• Hypoxia and its modification in bladder cancer: current and future perspectives

      Lodhi, T; Song, Yee Pei; West, Catharine M L; Hoskin, P; Choudhury, Ananya; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester (2021)
      Radiotherapy plays an essential role in the curative treatment of muscle-invasive bladder cancer (MIBC). Hypoxia affects the response to MIBC radiotherapy, limiting radiocurability. Likewise, hypoxia influences MIBC genetic instability and malignant progression being associated with metastatic disease and a worse prognosis. Hypoxia identification in MIBC enables treatment stratification and the promise of improved survival. The most promising methods are histopathological markers such as necrosis; biomarkers of protein expression such as HIF-1α, GLUT-1 and CAIX; microRNAs; and novel mRNA signatures. Although hypoxia modification can take different forms, the gold standard remains carbogen and nicotinamide, which improve local control rates in bladder preservation and absolute overall survival with no significant increase in late toxicity. This is an exciting time for evolving therapies such as bioreductive agents, novel oxygen delivery techniques, immunotherapy and poly (ADP-ribose) polymerase 1 (PARP) inhibitors, all in development and representing upcoming trends in MIBC hypoxia modification. Whatever the future holds for hypoxia-modified radiotherapy, there is no doubt of its importance in MIBC. mRNA signatures provide an ideal platform for the selection of those with hypoxic tumours but are yet to qualified and integrated into the clinic. Future interventional trials will require biomarker stratification to ensure optimal treatment response to improve outcomes for patients with MIBC.
    • Effect of oxaliplatin plus 5-fluorouracil or capecitabine on circulating and imaging biomarkers in patients with metastatic colorectal cancer: a prospective biomarker study

      Mahmood, Reem D; Shaw, D.; Descamps, Tine; Zhou, Cong; Morgan, Robert David; Mullamitha, Saifee; Saunders, Mark P; Mescallado, Nerissa; Backen, Alison C; Morris, K.; et al. (2021)
      Background: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers. Methods: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS). Results: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, Ktrans, increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025). Conclusions: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, Ktrans, offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.
    • Trifluridine/tipiracil in patients with metastatic gastroesophageal junction cancer: a subgroup analysis from the phase 3 TAGS study

      Mansoor, Was; Arkenau, H. T.; Alsina, M.; Shitara, K.; Thuss-Patience, P.; Cuffe, S.; Dvorkin, M.; Park, D.; Ando, T.; Van Den Eynde, M.; et al. (2021)
      Background: Patients with advanced gastroesophageal junction cancer (GEJC) have poor survival outcomes, and GEJC-specific data from trials evaluating agents in gastric cancers (GCs) as a whole are lacking. Trifluridine/tipiracil (FTD/TPI) was approved for previously treated metastatic GC or GEJC (mGC/mGEJC) based on results of the phase 3 TAGS trial. Subgroup analyses by primary tumor type (GC or GEJC) in TAGS are reported here. Methods: Pa tients with mGC/mGEJC treated with ≥ 2 prior chemotherapy regimens were randomized (2:1) to receive FTD/TPI or placebo, plus best supportive care. A pre-planned sub-analysis was performed to evaluate efficacy and safety outcomes by primary tumor type (GEJC or GC). Results: Of 507 randomized patients, 145 (29%) had GEJC and 360 (71%) had GC as the primary disease site. Baseline characteristics were generally similar between the GEJC and GC subgroups, except that more patients in the GEJC subgroup had received ≥ 3 prior regimens (72 vs. 59% in the GC subgroup). Survival benefit with FTD/TPI was observed in both subgroups. The overall survival hazard ratio for FTD/TPI vs placebo was 0.75 (95% CI 0.50-1.11) and 0.67 (95% CI 0.52-0.87) in the GEJC and GC subgroups, respectively. Grade ≥ 3 adverse events of any cause were reported in 75 (77%) and 192 (81%) FTD/TPI-treated patients in the GEJC and GC subgroups, respectively. No new safety concerns were noted with FTD/TPI. Conclusion: As in patients with GC, FTD/TPI showed an efficacy benefit in patients with GEJC in the TAGS trial, along with demonstrating a manageable safety profile.
    • Editorial: Quality of life and side effects management in lung cancer treatment

      Molassiotis, A.; Yates, P.; Yorke, Janelle; School of Nursing, The Hong Kong Polytechnic University, Kowloon, Hong Kong (2021)
    • Variations in demand across England for the magnetic resonance-linac technology, simulated utilising local-level demographic and cancer data in the Malthus project

