Pub Date : 2024-08-01Epub Date: 2024-07-05DOI: 10.1016/S1470-2045(24)00259-6
Dimitris Bertsimas, Georgios Antonios Margonis, Suleeporn Sujichantararat, Angelos Koulouras, Yu Ma, Cristina R Antonescu, Murray F Brennan, Javier Martín-Broto, Seehanah Tang, Piotr Rutkowski, Martin E Kreis, Katharina Beyer, Jane Wang, Elzbieta Bylina, Pawel Sobczuk, Antonio Gutierrez, Bhumika Jadeja, William D Tap, Ping Chi, Samuel Singer
<p><strong>Background: </strong>Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy.</p><p><strong>Methods: </strong>In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011.</p><p><strong>Findings: </strong>Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm<sup>2</sup> or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm<sup>2</sup>. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5
{"title":"Interpretable artificial intelligence to optimise use of imatinib after resection in patients with localised gastrointestinal stromal tumours: an observational cohort study.","authors":"Dimitris Bertsimas, Georgios Antonios Margonis, Suleeporn Sujichantararat, Angelos Koulouras, Yu Ma, Cristina R Antonescu, Murray F Brennan, Javier Martín-Broto, Seehanah Tang, Piotr Rutkowski, Martin E Kreis, Katharina Beyer, Jane Wang, Elzbieta Bylina, Pawel Sobczuk, Antonio Gutierrez, Bhumika Jadeja, William D Tap, Ping Chi, Samuel Singer","doi":"10.1016/S1470-2045(24)00259-6","DOIUrl":"10.1016/S1470-2045(24)00259-6","url":null,"abstract":"<p><strong>Background: </strong>Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy.</p><p><strong>Methods: </strong>In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011.</p><p><strong>Findings: </strong>Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm<sup>2</sup> or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm<sup>2</sup>. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 ","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"1025-1037"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141559069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-08DOI: 10.1016/S1470-2045(24)00345-0
Ajay Aggarwal, Richard Simcock, Pat Price, Bernard Rachet, Georgios Lyratzopoulos, Kate Walker, Katie Spencer, Tom Roques, Richard Sullivan
In this Policy Review we discuss ten key pressure points in the NHS in the delivery of cancer care services that need to be urgently addressed by a comprehensive national cancer control plan. These pressure points cover areas such as increasing workforce capacity and its productivity, delivering effective cancer survivorship services, addressing variation in quality, fixing the reimbursement system for cancer care, and balancing of the cancer research agenda. These areas have been selected based on their relative importance to ensuring sustainable cancer services, persistence as key issues in the NHS, and their impact on delivering better and more equitable and affordable patient outcomes. Many of these pressure points are not acknowledged explicitly in any current discourse. The evidence we provide points to their impact on the ability to deliver world class cancer care, but also to their amenability to affordable solutions if given the relevant prioritisation and investment. The current narrative needs to move away from a technocentric approach to improving care, to one focused on understanding the complexity of cancer services and the wider health system to drive improvements in survival, quality of life, and experience for patients.
{"title":"NHS cancer services and systems-ten pressure points a UK cancer control plan needs to address.","authors":"Ajay Aggarwal, Richard Simcock, Pat Price, Bernard Rachet, Georgios Lyratzopoulos, Kate Walker, Katie Spencer, Tom Roques, Richard Sullivan","doi":"10.1016/S1470-2045(24)00345-0","DOIUrl":"10.1016/S1470-2045(24)00345-0","url":null,"abstract":"<p><p>In this Policy Review we discuss ten key pressure points in the NHS in the delivery of cancer care services that need to be urgently addressed by a comprehensive national cancer control plan. These pressure points cover areas such as increasing workforce capacity and its productivity, delivering effective cancer survivorship services, addressing variation in quality, fixing the reimbursement system for cancer care, and balancing of the cancer research agenda. These areas have been selected based on