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  • Biodegradable oesophageal stents: a potentially useful adjunct in the treatment of dysphagia in patients undergoing radiotherapy for oesophageal carcinoma

    White, K; Thampy, S; Sheikh, H; Bhatt, Lubna; Mullan, Damian; Laasch, Hans-Ulrich; Manchester NHS Foundation Trust (2019)
    Aim Dysphagia is common in patients presenting with oesophageal malignancy. This study aimed to determine the clinical effectiveness of biodegradable stents to help with malignant dysphagia due to radiotherapy for oesophageal cancer and furthermore to establish the complication and re-intervention rates associated with their use. Methods This was a retrospective, observational study of 22 patients between 2008 and 2013. Complications within 2 weeks and episodes of re-intervention required within 4 months of stent insertion prior to radiotherapy were recorded. Results Pre-stent insertion, the mean O�Rourke dysphagia score was 3�5 (median 3, range 2�5). This improved to a mean score of 2�8 (median 3, range 1�4) 1�3 weeks following stent insertion. Complications occurred in seven patients (32%) in an immediate 2-week period, including: pain (2), dysphagia requiring dilatation (1), food obstruction not requiring intervention (1), food obstruction requiring intervention (2) and upper gastrointestinal bleed not requiring intervention (1). Re-intervention was required in 18% within a 4-month period. Findings We propose that biodegradable oesophageal stents are safe and may have benefit over self-expanding metal stents. We recommend they are placed alongside a radiologically inserted gastrostomy in a combined procedure prior to radiotherapy planning.
  • Timing of high-dose methotrexate CNS prophylaxis in DLBCL: an analysis of toxicity and impact on R-CHOP delivery

    Wilson, M. R.; Eyre, T. A.; Martinez-Calle, N.; Ahearne, M.; Parsons, K. E.; Preston, G.; Khwaja, J.; Schofield, J.; Elliot, Johnathon; Mula Kh, A.; et al. (2020)
    High-dose methotrexate (HD-MTX) is increasingly used as prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) at high risk of central nervous system (CNS) relapse. However, there is limited evidence to guide whether to intercalate HD-MTX (i-HD-MTX) between R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone given at 21-day intervals) or to give it at the end of treatment (EOT) with R-CHOP-21. We conducted a retrospective, multicenter analysis of 334 patients with DLBCL who received CNS prophylaxis with i-HD-MTX (n = 204) or EOT HD-MTX (n = 130). Primary end points were R-CHOP delay rates and HD-MTX toxicity. Secondary end points were CNS relapse rate, progression-free survival, and overall survival. The EOT group had more patients with a high CNS international prognostic index (58% vs 39%; P < .001) and more concurrent intrathecal prophylaxis (56% vs 34%; P < .001). Of the 409 cycles of i-HD-MTX given, 82 (20%) were associated with a delay of next R-CHOP (median, 7 days). Delays were significantly increased when i-HD-MTX was given after day 9 post-R-CHOP (26% vs 16%; P = .01). On multivariable analysis, i-HD-MTX was independently associated with increased R-CHOP delays. Increased mucositis, febrile neutropenia, and longer median inpatient stay were recorded with i-HD-MTX delivery. Three-year cumulative CNS relapse incidence was 5.9%, with no differences between groups. There was no difference in survival between groups. We report increased toxicity and R-CHOP delay with i-HD-MTX compared with EOT delivery but no difference in CNS relapse or survival. Decisions on HD-MTX timing should be individualized and, where i-HD-MTX is favored, we recommend scheduling before day 10 of R-CHOP cycles.
  • Glioma consensus contouring recommendations from a MR-Linac International Consortium Research Group and evaluation of a CT-MRI and MRI-only workflow

