BACKGROUNDWe developed a high-intensity parenting intervention (HIP) to help parents support the academic success of childhood cancer survivors (CCSs), who often face post-treatment challenges affecting their school-related functioning. This randomized controlled trial (NCT03178617) evaluated HIP's efficacy compared to lower-intensity, single-session, treatment-as-usual services (LIP) in Latino families. Primary outcomes were parenting efficacy and CCSs' school functioning; secondary outcomes included parenting knowledge and measures of CCSs' academic performance, attention, and functioning outside of school.METHODS106 Latino survivors of childhood leukemia and lymphoblastic lymphoma (aged 6-12 years) and their parents were randomly assigned to HIP (n = 54) or LIP (n = 52). Linear mixed-effects models evaluated group differences across baseline, 6-month (T2), and 12-month (T3) assessments.RESULTSParenting efficacy and knowledge improved significantly in the HIP arm, resulting in higher scores vs LIP at T2 and T3 (P ≤ .01). No significant between-group differences were found in child school functioning; however, HIP children showed significantly better social functioning and performance on one measure of attention (CPT-3 commissions) at T3 (P < .05). While HIP adherence challenges were observed, with only 33 (61%) completing the intervention, exploratory analyses suggest that benefits were most evident among those who fully engaged. Satisfaction and perceived benefit were greater for HIP vs LIP at both time points (P < .05).CONCLUSIONSOur results suggest the potential value of parent-directed behavioral interventions like HIP for CCSs and their families. Further studies are needed to address participation barriers and enhance engagement to maximize and sustain benefits.
背景我们开发了一种高强度父母教育干预（HIP），以帮助父母支持儿童癌症幸存者（CCSs）在学业上取得成功。这项随机对照试验（NCT03178617）评估了 HIP 在拉丁裔家庭中与强度较低、单次疗程、照常治疗服务（LIP）相比的疗效。主要结果是养育效果和儿童白血病患者的学校功能；次要结果包括养育知识以及儿童白血病患者的学业成绩、注意力和校外功能。线性混合效应模型评估了各组在基线、6 个月（T2）和 12 个月（T3）评估中的差异。结果HIP 组的育儿效果和知识显著提高，因此在 T2 和 T3 分数高于 LIP 组（P ≤ .01）。在儿童的学校功能方面，没有发现明显的组间差异；但是，HIP 儿童在 T3 阶段的社会功能和一项注意力测量（CPT-3 委员会）上的表现明显更好（P < .05）。虽然在坚持 HIP 的过程中遇到了挑战，只有 33 人（61%）完成了干预，但探索性分析表明，完全参与干预的儿童获益最明显。在两个时间点上，HIP 与 LIP 相比，满意度和感知到的益处更高（P < .05）。还需要进一步的研究来解决参与障碍和提高参与度，以最大限度地提高和保持收益。
{"title":"Reducing Learning and Psychosocial Disparities in Latino Children with Cancer: A Randomized Intervention Trial.","authors":"Sunita K Patel,Seong-Hyeon Kim,Kathleen Ingman,Van Huynh,Heather Huszti,Kimberly Kayser,Grace Mucci,Melissa Balderrama,Laura Bava,Abigail Onderwyzer Gold,Alicia Wuth,Nicole Delgado,Alysia Bosworth,Emily Nishimura,Harneet Hara,Anna Pawlowska,Lisa Mueller,F Lennie Wong","doi":"10.1093/jnci/djae256","DOIUrl":"https://doi.org/10.1093/jnci/djae256","url":null,"abstract":"BACKGROUNDWe developed a high-intensity parenting intervention (HIP) to help parents support the academic success of childhood cancer survivors (CCSs), who often face post-treatment challenges affecting their school-related functioning. This randomized controlled trial (NCT03178617) evaluated HIP's efficacy compared to lower-intensity, single-session, treatment-as-usual services (LIP) in Latino families. Primary outcomes were parenting efficacy and CCSs' school functioning; secondary outcomes included parenting knowledge and measures of CCSs' academic performance, attention, and functioning outside of school.METHODS106 Latino survivors of childhood leukemia and lymphoblastic lymphoma (aged 6-12 years) and their parents were randomly assigned to HIP (n = 54) or LIP (n = 52). Linear mixed-effects models evaluated group differences across baseline, 6-month (T2), and 12-month (T3) assessments.RESULTSParenting efficacy and knowledge improved significantly in the HIP arm, resulting in higher scores vs LIP at T2 and T3 (P ≤ .01). No significant between-group differences were found in child school functioning; however, HIP children showed significantly better social functioning and performance on one measure of attention (CPT-3 commissions) at T3 (P < .05). While HIP adherence challenges were observed, with only 33 (61%) completing the intervention, exploratory analyses suggest that benefits were most evident among those who fully engaged. Satisfaction and perceived benefit were greater for HIP vs LIP at both time points (P < .05).CONCLUSIONSOur results suggest the potential value of parent-directed behavioral interventions like HIP for CCSs and their families. Further studies are needed to address participation barriers and enhance engagement to maximize and sustain benefits.