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Purpose: National Wilms Tumor Study-5 (NWTS-5) and AREN0321 evaluated the outcomes of children with rhabdoid tumor of the kidney (RTK) and malignant rhabdoid tumor of soft tissues (MRT)., Patients and Methods: Eligible patients with RTK were enrolled prospectively on NWTS-5 (1995-2002) and treated with carboplatin and etoposide alternating with cyclophosphamide (Regimen RTK). Patients with RTK or MRT were enrolled on AREN0321 (2005-2012) and received vincristine, doxorubicin, and cyclophosphamide alternating with carboplatin, cyclophosphamide, and etoposide (Regimens UH-1 or dose-reduced Revised UH-1). We report event-free survival (EFS) and overall survival (OS) from each study., Results: Thirty patients received Regimen RTK on NWTS-5; on AREN0321, 20 received UH-1 and 19 received Revised UH-1. Patient and disease characteristics were statistically similar between studies. Patients on AREN0321 had significantly improved EFS and OS compared to those on NWTS-5 (4-year EFS = 23.1% vs. 16.7%; p = 0.020; 4-year OS = 30.6% vs. 20.0%; p = 0.014), mostly driven by patients with Stage I/II disease (p = 0.05). Median time to an event was 3.6 months on NWTS-5 compared to 7.2 months on AREN0321. There were no differences in EFS or OS by revised versus original Regimen UH-1 on AREN0321, or by renal versus extra-renal primary disease when the studies were pooled., Conclusions: The more intensive treatment regimen used on AREN0321 improved EFS and OS overall, a result driven by patients with Stage I/II disease. Despite this improvement, outcomes for patients with rhabdoid tumor remain unsatisfactory and there is a need for novel therapeutic strategies., (© 2024 Wiley Periodicals LLC.)

A better understanding of positron emission tomography (PET) response in nodular lymphocyte-predominant Hodgkin lymphoma (nLPHL) is critical for incorporating PET into prospective trials. PET scans from Children's Oncology Group study AHOD03P1 for patients less than 22 years with low-risk nLPHL, treated with three cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide chemotherapy, were retrospectively reviewed and assigned Deauville 5-point scale (5PS) scores. Five-year post-PET event-free survival was 90.1% (80% CI: 85.2%-93.4%) for PET-negative (5PS 1-3) and 66.7% (80% CI: 36.4%-85.0%) for PET-positive (5PS 4-5) patients. PET response after three cycles of low-dose chemotherapy is predictive of relapse risk for low-risk nLPHL., (© 2025 Wiley Periodicals LLC.)

Background: In the fifth National Wilms Tumor Study, patients received vincristine and dactinomycin (VA) without radiation for stage I focal anaplastic Wilms tumor (FAWT) and VA plus doxorubicin (DD4A) and radiation for stage II-IV FAWT. Four-year event-free survival (EFS) and overall survival (OS) for stage I FAWT were 67.5% and 88.9% and for stage IV FAWT were 61.4% and 71.6%, respectively. Therapy intensification for stage I and IV FAWT was evaluated as secondary objectives in AREN0321., Methods: Central review in the AREN03B2 Renal Tumors Classification, Biology, and Banking Study confirmed patient stage and tumor histology. Patients were then enrolled in AREN0321 and received DD4A with radiation for stage I-III FAWT and vincristine, doxorubicin, cyclophosphamide, carboplatin, and etoposide (UH-1/revised UH-1) with radiation for stage IV FAWT. Outcomes of patients with FAWT who were treated in AREN0321 (n = 25) and in AREN03B2 (n = 20) treated as per AREN0321 were analyzed., Results: In the pooled data analysis from AREN0321 and AREN03B2, 4-year EFS and OS were both 100% for stage I-II FAWT (n = 21), 82.4% (95% CI, 66.1%-100%) and 87.8% (95% CI, 73.4%-100%) for stage III FAWT (n = 17), respectively, and both 85.7% (95% CI, 63.3%-100%) for stage IV FAWT (n = 7). Four patients enrolled in AREN0321 had events: treatment failure occurred in three patients with stage III FAWT, and one treatment-related death was observed in a patient with stage IV FAWT following revised UH-1. No EFS or OS events occurred in patients with FAWT enrolled in AREN03B2 only., Conclusions: Patients with stage I and II FAWT have outstanding survival when treated with DD4A and radiation. Intensification of therapy may have improved survival for stage IV FAWT, albeit with an increased toxicity risk., (© 2025 American Cancer Society.)