      Mee, Thomas; Vickers, Alexander J; Jena, R.; Kirkby, Karen J; Choudhury, Ananya; Kirkby, Norman; Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK (2021)
      Aims: Cancer incidence varies across England, which affects the local-level demand for treatments. The magnetic resonance-linac (MR-linac) is a new radiotherapy technology that combines imaging and treatment. Here we model the demand and demand variations for the MR-linac across England. Materials and methods: Initial clinical indications were provided by the MR-linac consortium and introduced into the Malthus radiotherapy clinical decision trees. The Malthus model contains Clinical Commissioning Group (CCG) population, cancer incidence and stage presentation data (for lung and prostate) and simulated the demand for the MR-linac for all CCGs and Radiotherapy Operational Delivery Networks (RODN) across England. Results: Based on the initial target clinical indications, the MR-linac could service 16% of England's fraction burden. The simulated fractions/million population demand/annum varies between 3000 and 10 600 fractions/million at the CCG level. Focussing only on the cancer population, the simulated fractions/1000 cancer cases demand/annum ranges from 1028 to 1195 fractions/1000 cases. If a national average for fractions/million demand was then used, at the RODN level, the variation from actual annual demand ranges from an overestimation of 8400 fractions to an underestimation of 5800 fractions. When using the national average fractions/1000 cases, the RODN demand varies from an overestimation of 3200 fractions to an underestimation of 3000 fractions. Conclusions: Planning cancer services is complex due to regional variations in cancer burden. The variations in simulated demand of the MR-linac highlight the requirement to use local-level data when planning to introduce a new technology.
    • Emergency presentations of immune checkpoint inhibitor-related endocrinopathies

      Knight, Thomas; Cooksley, Timothy J; The Christie Hospital, Manchester, United Kingdom. (2021)
      Background: Immune checkpoint inhibitors (ICI) are an important component of anticancer treatment, with indications across an increasing range of oncological diagnoses. ICIs are associated with a range of immune-mediated toxicities. Immune-related endocrinopathies pose a distinct challenge, given the nonspecific symptom profile and potentially life-threatening sequelae if not recognized. Objectives: To determine the frequency and clinical presentations of immune-mediated endocrinopathies in patients treated with ICIs presenting as emergencies. Methods: A prospective observational cohort study was undertaken at a specialist oncology hospital in North West England from May 20, 2018 to May 19, 2020. Within the hospital, the Oncology Assessment Unit (OAU) acts as the receiving unit in which assessments are undertaken of all emergency presentations. All patients treated with ICIs presenting to the OAU were included. The primary outcome was diagnosis of an immune-mediated endocrinopathy. Length of inpatient stay, and 7- and 30-day mortality rates were examined. Results: During the study period, 684 patients treated with ICIs presented to the OAU. Twenty-four (3.5%) patients had an acute immune-mediated endocrinopathy, of which 17 had hypophysitis, 4 diabetes mellitus, 2 thyrotoxicosis, and 1 adrenalitis. Median length of stay for patients with hypophysitis was 1 day. No patient with an immune-mediated endocrinopathy died within 30 days of presentation. Conclusions: Presentations to emergency settings with acute immune-mediated endocrinopathies are rare. Early recognition of immune-mediated toxicities is important, and particularly pertinent in ICI-related endocrinopathies, where even in life-threatening cases, the presentation can be vague and nonspecific.
    • Corrigendum to 'Considerations for the treatment of oesophageal cancer with radiotherapy during the COVID-19 pandemic' [Clin Oncol 32 (2020) 354-357]

      Jones, C. M.; Hawkins, M.; Mukherjee, S.; Radhakrishna, Ganesh; Crosby, T.; School of Molecular & Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds, UK (2021)
    • Advanced small-bowel well-differentiated neuroendocrine tumours: An international survey of practice on 3(rd)-line treatment

      Lamarca, Angela; Cives, M.; de Mestier, L.; Crona, J.; Spada, F.; Öberg, K.; Pavel, M.; Alonso-Gordoa, T.; Department of Medical Oncology, European Neuroendocrine Tumor Society Centre of Excellence, The Christie NHS Foundation Trust, University of Manchester, Manchester M20 4BX (2021)
      Background: Somatostatin analogues are an established first-line therapy for well differentiated small bowel neuroendocrine tumours (Wd-SBNETs), while and peptide receptor radionuclide therapy (PRRT) is frequently used as a second-line therapy. Adequate treatment selection of third-line treatment remains challenging due to the limited prospective data currently available on the best therapeutic sequence. Aim: To understand current practice and rationale for decision-making by physicians in the 3rd-line setting by building an online survey. Methods: 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: Replies from representatives of 28 centers were received (5/8/2020-21/9/2020); medical oncologist (53.6%), gastroenterologist (17.9%); United Kingdom (21.4%), Spain (17.9%), Italy (14.3%). Majority from European Neuroendocrine Tumor Society (ENETS) Centres of Excellence (57.1%), who followed ENETS guidelines (82.1%). Generally speaking, 3rd-line treatment for Wd-SBNETs was: everolimus (EVE) (66.7%), PRRT (18.5%), liver embolization (LE) (7.4%) and interferon-alpha (IFN) (3.7%); chemotherapy (0%); decision was based on clinical trial data (59.3%), or personal experience (22.2%). EVE was most 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); regardless of presence/absence of carcinoid syndrome (CS), rate of progression or extent of disease. Chemotherapy was mainly utilised only if rapid progression (within 6 mo) (WA 3.35/4), Ki-67 10%-20% (WA 2.77/4), negative somatostatin receptor imaging (WA 2.65/4) or high tumour burden (WA 2.77/4); temozolomide or streptozocin was used with capecitabine or 5-fluorouracil (5-FU) (57.7%), FOLFOX (5-FU combined with oxaliplatin) (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: Everolimus was the most frequently used therapeutic option in the third-line setting. The most important factors for decision-making included Ki-67, rate of progression, functionality and tumour burden; since this decision is based on multiple factors, it highlights the need for a multidisciplinary assessment.
    • Second-line FOLFOX chemotherapy versus active symptom control for advanced biliary tract cancer (ABC-06): a phase 3, open-label, randomised, controlled trial