    Tseng, C. L.; Stewart, J.; Whitfield, Gillian A; Verhoeff, J. J. C.; Bovi, J.; Soliman, H.; Chung, C.; Myrehaug, S.; Campbell, M.; Atenafu, E. G.; et al. (2020)
    Introduction: This study proposes contouring recommendations for radiation treatment planning target volumes and organs-at-risk (OARs) for both low grade and high grade gliomas. Methods: Ten cases consisting of 5 glioblastomas and 5 grade II or III gliomas, including their respective gross tumor volume (GTV), clinical target volume (CTV), and OARs were each contoured by 6 experienced neuro-radiation oncologists from 5 international institutions. Each case was first contoured using only MRI sequences (MRI-only), and then re-contoured with the addition of a fused planning CT (CT-MRI). The level of agreement among all contours was assessed using simultaneous truth and performance level estimation (STAPLE) with the kappa statistic and Dice similarity coefficient. Results: A high level of agreement was observed between the GTV and CTV contours in the MRI-only workflow with a mean kappa of 0.88 and 0.89, respectively, with no statistically significant differences compared to the CT-MRI workflow (p = 0.88 and p = 0.82 for GTV and CTV, respectively). Agreement in cochlea contours improved from a mean kappa of 0.39 to 0.41, to 0.69 to 0.71 with the addition of CT information (p < 0.0001 for both cochleae). Substantial to near perfect level of agreement was observed in all other contoured OARs with a mean kappa range of 0.60 to 0.90 in both MRI-only and CT-MRI workflows. Conclusions: Consensus contouring recommendations for low grade and high grade gliomas were established using the results from the consensus STAPLE contours, which will serve as a basis for further study and clinical trials by the MR-Linac Consortium. Keywords: Consensus contouring recommendations; Glioma; MR-linac; Organs-at-risk; Radiotherapy.
  • Randomised clinical trial of a gastrointestinal care bundle to reduce symptoms in patients with pelvic cancer undergoing chemoradiotherapy

    White, K. L.; Henson, C. C.; Hann, M.; Eden, M.; Burden, S. T.; Lal, S.; Davidson, Susan E; McLaughlin, J. T.; Gastroenterology, Manchester Foundation Trust, Wythenshawe Hospital, Manchester, UK. (2020)
    Objective: Pelvic radiotherapy is used to treat 17 000 people in the UK each year. Eight in 10 develop difficult bowel problems during pelvic treatment, especially diarrhoea, urgency and incontinence. Some cannot complete treatment, reducing the chance of cancer cure. Undertaking gastroenterologist-led investigation and management during pelvic radiotherapy has never been evaluated. In this study, we aimed to assess whether patients could successfully receive a novel gastrointestinal (GI) care bundle during chemoradiotherapy (feasibility aim) and would experience reduced symptom severity (clinical impact aim). Design: This randomised controlled trial recruited patients with cervical and bladder cancers undergoing radical chemoradiotherapy. Participants were randomised to intervention or control groups. Questionnaire and anthropometric data were collected. All intervention group patients received individualised dietary counselling weekly throughout treatment, and if bowel symptoms developed they were offered rapid-access investigation and treatment for any identified pathology: lactose intolerance, bacterial overgrowth or bile acid malabsorption. Results: Feasibility: 50 participants were recruited, 24 were randomised to the intervention group and 26 to the control group. All completed 20 fractions of external beam pelvic radiotherapy. It was possible to perform 57/72 (79%) of proposed intervention tests with no disruption of oncological management. Clinical impact: All participants developed GI symptoms during radiotherapy. The median symptom score for each group increased from baseline at 6 weeks. This was from 0.156 (0.000-0.333) to 0.600 (0.250-1.286) in the control group, and from 0.00 (0.000-0.300) to 0.402 (0.000-0.667) in the intervention group. Conclusion: It was feasible to recruit to and deliver a randomised controlled trial of interventions in patients undergoing pelvic chemoradiotherapy. Lower median bowel scores were reported in the intervention group at 6 weeks, with fewer patients experiencing symptoms overall. Trial registration number: ISRCTN783488. Keywords: cancer; clinical trials; radiation enteritis; radiotherapy.
  • Identifying the radioresponsive genome for genomics-guided radiotherapy