their relative importance to ensuring sustainable cancer services, persistence as key issues in the NHS, and their impact on delivering better and more equitable and affordable patient outcomes. Many of these pressure points are not acknowledged explicitly in any current discourse. The evidence we provide points to their impact on the ability to deliver world class cancer care, but also to their amenability to affordable solutions if given the relevant prioritisation and investment. The current narrative needs to move away from a technocentric approach to improving care, to one focused on understanding the complexity of cancer services and the wider health system to drive improvements in survival, quality of life, and experience for patients.</p>","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"e363-e373"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Background: </strong>Project Orbis is a global initiative that aims to streamline regulatory review processes across international regulators in the USA, Canada, Australia, UK, Israel, Brazil, Singapore, and Switzerland to bring promising cancer drugs to patients earlier. We explored the clinical benefit, time to regulatory approval and health technology assessment recommendations, reimbursement outcomes, and monthly treatment prices of cancer drugs reviewed through this initiative.</p><p><strong>Methods: </strong>For this retrospective, comparative analysis, we identified cancer drug approvals reviewed through Project Orbis in the USA, Canada, and the UK between May 1, 2019, and Nov 1, 2023. Approvals of cancer drugs reviewed Project Orbis were extracted from the Food and Drug Administration (FDA) Oncology Centre of Excellence and all other FDA approvals from the Drugs@FDA database. The co-primary outcomes were time of regulatory review, time from regulatory approval to health technology assessment recommendation (England, Scotland, and Canada), reimbursement outcomes, clinical benefit (defined as median gains in progression-free survival and overall survival) between cancer drug approvals reviewed by Project Orbis and other FDA approval processes, and monthly treatment prices. The Wilcoxon rank-sum and Fisher's Exact tests were used to examine statistical significance between approvals reviewed through Project Orbis and other FDA approvals during the same period.</p><p><strong>Findings: </strong>Between May 1, 2019 and Nov 1, 2023, 81 (33%) of 244 cancer drugs approved by the FDA were reviewed through Project Orbis. The median overall survival gains were 4·1 months (IQR 3·3-5·1) compared with 2·7 months (2·1-3·9) for other FDA approvals. Similarly, progression-free survival gains were 2·6 months (IQR 1·7-4·9) for Project Orbis compared with 2·6 months (0·6-5·1) for other FDA approvals. Neither overall survival (p=0·11) nor progression-free survival (p=0·44) gains were significantly different between the two cohorts of approvals. Of the 14 UK Medicines and Healthcare products Regulatory Agency (MHRA) approvals reviewed by the Scottish Medicines Consortium (SMC), the agency gave positive recommendations for all 14 (100%). Of the 15 MHRA approvals reviewed by the National Institute for Health and Care Excellence (NICE), the agency gave positive recommendations for six (40%). Of the 49 approvals reviewed by the Canadian Agency for Drugs and Technologies in Health (CADTH), the agency conditionally recommended 44 (90%). The time between regulatory approval to NICE recommendation increased from a median of 137 days (IQR 102-172) in 2021 to 302 days (184-483) in 2023, SMC recommendation increased from 185 days (in 2021 for one drug only) to 368 days (IQR 313-476) in 2023, and CADTH decision increased from 97 days (in 2020 for one drug only) to 202 days (IQR 153-304) in 2023. The median monthly price of approvals reviewed through Project Orbi