Objective: Enhanced Recovery After Surgery (ERAS) clinical pathways have demonstrated improved perioperative outcomes after major surgery. However, its adoption within vascular surgery has been limited. In this study, we examined the impact of an ERAS protocol with multimodal anesthesia on open abdominal aortic aneurysm (AAA) repair by comparing early outcomes before and after its implementation., Methods: This retrospective study analyzed early outcomes after elective open repairs of intact AAA performed from 2013 to 2023 at a single institution. Eighty consecutive patients treated after implementation of an ERAS protocol with multimodal anesthesia were compared with 161 patients treated before its implementation. Propensity score matching based on age, gender, body mass index, Vascular Quality Initiative AAA Mortality Risk Score, Rockwood Frailty Scale, aortic cross clamp location, aneurysm size, and type of exposure was performed to achieve one:one matching using the nearest neighbor technique. Quantile and logistic regression assessed the impact of the ERAS protocol on length of stay, 30-day mortality, opioid consumption (morphine milligram equivalents), hospital cost, complications, and readmissions., Results: Both groups (ERAS vs pre-ERAS, respectively) were predominantly male (80% vs 73%; P = .27), with a median age of 74 years. Similar mean Vascular Quality Initiative predicted mortality (2.9% vs 4.0%; P = .13), clinical frailty score (3.1 vs 3.3; P = .17), aneurysm size (60 mm vs 62 mm; P = .06), rates of suprarenal cross-clamp (76% vs 88%; P = .07), chronic obstructive pulmonary disease (29% vs 31%; P = .73), chronic kidney disease (14% vs 16%; P = .66), myocardial disease (16% vs 20%; P = .54), and cerebrovascular disease (15% vs 19%; P = .53) were observed in the matched groups. ERAS was associated with a reduction in length of stay by 3 days (P < .001), a decrease in opioid consumption by 37 morphine milligram equivalents (P < .001), and a reduction in hospital costs by US$4704 (P < .001). There was a trend toward a lower risk of major complications (odds ratio, 0.44; 95% confidence interval, 0.2-1.1; P = .06). Thirty-day mortality (5% vs 6.3%; P = .73) and readmission (7.9% vs 13.2%; P = .29) rates were similar in both groups., Conclusions: An ERAS protocol using a multimodal anesthesia was associated with improved early outcomes compared with patients treated before ERAS implementation. These results mirror similar benefits seen in nonvascular ERAS programs, and broader application should be considered in institutions that perform a high volume of open aortic repairs., Competing Interests: Disclosures W.A.L. is a consultant for Terumo Aortic, Cook, and W. L. Gore & Associates., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective of this study is to report the long-term timing and patterns of relapse for children enrolled in Children's Oncology Group AREN0534, a multicenter phase III clinical trial conducted from 2009 to 2015. Participants included children with bilateral Wilms tumor (BWT) or unilateral WT with genetic predisposition to develop BWT followed for up to 10 years. Smoothed hazard (risk) functions for event-free survival (EFS) were plotted so that the timing of events could be visualized, both overall and within pre-specified groups. Two hundred and twenty-two children (190 BWT and 32 unilateral WT with BWT predisposition) were followed for a median of 8.6 years. Fifty events were reported, of which 48 were relapse/progression. The overall 8-year EFS was 75% (95% confidence interval: 69%-83%). The highest risk for an EFS event was immediately after diagnosis with a declining rate over 2 years. A second peak of events was observed around 4 years after diagnosis, and a small number of events were reported until the end of the follow-up period. In subset analyses, later increases in risk were more commonly observed in patients with female sex, anaplastic histology, negative lymph nodes or margins, and favorable histology Wilms tumor patients with post-chemotherapy intermediate risk. Among relapses that occurred after 2 years, most were to the kidney. These patterns suggest that late events may be second primary tumors occurring more commonly in females, although more investigation is required. Clinicians may consider observation of patients with BWT beyond 4 years from diagnosis., (© 2024 UICC.)

As cancer has become better understood on the molecular level with the evolution of gene sequencing techniques, considerations for individualized therapy using predictive biomarkers (those associated with a treatment's effect) have shifted to a new level. In the last decade or so, randomized "adaptive enrichment" clinical trials have become increasingly utilized to strike a balance between enrolling all patients with a given tumor type, versus enrolling only a subpopulation whose tumors are defined by a potential predictive biomarker related to the mechanism of action of the experimental therapy. In this review article, we review recent innovative design extensions and adaptations to adaptive enrichment designs proposed during the last few years in the clinical trial methodology literature, both from Bayesian and frequentist perspectives., (© 2024. The Author(s).)

