, Manchester (2021)
      Introduction: Lung neuroendocrine tumors (NETs) make up 25% of all NETs. Typical carcinoid (TC) and atypical carcinoid (AC) account for 2% and 0.2% of all lung NETs respectively, and AC tend to be more aggressive. Although both can metastasise, AC are more likely; common sites include bone and liver. Currently, brain imaging is not included in the work-up of TC/AC, as <5% of cases are thought to develop brain metastases (BM). However, evidence suggests this may be an underestimate. Identifying BM would inform management and could improve prognosis. Thus, evaluating the incidence in TC/AC is needed to ascertain whether there is justification for baseline brain imaging. Furthermore, Ki-67 could be useful as a predictive tool. Aim(s): To review the incidence of BM in TC/AC to determine whether there is justification for routine brain imaging and to explore factors which could increase the risk of BM. Materials and methods: Single site, retrospective analysis of 287 patients with TC/AC over a 13-year period. Incidence of BM (as detected on CT/MRI), at diagnosis or during the course of the disease, was reviewed. Results: None of the 215 TC patients developed BM, whereas 8 out of 72 (11.1%) with AC did; 50% of these were present at diagnosis. 13.04% of AC with BM had evidence of both bone and liver involvement. 75% of AC with BM had Ki-67 expression >15%. Conclusion: Over 10% of the AC developed BM, half of which were present at diagnosis. This provides convincing evidence of the need for baseline brain imaging in AC, particularly for patients with Ki-67 expression >15% or with bone and liver involvement, as these factors were associated with increased risk. Early detection and treatment of BM can improve outcomes
    • 4 Gy versus 24 Gy radiotherapy for follicular and marginal zone lymphoma (FoRT): long-term follow-up of a multicentre, randomised, phase 3, non-inferiority trial

      Hoskin, Peter J; Popova, B.; Schofield, O.; Brammer, C.; Robinson, M.; Brunt, A. M.; Madhavan, K.; Illidge, Timothy M; Gallop-Evans, E.; Syndikus, I.; et al. (2021)
      Background: The optimal radiotherapy dose for indolent non-Hodgkin lymphoma is uncertain. We aimed to compare 24 Gy in 12 fractions (representing the standard of care) with 4 Gy in two fractions (low-dose radiation). Methods: FoRT (Follicular Radiotherapy Trial) is a randomised, multicentre, phase 3, non-inferiority trial at 43 study centres in the UK. We enrolled patients (aged >18 years) with indolent non-Hodgkin lymphoma who had histological confirmation of follicular lymphoma or marginal zone lymphoma requiring radical or palliative radiotherapy. No limit on performance status was stipulated, and previous chemotherapy or radiotherapy to another site was permitted. Radiotherapy target sites were randomly allocated (1:1) either 24 Gy in 12 fractions or 4 Gy in two fractions using minimisation and stratified by histology, treatment intent, and study centre. Randomisation was centralised through the Cancer Research UK and University College London Cancer Trials Centre. Patients, treating clinicians, and investigators were not masked to random assignments. The primary endpoint was time to local progression in the irradiated volume based on clinical and radiological evaluation and analysed on an intention-to-treat basis. The non-inferiority threshold aimed to exclude the chance that 4 Gy was more than 10% inferior to 24 Gy in terms of local control at 2 years (HR 1·37). Safety (in terms of adverse events) was analysed in patients who received any radiotherapy and who returned an adverse event form. FoRT is registered with ClinicalTrials.gov, NCT00310167, and the ISRCTN Registry, ISRCTN65687530, and this report represents the long-term follow-up. Findings: Between April 7, 2006, and June 8, 2011, 614 target sites in 548 patients were randomly assigned either 24 Gy in 12 fractions (n=299) or 4 Gy in two fractions (n=315). At a median follow-up of 73·8 months (IQR 61·9-88·0), 117 local progression events were recorded, 27 in the 24 Gy group and 90 in the 4 Gy group. The 2-year local progression-free rate was 94·1% (95% CI 90·6-96·4) after 24 Gy and 79·8% (74·8-83·9) after 4 Gy; corresponding rates at 5 years were 89·9% (85·5-93·1) after 24 Gy and 70·4% (64·7-75·4) after 4 Gy (hazard ratio 3·46, 95% CI 2·25-5·33; p<0·0001). The difference at 2 years remains outside the non-inferiority margin of 10% at -13·0% (95% CI -21·7 to -6·9). The most common events at week 12 were alopecia (19 [7%] of 287 sites with 24 Gy vs six [2%] of 301 sites with 4 Gy), dry mouth (11 [4%] vs five [2%]), fatigue (seven [2%] vs five [2%]), mucositis (seven [2%] vs three [1%]), and pain (seven [2%] vs two [1%]). No treatment-related deaths were reported. Interpretation: Our findings at 5 years show that the optimal radiotherapy dose for indolent lymphoma is 24 Gy in 12 fractions when durable local control is the aim of treatment.
    • Improved survival prediction for oropharyngeal cancer beyond TNMv8