{"title":"Clinical benefit, reimbursement outcomes, and prices of FDA-approved cancer drugs reviewed through Project Orbis in the USA, Canada, England, and Scotland: a retrospective, comparative analysis.","authors":"Kristina Jenei, Arianna Gentilini, Alyson Haslam, Vinay Prasad","doi":"10.1016/S1470-2045(24)00286-9","DOIUrl":"10.1016/S1470-2045(24)00286-9","url":null,"abstract":"<p><strong>Background: </strong>Project Orbis is a global initiative that aims to streamline regulatory review processes across international regulators in the USA, Canada, Australia, UK, Israel, Brazil, Singapore, and Switzerland to bring promising cancer drugs to patients earlier. We explored the clinical benefit, time to regulatory approval and health technology assessment recommendations, reimbursement outcomes, and monthly treatment prices of cancer drugs reviewed through this initiative.</p><p><strong>Methods: </strong>For this retrospective, comparative analysis, we identified cancer drug approvals reviewed through Project Orbis in the USA, Canada, and the UK between May 1, 2019, and Nov 1, 2023. Approvals of cancer drugs reviewed Project Orbis were extracted from the Food and Drug Administration (FDA) Oncology Centre of Excellence and all other FDA approvals from the Drugs@FDA database. The co-primary outcomes were time of regulatory review, time from regulatory approval to health technology assessment recommendation (England, Scotland, and Canada), reimbursement outcomes, clinical benefit (defined as median gains in progression-free survival and overall survival) between cancer drug approvals reviewed by Project Orbis and other FDA approval processes, and monthly treatment prices. The Wilcoxon rank-sum and Fisher's Exact tests were used to examine statistical significance between approvals reviewed through Project Orbis and other FDA approvals during the same period.</p><p><strong>Findings: </strong>Between May 1, 2019 and Nov 1, 2023, 81 (33%) of 244 cancer drugs approved by the FDA were reviewed through Project Orbis. The median overall survival gains were 4·1 months (IQR 3·3-5·1) compared with 2·7 months (2·1-3·9) for other FDA approvals. Similarly, progression-free survival gains were 2·6 months (IQR 1·7-4·9) for Project Orbis compared with 2·6 months (0·6-5·1) for other FDA approvals. Neither overall survival (p=0·11) nor progression-free survival (p=0·44) gains were significantly different between the two cohorts of approvals. Of the 14 UK Medicines and Healthcare products Regulatory Agency (MHRA) approvals reviewed by the Scottish Medicines Consortium (SMC), the agency gave positive recommendations for all 14 (100%). Of the 15 MHRA approvals reviewed by the National Institute for Health and Care Excellence (NICE), the agency gave positive recommendations for six (40%). Of the 49 approvals reviewed by the Canadian Agency for Drugs and Technologies in Health (CADTH), the agency conditionally recommended 44 (90%). The time between regulatory approval to NICE recommendation increased from a median of 137 days (IQR 102-172) in 2021 to 302 days (184-483) in 2023, SMC recommendation increased from 185 days (in 2021 for one drug only) to 368 days (IQR 313-476) in 2023, and CADTH decision increased from 97 days (in 2020 for one drug only) to 202 days (IQR 153-304) in 2023. The median monthly price of approvals reviewed through Project Orbi","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"979-988"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1016/S1470-2045(24)00388-7
Luis Paz-Ares, Bhakti Mehta, Yang Wang, David Waterhouse, Adrianus Johannes de Langen
{"title":"Sotorasib versus docetaxel: evidence supporting CodeBreaK 200.","authors":"Luis Paz-Ares, Bhakti Mehta, Yang Wang, David Waterhouse, Adrianus Johannes de Langen","doi":"10.1016/S1470-2045(24)00388-7","DOIUrl":"10.1016/S1470-2045(24)00388-7","url":null,"abstract":"","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":"25 8","pages":"e334"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-06-25DOI: 10.1016/S1470-2045(24)00211-0
Mohamad E Allaf, Se-Eun Kim, Viraj Master, David F McDermott, Lauren C Harshman, Suzanne M Cole, Charles G Drake, Sabina Signoretti, Mahmut Akgul, Nicholas Baniak, Elsa Li-Ning, Matthew B Palmer, Hamid Emamekhoo, Nabil Adra, Hristos Kaimakliotis, Yasser Ged, Phillip M Pierorazio, E Jason Abel, Mehmet A Bilen, Kenneth Ogan, Helen H Moon, Krishna A Ramaswamy, Eric A Singer, Tina M Mayer, Jay Lohrey, Vitaly Margulis, Jessie Gills, Scott E Delacroix, Mark J Waples, Andrew C James, Peng Wang, Toni Choueiri, M Dror Michaelson, Anil Kapoor, Daniel Y Heng, Brian Shuch, Bradley C Leibovich, Primo N Lara, Judith Manola, Deborah Maskens, Dena Battle, Robert Uzzo, Gennady Bratslavsky, Naomi B Haas, Michael A Carducci