Study designs incorporate interim analyses to allow for modifications to the trial design. These analyses may aid decisions regarding sample size, futility, and safety. Furthermore, they may provide evidence about potential differences between treatment arms. Bayesian response adaptive randomization (RAR) skews allocation proportions such that fewer participants are assigned to the inferior treatments. However, these allocation changes may introduce covariate imbalances. We discuss two versions of Bayesian RAR (with and without covariate adjustment for a binary covariate) for continuous outcomes analyzed using change scores and repeated measures, while considering either regression or mixed models for interim analysis modeling. Through simulation studies, we show that RAR (both versions) allocates more participants to better treatments compared to equal randomization, while reducing potential covariate imbalances. We also show that dynamic allocation using mixed models for repeated measures yields a smaller allocation proportion variance while having a similar covariate imbalance as regression models. Additionally, covariate imbalance was smallest for methods using covariate-adjusted RAR (CARA) in scenarios with small sample sizes and covariate prevalence less than 0.3. Covariate imbalance did not differ between RAR and CARA in simulations with larger sample sizes and higher covariate prevalence. We thus recommend a CARA approach for small pilot/exploratory studies for the identification of candidate treatments for further confirmatory studies., (© 2024 The Author(s). Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

Context.—: The distinction between well-differentiated epithelial favorable-histology Wilms tumor (EFHWT) and metanephric adenoma (MA) in children has historically been determined by the required absence of both a fibrous pseudocapsule and mitotic activity in MA. More recently these features have been allowed in adult MA. Mutations in exon 15 of the BRAF gene are reported in up to 88% of MAs but have not been reported in EFHWTs in children lacking MA features., Objective.—: To clarify the pathologic and molecular features used to distinguish between pediatric MA and EFHWT., Design.—: Stage I epithelial tumors classified as EFHWT on central review (36 patients) were identified from the Children's Oncology Group AREN03B2 study. Thirteen tumors had morphologic features overlapping those of MA and 23 lacked such features; 35 of 36 had tissue available for sequencing of BRAF., Results.—: Patients with EFHWTs with MA features (13) were older (mean, 8.4 versus 1.9 years; P < .001), had smaller tumor diameters (mean, 6.0 versus 9.7 cm; P < .001), and had fewer mitoses (mean, 1 versus 48 mitoses per 10 high-power fields; P < .001) than patients with EFHWT lacking MA features (23). All EFHWTs with MA features contained at least a partial fibrous pseudocapsule; 7 of 12 (58%) had a BRAF exon 15 mutation. No BRAF exon 15 mutations were identified in 23 EFHWTs lacking MA features. None of the 13 EFHWT patients with MA features have experienced relapse (median follow-up 5.9 years)., Conclusions.—: Pediatric epithelial neoplasms with features of MA that show partial encapsulation and/or modest mitotic activity may be classified as MAs. Although BRAF mutation supports the diagnosis of MA, it is not required for the diagnosis., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Purpose: Brentuximab vedotin (BV) incorporation into frontline chemotherapy regimens improved outcomes for classic Hodgkin lymphoma (cHL). The shared mechanism of action of BV and vinca alkaloids as microtubulin inhibitors increased the potential risk of chemotherapy-induced peripheral neuropathy (CIPN). Rates of CIPN and use of protocol-stipulated dose modifications of a microtubulin inhibitor were examined on the Children's Oncology Group AHOD1331 study, which compared BV, doxorubicin, vincristine (VCR), etoposide, prednisone, cyclophosphamide (BV-AVE-PC; BV arm) with bleomycin containing doxorubicin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide (ABVE-PC; standard arm) in patients with high-risk cHL ages 2-21 years., Methods: AHOD1331 required clinician grading and reporting of ≥grade 2 CIPN. Protocol-stipulated dose modifications of VCR preceded modification of BV for ≥grade 2 CIPN in the BV arm, but only required modification of VCR for ≥grade 3 in the standard arm. Outcomes included CIPN rates, dose modification of microtubulin inhibitors by study arm, clinical factors associated with dose modifications, and event-free survival (EFS) by the presence of dose modification., Results: Among the 582 patients who began protocol therapy, 112 developed ≥grade 2 CIPN. Cumulative incidence of CIPN did not differ by study arm (19.2 v 19.8%, P = .91). CIPN dose modifications occurred more frequently in the BV arm (9.5% v 2.8%, P = .001); however, most patients with CIPN on the BV arm received full-dose BV. EFS did not differ by the presence of dose modifications after accounting for study arm, age, sex, and stage, although older age was significantly associated with the risk of VCR dose modifications for CIPN., Conclusion: A staged dose modification plan for vinca alkaloids and BV as administered in AHOD1331 minimized the effect of incorporating a second microtubulin inhibitor on CIPN without compromising treatment efficacy in the BV arm.

