The Christie School of Oncology: Christie Research Publications Repository
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International Society of Urological Pathology (ISUP) multidisciplinary consensus on premalignant and putative precursor lesions of penile cancer: working group 5 report on terminology, grading, and molecular testing practices
No full textThe classification and diagnosis of penile intraepithelial neoplasia (PeIN) remains inconsistent among pathologists, despite its recognized role and understanding as a precursor to penile squamous cell carcinoma (PSCC). The International Society of Urological Pathology (ISUP) convened a consensus group of multidisciplinary thought leaders to assess current global practices regarding the usage of terminology, grading, and molecular testing in penile cancer precursor lesions. A preconference survey was distributed to ISUP members in 2024, collecting responses from 112 pathologists, predominantly genitourinary specialists, to evaluate the use of penile cancer precursor lesion classification systems, grading approaches, and diagnostic biomarkers. The results were presented at the ISUP Multidisciplinary Consensus Conference on Cancer Precursor Lesions in September 2024, where further consensus was achieved through electronic voting. The survey revealed that 89.4% of respondents classify PeIN based on HPV association, with 76% supporting further subtyping into basaloid, warty, and differentiated subtypes. Grading of PeIN remains controversial; 51.3% initially favored grading, but 82% finally voted that PeIN should not be graded. p16 immunohistochemistry (IHC) was widely utilized (91.5%) to distinguish HPV-associated from HPV-independent PeIN, whereas p53 IHC and HPV genotyping lacked consensus for routine use. Reporting practices for PeIN margins and their association with lichen sclerosis were widely endorsed, while the value and concordance of subtyping HPV-independent PeIN remains an area for further investigation. This ISUP consensus paper guides PeIN classification, confirming the importance of HPV-related stratification and p16 IHC staining and reporting as standard practice. However, significant variability persists in PeIN grading and molecular testing strategies. These findings highlight the need for further research and standardization to optimize diagnostic accuracy and clinical relevance in PeIN
Association of candidate surrogate endpoints with overall survival in advanced biliary tract cancer
No full textBACKGROUND & AIMS: Surrogate endpoints are increasingly used in biliary tract cancer (BTC) trials. While this may expedite drug approval and decrease costs, surrogate endpoints may not always correlate with an overall survival (OS) advantage. We aimed to explore the association of progression-free survival (PFS), objective response rate (ORR) and disease control rate (DCR) with OS at the trial- and patient-level. METHODS: For the trial-level analysis, we performed a systematic review of Pubmed/MEDLINE, Embase, Cochrane, clinicaltrials.gov and conference proceedings for phase II-III trials in advanced BTC. We used a weighted linear regression to measure the correlation of OS with PFS, ORR and DCR. For the patient-level analysis, we analyzed patients included in five randomized trials and three real-world datasets. The protocol is registered with PROSPERO, CRD42023398279. RESULTS: For the trial-level analysis, we included 41 studies, involving 88 treatment arms and 7,817 patients. The coefficient of determination (R(2)) of the model was 0.71 (95% CI 0.56-0.86) for PFS, 0.01 (0-0.08) for ORR and 0.39 (0.14-0.64) for DCR. Predefined subgroup analysis showed consistent results. For the patient-level analysis, we included a total of 2,506 patients, 783 in randomized trials (first-line 512, second-line 271) and 1,723 in routine clinical care (first-line chemotherapy 773, first-line chemotherapy-durvalumab 628, second-line chemotherapy 322). Across the distinct datasets, the correlation coefficient ranged from 0.73 to 0.86 for PFS. A responder analysis found no association between response and survival. CONCLUSION: PFS shows a moderate correlation with OS both at the trial- and patient-level, while ORR and DCR show a low correlation. Whilst PFS is currently the best candidate surrogate marker for OS, our results highlight the need for novel endpoints in this field. IMPACT AND IMPLICATIONS: The use of validated surrogate endpoints in biliary tract cancer trials may decrease costs and improve study feasibility, particularly with agents that only target small subsets of patients or in trials that incorporate a crossover design. A formal statistical validation of surrogacy requires patient-level and trial-level data. This is the first comprehensive analysis to incorporate novel agents (including immunotherapies and targeted agents), include patient-level data and rigorously and homogeneously extract appropriate measures of treatment effect for endpoint correlation. These results show a moderate correlation for progression-free survival both at the trial- and patient-level and a low correlation for disease control rate and response rate. This information will aid clinicians in appropriately interpreting contemporary clinical trials and guide clinical researchers and trial sponsors involved in clinical trial design. Furthermore, it has important implications for the regulatory approval process and may aid agencies in appropriately evaluating novel drugs