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"25 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142443730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDThe NHS-Galleri trial has demonstrated feasibility for multi-cancer screening trial design where all participants provide a 'sample' for screening, but only samples from the intervention arm are tested and acted upon during the trial. We assess efficiency of analysis methods when the control arm may be retrospectively tested at time of analysis.METHODSAnalyses considered are: (1, traditional) by randomised allocation with all events included; (2, 'intended-effect') nested in those who tested positive in both arms and all events therein; and (3, targeted) by randomised allocation but with endpoint 'test-positive event'. They are compared using approximate statistical methods and scenario analysis.RESULTSProvided the number who die from cancer after a test-positive sample is a small fraction of the total number who die from cancer, intended-effect and targeted analyses require a much smaller sample size to evaluate cancer-specific mortality than the traditional approach. Intended-effect analysis has a smaller sample size requirement than targeted analysis. This gain is only substantial when the risk of cancer death in test positives is high.CONCLUSIONIntended-effect or targeted analysis will substantially reduce the sample size needed to evaluate cancer-specific mortality in blood-based screening trials. Targeted analysis requires many fewer retrospective tests and avoids potential effects of needing to inform those whose stored samples test positive. Trialists should consider the trade-off of costs between sample size and retrospective testing requirements when choosing the analysis.
{"title":"More Efficient Smaller Multi-Cancer Screening Trials.","authors":"Peter Sasieni,Adam R Brentnall","doi":"10.1093/jnci/djae251","DOIUrl":"https://doi.org/10.1093/jnci/djae251","url":null,"abstract":"BACKGROUNDThe NHS-Galleri trial has demonstrated feasibility for multi-cancer screening trial design where all participants provide a 'sample' for screening, but only samples from the intervention arm are tested and acted upon during the trial. We assess efficiency of analysis methods when the control arm may be retrospectively tested at time of analysis.METHODSAnalyses considered are: (1, traditional) by randomised allocation with all events included; (2, 'intended-effect') nested in those who tested positive in both arms and all events therein; and (3, targeted) by randomised allocation but with endpoint 'test-positive event'. They are compared using approximate statistical methods and scenario analysis.RESULTSProvided the number who die from cancer after a test-positive sample is a small fraction of the total number who die from cancer, intended-effect and targeted analyses require a much smaller sample size to evaluate cancer-specific mortality than the traditional approach. Intended-effect analysis has a smaller sample size requirement than targeted analysis. This gain is only substantial when the risk of cancer death in test positives is high.CONCLUSIONIntended-effect or targeted analysis will substantially reduce the sample size needed to evaluate cancer-specific mortality in blood-based screening trials. Targeted analysis requires many fewer retrospective tests and avoids potential effects of needing to inform those whose stored samples test positive. Trialists should consider the trade-off of costs between sample size and retrospective testing requirements when choosing the analysis.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"481 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Judith E Carroll, Catherine M Crespi, Steve Cole, Patricia A Ganz, Laura Petersen, Julienne E Bower
Background The purpose of this study was to examine the impact of breast cancer therapy on biological aging as measured by expression of genes for cellular senescence (p16INK4a, SenMayo), DNA damage response, and proinflammatory senescence-associated secretory phenotype. Methods This longitudinal, observational study evaluated women diagnosed with breast cancer (stage 0-III) prior to radiation therapy (RT) and/or chemotherapy (CT) and at repeated visits out to 2 years. Peripheral blood mononuclear cell gene expression was assessed using RNA sequencing on quality-verified RNA. Longitudinal data were analyzed using mixed linear models and a zero-inflated 2-part model. Results Women (mean age = 55.5 years) receiving CT with or without RT (n = 73) had higher odds (odds ratio = 2.97, 95% confidence interval = 1.52 to 5.8) of having detectable p16INK4a