    West, Catharine ML; Division of Cancer Studies, University of Manchester, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust Hospital, Manchester, M20 4BX, UK. (2020)
  • Multinational Association of Supportive Care in Cancer (MASCC) 2020 clinical practice recommendations for the management of immune-mediated cardiovascular, rheumatic, and renal toxicities from checkpoint inhibitors

    Suarez-Almazor, M. E.; Pundole, X.; Abdel-Wahab, N.; Johnson, D. B.; Gupta, D.; Glezerman, I.; Cooksley, Timothy J; Anderson, R.; Blidner, A.; Choi, J.; et al. (2020)
    Immune checkpoint inhibitors (ICIs) have emerged as the newest pillar of cancer treatment. Immune-mediated toxicities, stemming from increased activity within the T cell lineage, range from asymptomatic or mild complications to those that are fulminant and potentially fatal. Although they are of variable occurrence, cardiovascular, rheumatic, and renal immune-mediated toxicities are among the most serious of these adverse events. We present MASCC recommendations with respect to the workup and management of cardiovascular, rheumatic, and renal immune-mediated toxicities with a focus on presentations that require treatment with immunomodulating agents. Keywords: Arthralgia; Arthritis; Cardiomyopathy; Corticosteroids; Immunomodulation agents; Myocarditis; Myositis; Other immunosuppressive agents; Polymyalgia.
  • When what you see is not always what you get: raising the bar of evidence for new diagnostic imaging modalities

    Sundahl, N.; Gillessen, Silke; Sweeney, C.; Ost, P.; Department of Radiation Oncology, Ghent University Hospital, Ghent, Belgium; Division of Radiotherapy and Imaging, Institute of Cancer Research, London, UK. (2020)
    Even though prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)-computed tomography (CT) is more accurate than conventional imaging in prostate cancer patients, its impact on patient-relevant outcomes is unknown. We argue that more evidence is required before using PSMA-PET-CT as the standard of care for staging.
  • Radiation fractionation schedules published during the COVID-19 pandemic: a systematic review of the quality of evidence and recommendations for future development

    Thomson, David J; Yom, S. S.; Saeed, H.; El Naqa, I.; Ballas, L.; Bentzen, S. M.; Chao, S. T.; Choudhury, Ananya; Coles, C. E.; Dover, L.; et al. (2020)
    Purpose: Numerous publications during the COVID-19 pandemic recommended the use of hypofractionated radiation therapy. This project assessed aggregate changes in the quality of the evidence supporting these schedules to establish a comprehensive evidence base for future reference and highlight aspects for future study. Methods and materials: Based on a systematic review of published recommendations related to dose fractionation during the COVID-19 pandemic, 20 expert panelists assigned to 14 disease groups named and graded the highest quality of evidence schedule(s) used routinely for each condition and also graded all COVID-era recommended schedules. The American Society for Radiation Oncology quality of evidence criteria were used to rank the schedules. Process-related statistics and changes in distributions of quality ratings of the highest-rated versus recommended COVID-19 era schedules were described by disease groups and for specific clinical scenarios. Results: From January to May 2020 there were 54 relevant publications, including 233 recommended COVID-19-adapted dose fractionations. For site-specific curative and site-specific palliative schedules, there was a significant shift from established higher-quality evidence to lower-quality evidence and expert opinions for the recommended schedules (P = .022 and P < .001, respectively). For curative-intent schedules, the distribution of quality scores was essentially reversed (highest levels of evidence "pre-COVID" vs "in-COVID": high quality, 51.4% vs 4.8%; expert opinion, 5.6% vs 49.3%), although there was variation in the magnitude of shifts between disease sites and among specific indications. Conclusions: A large number of publications recommended hypofractionated radiation therapy schedules across numerous major disease sites during the COVID-19 pandemic, which were supported by a lower quality of evidence than the highest-quality routinely used dose fractionation schedules. This work provides an evidence-based assessment of these potentially practice-changing recommendations and informs individualized decision-making and counseling of patients. These data could also be used to support radiation therapy practices in the event of second waves or surges of the pandemic in new regions of the world.
  • The rare YAP1 subtype of SCLC revisited in a biobank of 39 circulating tumor cell patient derived explant models: a brief report