First-line chemo-immunotherapy in SCLC: outcomes of a binational real-world study
No full textINTRODUCTION: SCLC is characterized by aggressiveness and limited treatment options, especially in extensive-stage SCLC (ES-SCLC). Immunotherapy added to the platinum-etoposide combination has recently become standard in this setting. This retrospective study aims to evaluate the real-world effectiveness of chemo-immunotherapy in patients with ES-SCLC, focusing on subpopulations excluded from clinical trials. METHODS: A retrospective binational multicenter study was conducted, involving consecutive patients with ES-SCLC from 10 British and 10 Swiss institutions. Patients received platinum-etoposide chemotherapy in combination with immunotherapy (atezolizumab or durvalumab). Patient, tumor, and treatment details were collected. Overall survival (OS), progression-free survival, objective response rate, and safety outcomes were analyzed. RESULTS: A total of 436 patients were included. One hundred forty-two patients (32.6%) in our cohort would not have been eligible for the pivotal registrational trials owing to an Eastern Cooperative Oncology Group performance status of 2 or higher, autoimmune disease, active brain metastases, or steroid use. Most patients received carboplatin (96.8%) and atezolizumab (97.9%). The median progression-free survival was 5.5 months and the median OS was 9.3 months. The two-year OS was 14%. Patients with liver or bone metastases or an Eastern Cooperative Oncology Group performance status of 2 or higher had worse survival outcomes. Treatment-related adverse events were reported in 222 patients (51%) whereas immune-related adverse events occurred in 95 patients (22%). Three out of five grade 5 immune-related adverse events were caused by pneumonitis. CONCLUSIONS: To our knowledge, this is the largest real-world cohort of patients treated with chemo-immunotherapy for ES-SCLC. Although one-third of patients would not have been eligible for pivotal trials, the survival outcomes in our cohort are similar to those in registrational trials. In particular, the number of long-term survivors and the safety data are comparable, supporting the use of chemo-immunotherapy as first-line treatment for ES-SCLC in daily clinical practice
RATIONALE-306 subgroup analysis of patients (pts) with advanced/metastatic esophageal squamous cell cancer (ESCC) and tumor area positivity (TAP) score ≳5%
No full textPhase II randomised controlled basket feasibility trial of a personalised, remotely delivered exercise programme on disease-free survival among early-stage, high-risk cancers: CANFit study protocol
No full textINTRODUCTION: Evidence suggests a 38% risk reduction in breast and bowel cancer-specific mortality with higher levels of exercise, however, most of this evidence is observational. More clinical trials are needed to build strong evidence for exercise's impact on recurrence and survival. This study aims to assess the feasibility, acceptability and potential efficacy of a remote, tailored exercise programme on disease-free survival in patients recently completing curative treatment for early-stage, high-risk lung, breast or bowel cancer. METHODS AND ANALYSIS: This UK-based, multicentre randomised controlled basket feasibility trial compares a personalised, remote-delivered exercise programme supported by exercise professionals against usual care. Potential participants are approached if they are: aged 18 or over, diagnosed with high-risk, early-stage breast, bowel or lung cancer, and within 24 weeks of completing primary curative treatments. Participants complete objective measures of physical function (submaximal cardiovascular fitness, endurance, muscle strength and balance), body composition (bioelectrical impedance) and self-reported outcomes (total physical activity, sleep quality, general quality of life (QoL), cancer-related QoL and exercise confidence/motivation). Clinical case note review provides disease-free survival outcomes at 6, 12 and 24 months. The 12-week programme is delivered remotely (via phone, email and/or video conference) with trainer contact tapering off over the subsequent 12 weeks (24 weeks total). Recruitment is ongoing with a 660-participant goal. Descriptive measures (quantitative and