following treatment compared with RT (n = 76) or surgery alone (n = 37). The proportion of women expressing 16INK4a over the follow-up period increased in all treatment groups (P < .001), with no interaction by treatment. All groups also increased over time in DNA damage response (P < .001), SenMayo (P < .001), and senescence-associated secretory phenotype (P < .001). Groups differed in the pattern of increase over time with statistically significant quadratic time by group differences for CT with or without RT compared with RT alone for DNA damage response (P = .05), SenMayo (P = .006), and the senescence-associated secretory phenotype (P = .02). Conclusions Results revealed activation of genes associated with biological aging in women with breast cancer from diagnosis through early survivorship, including DNA damage response, cell senescence, and the inflammatory secretome. Increases were evident across cancer treatments, although women receiving CT showed sustained increases, whereas RT exhibited slowing at later time points. Overall, findings suggest that women treated for breast cancer are aging within their immune cells.
{"title":"Transcriptomic markers of biological aging in breast cancer survivors: a longitudinal study","authors":"Judith E Carroll, Catherine M Crespi, Steve Cole, Patricia A Ganz, Laura Petersen, Julienne E Bower","doi":"10.1093/jnci/djae201","DOIUrl":"https://doi.org/10.1093/jnci/djae201","url":null,"abstract":"Background The purpose of this study was to examine the impact of breast cancer therapy on biological aging as measured by expression of genes for cellular senescence (p16INK4a, SenMayo), DNA damage response, and proinflammatory senescence-associated secretory phenotype. Methods This longitudinal, observational study evaluated women diagnosed with breast cancer (stage 0-III) prior to radiation therapy (RT) and/or chemotherapy (CT) and at repeated visits out to 2 years. Peripheral blood mononuclear cell gene expression was assessed using RNA sequencing on quality-verified RNA. Longitudinal data were analyzed using mixed linear models and a zero-inflated 2-part model. Results Women (mean age = 55.5 years) receiving CT with or without RT (n = 73) had higher odds (odds ratio = 2.97, 95% confidence interval = 1.52 to 5.8) of having detectable p16INK4a following treatment compared with RT (n = 76) or surgery alone (n = 37). The proportion of women expressing 16INK4a over the follow-up period increased in all treatment groups (P &lt; .001), with no interaction by treatment. All groups also increased over time in DNA damage response (P &lt; .001), SenMayo (P &lt; .001), and senescence-associated secretory phenotype (P &lt; .001). Groups differed in the pattern of increase over time with statistically significant quadratic time by group differences for CT with or without RT compared with RT alone for DNA damage response (P = .05), SenMayo (P = .006), and the senescence-associated secretory phenotype (P = .02). Conclusions Results revealed activation of genes associated with biological aging in women with breast cancer from diagnosis through early survivorship, including DNA damage response, cell senescence, and the inflammatory secretome. Increases were evident across cancer treatments, although women receiving CT showed sustained increases, whereas RT exhibited slowing at later time points. Overall, findings suggest that women treated for breast cancer are aging within their immune cells.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"29 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sheila A Prindiville, Sumithra J Mandrekar, Neal J Meropol, Andrea Denicoff, Oren Grad, Judith A Hautala, James H Doroshow
The increase in the complexity of cancer clinical trials over the past several decades has led to a dramatic growth in trial cost and operational burden. The extent and frequency of data collection, particularly in late phase trials which enroll many participants, have been major contributors to this problem. The Clinical Trials and Translational Research Advisory Committee of the National Cancer Institute (NCI) recently assessed the impact of these stressors on the NCI National Clinical Trials Network (NCTN) and recommended that data collection in late phase NCTN trials be limited to data elements essential to address the primary and secondary objectives of the trial. The purpose of this commentary is to describe the rationale for this recommendation, progress towards implementation, and the development of new streamlined standard practices for data collection for late phase NCTN trials effective January 1, 2025.