    Pearsall, Sarah M; Humphrey, Sam; Revill, Mitchell; Morgan, Derrick; Frese, Kristopher K; Galvin, Melanie; Kerr, Alistair; Carter, Mathew; Priest, Lynsey; Blackhall, Fiona H; et al. (2020)
    Introduction: Recent consensus defines four SCLC subtypes on the basis of transcription factor expression: ASCL1, NEUROD1, POU2F3, and YAP1. The rare YAP1 subtype is associated with "neuroendocrine (NE)-low" cells among SCLC cell lines and patient samples. We evaluated YAP1 in 39 patients with phenotypically diverse circulating tumor cell-derived explant (CDX) models and revisited YAP1 in terms of prevalence, cell phenotype, and intertumor and intratumor heterogeneity. Methods: YAP1 transcript and protein expression were assessed by RNA sequencing and immunohistochemistry or multiplexed immunofluorescence of NE and non-NE CDX subpopulations. Physically separated NE and non-NE CDX ex vivo culture lysates were Western blotted for YAP1, NE marker SYP, and AXL. Results: RNA sequencing normalized for the four subtype transcription factors identified YAP1 expression in 14 of 39 CDX. A total of 10 CDX expressed YAP1 protein, and eight had strong YAP1 expression confined to rare non-NE cell clusters. This was confirmed in ex vivo CDX cultures in which adherent non-NE cells lacking SYP expression expressed YAP1. However, in two CDX, weaker cellular YAP1 expression was observed, widely dispersed in SYP-positive NE cells. Conclusions: YAP1 was predominantly expressed in non-NE cell clusters in SCLC CDX, but two of 39 CDX expressed YAP1 in NE cells. CDX22P, with relatively high YAP1 expression, is an ASCL1 NE subtype with a low NE score and an outlier within this subtype in our CDX biobank. These descriptive data reveal subtly different YAP1 expression profiles, paving the way for functional studies to compare YAP1 signaling in non-NE and low NE cell contexts for potentially personalized therapeutic approaches. Keywords: Intratumoral heterogeneity; Neuroendocrine; Nonneuroendocrine; Small cell lung cancer (SCLC); YAP1.
  • BRIGHTLIGHT researchers as 'dramaturgs': creating There is a Light from complex research data

    Taylor, R. M.; Lobel, B.; Thompson, K.; Onashile, A.; Croasdale, M.; Hall, N.; Gibson, F.; Martins, A.; Wright, David; Morgan, S.; et al. (2020)
    Background: BRIGHTLIGHT is a national evaluation of cancer services for young people aged 13-24 years in England. It is a mixed methods study with six interlinked studies aiming to answer the question: do specialist cancer services for teenagers and young adults add value? Young people have been integral to study development and management, working as co-researchers, consultants and collaborators throughout. We aimed to share results in a way that was meaningful to young people, the public, and multidisciplinary professionals. This paper reports the development of 'There is a Light: BRIGHTLIGHT', a theatrical interpretation of study results by young people, and offers insight into the impact on the cast, researchers and audiences. Methods: The BRIGHTLIGHT team collaborated with Contact Young Company, a youth theatre group in Manchester. Twenty members of Contact Young Company and four young people with cancer worked together over an eight-week period during which BRIGHTLIGHT results were shared along with explanations of cancer, healthcare policy and models of care in interactive workshops. Through their interpretation, the cast developed the script for the performance. The impact of the process and performance on the cast was evaluated through video diaries. The research team completed reflective diaries and audiences completed a survey. Results: 'There is a Light' contained five acts and lasted just over an hour. It played 11 performances in six cities in the United Kingdom, to approximately 1377 people. After nine performances, a 30-min talk-back between members of the cast, creative team, an expert healthcare professional, and the audience was conducted, which was attended by at least half the audience. Analysis of cast diaries identified six themes: initial anxieties; personal development; connections; cancer in young people; personal impact; interacting with professionals. The cast developed strong trusting relationships with the team. Professionals stated they felt part of the process rather than sitting on the periphery sharing results. Both professional and lay audiences described the performance as meaningful and understandable. Feedback was particularly positive from those who had experienced cancer themselves. Conclusions: Using theatre to present research enabled BRIGHTLIGHT results to be accessible to a larger, more diverse audience. Keywords: Adolescents; Art; BRIGHTLIGHT; Cancer; Dissemination; Patient and public involvement; Teenagers; Theatre; Young adults.
  • Reprint of: Practice recommendations for risk-adapted head and neck cancer radiotherapy during the COVID-19 pandemic: An ASTRO-ESTRO consensus statement