<p><strong>Background: </strong>The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only.</p><p><strong>Methods: </strong>In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or T<sub>any</sub> N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual.</p><p><strong>Findings: </strong>Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group
{"title":"Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.","authors":"Mohamad E Allaf, Se-Eun Kim, Viraj Master, David F McDermott, Lauren C Harshman, Suzanne M Cole, Charles G Drake, Sabina Signoretti, Mahmut Akgul, Nicholas Baniak, Elsa Li-Ning, Matthew B Palmer, Hamid Emamekhoo, Nabil Adra, Hristos Kaimakliotis, Yasser Ged, Phillip M Pierorazio, E Jason Abel, Mehmet A Bilen, Kenneth Ogan, Helen H Moon, Krishna A Ramaswamy, Eric A Singer, Tina M Mayer, Jay Lohrey, Vitaly Margulis, Jessie Gills, Scott E Delacroix, Mark J Waples, Andrew C James, Peng Wang, Toni Choueiri, M Dror Michaelson, Anil Kapoor, Daniel Y Heng, Brian Shuch, Bradley C Leibovich, Primo N Lara, Judith Manola, Deborah Maskens, Dena Battle, Robert Uzzo, Gennady Bratslavsky, Naomi B Haas, Michael A Carducci","doi":"10.1016/S1470-2045(24)00211-0","DOIUrl":"10.1016/S1470-2045(24)00211-0","url":null,"abstract":"<p><strong>Background: </strong>The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only.</p><p><strong>Methods: </strong>In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or T<sub>any</sub> N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual.</p><p><strong>Findings: </strong>Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"1038-1052"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11323681/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141469144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-25DOI: 10.1016/S1470-2045(24)00344-9
F Anthony Greco, Chris Labaki, Elie Rassy
{"title":"Molecular diagnosis and site-specific therapy in cancer of unknown primary: an important milestone.","authors":"F Anthony Greco, Chris Labaki, Elie Rassy","doi":"10.1016/S1470-2045(24)00344-9","DOIUrl":"10.1016/S1470-2045(24)00344-9","url":null,"abstract":"","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"955-956"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-04DOI: 10.1016/S1470-2045(24)00382-6
Manjulika Das
{"title":"New report from STRONG-AYA on addressing needs of adolescents and young adults with cancer in Europe.","authors":"Manjulika Das","doi":"10.1016/S1470-2045(24)00382-6","DOIUrl":"10.1016/S1470-2045(24)00382-6","url":null,"abstract":"","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"960"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555147","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01Epub Date: 2024-07-18DOI: 10.1016/S1470-2045(24)00399-1
Manjulika Das
{"title":"Call for stricter tobacco control laws in Ghana.","authors":"Manjulika Das","doi":"10.1016/S1470-2045(24)00399-1","DOIUrl":"10.1016/S1470-2045(24)00399-1","url":null,"abstract":"","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"e338"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141734510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p><strong>Background: </strong>Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP.</p><p><strong>Methods: </strong>This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m<sup>2</sup> by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m<sup>2</sup> or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m<sup>2</sup> by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600).</p><p><strong>Findings: </strong>Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequen
背景：经验性化疗仍是原发灶不明的恶性肿瘤（CUP）患者的标准治疗方法。目前已开发出基因表达谱分析方法来确定 CUP 患者的原发组织，但其临床疗效尚未得到证实。我们的目的是评估 90 个基因表达检测法与经验性化疗相比，对 CUP 患者进行部位特异性治疗的有效性和安全性：这项随机对照试验在复旦大学上海肿瘤中心（中国上海）进行。我们招募了年龄在18-75岁之间、既往未接受过治疗的CUP患者（组织学证实为转移性腺癌、鳞癌、分化不良癌或分化差的肿瘤），以及东部合作肿瘤学组（ECOG）表现状态为0-2、无法接受局部根治性治疗的患者。患者按波科克和西蒙最小化法随机分配（1:1）接受部位特异性治疗或经验性化疗（紫杉类药物[第1天静脉注射175毫克/平方米]加铂类药物[第1天静脉注射顺铂75毫克/平方米或卡铂曲线下面积5]，或吉西他滨[第1天和第8天静脉注射1000毫克/平方米]加铂类药物[同上]）。最小化因素为 ECOG 表现状态和疾病程度。临床医生和患者均未被蒙蔽。特定部位治疗组的肿瘤来源可通过 90 基因表达检测进行预测，并据此进行治疗。主要终点是意向治疗人群的无进展生存期。试验已经结束，分析结果也已完成。该研究已在ClinicalTrials.gov（NCT03278600）上注册：2017年9月18日至2021年3月18日期间，182名患者（男性105人[58%]，女性77人[42%]）被随机分配接受部位特异性治疗（91人）或经验性化疗（91人）。在部位特异性治疗组中，最常预测的五个原发组织是胃食道（14 [15%]）、肺（12 [13%]）、卵巢（11 [12%]）、宫颈（11 [12%]）和乳腺（9 [10%]）。截至数据截止日（2023 年 4 月 30 日），部位特异性治疗组的中位随访时间为 33-3 个月（IQR 30-4-51-0），经验性化疗组的中位随访时间为 30-9 个月（27-6-35-5）。部位特异性疗法的中位无进展生存期明显长于经验性化疗（9-6 个月 [95% CI 8-4-11-9] vs 6-6 个月 [5-5-7-9]；未调整危险比 0-68 [95% CI 0-49-0-93]；P=0-017）。在开始计划治疗的 167 例患者中，82 例部位特异性治疗组患者中有 46 例（56%）和 85 例经验性化疗组患者中有 52 例（61%）出现了 3 级或更严重的治疗相关不良事件；在部位特异性治疗组和经验性化疗组中，最常见的不良事件是中性粒细胞计数减少（36 例 [44%] vs 42 例 [49%]）、白细胞计数减少（17 例 [21%] vs 26 例 [31%]）和贫血（10 例 [12%] vs 9 例 [11%]）。治疗相关的严重不良事件在特定部位治疗组中有 5 例（6%），在经验性化疗组中有 2 例（2%）。未发现与治疗相关的死亡病例：这项单中心随机试验表明，与经验性化疗相比，90基因表达检测法指导的部位特异性疗法可提高既往未接受过治疗的CUP患者的无进展生存率。通过90-基因表达检测进行位点特异性预测，可为这些患者提供更多疾病信息，扩大治疗手段：基金：上海市医院发展中心临床研究计划、上海市优秀学术带头人项目、上海市抗癌协会SOAR项目：摘要中译文见补充材料部分。