{"title":"Streamlining the Conduct of Cancer Clinical Trials: New Standard Data Collection Practices for National Cancer Institute Late Phase Clinical Studies","authors":"Sheila A Prindiville, Sumithra J Mandrekar, Neal J Meropol, Andrea Denicoff, Oren Grad, Judith A Hautala, James H Doroshow","doi":"10.1093/jnci/djae239","DOIUrl":"https://doi.org/10.1093/jnci/djae239","url":null,"abstract":"The increase in the complexity of cancer clinical trials over the past several decades has led to a dramatic growth in trial cost and operational burden. The extent and frequency of data collection, particularly in late phase trials which enroll many participants, have been major contributors to this problem. The Clinical Trials and Translational Research Advisory Committee of the National Cancer Institute (NCI) recently assessed the impact of these stressors on the NCI National Clinical Trials Network (NCTN) and recommended that data collection in late phase NCTN trials be limited to data elements essential to address the primary and secondary objectives of the trial. The purpose of this commentary is to describe the rationale for this recommendation, progress towards implementation, and the development of new streamlined standard practices for data collection for late phase NCTN trials effective January 1, 2025.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yeonju Kim, Terri S Armstrong, Mark R Gilbert, Orieta Celiku
We conducted an extensive assessment and quantification of the reach of the oncology clinical trial supporting infrastructure in the United States (US). While our primary focus was on identifying avenues to expand the reach of neuro-oncology clinical trials, we considered infrastructure layers with important implications for broader cancer research and care. Specifically, we examined the geographic, population, and socioeconomic reach of national collaboratives (including over 1,500 institutions), over 600 academic oncology and neurosurgery training programs, and networks of over 25,000 individual neuro-oncology, neurosurgery, and general oncology (including hematology/medical/gynecological oncology, surgical oncology, and radiation oncology) providers. Our study found that over 57% of the US population lacks direct access to trial-supporting infrastructure. More than 71% of the locations with infrastructure are urban, and over 72% are in socioeconomically-advantaged areas. Our findings reveal critical disparities in oncology care access and suggest actionable strategies to optimize and expand the existing infrastructure’s reach.
{"title":"Disparities in the availability and access to Neuro-Oncology Trial-Supporting infrastructure in the United States","authors":"Yeonju Kim, Terri S Armstrong, Mark R Gilbert, Orieta Celiku","doi":"10.1093/jnci/djae240","DOIUrl":"https://doi.org/10.1093/jnci/djae240","url":null,"abstract":"We conducted an extensive assessment and quantification of the reach of the oncology clinical trial supporting infrastructure in the United States (US). While our primary focus was on identifying avenues to expand the reach of neuro-oncology clinical trials, we considered infrastructure layers with important implications for broader cancer research and care. Specifically, we examined the geographic, population, and socioeconomic reach of national collaboratives (including over 1,500 institutions), over 600 academic oncology and neurosurgery training programs, and networks of over 25,000 individual neuro-oncology, neurosurgery, and general oncology (including hematology/medical/gynecological oncology, surgical oncology, and radiation oncology) providers. Our study found that over 57% of the US population lacks direct access to trial-supporting infrastructure. More than 71% of the locations with infrastructure are urban, and over 72% are in socioeconomically-advantaged areas. Our findings reveal critical disparities in oncology care access and suggest actionable strategies to optimize and expand the existing infrastructure’s reach.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142325470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Josh McGovern,Ross D Dolan,Richard J E Skipworth,Barry J A Laird,Donald C McMillan