      Price, J M; West, Catharine M L; Mistry, Hitesh; Betts, G.; Bishop, P.; Kennedy, Jason; Dixon, Lynne; Homer, J. J.; Garcez, Kate; Lee, Lip W; et al. (2021)
      Purpose: For oropharynx squamous cell carcinoma (OPSCC) this study aimed to: (i) compare 5-year overall survival (OS) stratification by AJCC/UICC TNM versions 7 (TNMv7) and 8 (TNMv8), (ii) determine whether changes to T and N stage groupings improve prognostication and (iii) develop and validate a model incorporating additional clinical characteristics to improve 5-year OS prediction. Material and methods: All OPSCC treated with curative-intent at our institution between 2011 and 2017 were included. The primary endpoint was 5-year OS. Survival curves were produced for TNMv7 and TNMv8. A three-way interaction between T, N stage and p16 status was evaluated for improved prognostication. Cox proportional hazards modelling was used to derive a new predictive model. Results: Of 750 OPSCC cases, 574 (77%) were p16-positive. TNMv8 was more prognostic than TNMv7 (concordance probability estimate [CPE] ± SE = 0.72 ± 0.02 vs 0.53 ± 0.02). For p16-positive disease, TNMv8 discriminated stages II vs I (HR 2.32, 95% CI 1.47-3.67) and III vs II (HR 1.75, 95% CI 1.13-2.72). For p16-negative disease, TNMv7 and TNMv8 demonstrated poor hazard discrimination. Different T, N stage and p16-status combinations did not improve prognostication after adjusting for other factors (CPE = 0.79 vs 0.79, p = 0.998). A model for p16-positive and p16-negative OPSCC including additional clinical characteristics improved 5-year OS prediction beyond TNMv8 (c-index 0.76 ± 0.02). Conclusions: TNMv8 is superior to TNMv7 for p16-positive OPSCC, but both performed poorly for p16-negative disease. A novel model incorporating additional clinical characteristics improved 5-year OS prediction for both p16-positive and p16-negative disease.
    • Association of breast cancer irradiation with cardiac toxic effects: a narrative review

      Meattini, I.; Poortmans, P. M.; Aznar, Marianne Camille; Becherini, C.; Bonzano, E.; Cardinale, D.; Lenihan, D. J.; Marrazzo, L.; Curigliano, G.; Livi, L.; et al. (2021)
      Importance: To promptly recognize and manage cardiovascular (CV) risk factors before, during, and after cancer treatment, decreasing the risk of cancer therapy-related cardiac dysfunction is crucial. After recent advances in breast cancer treatment, mortality rates from cancer have decreased, and the prevalence of survivors with a potentially higher CV disease risk has increased. Cardiovascular risks might be associated with the multimodal approach, including systemic therapies and breast radiotherapy (RT). Observations: The heart disease risk seems to be higher in patients with tumors in the left breast, when other classic CV risk factors are present, and when adjunctive anthracycline-based chemotherapy is administered, suggesting a synergistic association. Respiratory control as well as modern RT techniques and their possible further refinement may decrease the prevalence and severity of radiation-induced heart disease. Several pharmacological cardioprevention strategies for decreasing cardiac toxic effects have been identified in several guidelines. However, further research is needed to ascertain the feasibility of these strategies in routine practice. Conclusions and relevance: This review found that evidence-based recommendations are lacking on the modalities for and intensity of heart disease screening, surveillance of patients after RT, and treatment of these patients. A multidisciplinary and multimodal approach is crucial to guide optimal management.
    • Biliary tract cancer