qualitative) will be reported for feasibility outcomes: recruitment, adherence, retention rates, data collection quality, adverse events, intervention acceptability and fidelity. A process evaluation is being conducted concurrently and is reported separately. Kaplan-Meier curves will be plotted and median disease-free survival calculated for each arm. To determine intervention impact, a log-rank test (unadjusted) will compare 2-year disease-free survival between groups within and among cancer types. Secondary outcomes (physical function status, general/cancer-specific QoL and determinants of meeting activity guidelines) will be reported at each time point. ETHICS AND DISSEMINATION: Ethical approvals were obtained through Hull York Medical School (ID: 23/SS/0060) and UK NHS Health Research Authority (ID: 327663). Findings will be submitted for publication in high-impact journals, presentation at national and international conferences, press releases where appropriate, and dissemination activities to be decided on with the Patient Advisory Group. TRIAL REGISTRATION NUMBER: ISRCTN97662203
Telomere attrition becomes an instrument for clonal selection in aging hematopoiesis and leukemogenesis
No full textThe mechanisms through which mutations in splicing factor genes drive clonal hematopoiesis (CH) and myeloid malignancies, and their close association with advanced age, remain poorly understood. Here we show that telomere maintenance plays an important role in this phenomenon. First, by studying 454,098 UK Biobank participants, we find that, unlike most CH subtypes, splicing-factor-mutant CH is more common in those with shorter genetically predicted telomeres, as is CH with mutations in PPM1D and the TERT gene promoter. We go on to show that telomere attrition becomes an instrument for clonal selection in advanced age, with splicing factor mutations 'rescuing' HSCs from critical telomere shortening. Our findings expose the lifelong influence of telomere maintenance on hematopoiesis and identify a potential shared mechanism through which different splicing factor mutations drive leukemogenesis. Understanding the mechanistic basis of these observations can open new therapeutic avenues against splicing-factor-mutant CH and hematological or other cancers
Maintenance capecitabine plus ramucirumab after first-line chemotherapy in patients with advanced esophagogastric adenocarcinoma: results from the randomized PLATFORM study
No full textPURPOSE: PLATFORM is an adaptive phase II study assessing maintenance therapies in advanced esophagogastric adenocarcinoma (OGA). We evaluated the role of capecitabine plus a vascular endothelial growth factor receptor 2 inhibitor ramucirumab (cape-ram) in these patients. METHODS: Human epidermal growth factor receptor 2 (HER2)-negative patients with advanced OGA with stable or responding disease after 18 weeks of induction platinum-based chemotherapy were randomly assigned 1:1 to surveillance or cape-ram. The primary end point was progression-free survival (PFS), and key secondary end points were overall survival (OS) and safety. Recruitment to the cape-ram arm closed prematurely because of industry support withdrawal. A one-sided log-rank test with a 2.5% significance level was considered significant. RESULTS: Between April 2019 and November 2022, 25 surveillance and 22 cape-ram patients were contemporaneously randomly assigned. Median follow-up was 24.4 months. Compared with surveillance, cape-ram significantly prolonged PFS (hazard ratio [HR], 0.33 [95% CI, 0.17 to 0.63], P < .001; median PFS: 2.5 months with surveillance versus 5.5 months with cape-ram; 6-month PFS rate: 4% [95% CI, 0.3% to 17.0%] v 42.9% [95% CI, 21.9% to 62.3%], respectively) and OS (HR, 0.51 [95% CI, 0.26 to 1.00], P = .023; median OS: 7.1 months with surveillance v 14.4 months with cape-ram; median OS from start of induction chemotherapy was 12.1 months v 19.5 months, respectively). Of 10 cape-ram patients with measurable disease, 1 had an incremental partial response. Grade ≥3 adverse events (AEs) were seen in 32% surveillance and 57% cape-ram patients. Six cape-ram patients had grade 3 treatment-related AEs, and no new safety signals were identified. CONCLUSION: Maintenance cape-ram after induction chemotherapy for patients with HER2-negative OGA significantly improved survival compared with surveillance. To our knowledge, this is the first randomized maintenance study demonstrating survival benefit and provides support for maintenance treatment
PROMETCO: real-world characteristics and safety outcomes of patients with metastatic colorectal cancer (mCRC) after two disease progressions, including patients with ECOG-PS >2
No full textNegative pressure dressings to prevent surgical site infection after emergency laparotomy: the SUNRRISE randomized clinical trial