{"title":"RE: Exercise and Nutrition to Improve Cancer Treatment-Related outcomes (ENICTO).","authors":"Josh McGovern,Ross D Dolan,Richard J E Skipworth,Barry J A Laird,Donald C McMillan","doi":"10.1093/jnci/djae230","DOIUrl":"https://doi.org/10.1093/jnci/djae230","url":null,"abstract":"","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"217 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Darren Cowzer, Kevin Soares, Henry Walch, Mithat Gönen, Taryn M Boucher, Richard K G Do, James J Harding, Anna M Varghese, Diane Reidy-Lagunes, Leonard Saltz, Louise C Connell, Ghassan K Abou-Alfa, Alice C Wei, Nikolaus Schultz, T Peter Kingham, Michael I D’Angelica, Jeffrey A Drebin, Vinod Balachandran, Francisco Sanchez-Vega, Nancy E Kemeny, William R Jarnagin, Andrea Cercek
Introduction Hepatic artery infusion (HAI) of chemotherapy has demonstrated disease control and suggested improvement in overall survival (OS) in intrahepatic cholangiocarcinoma (IHC). We report herein the long-term results and role of molecular alterations of a phase II clinical trial of HAI chemotherapy plus systemic chemotherapy, with a retrospective cohort of patients treated with HAI at Memorial Sloan Kettering Cancer Center. Methods This secondary analysis of a single-institution, phase 2 trial and retrospective cohort of unresectable IHC treated with HAI floxuridine (FUDR) plus systemic gemcitabine and oxaliplatin. The primary aim was to assess long-term oncologic outcomes. A subset underwent tissue-based genomic sequencing, and molecular alterations were correlated with progression-free survival (PFS) and OS. Results Thirty-eight patients were treated on trial with a median follow up of 76.9 months. Median PFS was 11.8 months (95% CI11-15.1). The median OS was 26.8 months (95% CI20.9-40.6). The 1-, 2- and 5-year OS rate was 89.5%, 55%, and 21% respectively. Nine (24%) received HAI with mitomycin C post FUDR progression with an objective response rate of 44% and a median PFS of 3.93 (2.33-NR) months. One-hundred and seventy patients not treated on the clinical trial were included in a retrospective analysis. Median PFS and OS was 7.93 (95%CI: 7.27-10.07) and 22.5 (95%CI : 19.5-28.3) months, respectively. Alterations in the TP53 and cell-cycle pathway had a worse PFS to HAI based therapy compared to wildtype disease. Conclusion In locally advanced IHC, HAI with FUDR in combination with systemic therapy can offer long term durable disease control. Molecular alterations may predict for response.
导言：肝动脉灌注化疗（HAI）已证明可控制疾病，并可改善肝内胆管癌（IHC）的总生存期（OS）。我们在此报告 HAI 化疗加全身化疗 II 期临床试验的长期结果和分子改变的作用，以及纪念斯隆-凯特琳癌症中心接受 HAI 治疗患者的回顾性队列。方法 本研究对一项单一机构的二期临床试验和接受 HAI 氟尿苷（FUDR）加全身吉西他滨和奥沙利铂治疗的不可切除 IHC 的回顾性队列进行了二次分析。主要目的是评估长期肿瘤学结果。一部分患者接受了组织基因组测序，分子改变与无进展生存期（PFS）和OS相关。结果 38名患者接受了试验治疗，中位随访时间为76.9个月。中位生存期为 11.8 个月（95% CI11-15.1）。中位 OS 为 26.8 个月（95% CI20.9-40.6）。1年、2年和5年的OS率分别为89.5%、55%和21%。9例（24%）患者在FUDR进展后接受了HAI联合丝裂霉素C治疗，客观反应率为44%，中位PFS为3.93个月（2.33-NR）。一项回顾性分析纳入了 170 名未接受临床试验治疗的患者。中位 PFS 和 OS 分别为 7.93 个月（95%CI：7.27-10.07）和 22.5 个月（95%CI：19.5-28.3）。与野生型疾病相比，TP53和细胞周期途径发生改变的患者接受以HAI为基础的治疗的PFS较差。结论 在局部晚期IHC患者中，HAI与FUDR联合全身治疗可提供长期持久的疾病控制。分子改变可预测反应。