    Thomson, David J; Palma, D.; Guckenberger, M.; Balermpas, P.; Beitler, J. J.; Blanchard, P.; Brizel, D.; Budach, W.; Caudell, J.; Corry, J.; et al. (2020)
    Purpose: Because of the unprecedented disruption of health care services caused by the COVID-19 pandemic, the American Society of Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) identified an urgent need to issue practice recommendations for radiation oncologists treating head and neck cancer (HNC) in a time of limited resources and heightened risk for patients and staff. Methods and materials: A panel of international experts from ASTRO, ESTRO, and select Asia-Pacific countries completed a modified rapid Delphi process. Topics and questions were presented to the group, and subsequent questions were developed from iterative feedback. Each survey was open online for 24 hours, and successive rounds started within 24 hours of the previous round. The chosen cutoffs for strong agreement (?80%) and agreement (?66%) were extrapolated from the RAND methodology. Two pandemic scenarios, early (risk mitigation) and late (severely reduced radiation therapy resources), were evaluated. The panel developed treatment recommendations for 5 HNC cases. Results: In total, 29 of 31 of those invited (94%) accepted, and after a replacement 30 of 30 completed all 3 surveys (100% response rate). There was agreement or strong agreement across a number of practice areas, including treatment prioritization, whether to delay initiation or interrupt radiation therapy for intercurrent SARS-CoV-2 infection, approaches to treatment (radiation dose-fractionation schedules and use of chemotherapy in each pandemic scenario), management of surgical cases in event of operating room closures, and recommended adjustments to outpatient clinic appointments and supportive care. Conclusions: This urgent practice recommendation was issued in the knowledge of the very difficult circumstances in which our patients find themselves at present, navigating strained health care systems functioning with limited resources and at heightened risk to their health during the COVID-19 pandemic. The aim of this consensus statement is to ensure high-quality HNC treatments continue, to save lives and for symptomatic benefit.
  • The evolving practice of palliative radiotherapy

    Rembielak, Agata; Dennis, K.; The Christie NHS Foundation Trust, Wilmslow Road, Manchester, M20 4BX, UK; The University of Manchester, Oxford Road, Manchester, M13 9PL, UK (2020)
  • Tebentafusp, a TCR/anti-CD3 bispecific fusion protein targeting gp100, potently activated anti-tumor immune responses in patients with metastatic melanoma

