{"title":"Systemic Treatment for Biochemical Recurrence of Localized Prostate Cancer: Do Not EMBARK on When, If the Answer Is How.","authors":"Bertrand Tombal, Gianluca Giannarini","doi":"10.1200/JCO.24.01134","DOIUrl":"https://doi.org/10.1200/JCO.24.01134","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143083","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}
Komal L Jhaveri, Melissa K Accordino, Philippe L Bedard, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Mafalda Oliveira, Peter Schmid, Cristina Saura, Nicholas C Turner, Andrea Varga, Sravanthi Cheeti, Stephanie Hilz, Katherine E Hutchinson, Yanling Jin, Stephanie Royer-Joo, Ubong Peters, Noopur Shankar, Jennifer L Schutzman, Dejan Juric
Purpose: To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with PIK3CA-mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172).
Methods: Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability.
Results: Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response.
Conclusion: Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.
研究目的目的:在PIK3CA突变、激素受体阳性/内分泌治疗(ET)患者的I/Ib期研究中,研究inavolisib(一种强效、选择性的p110α小分子抑制剂,可促进突变p110α的降解)的安全性、耐受性、药代动力学(PK)和初步抗肿瘤活性、在一项针对PIK3CA突变、激素受体阳性/人表皮生长因子受体2阴性的局部晚期/转移性乳腺癌患者的I/Ib期研究中,与palbociclib和内分泌治疗(ET)联合使用(ClinicalTrials.gov标识符:NCT03006172):年龄≥18岁的女性接受依那西普、帕博西利和来曲唑(依那西普+帕博+来曲臂)或氟维司群(依那西普+帕博+氟维司群臂)治疗,直至出现不可接受的毒性或疾病进展。主要目的是评估安全性或耐受性:共纳入53例患者,其中33例在伊纳沃+帕博+来曲治疗组,20例在伊纳沃+帕博+氟维司群治疗组。依那韦利西治疗的中位持续时间分别为15.7个月和20.8个月(截止日期:2023年3月27日)。所有患者均发生了治疗相关不良事件(TRAEs);最常见的不良事件是口腔炎、高血糖和腹泻;≥3级的任何TRAE发生率分别为87.9%和85.0%;因TRAEs而中断任何治疗的患者在伊那沃+帕博+乐妥和伊那沃+帕博+Fulv两组分别占6.1%和10.0%。在用药过程中,未观察到研究治疗药物之间的 PK 药物相互作用 (DDI)。可测量疾病患者的确诊客观反应率分别为52.0%和40.0%,Inavo + Palbo + Letro治疗组和Inavo + Palbo + Fulv治疗组的中位无进展生存期分别为23.3个月和35.0个月。现有的治疗前和治疗中肿瘤组织和循环肿瘤DNA配对分析证实了研究治疗对反应的药效学和病理生理学生物标志物的影响:Inavolisib plus palbociclib and ET表现出了可控的安全性、无DDIs和良好的初步抗肿瘤活性。
{"title":"Phase I/Ib Trial of Inavolisib Plus Palbociclib and Endocrine Therapy for <i>PIK3CA</i>-Mutated, Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced or Metastatic Breast Cancer.","authors":"Komal L Jhaveri, Melissa K Accordino, Philippe L Bedard, Andrés Cervantes, Valentina Gambardella, Erika Hamilton, Antoine Italiano, Kevin Kalinsky, Ian E Krop, Mafalda Oliveira, Peter Schmid, Cristina Saura, Nicholas C Turner, Andrea Varga, Sravanthi Cheeti, Stephanie Hilz, Katherine E Hutchinson, Yanling Jin, Stephanie Royer-Joo, Ubong Peters, Noopur Shankar, Jennifer L Schutzman, Dejan Juric","doi":"10.1200/JCO.24.00110","DOIUrl":"https://doi.org/10.1200/JCO.24.00110","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the safety, tolerability, pharmacokinetics (PK), and preliminary antitumor activity of inavolisib, a potent and selective small-molecule inhibitor of p110α that promotes the degradation of mutated p110α, in combination with palbociclib and endocrine therapy (ET), in a phase I/Ib study in patients with <i>PIK3CA</i>-mutated, hormone receptor-positive/human epidermal growth factor receptor 2-negative locally advanced/metastatic breast cancer (ClinicalTrials.gov identifier: NCT03006172).</p><p><strong>Methods: </strong>Women ≥18 years of age received inavolisib, palbociclib, and letrozole (Inavo + Palbo + Letro arm) or fulvestrant (Inavo + Palbo + Fulv arm) until unacceptable toxicity or disease progression. The primary objective was to evaluate safety or tolerability.