No full textIMPORTANCE: Patients undergoing unplanned abdominal surgical procedures are at increased risk of surgical site infection (SSI). It is not known if incisional negative pressure wound therapy (iNPWT) can reduce SSI rates in this setting. OBJECTIVE: To evaluate the effectiveness of iNPWT in reducing the rate of SSI in adults undergoing emergency laparotomy with primary skin closure. DESIGN, SETTING, AND PARTICIPANTS: SUNRRISE was an assessor-masked, pragmatic, phase 3, individual-participant, randomized clinical trial. Adult patients undergoing emergency laparotomy in 22 hospitals in the UK and 12 hospitals in Australia between December 18, 2018, and May 25, 2021, were recruited. Patients were followed up for 30 days postprocedure; database closure was on August 25, 2021. INTERVENTIONS: Participants were randomized 1:1 to receive iNPWT (n = 411), which involved a specialized dressing used to create negative pressure over the closed wound vs the surgeon's choice of wound dressing (n = 410). Randomization and dressing application occurred in the operating room at the end of the surgical procedure. MAIN OUTCOMES AND MEASURES: The primary outcome measure was SSI up to 30 days postprocedure, evaluated by an assessor masked to the randomized allocation and using criteria from the US Centers for Disease Control and Prevention. There were 7 secondary outcomes, including length of hospital stay, postoperative complications up to 30 days, hospital readmission for wound-related complications within 30 days, wound pain, and quality of life. RESULTS: A total of 840 patients were randomized (536 from the UK; 304 from Australia). Overall, 52% were female; the mean age was 63.8 (range, 18.8 to 95.3) years. After postrandomization exclusions (N = 52), 394 participants per group were included in the primary analysis. The number of participants who had an SSI in the iNPWT group was 112 of 394 (28.4%), compared with 108 of 394 (27.4%) in the surgeon's preference group (relative risk, 1.03 [95% CI, 0.83-1.28]; P = .78). This finding was consistent across the preplanned subgroup analyses, including degree of contamination, presence of a stoma, participant body mass index, and skin preparation used, and across all preplanned sensitivity analyses. Of 7 secondary outcomes, 6 showed no significant difference, including hospital readmission, quality of life, and hospital stay (median [IQR], 8 [6-14] days in the iNPWT group and 9 [6-14.5] days in the surgeon's preference group [ratio of geometric means, 0.96 (95% CI, 0.88-1.06); P = .21]). CONCLUSIONS AND RELEVANCE: Routine application of iNPWT to the closed surgical wound after emergency laparotomy did not prevent SSI more than other dressings. TRIAL REGISTRATION: isrctn.com Identifier: ISRCTN17599457; anzctr.org.au Identifier: ACTRN12619000496112
Overall survival for bevacizumab therapy in metastatic colorectal cancer: an updated analysis of the TRAVASTIN study
No full textBACKGROUND: The TRAVASTIN study dentified plasma Tie2 as the first vascular response biomarker for bevacizumab in metastatic colorectal cancer. Tie2-defined vascular responders had significantly longer progression-free survival (PFS) compared to nonresponders. Here, we report overall survival (OS) in TRAVASTIN after 7.7 years of follow-up, explore efficacy of bevacizumab use and reuse, and assess plasma Tie2 performance as a response biomarker. METHODS: This single-center, prospective study recruited 70 patients with newly diagnosed, large volume, metastatic colorectal cancer. Patients received first-line oxaliplatin-fluoropyrimidine chemotherapy plus bevacizumab. After disease progression, 22 patients were randomized to receive second-line fluorouracil-irinotecan chemotherapy with or without bevacizumab. A vascular response was defined as a 5% or more reduction in plasma Tie2 within 9 weeks of starting treatment. Survival outcomes were estimated using Kaplan-Meier statistics and analyzed using Cox proportional hazards regression. RESULTS: The updated median PFS and OS were 9.7 months (95% confidence interval [CI] 8.7-11.6) and 19.2 months (95% CI, 16.7-22.0), respectively. Multivariable analysis of key prognostic variables showed Tie2-defined vascular response associated with a significantly improved PFS (hazard ratio [HR] 0.49, 95% CI, 0.29-0.85, P = .011) and moderately improved OS (HR 0.71, 95% CI, 0.42-1.2, P = .195). Patients with a Tie2-defined vascular response to first-line bevacizumab therapy had a 3.7-month longer median OS with bevacizumab reuse than chemotherapy alone (10.5 months vs. 6.8 months, respectively), although this was not statistically significant. CONCLUSION: Plasma Tie2 is a response biomarker for PFS benefit with first-line bevacizumab in metastatic colorectal cancer, although OS benefit was not significant in TRAVASTIN. Our study highlights the promising use of Tie2 to guide bevacizumab treatment, including retreatment, in colorectal cancer