    Middleton, M. R.; McAlpine, C.; Woodcock, V. K.; Corrie, P.; Infante, J. R.; Steven, N. M.; Evans, T. R. J.; Anthoney, A.; Shoushtari, A. N.; Hamid, O.; et al. (2020)
    Purpose: Tebentafusp is a first-in-class bispecific fusion protein designed to target gp100 (a melanoma-associated antigen) through a high affinity T cell receptor binding domain, and an anti-CD3 T cell engaging domain which redirects T cells to kill gp100-expressing tumor cells. Here we report from a multicentre Phase 1/2 trial of tebentafusp in metastatic melanoma (NCT01211262) focusing on the mechanism of action of tebentafusp Experimental Design: 84 patients with advanced melanoma received tebentafusp. Treatment efficacy, treatment-related AEs and biomarker assessments were performed for blood-derived and tumor biopsy samples obtained at baseline and on-treatment Results: Tebentafusp was generally well tolerated and active in both metastatic uveal melanoma (mUM) and metastatic cutaneous melanoma (mCM) patients. A 65% 1-year overall survival rate was achieved for both patient cohorts. On-treatment cytokine measurements were consistent with the induction of IFNg pathway-related markers in the periphery and tumor. Notably, tebentafusp induced an increase in serum CXCL10 (a T cell attractant), and a reduction in circulating CXCR3+ CD8+ T cells together with an increase in cytotoxic T cells in the tumor microenvironment. Furthermore, increased serum CXCL10 or the appearance of rash, (likely due to cytotoxic T cells targeting of gp100-expressing skin melanocytes) showed a positive association with patient survival. Conclusions: These data suggest that re-directing T cells using a gp100-targeting T cell receptor/anti-CD3 bispecific fusion protein may provide benefit to patients with metastatic melanoma. Furthermore, the activity observed in these two molecularly disparate melanoma classes hints at the broad therapeutic potential of tebentafusp.
  • ESMO consensus conference recommendations on the management of locoregional melanoma: the ESMO Guidelines Committee

    Michielin, O.; van Akkooi, A.; Lorigan, Paul C; Ascierto, P. A.; Dummer, R.; Robert, C.; Arance, A.; Blank, C. U.; Sileni, V. C.; Donia, M.; et al. (2020)
    The European Society for Medical Oncology (ESMO) held a consensus conference on melanoma on 5-7 September 2019 in Amsterdam, The Netherlands. The conference included a multidisciplinary panel of 32 leading experts in the management of melanoma. The aim of the conference was to develop recommendations on topics that are not covered in detail in the current ESMO Clinical Practice Guideline and where available evidence is either limited or conflicting. The main topics identified for discussion were: (i) the management of locoregional disease; (ii) targeted versus immunotherapies in the adjuvant setting; (iii) targeted versus immunotherapies for the first-line treatment of metastatic melanoma; (iv) when to stop immunotherapy or targeted therapy in the metastatic setting; and (v) systemic versus local treatment of brain metastases. The expert panel was divided into five working groups in order to each address questions relating to one of the five topics outlined above. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel for further discussion and amendment before voting. This manuscript presents the results relating to the management of locoregional melanoma, including findings from the expert panel discussions, consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript. Keywords: adjuvant; consensus; immunotherapy; melanoma; targeted therapy; treatment.
  • MILO/ENGOT-ov11: binimetinib versus physician's choice chemotherapy in recurrent or persistent low-grade serous carcinomas of the ovary, fallopian tube, or primary peritoneum

    Monk, B. J.; Grisham, R. N.; Banerjee, S.; Kalbacher, E.; Mirza, M. R.; Romero, I.; Vuylsteke, P.; Coleman, R. L.; Hilpert, F.; Oza, A. M.; et al. (2020)
    Purpose: Low-grade serous ovarian carcinomas (LGSOCs) have historically low chemotherapy responses. Alterations affecting the MAPK pathway, most commonly KRAS/BRAF, are present in 30%-60% of LGSOCs. The purpose of this study was to evaluate binimetinib, a potent MEK1/2 inhibitor with demonstrated activity across multiple cancers, in LGSOC. Methods: This was a 2:1 randomized study of binimetinib (45 mg twice daily) versus physician's choice chemotherapy (PCC). Eligible patients had recurrent measurable LGSOC after ? 1 prior platinum-based chemotherapy but ? 3 prior chemotherapy lines. The primary end point was progression-free survival (PFS) by blinded independent central review (BICR); additional assessments included overall survival (OS), overall response rate (ORR), duration of response (DOR), clinical-benefit rate, biomarkers, and safety. Results: A total of 303 patients were randomly assigned to an arm of the study at the time of interim analysis (January 20, 2016). Median PFS by BICR was 9.1 months (95% CI, 7.3 to 11.3) for binimetinib and 10.6 months (95% CI, 9.2 to 14.5) for PCC (hazard ratio,1.21; 95%CI, 0.79 to 1.86), resulting in early study closure according to a prespecified futility boundary after 341 patients had enrolled. Secondary efficacy end points were similar in the two groups: ORR 16% (complete response [CR]/partial responses[PRs], 32) versus 13% (CR/PRs, 13); median DOR, 8.1 months (range, 0.03 to ? 12.0 months) versus 6.7 months (0.03 to ? 9.7 months); and median OS, 25.3 versus 20.8 months for binimetinib and PCC, respectively. Safety results were consistent with the known safety profile of binimetinib; the most common grade ? 3 event was increased blood creatine kinase level (26%). Post hoc analysis suggests a possible association between KRAS mutation and response to binimetinib. Results from an updated analysis (n = 341; January 2019) were consistent. Conclusion: Although the MEK Inhibitor in Low-Grade Serous Ovarian Cancer Study did not meet its primary end point, binimetinib showed activity in LGSOC across the efficacy end points evaluated. A higher response to chemotherapy than expected was observed and KRAS mutation might predict response to binimetinib.
  • Patient-centered outcomes in ARIEL3, a phase III, randomized, placebo-controlled trial of rucaparib maintenance treatment in patients with recurrent ovarian carcinoma