</p><p><strong>Results: </strong>Fifty-three patients were included, 33 in the Inavo + Palbo + Letro arm and 20 in the Inavo + Palbo + Fulv arm. Median duration of inavolisib treatment was 15.7 and 20.8 months (cutoff: March 27, 2023), respectively. Treatment-related adverse events (TRAEs) occurred in all patients; the most frequent were stomatitis, hyperglycemia, and diarrhea; grade ≥3 any TRAE rates were 87.9% and 85.0%; 6.1% and 10.0% discontinued any treatment due to TRAEs in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. No PK drug-drug interactions (DDIs) were observed among the study treatments when administered. Confirmed objective response rates were 52.0% and 40.0% in patients with measurable disease, and median progression-free survival was 23.3 and 35.0 months in the Inavo + Palbo + Letro and Inavo + Palbo + Fulv arms, respectively. Available paired pre- and on-treatment tumor tissue and circulating tumor DNA analyses confirmed the effects of study treatment on pharmacodynamic and pathophysiologic biomarkers of response.</p><p><strong>Conclusion: </strong>Inavolisib plus palbociclib and ET demonstrated a manageable safety profile, lack of DDIs, and promising preliminary antitumor activity.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142140256","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}
Babar Bashir, Judy S Wang, Gerald Falchook, Elisa Fontana, Hendrik-Tobias Arkenau, Louise Carter, Rachel Galot, Bristi Basu, Alastair Greystoke, Vivek Subbiah, Debra L Richardson, Hanna Orr, Gavin Bennett, Rajiv Sharma, Hongmei Xu, Paola Paganoni, Cong Xu, Carly Campbell, Meredith McKean
Purpose: BT5528 is a Bicycle Toxin Conjugate, a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting EphA2 tumor antigen, linked to a cytotoxin (monomethyl auristatin E [MMAE]). EphA2 is overexpressed in many solid tumors and contributes to oncogenesis, tumor-associated angiogenesis, and metastasis.
Materials and methods: The primary objectives were to investigate the safety and tolerability of BT5528 and to define the maximum-tolerated dose, if observed, and recommended phase II dose (RP2D)/expansion dose. Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a Bayesian logistic regression model. Secondary and exploratory end points included preliminary efficacy and the pharmacokinetics of BT5528 and MMAE.
Results: Forty-five patients were enrolled and received BT5528 doses between 2.2 mg/m2 once every week to 10.0 mg/m2 once every 2 weeks within the dose-escalation stage of the study. The most frequent BT5528-related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%), and the most common grade ≥3 BT5528-related AE was neutropenia/neutrophil count decrease (22.2%). Dose level 6.5 mg/m2 once every 2 weeks was selected as a RP2D. At 6.5 mg/m2 once every 2 weeks, the overall response rate was 6.7%, and the disease control rate was 20.0%. BT5528 and MMAE pharmacokinetics are generally dose proportional. BT5528 has a short half-life (0.4-0.7 hours), and the half-life of MMAE is longer (35-47 hours).
Conclusion: BT5528 was well tolerated and demonstrated favorable and preliminary antitumor activity. We believe these data provide preliminary validation of a Bicycle Toxin Conjugate approach to EphA2 tumor antigen. The study is ongoing and is evaluating BT5528 as monotherapy at a RP2D of 6.5 mg/m2 once every 2 weeks.