Background: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT., Methods: Four-year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy., Results: Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p = .28). When combining studies, the 4-year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic., Conclusions: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365)., (© 2024 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Background: Open abdominal aortic aneurysm (AAA) repairs can be associated with significant pain and morbidity. Previous studies have demonstrated utility of adjunctive epidural analgesia (EA) in addition to general anesthesia (GA) to reduce pain and blunt the maladaptive surgical stress response. However, EA may be complicated by epidural hematomas and severe hypotension. Recently, we started using continuous paravertebral block (PVB) for perioperative analgesia after retroperitoneal AAA repair. PVB has some distinct advantages over EA such as unilateral localization, reduced risk of hypotension, and minimal risk of epidural hematoma in the setting of systemic heparinization. This study aimed to examine the utility of PVB by comparing total opioid consumption in the postoperative period among patients who received GA + PVB and those who received GA alone., Methods: This retrospective matched cohort study included 62 patients who underwent elective retroperitoneal AAA repair between January 2019 and August 2022. Thirty-one subjects managed with GA + PVB were compared with 31 control subjects treated with GA alone, matched on following criteria: age, sex, and cross-clamp location. Outcome measures included total opioid analgesics administered during their inhospital postoperative course, time to extubation, time to return to baseline activity, time to normal bowel function, and length of stay. Opioid doses were converted to morphine milligram equivalents (MMEs)., Results: The GA + PVB group required significantly less opioid analgesics (81 ± 53 MME) than the GA group (171 ± 121 MME) (P < 0.001). Compared to GA alone, GA + PVB was superior in every clinical metric examined: time to extubation (3 vs. 1 hr, P < 0.001), recovery of bowel function (3 vs. 2 days, P = 0.002), recovery of baseline physical activity (4 vs. 2 days, P = 0.019), and length of stay (5 vs. 3 days, P < 0.001)., Conclusions: Continuous paravertebral block provides better pain management with significantly decreased opioid requirements in the postoperative period compared to GA-alone for patients undergoing elective retroperitoneal AAA repair., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials., Methods: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed., Results: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months., Conclusion: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed., (© 2024 Wiley Periodicals LLC.)

Due to increased use of gene sequencing techniques, understanding of cancer on a molecular level has evolved, in terms of both diagnosis and evaluation in response to initial therapies. In parallel, clinical trials meant to evaluate molecularly-driven interventions through assessment of both treatment effects and putative predictive biomarker effects are being employed to advance the goals of precision medicine. Basket trials investigate one or more biomarker-targeted therapies across multiple cancer types in a tumor location agnostic fashion. The review article offers an overview of the traditional forms of such designs, the practical challenges facing each type of design, and then review novel adaptations proposed in the last few years, categorized into Bayesian and Classical Frequentist perspectives. The review article concludes by summarizing potential advantages and limitations of the new trial design solutions.