{"title":"Long term outcomes in patients with advanced intrahepatic cholangiocarcinoma treated with hepatic arterial infusion chemotherapy","authors":"Darren Cowzer, Kevin Soares, Henry Walch, Mithat Gönen, Taryn M Boucher, Richard K G Do, James J Harding, Anna M Varghese, Diane Reidy-Lagunes, Leonard Saltz, Louise C Connell, Ghassan K Abou-Alfa, Alice C Wei, Nikolaus Schultz, T Peter Kingham, Michael I D’Angelica, Jeffrey A Drebin, Vinod Balachandran, Francisco Sanchez-Vega, Nancy E Kemeny, William R Jarnagin, Andrea Cercek","doi":"10.1093/jnci/djae202","DOIUrl":"https://doi.org/10.1093/jnci/djae202","url":null,"abstract":"Introduction Hepatic artery infusion (HAI) of chemotherapy has demonstrated disease control and suggested improvement in overall survival (OS) in intrahepatic cholangiocarcinoma (IHC). We report herein the long-term results and role of molecular alterations of a phase II clinical trial of HAI chemotherapy plus systemic chemotherapy, with a retrospective cohort of patients treated with HAI at Memorial Sloan Kettering Cancer Center. Methods This secondary analysis of a single-institution, phase 2 trial and retrospective cohort of unresectable IHC treated with HAI floxuridine (FUDR) plus systemic gemcitabine and oxaliplatin. The primary aim was to assess long-term oncologic outcomes. A subset underwent tissue-based genomic sequencing, and molecular alterations were correlated with progression-free survival (PFS) and OS. Results Thirty-eight patients were treated on trial with a median follow up of 76.9 months. Median PFS was 11.8 months (95% CI11-15.1). The median OS was 26.8 months (95% CI20.9-40.6). The 1-, 2- and 5-year OS rate was 89.5%, 55%, and 21% respectively. Nine (24%) received HAI with mitomycin C post FUDR progression with an objective response rate of 44% and a median PFS of 3.93 (2.33-NR) months. One-hundred and seventy patients not treated on the clinical trial were included in a retrospective analysis. Median PFS and OS was 7.93 (95%CI: 7.27-10.07) and 22.5 (95%CI : 19.5-28.3) months, respectively. Alterations in the TP53 and cell-cycle pathway had a worse PFS to HAI based therapy compared to wildtype disease. Conclusion In locally advanced IHC, HAI with FUDR in combination with systemic therapy can offer long term durable disease control. Molecular alterations may predict for response.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328687","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BACKGROUNDSurgery with both neoadjuvant and adjuvant chemotherapy represents the standard of care for extremity osteosarcoma despite a lack of high-quality evidence for its use, and trial evidence that suggests that up-front surgery may result in better outcomes. This study estimated the difference in overall survival for the standard of care ("Neoadjuvant First") vs upfront surgery first followed by adjuvant chemotherapy ("Surgery First").PATIENTS AND METHODSUsing Surveillance, Epidemiology, and End Results data, we identified patients age 5-29, diagnosed with a primary cancer of upper or lower extremity osteosarcoma between 2007 and 2019 who received surgery and chemotherapy. Our primary endpoint was the 5-year survival difference between the Surgery First and Neoadjuvant First groups.RESULTSAdjusted 5-year survival was 74% for Surgery First patients and 67% for Neoadjuvant First patients, with a survival difference of 6.9% (95% CI -4.2% - 16.1%). In sensitivity analyses of 5-year survival, the results were consistent, showing a 6.8% to 13.7% higher 5-year survival in Surgery First patients. Significant mortality risk factors included older age, larger tumor size, the type of resection (salvage vs amputation), and stage 3-4 disease (vs stage 1-2 disease).CONCLUSIONThe evidence supporting neoadjuvant therapy in osteosarcoma care is weak. However, there is evidence that pausing chemotherapy in the peri-surgical period might affect outcomes. Consequently, this study, and its consistency with the results from the only randomized trial, suggests that there is reason to revisit a prospective, randomized trial of osteosarcoma treatment regarding the timing of surgery and chemotherapy.