{"title":"Results From First-in-Human Phase I Dose-Escalation Study of a Novel Bicycle Toxin Conjugate Targeting EphA2 (BT5528) in Patients With Advanced Solid Tumors.","authors":"Babar Bashir, Judy S Wang, Gerald Falchook, Elisa Fontana, Hendrik-Tobias Arkenau, Louise Carter, Rachel Galot, Bristi Basu, Alastair Greystoke, Vivek Subbiah, Debra L Richardson, Hanna Orr, Gavin Bennett, Rajiv Sharma, Hongmei Xu, Paola Paganoni, Cong Xu, Carly Campbell, Meredith McKean","doi":"10.1200/JCO.23.01107","DOIUrl":"https://doi.org/10.1200/JCO.23.01107","url":null,"abstract":"<p><strong>Purpose: </strong>BT5528 is a Bicycle Toxin Conjugate, a novel class of chemically synthesized molecules, comprising a bicyclic peptide targeting EphA2 tumor antigen, linked to a cytotoxin (monomethyl auristatin E [MMAE]). EphA2 is overexpressed in many solid tumors and contributes to oncogenesis, tumor-associated angiogenesis, and metastasis.</p><p><strong>Materials and methods: </strong>The primary objectives were to investigate the safety and tolerability of BT5528 and to define the maximum-tolerated dose, if observed, and recommended phase II dose (RP2D)/expansion dose. Dose escalation exploring once every week or once every 2 weeks administration of BT5528 employed a 3 + 3 dose-escalation design for the first two dose levels, followed by a Bayesian logistic regression model. Secondary and exploratory end points included preliminary efficacy and the pharmacokinetics of BT5528 and MMAE.</p><p><strong>Results: </strong>Forty-five patients were enrolled and received BT5528 doses between 2.2 mg/m<sup>2</sup> once every week to 10.0 mg/m<sup>2</sup> once every 2 weeks within the dose-escalation stage of the study. The most frequent BT5528-related adverse events (AEs) were nausea (44.4%), diarrhea (35.6%), and fatigue (33.3%), and the most common grade ≥3 BT5528-related AE was neutropenia/neutrophil count decrease (22.2%). Dose level 6.5 mg/m<sup>2</sup> once every 2 weeks was selected as a RP2D. At 6.5 mg/m<sup>2</sup> once every 2 weeks, the overall response rate was 6.7%, and the disease control rate was 20.0%. BT5528 and MMAE pharmacokinetics are generally dose proportional. BT5528 has a short half-life (0.4-0.7 hours), and the half-life of MMAE is longer (35-47 hours).</p><p><strong>Conclusion: </strong>BT5528 was well tolerated and demonstrated favorable and preliminary antitumor activity. We believe these data provide preliminary validation of a Bicycle Toxin Conjugate approach to EphA2 tumor antigen. The study is ongoing and is evaluating BT5528 as monotherapy at a RP2D of 6.5 mg/m<sup>2</sup> once every 2 weeks.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132866","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}
Elizabeth H Baldini, B Ashleigh Guadagnolo, Kilian E Salerno, Peter Chung, Andrew J Bishop, Anusha Kalbasi, Aisha Miah, Meena Bedi, Jeremy P Harris, Ivy Petersen, Charles Gillham, Lisette M Wiltink, Kaled M Alektiar, Rick L Haas, David G Kirsch
Hypofractionated radiation therapy regimens should not be used as standard of care for localized soft tissue sarcoma.
局部软组织肉瘤不应将低分次放射治疗方案作为标准治疗方法。
{"title":"Hypofractionated Preoperative Radiation Should Not Yet Be Used as Standard of Care for Extremity and Truncal Soft Tissue Sarcoma.","authors":"Elizabeth H Baldini, B Ashleigh Guadagnolo, Kilian E Salerno, Peter Chung, Andrew J Bishop, Anusha Kalbasi, Aisha Miah, Meena Bedi, Jeremy P Harris, Ivy Petersen, Charles Gillham, Lisette M Wiltink, Kaled M Alektiar, Rick L Haas, David G Kirsch","doi":"10.1200/JCO.24.00238","DOIUrl":"https://doi.org/10.1200/JCO.24.00238","url":null,"abstract":"<p><p>Hypofractionated radiation therapy regimens should not be used as standard of care for localized soft tissue sarcoma.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132864","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}
Bryan A Vallejo, Ahmed Ansari, Sameer A Parikh, Sara J Achenbach, Kari G Rabe, Aaron D Norman, Janet E Olson, Neil E Kay, Esteban Braggio, Curtis A Hanson, Celine M Vachon, James R Cerhan, Cristian L Baum, Tait D Shanafelt, Susan L Slager
Purpose: Chronic lymphocytic leukemia (CLL)-phenotype monoclonal B-cell lymphocytosis (MBL) is a premalignant condition that is roughly 500-fold more common than CLL. It is unknown whether the two-fold increased risk of developing melanoma associated with CLL extends to individuals with MBL.