      Lamarca, Angela; Palmer, D. H.; Wasan, H. S.; Ross, P. J.; Ma, Y. T.; Arora, A.; Falk, S.; Gillmore, R.; Wadsley, J.; Patel, K.; et al. (2021)
      Background: Advanced biliary tract cancer has a poor prognosis. Cisplatin and gemcitabine is the standard first-line chemotherapy regimen, but no robust evidence is available for second-line chemotherapy. The aim of this study was to determine the benefit derived from second-line FOLFOX (folinic acid, fluorouracil, and oxaliplatin) chemotherapy in advanced biliary tract cancer. Methods: The ABC-06 clinical trial was a phase 3, open-label, randomised trial done in 20 sites with expertise in managing biliary tract cancer across the UK. Adult patients (aged ≥18 years) who had histologically or cytologically verified locally advanced or metastatic biliary tract cancer (including cholangiocarcinoma and gallbladder or ampullary carcinoma) with documented radiological disease progression to first-line cisplatin and gemcitabine chemotherapy and an Eastern Cooperative Oncology Group performance status of 0-1 were randomly assigned (1:1) centrally to active symptom control (ASC) and FOLFOX or ASC alone. FOLFOX chemotherapy was administered intravenously every 2 weeks for a maximum of 12 cycles (oxaliplatin 85 mg/m2, L-folinic acid 175 mg [or folinic acid 350 mg], fluorouracil 400 mg/m2 [bolus], and fluorouracil 2400 mg/m2 as a 46-h continuous intravenous infusion). Randomisation was done following a minimisation algorithm using platinum sensitivity, serum albumin concentration, and stage as stratification factors. The primary endpoint was overall survival, assessed in the intention-to-treat population. Safety was also assessed in the intention-to-treat population. The study is complete and the final results are reported. This trial is registered with ClinicalTrials.gov, NCT01926236, and EudraCT, 2013-001812-30. Findings: Between March 27, 2014, and Jan 4, 2018, 162 patients were enrolled and randomly assigned to ASC plus FOLFOX (n=81) or ASC alone (n=81). Median follow-up was 21·7 months (IQR 17·2-30·8). Overall survival was significantly longer in the ASC plus FOLFOX group than in the ASC alone group, with a median overall survival of 6·2 months (95% CI 5·4-7·6) in the ASC plus FOLFOX group versus 5·3 months (4·1-5·8) in the ASC alone group (adjusted hazard ratio 0·69 [95% CI 0·50-0·97]; p=0·031). The overall survival rate in the ASC alone group was 35·5% (95% CI 25·2-46·0) at 6 months and 11·4% (5·6-19·5) at 12 months, compared with 50·6% (39·3-60·9) at 6 months and 25·9% (17·0-35·8) at 12 months in the ASC plus FOLFOX group. Grade 3-5 adverse events were reported in 42 (52%) of 81 patients in the ASC alone group and 56 (69%) of 81 patients in the ASC plus FOLFOX group, including three chemotherapy-related deaths (one each due to infection, acute kidney injury, and febrile neutropenia). The most frequently reported grade 3-5 FOLFOX-related adverse events were neutropenia (ten [12%] patients), fatigue or lethargy (nine [11%] patients), and infection (eight [10%] patients). Interpretation: The addition of FOLFOX to ASC improved median overall survival in patients with advanced biliary tract cancer after progression on cisplatin and gemcitabine, with a clinically meaningful increase in 6-month and 12-month overall survival rates. To our knowledge, this trial is the first prospective, randomised study providing reliable, high-quality evidence to allow an informed discussion with patients of the potential benefits and risks from second-line FOLFOX chemotherapy in advanced biliary tract cancer. Based on these findings, FOLFOX should become standard-of-care chemotherapy in second-line treatment for advanced biliary tract cancer and the reference regimen for further clinical trials.
    • Phase I/II trial of H3B-6545, a novel selective estrogen receptor covalent antagonist (SERCA), in estrogen receptor positive (ER plus ), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer

      Hamilton, E. P.; Wang, J. S.; Pluard, T.; Johnston, S.; Morikawa, A. A.; Dees, C. E.; Jones, R. H.; Haley, B.; Armstrong, Anne C; Cohen, A. L.; et al. (2021)
      Background: Addition of CDK 4/6 inhibitors to endocrine therapy has provided significant improvements in outcomes for patients (pts) with metastatic breast cancer (mBC). However, acquired resistance to front-line therapy remains a challenge, and response to late lines of therapy is poor. H3B-6545 is a selective, orally available, small molecule covalent antagonist of the estrogen receptor (ERα) H3B-6545 binds covalently to a cysteine residue at position 530 of both wild-type and the constitutively active mutant ERα proteins, including Y537S. H3B-6545 demonstrated significant antitumor activity in multiple PDX breast cancer models, including those with mutated ESR1 (the gene encoding ERα).Methods: This is a multicenter phase I/II trial. The primary objective of the phase I is to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) in pretreated pts with ER+, HER2- mBC. Secondary objectives include safety and antitumor activity. The primary objective of the phase II is to estimate the objective response rate (ORR) and secondary objectives include clinical benefit rate (CBR), progression-free survival (PFS) and safety. The trial was designed to exclude a lower limit of ORR of 5% at one-sided level of significance of 0.05 and a power of 90%. Results: Between August 2017 and February 2020, 130 pts were enrolled; 47 in the Phase I part and 83 in the Phase II part of the trial. A total of 105 pts, including 73 patients on 450 mg, were response-evaluable. The phase I evaluated once daily doses from 100 to 600 mg. No dose-limiting toxicities (DLT) were observed at doses up to 450 mg and 2 DLTs were observed in 2 (grade 3 fatigue and grade 3 drug eruption) of 7 pts on the 600 mg cohort. Consequently, the dose of 450 mg was selected as the RP2D. Median age was 62 years (range: 31 to 87 years), 82% had liver and/or lung metastases, and the median number of prior therapies for metastatic disease was 3 (range: 1 to 10), with 41% of the pts receiving ≥ 4 prior therapies in the metastatic setting. Prior CDK4/6 inhibitors, fulvestrant, and chemotherapy were received by 87%, 71%, and 54% of the pts, respectively. 75 pts (58%) had detectable ESR1 mutations. As of May 31, 2020, grade 2 or higher adverse events reported in ≥10% were anemia (20%), fatigue (16%), nausea (14%), diarrhea (11%) and AST increase (11%). Three cases of grade 4 AE were reported (serum bilirubin, urinary tract obstruction, and hyponatremia), all considered related to disease progression. Grade 1 sinus bradycardia (asymptomatic) was reported in 35% and grade 2 (symptomatic, no intervention needed) was reported in 4%. Grade 2 and 3. QTcF prolongation were reported in 2 and 3 patients, respectively. There were no treatment-related deaths. In the response-evaluable group, 13 confirmed partial responses (PR, 12%. 90% confidence limits: 7.5%-19%), including 11 PRs (15%, 90% confidence limits: 8.7%-23.7) on 450 mg dose, were observed, thus achieving the primary objective of the trial. Stable disease (SD) and clinical benefit rates (≥23 weeks) were 45% and 33% respectively at 450 mg and 46% and 34%, respectively on all doses. Responses were observed in heavily pretreated pts, pts with visceral metastases and in pts who received prior fulvestrant, prior CDK4/6 inhibitor, and/or prior chemotherapy, in the metastatic setting. Three PRs (25%) and 4 SDs were observed in 12 pts in whom clonal ESR1 Y537S was the main ERα driver. Median PFS, in all pts and in pts with clonal ESR1 Y537S was 3.7 months and 7.3 months, respectively. Conclusions: H3B-6545 has a manageable safety profile and demonstrated single-agent anti-tumor activity in heavily pretreated ER+, HER2- mBC patients including those with a constitutively active clonal ESR1 Y537S mutation.
    • Novel methodology to assess the effect of contouring variation on treatment outcome

      Jenkins, A.; Soares Mullen, T.; Johnson-Hart, Corinne; Green, Andrew; McWilliam, Alan; Aznar, Marianne Camille; van Herk, Marcel; Vasquez Osorio, Eliana; University of Manchester, School of Physics & Astronomy - Faculty of Science and Engineering, Manchester, M13 9P (2021)
      Purpose: Contouring variation is one of the largest systematic uncertainties in radiotherapy, yet its effect on clinical outcome has never been analysed quantitatively. We propose a novel, robust methodology to locally quantify target contour variation in a large patient cohort and find where this variation correlates with treatment outcome. We demonstrate its use on biochemical recurrence for prostate cancer patients. Method: We propose to compare each patient's target contours to a consistent and unbiased reference. This reference was created by auto-contouring each patient's target using an externally trained deep learning algorithm. Local contour deviation measured from the reference to the manual contour were projected to a common frame of reference, creating contour deviation maps for each patient. By stacking the contour deviation maps, time to event was modelled pixel-wise using a multivariate Cox proportional hazards model (CPHM). Hazard ratio (HR) maps for each covariate were created, and regions of significance found using cluster-based permutation testing on the z-statistics. This methodology was applied to Clinical Target Volume (CTV) contours, containing only the prostate gland, from 232 intermediate- and high-risk prostate cancer patients. The reference contours were created using ADMIRE® v3.4 (Elekta AB, Sweden). Local contour deviations were computed in a spherical coordinate frame, where differences between reference and clinical contours were projected in a 2D map corresponding to sampling across the coronal and transverse angles every 3°. Time to biochemical recurrence was modelled using the pixel-wise CPHM analysis accounting for contour deviation, patient age, Gleason score and treated CTV volume. Results: We successfully applied the proposed methodology to a large patient cohort containing data from 232 patients. In this patient cohort, our analysis highlighted regions where the contour variation was related to biochemical recurrence, producing expected and unexpected results: 1) the interface between prostate-bladder and prostate-seminal vesicle interfaces where increase of the manual contour relative to the reference was related to a reduction of risk of biochemical recurrence by 4-8% per mm and 2) the prostate's right, anterior and posterior regions where an increase of the manual contour relative to the reference contours was related to an increase of risk of biochemical recurrence by 8-24% per mm. Conclusion: We proposed and successfully applied a novel methodology to explore the correlation between contour variation and treatment outcome. We analysed the effect of contour deviation of the prostate CTV on biochemical recurrence for a cohort of more than 200 prostate cancer patients while taking basic clinical variables into account. Applying this methodology to a larger dataset including additional clinically important covariates and externally validating it can more robustly identify regions where contour variation directly relates to treatment outcome. For example, in the prostate case we use to demonstrate our novel methodology, external validation will help confirm or reject the counter-intuitive results (larger contours resulting in higher risk). Ultimately, the results of this methodology could inform contouring protocols based on actual patient outcomes.
    • Phase I trial of the MEK inhibitor selumetinib in combination with thoracic radiotherapy in non-small cell lung cancer