Background: To review race and ethnic group enrollment and outcomes for Wilms tumor (WT) across all 4 risk-assigned therapeutic trials from the current era Children's Oncology Group Renal Tumor Biology and Risk Stratification Protocol, AREN03B2., Study Design: For patients with WT enrolled in AREN03B2 (2006 to 2019), disease and biologic features, therapeutic study-specific enrollment, and event-free (EFS) and overall (OS) 4-year survival were compared between institutionally reported race and ethnic groups., Results: Among 5,146 patients with WT, no statistically significant differences were detected between race and ethnic groups regarding subsequent risk-assigned therapeutic study enrollment, disease stage, histology, biologic factors, or overall EFS or OS, except the following variables: Black children were older and had larger tumors at enrollment, whereas Hispanic children had lower rates of diffuse anaplasia WT and loss of heterozygosity at 1p. The only significant difference in EFS or OS between race and ethnic groups was observed among the few children treated for diffuse anaplasia WT with regimen UH-1 and -2 on high-risk protocol, AREN0321. On this therapeutic arm only, Black children showed worse EFS (hazard ratio = 3.18) and OS (hazard ratio = 3.42). However, this finding was not replicated for patients treated with regimen UH-1 and -2 under AREN03B2 but not on AREN0321., Conclusions: Race and ethnic group enrollment appeared constant across AREN03B2 risk-assigned therapeutic trials. EFS and OS on these therapeutic trials when analyzed together were comparable regarding race and ethnicity. Black children may have experienced worse stage-specific survival when treated with regimen UH-1 and -2 on AREN0321, but this survival gap was not confirmed when analyzing additional high-risk AREN03B2 patients., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with stage IV favorable histology Wilms tumor (FHWT) with extrapulmonary metastases (EPM) constitute a small subset of patients with FHWT. Because of their rarity and heterogeneity, optimal FHWT treatment is not well understood. Children's Oncology Group protocol AREN0533 assigned patients with FHWT and EPM to intensified chemotherapy, regimen M, after initial DD-4A chemotherapy. To improve understanding of prognostic factors and best therapies, experiences of patients with EPM on AREN0533, as well as on protocols AREN03B2 and NWTS-5, were reviewed., Methods: Combined outcomes for patients with EPM from NWTS-5, AREN0533, and AREN03B2 were determined. Those treated on AREN0533 were compared with those treated on NWTS-5. Prognostic factors were explored in the pooled cohort., Results: Forty-seven patients with FHWT with EPM enrolled on AREN0533, 37 enrolled on NWTS-5, and 64 were followed only on AREN03B2. The pooled cohort of all 148 patients demonstrated a 4-year event-free survival (EFS) of 77.3% (95% CI, 70.8-84.4) and 4-year overall survival of 88.9% (95% CI, 83.9-94.2). Four-year EFS of patients with EPM treated on AREN0533 was 76.0% (95% CI, 64.6-89.4) vs 64.9% (95% CI, 51.7-82.2) on NWTS-5; hazard ratio, 0.64, p = .26; no difference in overall survival was observed. Increasing linear age and slow incomplete lung response were associated with worse EFS in a pooled cohort., Conclusions: Outcomes for patients with EPM are among the lowest for children with FHWT. Further trials with standardized surgical and radiation treatment to metastatic sites, and prospectively collected biologic and treatment details are needed., Clinical Trial Registration: Clinical Trials.gov identifiers: NCT00379340, NCT00898365, and NCT00002611., (© 2023 American Cancer Society.)

Introduction: The prognostic impact of positive lymph nodes (LN+) and/or singular loss of heterozygosity (LOH) of 1p or 16q were assessed in children with stage III favorable histology Wilms tumor (FHWT) enrolled on AREN0532 or AREN03B2 alone., Patients and Methods: A total of 635 stage III FHWT vincristine/dactinomycin/doxorubicin (DD4A)-treated patients met inclusion criteria. Event-free survival (EFS) and overall survival are reported overall and by LN sampling, LN status, LOH 1p, LOH 16q, and a combination of LN status and singular LOH. Patients with unknown or positive combined LOH of 1p and 16q status and AREN03B2-only patients with unknown outcomes or treatment other than DD4A were excluded., Results: EFS did not differ by study, supporting pooling. Lack of LN sampling (hazard ratio [HR], 2.12; p = .0037), LN positivity (HR, 2.78; p = .0002), LOH 1p (HR, 2.18; p = .0067), and LOH 16q (HR, 1.72; p = .042) were associated with worse EFS. Compared with patients with both LN- and LOH-, those with negative nodes but positive LOH 1p or 16q and those with LN+ but LOH- for 1p or 16q had significantly worse EFS (HR, 3.05 and 3.57, respectively). Patients positive for both LN and LOH had the worst EFS (HR, 6.33; overall group factor, p < .0001)., Conclusion: Findings confirm LN+ status as an adverse prognostic factor amplified by presence of singular LOH 1p or 16q, supporting study of intensified therapy for patients with LN+ in combination with singular LOH in a prospective clinical trial., (© 2023 American Cancer Society.)

Pediatric cancer consists of a diverse group of rare diseases. Due to limited patient populations, standard randomized and controlled trials are often infeasible. As a result, single-arm trials are common in pediatric oncology and the use of external controls is often desirable or necessary to help generate actionable evidence and contextualize trial results. In this paper, we illustrate unique features in pediatric oncology clinical trials and describe their impact on the use of external controls. Various types of relevant external control data sources are described in terms of their utility and drawbacks. Statistical methodologies and design implications with external control are discussed. Two recent case studies using external controls to support pediatric oncology drug development are described in detail., Competing Interests: Conflicts of Interest Statement Yuan Ji: Co-Founder of Bayesoft Inc., a statistical company providing consultation and software service for pharmaceutical and biotech industry. IDMC member for Astellas, Boehringer Ingelheim and Lyell. Executive Advisor for Cytel Inc. Haitao Pan was partially supported by American Lebanese Syrian Associated Charities (ALSAC).