{"title":"Effect of Chemotherapy and Surgery Timing on Mortality in Upper and Lower Extremity Osteosarcoma.","authors":"Mark D Danese,John S Groundland","doi":"10.1093/jnci/djae229","DOIUrl":"https://doi.org/10.1093/jnci/djae229","url":null,"abstract":"BACKGROUNDSurgery with both neoadjuvant and adjuvant chemotherapy represents the standard of care for extremity osteosarcoma despite a lack of high-quality evidence for its use, and trial evidence that suggests that up-front surgery may result in better outcomes. This study estimated the difference in overall survival for the standard of care (\"Neoadjuvant First\") vs upfront surgery first followed by adjuvant chemotherapy (\"Surgery First\").PATIENTS AND METHODSUsing Surveillance, Epidemiology, and End Results data, we identified patients age 5-29, diagnosed with a primary cancer of upper or lower extremity osteosarcoma between 2007 and 2019 who received surgery and chemotherapy. Our primary endpoint was the 5-year survival difference between the Surgery First and Neoadjuvant First groups.RESULTSAdjusted 5-year survival was 74% for Surgery First patients and 67% for Neoadjuvant First patients, with a survival difference of 6.9% (95% CI -4.2% - 16.1%). In sensitivity analyses of 5-year survival, the results were consistent, showing a 6.8% to 13.7% higher 5-year survival in Surgery First patients. Significant mortality risk factors included older age, larger tumor size, the type of resection (salvage vs amputation), and stage 3-4 disease (vs stage 1-2 disease).CONCLUSIONThe evidence supporting neoadjuvant therapy in osteosarcoma care is weak. However, there is evidence that pausing chemotherapy in the peri-surgical period might affect outcomes. Consequently, this study, and its consistency with the results from the only randomized trial, suggests that there is reason to revisit a prospective, randomized trial of osteosarcoma treatment regarding the timing of surgery and chemotherapy.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273389","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Although use of comprehensive genomic profiling (CGP) was approved by a novel CMS/FDA parallel review process, the quality of the supporting evidence is unclear. We evaluated the rigor of the peer-reviewed literature cited in the National Coverage Determination Memorandum for the FoundationOne CDx (F1CDx). Methods We identified studies cited in the memorandum. Two independent researchers evaluated each study and applied a modified version of the Fryback and Thornbury hierarchy[1], an established framework for evaluating the efficacy of diagnostic tests. Studies focused on clinical outcomes were then categorized by study design, guided by recommendations from the Center for Medical Technology Policy. Results The sample included 113 scientific studies. The majority (n = 60, 53.1%) used CGP outside the course of clinical care, and there was significant heterogeneity in the cancer types assessed and sequencing depth. We found 8 (7.1%) studies that assessed whether clinical care had changed due to CGP testing, and 38 (33.6%) assessed clinical outcomes. After excluding studies that tested for five or fewer genomic alterations, 25 remained in the clinical outcomes sample: Of these, only one included a comparator group that did not receive CGP testing. Only four studies used F1CDx as the primary genomic test, none of which compared the outcomes of patients who did vs did not receive the F1CDx test. Conclusions The findings indicate gaps in the supporting evidence for broad CGP use in patients with solid tumors. More rigorous studies that assess clinical utility would better inform the approval process for novel diagnostic tests.
{"title":"Strength of Evidence Underlying the CMS-FDA Parallel Review of Comprehensive Genomic Profiling Tests in the Cancer Setting","authors":"Sydnie Stackland, Dominic Schnabel, Michaela Dinan, Carolyn J Presley, Cary P Gross","doi":"10.1093/jnci/djae196","DOIUrl":"https://doi.org/10.1093/jnci/djae196","url":null,"abstract":"Background Although use of comprehensive genomic profiling (CGP) was approved by a novel CMS/FDA parallel review process, the quality of the supporting evidence is unclear. We evaluated the rigor of the peer-reviewed literature cited in the National Coverage Determination Memorandum for the FoundationOne CDx (F1CDx). Methods We identified studies cited in the memorandum. Two independent researchers evaluated each study and applied a modified version of the Fryback and Thornbury hierarchy[1], an established framework for evaluating the efficacy of diagnostic tests. Studies focused on clinical outcomes were then categorized by study design, guided by recommendations from the Center for Medical Technology Policy. Results The sample included 113 scientific studies. The majority (n = 60, 53.1%) used CGP outside the course of clinical care, and there was significant heterogeneity in the cancer types assessed and sequencing depth. We found 8 (7.1%) studies that assessed whether clinical care had changed due to