Methods: Using the Mayo Clinic Biobank, we identified participants who were 40 years or older with no previous hematological malignancies, who resided in the 27 counties around Mayo Clinic, and who had available biospecimens for screening. Eight-color flow cytometry was used to screen for MBL. Individuals with MBL were classified as low-count MBL (LC-MBL) or high-count MBL on the basis of clonal B-cell percent. Incident melanomas were identified using International Classification of Diseases codes and confirmed via medical records review. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI.
Results: Of the 7,334 participants screened, 1,151 were identified with a CD5-positive MBL, of whom 1,098 had LC-MBL. After a median follow-up of 3.2 years (range, 0-13.5), 131 participants developed melanoma, of whom 36 individuals were positive for MBL. The estimated 5-year cumulative incidence of melanoma was 3.4% and 2.0% among those with and without MBL, respectively. After adjusting for age, sex, and history of previous melanoma, individuals with MBL exhibited a 1.86-fold (95% CI, 1.25 to 2.78) risk of melanoma. This elevated risk persisted when analysis was restricted to those without a history of melanoma (HR, 2.05 [95% CI, 1.30 to 3.23]). Individuals with LC-MBL had a 1.92-fold (95% CI, 1.29 to 2.87) increased risk of developing melanoma overall and a 2.74-fold increased risk (95% CI, 1.50 to 5.03) of melanoma in situ compared with those without MBL.
Conclusion: LC-MBL is associated with an approximately two-fold increased risk of melanoma overall and a 2.74-fold increased risk of melanoma in situ.
{"title":"Risk of Incident Melanoma Among Individuals With Low-Count Monoclonal B-Cell Lymphocytosis.","authors":"Bryan A Vallejo, Ahmed Ansari, Sameer A Parikh, Sara J Achenbach, Kari G Rabe, Aaron D Norman, Janet E Olson, Neil E Kay, Esteban Braggio, Curtis A Hanson, Celine M Vachon, James R Cerhan, Cristian L Baum, Tait D Shanafelt, Susan L Slager","doi":"10.1200/JCO.24.00332","DOIUrl":"https://doi.org/10.1200/JCO.24.00332","url":null,"abstract":"<p><strong>Purpose: </strong>Chronic lymphocytic leukemia (CLL)-phenotype monoclonal B-cell lymphocytosis (MBL) is a premalignant condition that is roughly 500-fold more common than CLL. It is unknown whether the two-fold increased risk of developing melanoma associated with CLL extends to individuals with MBL.</p><p><strong>Methods: </strong>Using the Mayo Clinic Biobank, we identified participants who were 40 years or older with no previous hematological malignancies, who resided in the 27 counties around Mayo Clinic, and who had available biospecimens for screening. Eight-color flow cytometry was used to screen for MBL. Individuals with MBL were classified as low-count MBL (LC-MBL) or high-count MBL on the basis of clonal B-cell percent. Incident melanomas were identified using International Classification of Diseases codes and confirmed via medical records review. Cox regression models were used to estimate hazard ratios (HRs) and 95% CI.</p><p><strong>Results: </strong>Of the 7,334 participants screened, 1,151 were identified with a CD5-positive MBL, of whom 1,098 had LC-MBL. After a median follow-up of 3.2 years (range, 0-13.5), 131 participants developed melanoma, of whom 36 individuals were positive for MBL. The estimated 5-year cumulative incidence of melanoma was 3.4% and 2.0% among those with and without MBL, respectively. After adjusting for age, sex, and history of previous melanoma, individuals with MBL exhibited a 1.86-fold (95% CI, 1.25 to 2.78) risk of melanoma. This elevated risk persisted when analysis was restricted to those without a history of melanoma (HR, 2.05 [95% CI, 1.30 to 3.23]). Individuals with LC-MBL had a 1.92-fold (95% CI, 1.29 to 2.87) increased risk of developing melanoma overall and a 2.74-fold increased risk (95% CI, 1.50 to 5.03) of melanoma in situ compared with those without MBL.