    Oza, A. M.; Lorusso, D.; Aghajanian, C.; Oaknin, A.; Dean, A.; Colombo, N.; Weberpals, J. I.; Clamp, Andrew R; Scambia, G.; Leary, A.; et al. (2020)
    Purpose: To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo. Patients and methods: Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function � the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ? 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ? 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as ?TOX � TOX + TWiST, with ?TOX calculated using EQ-5D-3L data. Results: The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ? 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ? 2 TEAEs also consistently favored rucaparib. Conclusion: The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.
  • Surgical and radiotherapeutic management of malignant extradural spinal cord compression

    Loblaw, A.; George, K. J.; Misra, Vivek; Sunnybrook Health Sciences Centre, Toronto, Canada. (2020)
    Malignant spinal cord compression is one of the most dreaded complications of advanced malignancy, with patients presenting with progressive paralysis, paresthesia and/or autonomic dysfunction. The choice of management should be guided by the expected prognosis and outcome, not just from a neurological function point-of-view but also from the metastatic cancer itself. The main indications for surgery are: impending cord compression, spinal instability from tumour progression, bony retropulsion, for tissue diagnosis and for pain resistant to conventional therapies. Here, surgical principles, traditional and novel techniques and complications will be reviewed. For radiotherapy, multiple randomised studies have shown that for most patients a single fraction of external radiation has the same functional outcomes compared with multi-fractionation protocols. The experience of a specialised centralised interdisciplinary team will also be discussed. Keywords: Quality of life; radiation; spinal cord compression; surgery; toxicity.
  • Impact of high tumor mutational burden in solid tumors and challenges for biomarker application

    McNamara, Mairead G; Jacobs, Timothy; Lamarca, Angela; Hubner, Richard A; Valle, Juan W; Amir, E.; Division of Cancer Sciences, University of Manchester/Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. (2020)
    Accurate identification of patients with solid tumors likely to respond to immunotherapy is crucial. Tumor mutational burden (TMB) measures the number of somatic mutations in a tumor and is an emerging prognostic and predictive biomarker for anti-programmed cell death (PD) 1/anti-PD-ligand 1 therapy and other immunotherapeutic agents. Tumor mutational burden is assessed optimally by whole exome sequencing, but next generation sequencing provides TMB estimates in a more timely and cost-effective manner. Blood-based measurement of TMB in plasma offers an alternative to the need for adequate tumor tissue for molecular testing, and has demonstrated the ability to identify patients who derive benefit from immunotherapy. Tumor mutational burden has diverse prognostic impact in different solid tumor types and also has a demonstrated role in predicting improved survival in patients receiving immunotherapy. There are challenges to TMB adoption into standard clinical practice, including variations in its definition, with the mutational number defining TMB-high appearing to vary across cancer types. The magnitude of TMB also varies across different tumor types, with the highest levels reported in melanoma and other skin cancers (where ultraviolet light is the dominant mutational process), followed by non-small cell lung cancer and other squamous carcinomas. Concerns regarding inter-laboratory and inter-platform variations in analysis methods have been raised, highlighting the need for standardization. Integration of other genomic or pathological biomarkers with TMB may increase its prognostic and predictive capabilities and validation of individual or combination models in prospective trials is warranted. Keywords: Biomarkers; Immune checkpoint blockade; Next-generation sequencing; Predictive; Prognostic; Tumor mutational burden.
  • Fibrolamellar carcinoma: Challenging the challenge