Developing synchronous bilateral Wilms tumor suggests an underlying (epi)genetic predisposition. Here, we evaluate this predisposition in 68 patients using whole exome or genome sequencing (n = 85 tumors from 61 patients with matched germline blood DNA), RNA-seq (n = 99 tumors), and DNA methylation analysis (n = 61 peripheral blood, n = 29 non-diseased kidney, n = 99 tumors). We determine the predominant events for bilateral Wilms tumor predisposition: 1)pre-zygotic germline genetic variants readily detectable in blood DNA [WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%), and BRCA-related genes (5%)] or 2)post-zygotic epigenetic hypermethylation at 11p15.5 H19/ICR1 that may require analysis of multiple tissue types for diagnosis. Of 99 total tumor specimens, 16 (16.1%) have 11p15.5 normal retention of imprinting, 25 (25.2%) have 11p15.5 copy neutral loss of heterozygosity, and 58 (58.6%) have 11p15.5 H19/ICR1 epigenetic hypermethylation (loss of imprinting). Here, we ascertain the epigenetic and genetic modes of bilateral Wilms tumor predisposition., (© 2023. The Author(s).)

Purpose: The safety of reintroducing chemotherapy in the pediatric renal tumor setting after severe hepatopathy (SH), including sinusoidal obstruction syndrome (SOS), is uncertain. We describe the incidence, severity, outcomes, and impact on subsequent treatment for patients with SH from National Wilms Tumor Study (NWTS) protocols 3-5., Patients and Methods: Archived charts for patients enrolled on NWTS 3-5 who met study inclusion criteria for SH by using established hepatopathy grading scales and clinical criteria were reviewed for demographics, tumor characteristics, radio- and chemotherapy details, SH-related dose modifications, and oncologic outcomes. Genomic analysis for candidate polymorphisms associated with SH was performed in 14 patients., Results: Seventy-one of 8,862 patients (0.8%) met study inclusion criteria. The median time from therapy initiation to SH was 51 days (range, 2-293 days). Sixty percent received radiotherapy, and 56% had right-sided tumors. Grade 1-4 thrombocytopenia was noted in 70% at initial occurrence of SH (median 22,000/microliter). Among 69 of 71 children with SH occurring before the end of therapy (EOT) and post-SH treatment information available, chemotherapy was delayed posthepatopathy for 65% (69% of these at a reduced dose), continued without delay for 20% (57% of these at reduced dose), and stopped completely for 15% (4 of 10 of whom died of SH). Overall, 42% of patients with dose reductions achieved full dose by EOT. The five-year post-SH event-free survival for patients who continued therapy was 89% (95% CI, 81 to 98), with no significant differences by whether delay or dose reduction occurred. We identified no SH-associated pharmacogenomic polymorphism., Conclusion: The incidence of SH on NWTS 3-5 was low; many had associated severe thrombocytopenia. Careful reintroduction of chemotherapy appeared to be feasible for the majority of patients who developed severe chemotherapy- and/or radiotherapy-induced liver toxicity.

Every year, approximately 600 infants, children, and adolescents are diagnosed with renal cancer in the United States. In addition to Wilms tumor (WT), which accounts for about 80% of all pediatric renal cancers, clear cell sarcoma of the kidney, renal cell carcinoma, malignant rhabdoid tumor, as well as more rare cancers (other sarcomas, rare carcinomas, lymphoma) and benign tumors can originate within the kidney. WT itself can be divided into favorable histology (FHWT), with a 5-year overall survival (OS) exceeding 90%, and anaplastic histology, with 4-year OS of 73.7%. Outcomes of the other pediatric renal cancers include clear cell sarcoma (5-year OS: 90%), malignant rhabdoid tumor (5-year OS: 10% for stages 3 and 4), and renal cell carcinoma (4-year OS: 84.8%). Recent clinical trials have identified novel biological prognostic markers for FHWT, and a series of Children's Oncology Group (COG) trials have demonstrated improving outcomes with therapy modification, and opportunities for further care refinement., (© 2023 Wiley Periodicals LLC.)