</p><p><strong>Conclusion: </strong>LC-MBL is associated with an approximately two-fold increased risk of melanoma overall and a 2.74-fold increased risk of melanoma in situ.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132867","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}
{"title":"New Benchmark for Targeted Therapies in Lung Cancer: Median Progression-Free Survival for Lorlatinib in Advanced ALK+ Non-Small Cell Lung Cancer Surpasses 5 years.","authors":"Christine M Lovly","doi":"10.1200/JCO.24.01147","DOIUrl":"https://doi.org/10.1200/JCO.24.01147","url":null,"abstract":"","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132865","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}
Benoist Chibaudel, Morteza Raeisi, Romain Cohen, Greg Yothers, Richard M Goldberg, Jean-Baptiste Bachet, Norman Wolmark, Takayuki Yoshino, Hans-Joachim Schmoll, Rachel Kerr, Sara Lonardi, Thomas J George, Einat Shacham-Shmueli, Qian Shi, Thierry André, Aimery de Gramont
Purpose: The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined.
Patients and methods: One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage.
Results: In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; P = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; P = .001; Pint = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; P = .349).
Conclusion: No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.
{"title":"Assessment of the Addition of Oxaliplatin to Fluoropyrimidine-Based Adjuvant Chemotherapy in Patients With High-Risk Stage II Colon Cancer: An ACCENT Pooled Analysis.","authors":"Benoist Chibaudel, Morteza Raeisi, Romain Cohen, Greg Yothers, Richard M Goldberg, Jean-Baptiste Bachet, Norman Wolmark, Takayuki Yoshino, Hans-Joachim Schmoll, Rachel Kerr, Sara Lonardi, Thomas J George, Einat Shacham-Shmueli, Qian Shi, Thierry André, Aimery de Gramont","doi":"10.1200/JCO.24.00394","DOIUrl":"https://doi.org/10.1200/JCO.24.00394","url":null,"abstract":"<p><strong>Purpose: </strong>The adjuvant treatment for stage III colon cancer (CC) is chemotherapy combining fluoropyrimidine (FP) and oxaliplatin (OX). FP regimen plus OX (FPOX) may benefit in high-risk stage II CC. We performed a pooled analysis of pivotal MOSAIC and C-07 studies evaluating FPOX for the treatment of high-risk stage II CC according to prognostic factors, number of high-risk factors, and current clinicopathologic risk classification on the basis of T stage, tumor perforation, and number of lymph nodes examined.</p><p><strong>Patients and methods: </strong>One thousand five hundred and ninety-five patients with stage II CC receiving FP or FPOX were pooled. The overall survival (OS) benefit of OX was analyzed using Kaplan-Meier curves and unadjusted Cox models stratified by study. Three thousand and fifty-nine patients with stage III CC were used only for interaction tests between the allocated chemotherapy and stage.