{"title":"Site-specific therapy guided by a 90-gene expression assay versus empirical chemotherapy in patients with cancer of unknown primary (Fudan CUP-001): a randomised controlled trial.","authors":"Xin Liu, Xiaowei Zhang, Shiyu Jiang, Miao Mo, Qifeng Wang, Yanli Wang, Liangping Zhou, Silong Hu, Huijuan Yang, Yifeng Hou, Yong Chen, Xueguan Lu, Yu Wang, Xiaoyan Zhou, Wentao Li, Cai Chang, Xiujiang Yang, Ke Chen, Jun Cao, Qinghua Xu, Yifeng Sun, Jianfeng Luo, Zhiguo Luo, Xichun Hu","doi":"10.1016/S1470-2045(24)00313-9","DOIUrl":"10.1016/S1470-2045(24)00313-9","url":null,"abstract":"<p><strong>Background: </strong>Empirical chemotherapy remains the standard of care in patients with unfavourable cancer of unknown primary (CUP). Gene-expression profiling assays have been developed to identify the tissue of origin in patients with CUP; however, their clinical benefit has not yet been demonstrated. We aimed to evaluate the efficacy and safety of site-specific therapy directed by a 90-gene expression assay compared with empirical chemotherapy in patients with CUP.</p><p><strong>Methods: </strong>This randomised controlled trial was conducted at Fudan University Shanghai Cancer Center (Shanghai, China). We enrolled patients aged 18-75 years, with previously untreated CUP (histologically confirmed metastatic adenocarcinoma, squamous cell carcinoma, poorly differentiated carcinoma, or poorly differentiated neoplasms) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, who were not amenable to local radical treatment. Patients were randomly assigned (1:1) by the Pocock and Simon minimisation method to receive either site-specific therapy or empirical chemotherapy (taxane [175 mg/m<sup>2</sup> by intravenous infusion on day 1] plus platinum [cisplatin 75 mg/m<sup>2</sup> or carboplatin area under the curve 5 by intravenous infusion on day 1], or gemcitabine [1000 mg/m<sup>2</sup> by intravenous infusion on days 1 and 8] plus platinum [same as above]). The minimisation factors were ECOG performance status and the extent of the disease. Clinicians and patients were not masked to interventions. The tumour origin in the site-specific therapy group was predicted by the 90-gene expression assay and treatments were administered accordingly. The primary endpoint was progression-free survival in the intention-to-treat population. The trial has been completed and the analysis is final. This study is registered with ClinicalTrials.gov (NCT03278600).</p><p><strong>Findings: </strong>Between Sept 18, 2017, and March 18, 2021, 182 patients (105 [58%] male, 77 [42%] female) were randomly assigned to receive site-specific therapy (n=91) or empirical chemotherapy (n=91). The five most commonly predicted tissues of origin in the site-specific therapy group were gastro-oesophagus (14 [15%]), lung (12 [13%]), ovary (11 [12%]), cervix (11 [12%]), and breast (nine [10%]). At the data cutoff date (April 30, 2023), median follow-up was 33·3 months (IQR 30·4-51·0) for the site-specific therapy group and 30·9 months (27·6-35·5) for the empirical chemotherapy group. Median progression-free survival was significantly longer with site-specific therapy than with empirical chemotherapy (9·6 months [95% CI 8·4-11·9] vs 6·6 months [5·5-7·9]; unadjusted hazard ratio 0·68 [95% CI 0·49-0·93]; p=0·017). Among the 167 patients who started planned treatment, 46 (56%) of 82 patients in the site-specific therapy group and 52 (61%) of 85 patients in the empirical chemotherapy group had grade 3 or worse treatment-related adverse events; the most frequen","PeriodicalId":17942,"journal":{"name":"Lancet Oncology","volume":" ","pages":"1092-1102"},"PeriodicalIF":41.6,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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