This study comprehensively evaluated the landscape of genetic and epigenetic events that predispose to synchronous bilateral Wilms tumor (BWT). We performed whole exome or whole genome sequencing, total-strand RNA-seq, and DNA methylation analysis using germline and/or tumor samples from 68 patients with BWT from St. Jude Children's Research Hospital and the Children's Oncology Group. We found that 25/61 (41%) of patients evaluated harbored pathogenic or likely pathogenic germline variants, with WT1 (14.8%), NYNRIN (6.6%), TRIM28 (5%) and the BRCA-related genes (5%) BRCA1, BRCA2, and PALB2 being most common. Germline WT1 variants were strongly associated with somatic paternal uniparental disomy encompassing the 11p15.5 and 11p13/ WT1 loci and subsequent acquired pathogenic CTNNB1 variants. Somatic coding variants or genome-wide copy number alterations were almost never shared between paired synchronous BWT, suggesting that the acquisition of independent somatic variants leads to tumor formation in the context of germline or early embryonic, post-zygotic initiating events. In contrast, 11p15.5 status (loss of heterozygosity, loss or retention of imprinting) was shared among paired synchronous BWT in all but one case. The predominant molecular events for BWT predisposition include pathogenic germline variants or post-zygotic epigenetic hypermethylation at the 11p15.5 H19/ICR1 locus (loss of imprinting). This study demonstrates that post-zygotic somatic mosaicism for 11p15.5 hypermethylation/loss of imprinting is the single most common initiating molecular event predisposing to BWT. Evidence of somatic mosaicism for 11p15.5 loss of imprinting was detected in leukocytes of a cohort of BWT patients and long-term survivors, but not in unilateral Wilms tumor patients and long-term survivors or controls, further supporting the hypothesis that post-zygotic 11p15.5 alterations occurred in the mesoderm of patients who go on to develop BWT. Due to the preponderance of BWT patients with demonstrable germline or early embryonic tumor predisposition, BWT exhibits a unique biology when compared to unilateral Wilms tumor and therefore warrants continued refinement of its own treatment-relevant biomarkers which in turn may inform directed treatment strategies in the future., Competing Interests: Conflict of Interest Statement: The authors have no conflicts of interest to declare.

As diseases like cancer are increasingly understood on a molecular level, clinical trials are being designed to reveal or validate subpopulations in which an experimental therapy has enhanced benefit. Such biomarker-driven designs, particularly "adaptive enrichment" designs that initially enroll an unselected population and then allow for later restriction of accrual to "marker-positive" patients based on interim results, are increasingly popular. Many biomarkers of interest are naturally continuous, however, and most existing design approaches either require upfront dichotomization or force monotonicity through algorithmic searches for a single marker threshold, thereby excluding the possibility that the continuous biomarker has a nondisjoint and truly nonlinear or nonmonotone prognostic relationship with outcome or predictive relationship with treatment effect. To address this, we propose a novel trial design that leverages both the actual shapes of any continuous marker effects (both prognostic and predictive) and their corresponding posterior uncertainty in an adaptive decision-making framework. At interim analyses, this marker knowledge is updated and overall or marker-driven decisions are reached such as continuing enrollment to the next interim analysis or terminating early for efficacy or futility. Using simulations and patient-level data from a multi-center Children's Oncology Group trial in Acute Lymphoblastic Leukemia, we derive the operating characteristics of our design and compare its performance to a traditional approach that identifies and applies a dichotomizing marker threshold., (© 2021 The International Biometric Society.)

Purpose: The utility of circulating tumor DNA (ctDNA) analyses has not been established in the risk stratification of Wilms tumor (WT). We evaluated the detection of ctDNA and selected risk markers in the serum and urine of patients with WT and compared findings with those of matched diagnostic tumor samples., Patients and Methods: Fifty of 395 children with stage III or IV WT enrolled on Children's Oncology Group trial AREN0533 had banked pretreatment serum, urine, and tumor available. Next-generation sequencing was used to detect ctDNA. Copy-number changes in 1q, 16q, and 1p, and single-nucleotide variants in serum and urine were compared with tumor biopsy data. Event-free survival (EFS) was compared between patients with and without ctDNA detection., Results: ctDNA was detected in the serum of 41/50 (82%) and in the urine in 13/50 (26%) patients. Agreement between serum ctDNA detection and tumor sequencing results was as follows: 77% for 1q gain, 88% for 16q deletions, and 70% for 1p deletions, with ĸ-coefficients of 0.56, 0.74, and 0.29, respectively. Sequencing also demonstrated that single-nucleotide variants detected in tumors could be identified in the ctDNA. There was a trend toward worse EFS in patients with ctDNA detected in the serum (4-year EFS 80% v 100%, P = .14)., Conclusion: ctDNA demonstrates promise as an easily accessible prognostic biomarker with potential to detect tumor heterogeneity. The observed trend toward more favorable outcome in patients with undetectable ctDNA requires validation. ctDNA profiling should be further explored as a noninvasive diagnostic and prognostic tool in the risk-adapted treatment of patients with WT.