      Haslett, Kate; Koh, Pek K; Hudson, Andrew M; Ryder, W David J; Falk, Sally; Mullan, Damian; Taylor, Ben; Califano, Raffaele; Blackhall, Fiona H; Faivre-Finn, Corinne; et al. (2021)
      Background: The RAS/RAF/MEK/ERK signalling pathway has a pivotal role in cancer proliferation and modulating treatment response. Selumetinib inhibits MEK and enhances effects of radiotherapy in preclinical studies. Patients and methods: Single-arm, single-centre, open-label phase I trial. Patients with stage III NSCLC unsuitable for concurrent chemo-radiotherapy, or stage IV with dominant thoracic symptoms, were recruited to a dose-finding stage (Fibonacci 3 + 3 design; maximum number = 18) then an expanded cohort (n = 15). Oral selumetinib was administered twice daily (starting dose 50 mg) commencing 7 days prior to thoracic radiotherapy, then with radiotherapy (6-6.5 weeks; 60-66 Gy/30-33 fractions). The primary objective was to determine the recommended phase II dose (RP2D) of selumetinib in combination with thoracic radiotherapy. Results: 21 patients were enrolled (06/2010-02/2015). Median age: 62y (range 50-73). M:F ratio 12(57%):9(43%). ECOG PS 0:1, 7(33%):14(67%). Stage III 16(76%); IV 5(24%). Median GTV 64 cm3 (range 1-224 cm3). 15 patients comprised the expanded cohort at starting dose. All 21 patients completed thoracic radiotherapy as planned and received induction chemotherapy. 13 (62%) patients received the full dose of selumetinib.In the starting cohort no enhanced radiotherapy-related toxicity was seen. Two patients had dose-limiting toxicity (1x grade 3 diarrhoea/fatigue and 1x pulmonary embolism). Commonest grade 3-4 adverse events: lymphopaenia (19/21 patients) and hypertension (7/21 patients). One patient developed grade 3 oesophagitis. No patients developed grade ≥3 radiation pneumonitis. Two patients were alive at the time of analysis (24 and 26 months follow-up, respectively). Main cause of first disease progression: distant metastases ± locoregional progression (12/21 [57.1%] patients). Six patients had confirmed/suspected pneumocystis jiroveci pneumonia. Conclusion: We report poor outcome and severe lymphopenia in most patients treated with thoracic radiotherapy and selumetinib at RP2D in combination, contributing to confirmed/clinically suspected pneumocystis jiroveci pneumonia. These results suggest that this combination should not be pursued in a phase II trial.ClinicalTrials.gov reference: NCT01146756.
    • Knowns and unknowns of bone metastases in patients with neuroendocrine neoplasms: A systematic review and meta-analysis

      Garcia-Torralba, Esmeralda; Spada, F.; Lim, Kok Haw Jonathan; Jacobs, Timothy; Barriuso, Jorge; Mansoor, Was; McNamara, Mairead G; Hubner, Richard A; Manoharan, Prakash; Fazio, Nicola; et al. (2021)
      Objective: This systematic review and meta-analysis aimed to develop an evidence-based summary of current knowledge of bone metastases (BMs) in neuroendocrine neoplasms (NENs), inform diagnosis and treatment and standardise management between institutions. Methods: PubMed, Medline, EMBASE and meeting proceedings were searched for eligible studies reporting data on patients with BMs and NENs of any grade of differentiation and site; poorly-differentiated large/small cell lung cancer were excluded. Data were extracted and analysed using STATA v.12. Meta-analysis of proportions for calculation of estimated pooled prevalence of BM and calculation of weighted pooled frequency and weighted pooled mean for other variables of interest was performed . Results: A total of 149 studies met the eligibility criteria. Pooled prevalence of BMs was 18.4% (95% CI 15.4-21.5). BMs were mainly metachronous with initial diagnosis of NEN (61.2%) and predominantly osteoblastic; around 61% were multifocal, with a predisposition in axial skeleton. PET/CT seemed to provide (together with MRI) the highest sensitivity and specificity for BM detection. Almost half of patients (46.4%) reported BM-related symptoms: pain (66%) and skeletal-related events (SREs, fracture/spinal cord compression) (26.2%; weightedweighted mean time-to-SRE 9.9 months). Management of BMs was multimodal [bisphosphonates and bone-modifying agents (45.2%), external beam radiotherapy (34.9%), surgery (14.8%)] and supported by little evidence. Overall survival (OS) from the time of diagnosis of BMs was long [weighted mean 50.9 months (95% CI 40.0-61.9)]. Patients with BMs had shorter OS [48.8 months (95% CI 37.9-59.6)] compared to patients without BMs [87.4 months (95% CI 74.9-100.0); p = 0.001]. Poor performance status and BM-related symptoms were also associated with worse OS. Conclusions: BMs in patients with NENs remain underdiagnosed and undertreated. Recommendations for management of BMs derived from current knowledge are provided. Prospective studies to inform management are required.
    • Skin toxicity profile of photon radiotherapy versus proton beam therapy in paediatric and young adult patients with sarcomas