    Lamarca, Angela; Frizziero, Melissa; Fulton, Alexander; McNamara, Mairead G; Filobbos, R.; Hubner, Richard A; Wardell, Steve; Valle, Juan W; Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Division Cancer Sciences, University of Manchester; Manchester, United Kingdom. (2020)
    Fibrolamellar carcinoma (FLC) is a rare and poorly understood malignancy, which seems to be more prevalent in young patients compared with conventional hepatocellular carcinoma (HCC). Performing prospective clinical trials recruiting patients diagnosed with FLC has proven challenging with scarce data available guiding clinical management. The use of a number of chemotherapy compounds in these patients, including cisplatin, epirubicin, 5-fluorouracil (5-FU) and recombinant interferon ?-2B (IFN-?-2B), has been reported in the literature, mainly in the form of case reports. The most promising systemic therapy tested so far is the combination of 5-FU infusion and 3-weekly IFN-?-2B, based on results from a phase II clinical trial. This article provides an overview of our own experience with this treatment schedule for patients with FLC, confirming its activity and treatment-derived benefit in the real world. Current challenges being faced by healthcare professionals treating patients with advanced FLC are discussed, especially the increasingly limited access to IFN-?-2B, which could compromise the access to an active therapy in the coming future, and the difficulties in the development of new treatment options for advanced FLC. Keywords: 5-FU; 5-fluorouracil treatment; Advanced; Chemotherapy; FLC; Fibrolamellar carcinoma; IFN; Interferon; Systemic therapy.
  • Brain microenvironment-driven resistance to immune and targeted therapies in acral melanoma

    Lee, Rebecca J; Khandelwal, Garima; Baenke, Franziska; Cannistraci, Alessio; Macleod, K.; Mundra, Piyushkumar; Ashton, Garry; Mandal, Amit; Viros, Amaya; Gremel, Gabriela; et al. (2020)
    Background: Combination treatments targeting the MEK-ERK pathway and checkpoint inhibitors have improved overall survival in melanoma. Resistance to treatment especially in the brain remains challenging, and rare disease subtypes such as acral melanoma are not typically included in trials. Here we present analyses from longitudinal sampling of a patient with metastatic acral melanoma that became resistant to successive immune and targeted therapies. Methods: We performed whole-exome sequencing and RNA sequencing on an acral melanoma that progressed on successive immune (nivolumab) and targeted (dabrafenib) therapy in the brain to identify resistance mechanisms. In addition, we performed growth inhibition assays, reverse phase protein arrays and immunoblotting on patient-derived cell lines using dabrafenib in the presence or absence of cerebrospinal fluid (CSF) in vitro. Patient-derived xenografts were also developed to analyse response to dabrafenib. Results: Immune escape following checkpoint blockade was not due to loss of tumour cell recognition by the immune system or low neoantigen burden, but was associated with distinct changes in the microenvironment. Similarly, resistance to targeted therapy was not associated with acquired mutations but upregulation of the AKT/phospho-inositide 3-kinase pathway in the presence of CSF. Conclusion: Heterogeneous tumour interactions within the brain microenvironment enable progression on immune and targeted therapies and should be targeted in salvage treatments. Keywords: acral melanoma; brain metastasis; immune therapy; targeted therapy.

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