CGP testing, and 38 (33.6%) assessed clinical outcomes. After excluding studies that tested for five or fewer genomic alterations, 25 remained in the clinical outcomes sample: Of these, only one included a comparator group that did not receive CGP testing. Only four studies used F1CDx as the primary genomic test, none of which compared the outcomes of patients who did vs did not receive the F1CDx test. Conclusions The findings indicate gaps in the supporting evidence for broad CGP use in patients with solid tumors. More rigorous studies that assess clinical utility would better inform the approval process for novel diagnostic tests.","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236872","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amit G Singal, Darine Daher, Manasa Narasimman, Sruthi Yekkaluri MHI, Yan Liu, Vanessa Cerda, Chaitra Banala, Aisha Khan, MinJae Lee, Karim Seif El Dahan, Caitlin C Murphy, Jennifer R Kramer, Ruben Hernaez
Background The value of hepatocellular carcinoma (HCC) screening is defined by the balance of benefits from early tumor detection vs harms due to false positive results. We evaluated the value of a mailed outreach strategy for HCC screening in patients with cirrhosis. Methods We conducted a multi-center pragmatic randomized clinical trial comparing mailed outreach for HCC screening (n = 1436) and usual care with visit-based screening (n = 1436) among patients with cirrhosis at three health systems from March 2018 to September 2021. Outcomes of interest were early-stage HCC detection (ie, screening benefit) and diagnostic evaluation for false positive or indeterminate results (ie, screening harm). Screening harm was categorized as mild, moderate, and severe based on number and type of diagnostic exams. All patients were included in intention-to-screen analyses. Results Of 125 patients diagnosed with HCC (67 outreach and 58 usual care), 71.2% were found at an early stage per the Milan Criteria. Early tumor detection did not significantly differ between the outreach and usual care arms (64.2% vs 79.3%, p = .06). The proportion of patients with physical harms also did not differ between the outreach and usual care arms (10.8% vs 10.7%, p = .95) with 5.9% in both arms having mild harms, 4.0% and 3.8% respectively with moderate harms, and 0.9% and 1.0% respectively with severe harms. Conclusion Most patients enrolled in HCC screening were detected at an early stage, and a minority experienced physical harms. A mailed outreach strategy did not significantly increase early HCC detection or physical harms compared to usual care. Clinical Trials number NCT02582918 and NCT03756051
{"title":"Benefits and Harms of Hepatocellular Carcinoma Screening Outreach in Patients with Cirrhosis: A Multi-Center Randomized Clinical Trial","authors":"Amit G Singal, Darine Daher, Manasa Narasimman, Sruthi Yekkaluri MHI, Yan Liu, Vanessa Cerda, Chaitra Banala, Aisha Khan, MinJae Lee, Karim Seif El Dahan, Caitlin C Murphy, Jennifer R Kramer, Ruben Hernaez","doi":"10.1093/jnci/djae228","DOIUrl":"https://doi.org/10.1093/jnci/djae228","url":null,"abstract":"Background The value of hepatocellular carcinoma (HCC) screening is defined by the balance of benefits from early tumor detection vs harms due to false positive results. We evaluated the value of a mailed outreach strategy for HCC screening in patients with cirrhosis. Methods We conducted a multi-center pragmatic randomized clinical trial comparing mailed outreach for HCC screening (n = 1436) and usual care with visit-based screening (n = 1436) among patients with cirrhosis at three health systems from March 2018 to September 2021. Outcomes of interest were early-stage HCC detection (ie, screening benefit) and diagnostic evaluation for false positive or indeterminate results (ie, screening harm). Screening harm was categorized as mild, moderate, and severe based on number and type of diagnostic exams. All patients were included in intention-to-screen analyses. Results Of 125 patients diagnosed with HCC (67 outreach and 58 usual care), 71.2% were found at an early stage per the Milan Criteria. Early tumor detection did not significantly differ between the outreach and usual care arms (64.2% vs 79.3%, p = .06). The proportion of patients with physical harms also did not differ between the outreach and usual care arms (10.8% vs 10.7%, p = .95) with 5.9% in both arms having mild harms, 4.0% and 3.8% respectively with moderate harms, and 0.9% and 1.0% respectively with severe harms. Conclusion Most patients enrolled in HCC screening were detected at an early stage, and a minority experienced physical harms. A mailed outreach strategy did not significantly increase early HCC detection or physical harms compared to usual care. Clinical Trials number NCT02582918 and NCT03756051","PeriodicalId":501635,"journal":{"name":"Journal of the National Cancer Institute","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236859","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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