      Gaito, Simona; Abravan, Azadeh; Richardson, Jenny C; Lowe, Mathew; Indelicato, D. J.; Burnet, Neil G; Smith, Ed; Clinical Oncology, Proton Beam Therapy Centre, The Christie NHS Foundation Trust, Manchester, UK (2021)
      Aims: Radiotherapy is key in the management of patients with both Ewing sarcoma and rhabdomyosarcoma. However, there is little evidence in the literature with regards to radiation-induced skin toxicities (RISTs) for patients treated with conventional radiotherapy with X-rays (XRT) or proton beam therapy (PBT) for these two conditions. In the present study we evaluated acute and late RIST in patients treated within European protocols with either PBT or XRT, taking both clinical and dosimetric variables into consideration. Materials and methods: This was a retrospective analysis of 79 paediatric/young adult patients treated with radical radiotherapy (with XRT or PBT) and concurrent chemotherapy. In all cases, radiotherapy was given in conventional fractionation (1.8 Gy/fraction). Acute and late RISTs were registered according to the Radiation Therapy Oncology Group (RTOG) scoring system. Results: With regards to acute RIST, 47.9% (23/48) of XRT patients and 48.4% (15/31) of PBT patients had acute grade 2/3 toxicity. When it comes to late RIST, 17.5% (7/40 with known toxicity profile) of XRT patients and 29.0% (9/31) of PBT patients had grade 1/2 toxicity. This difference of -11.5% (95% confidence interval -31.2 to 7.9%) in grade 1/2 toxicity between XRT and PBT was not statistically significant (P = 0.25). Regardless of the radiotherapy technique, V30Gy seems a good predictor of acute RIST. Moreover, for the same value of V30Gy, patients who receive PBT may have a higher risk of moderate-severe acute RIST. Perhaps due to the small sample, definitive conclusions on the predictive factors of late RIST could not be drawn. Conclusions: No clinically meaningful differences in acute and late RIST were observed between PBT and XRT subgroups. Systematic differences in the modelling of the build-up region may exist between XRT and PBT algorithms, which could make the comparison of dose metrics between techniques potentially biased. A more comprehensive analysis of dosimetric data on larger patient cohorts is needed to elucidate the most relevant skin dose metrics. Dose-effect models of RIST for this unique patient population would be an invaluable tool in radiotherapy plan optimisation.
    • Modeling radioimmune response-current status and perspectives

      Friedrich, T.; Henthorn, Nicholas; Durante, M.; Biophysics Department, GSI Helmholtz Center for Heavy Ion Research, Darmstadt, Germany (2021)
      The combination of immune therapy with radiation offers an exciting and promising treatment modality in cancer therapy. It has been hypothesized that radiation induces damage signals within the tumor, making it more detectable for the immune system. In combination with inhibiting immune checkpoints an effective anti-tumor immune response may be established. This inversion from tumor immune evasion raises numerous questions to be solved to support an effective clinical implementation: These include the optimum immune drug and radiation dose time courses, the amount of damage and associated doses required to stimulate an immune response, and the impact of lymphocyte status and dynamics. Biophysical modeling can offer unique insights, providing quantitative information addressing these factors and highlighting mechanisms of action. In this work we review the existing modeling approaches of combined 'radioimmune' response, as well as associated fields of study. We propose modeling attempts that appear relevant for an effective and predictive model. We emphasize the importance of the time course of drug and dose delivery in view to the time course of the triggered biological processes. Special attention is also paid to the dose distribution to circulating blood lymphocytes and the effect this has on immune competence.
    • The patient-reported outcome measures in oropharyngeal, laryngeal and hypopharyngeal cancer patients treated with Volumetric Modulated Arc based simultaneous integrated boost radiotherapy

      Elumalai, Thiraviyam; Mukherji, A.; Vijayaprabhu, N.; Periasamy, K.; Yadala, A.; Department of Radiotherapy, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India (2021)
      Objective: To assess the change in the quality of life (QOL) in head and neck cancer patients treated with Simultaneous Integrated Boost (SIB) by Volumetric Modulated Arc Therapy (VMAT) technique. Methods: Thirty patients with localised head and neck cancers (Stage II- IVa) were treated with VMAT and SIB technique. The three-dose levels prescribed were 68.2 Gy at 2.2 Gy/fraction, 62 Gy at 2 Gy/fraction and 55.8 Gy at 1.8 Gy/fraction to the high, intermediate and low-risk volumes respectively. Concurrent chemotherapy with cisplatin 100 mg/m2 was administered once in three weeks. Acute toxicities were evaluated and scored according to the RTOG grading system. Quality of life (QOL) was assessed using European Organization of Research and Treatment of Cancer (EORTC) QLQC30 and HN35 questionnaires at baseline and in three instances (immediately, one month and three months after the radiotherapy). Results: Out of the total 30, 80% patients had a complete response (CR) at the median follow up of 12 months, while three patients died because of progression, and the remaining 3 had stable disease. All planning objectives were achieved for organs at risk and planning target volume(PTV). There was a statiscally significant(p value < 0.001) reduction in global quality of life scores at the end of treatment when compared to baseline scores, but by three months, there was the return in the QOL scores in most scales similar to the baseline value. Conclusion: VMAT based Simultaneous boost radiotherapy is a feasible and safe strategy in terms of toxicity profile with an acceptable transient change in the quality of life and allows a faster return to baseline quality of life.
    • Lenvatinib plus pembrolizumab for previously treated, advanced triple-negative breast cancer: Early results from the multicohort phase 2 LEAP-005 study