</p><p><strong>Results: </strong>In the pooled analysis of stage II patients, independent prognostic factors in multivariable analysis were sex, age, perforation/obstruction, and tumor sidedness. There was a significant interaction in OS between stage and allocated chemotherapy with hazard ratios (HRs) of 1.03 for stage II (95% CI, 0.82 to 1.29; <i>P</i> = .813) and 0.82 for stage III (95% CI, 0.73 to 0.92; <i>P</i> = .001; <i>P</i><sub>int</sub> = .073). There was no benefit from the addition of OX to FP for any of the prognostic factors. The number of high-risk factors tested was not predictive of OX benefit. According to the currently agreed clinicopathologic risk classification, no OS benefit of OX was observed, as HR was 0.86 (95% CI, 0.63 to 1.18; <i>P</i> = .349).</p><p><strong>Conclusion: </strong>No OS benefit of adjuvant OX was found in high-risk stage II CC, regardless of the definition used to characterize tumors as having a high risk for recurrence. Hence, our analysis suggests that OX should not be the standard of care for adjuvant chemotherapy for stage II CC, even in high-risk patients.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132863","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}
Jurjen Versluis, Marlen Metzner, Ariel Wang, Patrycja Gradowska, Abin Thomas, Niels Asger Jakobsen, Alison Kennedy, Rachel Moore, Emma Boertjes, Christian M Vonk, Francois G Kavelaars, Melissa Rijken, Amanda Gilkes, Claire Schwab, H Berna Beverloo, Markus Manz, Otto Visser, Catharina H M J Van Elssen, Okke de Weerdt, Lidwine W Tick, Bart J Biemond, Marie-Christiane Vekemans, Sylvie D Freeman, Christine J Harrison, Jonathan A Cook, Mike Dennis, Steven Knapper, Ian Thomas, Charles Craddock, Gert J Ossenkoppele, Bob Löwenberg, Nigel Russell, Peter J M Valk, Paresh Vyas
Purpose: AML is a genetically heterogeneous disease, particularly in older patients. In patients older than 60 years, survival rates are variable after the most important curative approach, intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HCT). Thus, there is an urgent need in clinical practice for a prognostic model to identify older patients with AML who benefit from curative treatment.
Methods: We studied 1,910 intensively treated patients older than 60 years with AML and high-risk myelodysplastic syndrome (HR-MDS) from two cohorts (NCRI-AML18 and HOVON-SAKK). The median patient age was 67 years. Using a random survival forest, clinical, molecular, and cytogenetic variables were evaluated in an AML development cohort (n = 1,204) for association with overall survival (OS). Relative weights of selected variables determined the prognostic model, which was validated in AML (n = 491) and HR-MDS cohorts (n = 215).
Results: The complete cohort had a high frequency of poor-risk features, including 2022 European LeukemiaNet adverse-risk (57.3%), mutated TP53 (14.4%), and myelodysplasia-related genetic features (65.1%). Nine variables were used to construct four groups with highly distinct 4-year OS in the (1) AML development, (2) AML validation, and (3) HR-MDS test cohorts ([1] favorable: 54% ± 4%, intermediate: 38% ± 2%, poor: 21% ± 2%, very poor: 4% ± 1%; [2] 54% ± 9%, 43% ± 4%, 27% ± 4%, 4% ± 3%; and [3] 54% ± 10%, 33% ± 6%, 14% ± 5%, 0% ± 3%, respectively). This new AML60+ classification improves current prognostic classifications. Importantly, patients within the AML60+ intermediate- and very poor-risk group significantly benefited from allo-HCT, whereas the poor-risk patients showed an indication, albeit nonsignificant, for improved outcome after allo-HCT.
Conclusion: The new AML60+ classification provides prognostic information for intensively treated patients 60 years and older with AML and HR-MDS and identifies patients who benefit from intensive chemotherapy and allo-HCT.