      Valle, Juan W; Kelley, R. K.; Nervi, B.; Oh, D. Y.; Zhu, A. X.; Division of Cancer Sciences, University of Manchester, Manchester (2021)
      Biliary tract cancers, including intrahepatic, perihilar, and distal cholangiocarcinoma as well as gallbladder cancer, are low-incidence malignancies in most high-income countries, but represent a major health problem in endemic areas; moreover, the incidence of intrahepatic cholangiocarcinoma is rising globally. Surgery is the cornerstone of cure; the optimal approach depends on the anatomical site of the primary tumour and the best outcomes are achieved through management by specialist multidisciplinary teams. Unfortunately, most patients present with locally advanced or metastatic disease. Most studies in advanced disease have pooled the various subtypes of biliary tract cancer by necessity to achieve adequate sample sizes; however, differences in epidemiology, clinical presentation, natural history, surgical therapy, response to treatment, and prognosis have long been recognised. Additionally, the identification of distinct patient subgroups harbouring unique molecular alterations with corresponding targeted therapies (such as isocitrate dehydrogenase-1 mutations and fibroblast growth factor receptor-2 fusions in intrahepatic cholangiocarcinoma, among others) is changing the treatment paradigm. In this Seminar we present an update of the causes, diagnosis, molecular classification, and treatment of biliary tract cancer.
    • Uptake and efficacy of bilateral risk reducing surgery in unaffected female BRCA1 and BRCA2 carriers

      Marcinkute, R.; Woodward, E. R.; Gandhi, A.; Howell, Sacha J; Crosbie, E. J.; Wissely, J.; Harvey, J.; Highton, L.; Murphy, J.; Holland, C.; et al. (2021)
      Background: Women testing positive for BRCA1/2 pathogenic variants have high lifetime risks of breast cancer (BC) and ovarian cancer. The effectiveness of risk reducing surgery (RRS) has been demonstrated in numerous previous studies. We evaluated long-term uptake, timing and effectiveness of risk reducing mastectomy (RRM) and bilateral salpingo-oophorectomy (RRSO) in healthy BRCA1/2 carriers. Methods: Women were prospectively followed up from positive genetic test (GT) result to censor date. χ² testing compared categorical variables; Cox regression model estimated HRs and 95% CI for BC/ovarian cancer cases associated with RRS, and impact on all-cause mortality; Kaplan-Meier curves estimated cumulative RRS uptake. The annual cancer incidence was estimated by women-years at risk. Results: In total, 887 women were included in this analysis. Mean follow-up was 6.26 years (range=0.01-24.3; total=4685.4 women-years). RRS was performed in 512 women, 73 before GT. Overall RRM uptake was 57.9% and RRSO uptake was 78.6%. The median time from GT to RRM was 18.4 months, and from GT to RRSO-10.0 months. Annual BC incidence in the study population was 1.28%. Relative BC risk reduction (RRM versus non-RRM) was 94%. Risk reduction of ovarian cancer (RRSO versus non-RRSO) was 100%. Conclusion: Over a 24-year period, we observed an increasing number of women opting for RRS. We showed that the timing of RRS remains suboptimal, especially in women undergoing RRSO. Both RRM and RRSO showed a significant effect on relevant cancer risk reduction. However, there was no statistically significant RRSO protective effect on BC.
    • Survival from breast cancer in women with a BRCA2 mutation by treatment

      Evans, D. G.; Phillips, K. A.; Milne, R. L.; Fruscio, R.; Cybulski, C.; Gronwald, J.; Lubinski, J.; Huzarski, T.; Hyder, Z.; Forde, C.; et al. (2021)
      Background: The impact of various breast-cancer treatments on patients with a BRCA2 mutation has not been studied. We sought to estimate the impact of bilateral oophorectomy and other treatments on breast cancer-specific survival among patients with a germline BRCA2 mutation. Methods: We identified 664 women with stage I-III breast cancer and a BRCA2 mutation by combining five different datasets (retrospective and prospective). Subjects were followed for 7.2 years from diagnosis to death from breast cancer. Tumour characteristics and cancer treatments were patient-reported and derived from medical records. Predictors of survival were determined using Cox proportional hazard models, adjusted for other treatments and for prognostic features. Results: The 10-year breast-cancer survival for ER-positive patients was 78.9% and for ER-negative patients was 82.3% (adjusted HR = 1.23 (95% CI, 0.62-2.45, p = 0.55)). The 10-year breast-cancer survival for women who had a bilateral oophorectomy was 89.1% and for women who did not have an oophorectomy was 59.0% (adjusted HR = 0.45; 95% CI, 0.28-0.72, p = 0.001). The adjusted hazard ratio for chemotherapy was 0.83 (95% CI, 0.65-1.53: p = 0.56). Conclusions: For women with breast cancer and a germline BRCA2 mutation, positive ER status does not predict superior survival. Oophorectomy is associated with a reduced risk of death from breast cancer and should be considered in the treatment plan.