      Chung, H. C.; Saada-Bouzid, E.; Munoz, F. L.; Yanez, E.; Im, S. A.; Castanon, E.; Graham, Donna; Garcia-Corbacho, J.; Lopez, J.; Ghori, R.; et al. (2021)
      Background: Triple-negative breast cancer (TNBC) is associated with poor survival outcomes and treatment options are limited. These tumors lack therapeutic targets and become rapidly resistant to chemotherapy. The anti–PD-1 antibody pembrolizumab showed durable antitumor activity and manageable safety in patients with TNBC in the KEYNOTE-012, KEYNOTE-086, and KEYNOTE-119 studies. The combination of lenvatinib, an antiangiogenic multiple receptor tyrosine kinase inhibitor, with pembrolizumab has shown promising clinical outcomes in early-phase clinical trials across several cancer types. LEAP-005 (ClinicalTrials.gov, NCT03797326) is an ongoing study evaluating the efficacy and safety of lenvatinib combined with pembrolizumab in patients with previously treated advanced solid tumors. Here, we report the first results from the TNBC cohort of LEAP-005. Methods: This ongoing, multicohort, open-label, phase 2 study enrolled patients aged ≥18 y with previously treated, histologically or cytologically confirmed advanced TNBC. PD-L1 expression was assessed at a central laboratory using the PD-L1 IHC 22C3 pharmDx assay and measured using the combined positive score (CPS; number of PD-L1–positive tumor cells, lymphocytes, and macrophages divided by total number of tumor cells x 100). Patients received lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg every 3 weeks intravenously for a maximum of 35 pembrolizumab doses, then lenvatinib alone until progressive disease or unacceptable toxicity. Primary endpoints were objective response rate (ORR) by blinded independent central review per RECIST version 1.1 and safety. Key secondary endpoints were disease control rate (DCR; defined as best overall response of complete response [CR], partial response [PR], or stable disease [SD] per RECIST v1.1), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Safety was monitored through 30 days after the last dose of study drug (90 days for serious AEs), with AEs graded using NCI CTCAE v4.0. Results: 31 patients have been enrolled in the TNBC cohort of LEAP-005. Median age was 56 y (range, 37 to 85), 58% had received ≥2 prior lines of therapy, and 26% had CPS ≥10 tumors. As of the April 10, 2020 data cutoff, median follow-up was 7 mo (range, 4 to 13). ORR was 29% (95% CI: 14–48), with 1 CR and 8 PRs. 9 pts had SD, and the DCR (CR + PR + SD) was 58% (95% CI: 39–76). 4 responses (1 CR and 3 PRs) were in patients with CPS ≥10 tumors (n=8) for an ORR of 50% (95% CI: 16–84), and 5 responses (all PRs) were in patients with CPS <10 tumors (n=22) for an ORR of 23% (95% CI: 8–45). Median DOR was not reached (range, 0+ to 8+ mo); 7 (78%) responses were ongoing at data cutoff. Median PFS was 4 mo (95% CI: 2–NR), with a 6-mo rate of 49%. Treatment-related AEs (TRAEs) occurred in 97% of pts; 10% discontinued due to TRAEs. 55% of pts had grade 3-5 TRAEs (1 death due to subarachnoid hemorrhage). Conclusions: Lenvatinib in combination with pembrolizumab showed promising antitumor activity with manageable toxicity in patients with previously treated advanced TNBC. Based on these early data, the cohort will be expanded to include 100 patients.
    • Ceralasertib (cer) in combination with olaparib (ola) in patients (pts) with advanced breast cancer (BC): Results of phase I expansion cohorts