{"title":"Risk Stratification in Older Intensively Treated Patients With AML.","authors":"Jurjen Versluis, Marlen Metzner, Ariel Wang, Patrycja Gradowska, Abin Thomas, Niels Asger Jakobsen, Alison Kennedy, Rachel Moore, Emma Boertjes, Christian M Vonk, Francois G Kavelaars, Melissa Rijken, Amanda Gilkes, Claire Schwab, H Berna Beverloo, Markus Manz, Otto Visser, Catharina H M J Van Elssen, Okke de Weerdt, Lidwine W Tick, Bart J Biemond, Marie-Christiane Vekemans, Sylvie D Freeman, Christine J Harrison, Jonathan A Cook, Mike Dennis, Steven Knapper, Ian Thomas, Charles Craddock, Gert J Ossenkoppele, Bob Löwenberg, Nigel Russell, Peter J M Valk, Paresh Vyas","doi":"10.1200/JCO.23.02631","DOIUrl":"https://doi.org/10.1200/JCO.23.02631","url":null,"abstract":"<p><strong>Purpose: </strong>AML is a genetically heterogeneous disease, particularly in older patients. In patients older than 60 years, survival rates are variable after the most important curative approach, intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HCT). Thus, there is an urgent need in clinical practice for a prognostic model to identify older patients with AML who benefit from curative treatment.</p><p><strong>Methods: </strong>We studied 1,910 intensively treated patients older than 60 years with AML and high-risk myelodysplastic syndrome (HR-MDS) from two cohorts (NCRI-AML18 and HOVON-SAKK). The median patient age was 67 years. Using a random survival forest, clinical, molecular, and cytogenetic variables were evaluated in an AML development cohort (n = 1,204) for association with overall survival (OS). Relative weights of selected variables determined the prognostic model, which was validated in AML (n = 491) and HR-MDS cohorts (n = 215).</p><p><strong>Results: </strong>The complete cohort had a high frequency of poor-risk features, including 2022 European LeukemiaNet adverse-risk (57.3%), mutated <i>TP53</i> (14.4%), and myelodysplasia-related genetic features (65.1%). Nine variables were used to construct four groups with highly distinct 4-year OS in the (1) AML development, (2) AML validation, and (3) HR-MDS test cohorts ([1] favorable: 54% ± 4%, intermediate: 38% ± 2%, poor: 21% ± 2%, very poor: 4% ± 1%; [2] 54% ± 9%, 43% ± 4%, 27% ± 4%, 4% ± 3%; and [3] 54% ± 10%, 33% ± 6%, 14% ± 5%, 0% ± 3%, respectively). This new AML60+ classification improves current prognostic classifications. Importantly, patients within the AML60+ intermediate- and very poor-risk group significantly benefited from allo-HCT, whereas the poor-risk patients showed an indication, albeit nonsignificant, for improved outcome after allo-HCT.</p><p><strong>Conclusion: </strong>The new AML60+ classification provides prognostic information for intensively treated patients 60 years and older with AML and HR-MDS and identifies patients who benefit from intensive chemotherapy and allo-HCT.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132789","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}
Douglas M Dahl, Joseph P Rodgers, William U Shipley, M Dror Michaelson, Chin-Lee Wu, William Parker, Ashesh B Jani, Fabio L Cury, Richard S Hudes, Jeff M Michalski, Alan C Hartford, Daniel Song, Deborah E Citrin, Theodore G Karrison, Howard M Sandler, Felix Y Feng, Jason A Efstathiou
Purpose: To investigate the use of radiation with radiosensitizing chemotherapy following repeated transurethral resection (trimodality therapy) as an alternative to radical cystectomy in T1 bladder cancer which has failed Bacillus Calmette-Guerin (BCG).
Patients and methods: Patients with recurrent T1 bladders who had failed BCG and were recommended to undergo cystectomy were treated with trimodality therapy. The primary end point was 3-year freedom from cystectomy. Secondary end points were distant metastasis at 3 and 5 years, local recurrence, disease-specific and overall survival (OS), and safety.
Results: This single-arm phase II study enrolled 37 patients. Efficacy and safety were evaluated in 34 patients after three exclusions. The median follow-up was 5.1 years. The 3-year freedom from cystectomy rate was 88% (lower one-sided 97.5% confidence limit [CI], 72%), meeting the primary study goal. OS at 3 and 5 years was 69% (95% CI, 54 to 85) and 56% (95% CI, 39 to 74), respectively. The distant metastasis rates at 3 and 5 years were 12% (95% CI, 4 to 26) and 19% (95% CI, 7 to 34), respectively. Eight patients died due to urothelial cancer, 12 exhibited local recurrence at 3 years (cumulative incidence: 32%; 95% CI, 17 to 48), 18 experienced grade 3 adverse events, mostly hematological, and one developed grade 4 neutropenia.
Conclusion: Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder. At 3 years, 88% of the patients remained free of cystectomy.