      Dean, E.; Krebs, Matthew G; Im, S. A.; Campone, M.; Postel-Vinay, S.; Arkenau, T.; Lopez, J.; Abida, W.; Jodrell, D.; Lee, K. W.; et al. (2021)
      Background: Alterations in BRCA1/2 are associated with ~9% of all BCs. Ola (a poly ADP-ribose polymerase inhibitor [PARPi]) is approved for treating pts with HER2-negative metastatic BC with germline BRCA mutation (gBRCAm), demonstrating an improvement in progression-free survival (PFS). Ceralasertib (an ataxia telangiectasia and Rad3-related protein ATR inhibitor) targets DNA damage repair and cell cycle regulation. Preclinical studies show synergistic antitumor effects of ola+cer vs ola monotherapy supporting the clinical evaluation of this combination. Methods: Study 4 is a modular multicenter Phase I study of cer combinations (NCT02264678). Module 2 established the Recommended Phase 2 Dose of ola+cer as ola 300 mg bid daily + cer 160 mg qd D1-7 q 28d. We report the results of two expansion cohorts testing ola+cer in pts with triple negative breast cancer with no alterations in homologous recombination repair (HRR)-related genes (HRR wt group), and pts with advanced HER2- BRCAm BC (BRCAm group), with a data cut-off of 19th June 2019. Eligible pts had to have received 1-2 prior lines of chemotherapy for metastatic disease, and were PARPi naive. Patients may have enrolled directly based on a local BRCAm test result, but all pts submitted a tumor specimen for central confirmation of a deleterious (or suspected deleterious) germline or somatic BRCA1/2 mutation. The primary objective was to investigate the safety and tolerability of the combination; secondary objectives included assessment of objective response rate by RECIST 1.1. Results: Twenty-five pts were enrolled in the HRR wt group: median age 53 (31-75), ECOG PS 0/1 13 (52%)/12 (48%), median number of prior chemotherapy lines 2 of which 8 pts (32%) had received prior platinum. Thirty-seven pts enrolled in the BRCAm group: median age 51 (24-69), ECOG PS 0/1 20 (54%)/17 (46%), median number of prior chemotherapy lines 1 of which 19 pts (51%) had received prior platinum. The most frequent all causality Adverse Events (AEs) were nausea 43 (69%), anemia 36 (58%), diarrhea 20 (32%) and vomiting 20 (32%); CTCAE ≥ Grade 3 AEs included anemia 15 (24%), neutropenia 6 (10%) with few patients discontinuing treatment. In the HRR wt group, no responses were observed, 12 (48%) pts achieved a best response of stable disease and 13 (52%) had disease progression. The median PFS was 3.1 months (80%CI 2.0,3.9). In the BRCAm group, 13 (35%) pts achieved a confirmed response (including 1 complete response), 17 (46%) stable disease and 7 (19%) pts disease progression. The median PFS in pts with a centrally confirmed BRCAm was 11.5 months (80%CI 5.8-14.8, n=30), 7.7 months (80%CI 5.8-11.4, n=37) in all pts enrolled in the BRCAm group. Eleven of the 13 responders in the BRCAm group were on study treatment for a longer duration than their treatment immediately prior to enrollment. As of 18th June 20, preliminary data shows 10 pts are still ongoing with a treatment duration ranging 20 to 35 months. Conclusion: In pts with HER2- BRCAm breast cancer, clinical efficacy was observed with durable radiological response despite adverse prognostic features in this Phase I population. The observations in this study are currently being tested in a global multicenter open-label randomised Phase 2 study: VIOLETTE (NCT03330847).
    • MRI and CBCT for lymph node identification and registration in patients with NSCLC undergoing radical radiotherapy

      Dubec, Michael; Brown, S; Chuter, Robert; Hales, Rosie; Whiteside, Lee; Rodgers, John; Parker, Jacqui; Eccles, Cynthia L; van Herk, Marcel; Faivre-Finn, Corinne; et al. (2021)
      Purpose: This study compared MRI to CBCT for the identification and registration of lymph nodes (LN) in patients with locally advanced (LA)-NSCLC, to assess the suitability of targeting LNs in future MR-image guided radiotherapy (MRgRT) workflows. Method: Radiotherapy radiographers carried out Visual Grading Analysis (VGA) assessment of image quality, LN registration and graded their confidence in registration for each of the 24 LNs on CBCT and two MR sequences, MR1 (T2w Turbo Spin Echo) and MR2 (T1w DIXON water only image). Results: Pre-registration image quality assessment revealed MR1 and MR2 as significantly superior to CBCT in terms of image quality (p ≤ 0.01). No significant differences were noted in interobserver variability for LN registration between CBCT, MR1 and MR2. Observers were more confident in their MR registrations compared to their CBCT based LN registrations (p ≤ 0.02). Summary: Interobserver setup correction variability was not found to be significantly different between CBCT and MR. Image quality and registration confidence were found to be superior for MRI sequences. This is a promising step towards MR-guided radiotherapy for the treatment of LA-NSCLC
    • Initial clinical experience of MR-guided radiotherapy for non-small cell lung cancer

      Crockett, Cathryn B; Samson, P.; Chuter, Robert; Dubec, Michael; Faivre-Finn, Corinne; Green, O. L.; Hackett, S. L.; McDonald, F.; Robinson, C.; Shiarli, A. M.; et al. (2021)
      Curative-intent radiotherapy plays an integral role in the treatment of lung cancer and therefore improving its therapeutic index is vital. MR guided radiotherapy (MRgRT) systems are the latest technological advance which may help with achieving this aim. The majority of MRgRT treatments delivered to date have been stereotactic body radiation therapy (SBRT) based and include the treatment of (ultra-) central tumors. However, there is a move to also implement MRgRT as curative-intent treatment for patients with inoperable locally advanced NSCLC. This paper presents the initial clinical experience of using the two commercially available systems to date: the ViewRay MRIdian and Elekta Unity. The challenges and potential solutions associated with MRgRT in lung cancer will also be highlighted.