目的:研究在重复经尿道切除术(三联疗法)后使用放射线和放射增敏化疗替代根治性膀胱切除术治疗卡介苗(BCG)治疗失败的T1型膀胱癌的方法:卡介苗(BCG)治疗失败并被建议接受膀胱切除术的复发性T1膀胱癌患者接受了三联疗法。主要终点是3年内无膀胱切除术。次要终点是3年和5年的远处转移、局部复发、疾病特异性和总生存期(OS)以及安全性:这项单臂 II 期研究共招募了 37 名患者。结果:这项单臂 II 期研究共纳入 37 例患者,在排除 3 例患者后,对 34 例患者的疗效和安全性进行了评估。中位随访时间为 5.1 年。3年免于膀胱切除术的比例为88%(单侧97.5%置信下限[CI],72%),达到了主要研究目标。3年和5年的OS分别为69%(95% CI,54至85)和56%(95% CI,39至74)。3年和5年的远处转移率分别为12%(95% CI,4至26)和19%(95% CI,7至34)。8名患者死于尿道癌,12名患者3年后出现局部复发(累计发生率:32%;95% CI,17至48),18名患者出现3级不良反应,主要是血液方面的,1名患者出现4级中性粒细胞减少症:结论:对于复发性T1高级别膀胱尿路上皮癌,三联疗法是根治性膀胱切除术的有效替代方案。3年后,88%的患者仍未接受膀胱切除术。
{"title":"Bladder-Preserving Trimodality Treatment for High-Grade T1 Bladder Cancer: Results From Phase II Protocol NRG Oncology/RTOG 0926.","authors":"Douglas M Dahl, Joseph P Rodgers, William U Shipley, M Dror Michaelson, Chin-Lee Wu, William Parker, Ashesh B Jani, Fabio L Cury, Richard S Hudes, Jeff M Michalski, Alan C Hartford, Daniel Song, Deborah E Citrin, Theodore G Karrison, Howard M Sandler, Felix Y Feng, Jason A Efstathiou","doi":"10.1200/JCO.23.02510","DOIUrl":"10.1200/JCO.23.02510","url":null,"abstract":"<p><strong>Purpose: </strong>To investigate the use of radiation with radiosensitizing chemotherapy following repeated transurethral resection (trimodality therapy) as an alternative to radical cystectomy in T1 bladder cancer which has failed Bacillus Calmette-Guerin (BCG).</p><p><strong>Patients and methods: </strong>Patients with recurrent T1 bladders who had failed BCG and were recommended to undergo cystectomy were treated with trimodality therapy. The primary end point was 3-year freedom from cystectomy. Secondary end points were distant metastasis at 3 and 5 years, local recurrence, disease-specific and overall survival (OS), and safety.</p><p><strong>Results: </strong>This single-arm phase II study enrolled 37 patients. Efficacy and safety were evaluated in 34 patients after three exclusions. The median follow-up was 5.1 years. The 3-year freedom from cystectomy rate was 88% (lower one-sided 97.5% confidence limit [CI], 72%), meeting the primary study goal. OS at 3 and 5 years was 69% (95% CI, 54 to 85) and 56% (95% CI, 39 to 74), respectively. The distant metastasis rates at 3 and 5 years were 12% (95% CI, 4 to 26) and 19% (95% CI, 7 to 34), respectively. Eight patients died due to urothelial cancer, 12 exhibited local recurrence at 3 years (cumulative incidence: 32%; 95% CI, 17 to 48), 18 experienced grade 3 adverse events, mostly hematological, and one developed grade 4 neutropenia.</p><p><strong>Conclusion: </strong>Trimodality therapy is an effective potential alternative to radical cystectomy for recurrent high-grade T1 urothelial cancer of the bladder. At 3 years, 88% of the patients remained free of cystectomy.</p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125834","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}
The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.
{"title":"How We Monitor Cardiac Health in Breast Cancer Survivors.","authors":"Suparna C Clasen, Meagan E Miller","doi":"10.1200/JCO.24.00757","DOIUrl":"https://doi.org/10.1200/JCO.24.00757","url":null,"abstract":"<p><p><i>The Oncology Grand Rounds series is designed to place original reports published in the</i> Journal <i>into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in</i> Journal of Clinical Oncology<i>, to patients seen in their own clinical practice.</i></p>","PeriodicalId":15384,"journal":{"name":"Journal of Clinical Oncology","volume":null,"pages":null},"PeriodicalIF":42.1,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142125837","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}