Over the last decade, sequencing of primary tumors has clarified the genetic underpinnings of Wilms tumor but has not affected therapy, outcome, or toxicity. We now sharpen our focus on relapse samples from the umbrella AREN03B2 study. We show that over 40% of relapse samples contain mutations in SIX1 or genes of the MYCN network, drivers of progenitor proliferation. Not previously seen in large studies of primary Wilms tumors, DIS3 and TERT are now identified as recurrently mutated. The analysis of primary-relapse tumor pairs suggests that 11p15 loss of heterozygosity (and other copy number changes) and mutations in WT1 and MLLT1 typically occur early, but mutations in SIX1, MYCN, and WTX are late developments in some individuals. Most strikingly, 75% of relapse samples had gain of 1q, providing strong conceptual support for studying circulating tumor DNA in clinical trials to better detect 1q gain earlier and monitor response., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Refinements in surgery, radiation therapy, and chemotherapy since the mid-20th century have resulted in a survival rate exceeding 90% for patients with Wilms tumor (WT). Although this figure is remarkable, a significant proportion of patients continue to have event-free survival (EFS) estimates of <75%, and nearly 25% of survivors experience severe chronic medical conditions. The first-generation Children's Oncology Group (COG) renal tumor trials (AREN '0'), which opened to enrollment in 2006, focused on augmenting treatment regimens for WT subgroups with predicted EFS <75% to 80%, including those with the adverse prognostic marker of combined loss of heterozygosity (LOH) at chromosomes 1p/16q, pulmonary metastasis with incomplete lung nodule response after 6 weeks of chemotherapy, bilateral disease, and anaplastic histology. Conversely, therapy was reduced for patient subgroups with good outcomes and potential for long-term toxicity, such as those with lung metastasis with complete lung nodule response after 6 weeks of chemotherapy. This article summarizes the key findings of the first-generation COG renal tumor studies and their implications for clinical practice.

In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in two-stage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous., (© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.)

In the United States, cancer remains the leading cause of disease-related death in children. Although survival from any pediatric cancer has improved dramatically during past decades, a number of cancers continue to yield dismal prognoses, which has motivated the continued study of novel therapeutic strategies. Furthermore, even patients cured of pediatric cancer often experience severe adverse effects of treatment and other long-term health implications, such as cardiotoxicity or loss of fertility. For these patients, improved risk stratification to identify those who could safely receive alternate or less-intensive therapy without affecting prognosis is a key objective. Fortunately, pediatric cancers are rare overall, but even among patients with the same narrow cancer type, there is often broad heterogeneity in terms of prognosis, molecular features or pathology, current treatment strategies, and scientific objectives. As a result, the design of clinical trials in the pediatric cancer setting is challenged by a number of practical issues that must be addressed to ensure trial feasibility for this vulnerable group of patients. In this review, we discuss some of the unique trial design considerations often encountered in any rare tumor setting through the lens of our experiences as faculty statisticians for the Children's Oncology Group, the largest organization in the world dedicated exclusively to pediatric cancer research and clinical trials. These topics include risk stratification within individual trials, relaxation of trial operating characteristics and parameters, use of historical controls, and address of noninferiority-type objectives in small cohorts. We review each in terms of practical motivation, present challenges, and potential solutions described in the literature and implemented in selected example trials from the Children's Oncology Group., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Arzu Onar-ThomasHonoraria: Eli Lilly Research Funding: Novartis (Inst), Apexigen (Inst), Pfizer (Inst), Celgene (Inst), Merck (Inst) Travel, Accommodations, Expenses: Eli LillyJohn A. KairallaStock and Other Ownership Interests: Johnson & Johnson, Sophiris Bio No other potential conflicts of interest were reported., (© 2019 by American Society of Clinical Oncology.)

Purpose: Patients with left-sided colon tumours have better survival and respond differently to biologics compared with patients with right-sided tumours. Left-sided colon tumours and rectal cancers are often grouped together. Herein, we examined the clinicopathological differences and outcomes between left-sided colon and rectal cancers., Patients and Methods: Data from 2879 metastatic colorectal cancer patients enrolled on six first-line clinical trials during 2004-2010 were pooled. Patients were included if the primary tumour origin was clearly defined. Progression-free survival (PFS) and overall survival (OS) were compared in the two groups after adjusting for patient and tumour characteristics, metastatic sites and the first-line regimen., Results: In total, 1374 patients with metastatic left-sided colon cancer and 1505 patients with metastatic rectal cancers were evaluated. Left-sided colon cancer patients were more likely to be female (40.1% versus 32.6%; P < 0.0001) and older (31.0% ≥ 70 years versus 25.8%; P = 0.0033) compared with rectal cancers patients. Patients with left-sided colon cancer had higher rates of liver metastases (80.9% versus 72.3%, P < 0.0001) but lower rates of lung metastases (34.2% versus 53.8%, P < 0.0001). KRAS mutations were slightly less frequent among left-sided tumours (34.8% versus 40.5%; P = 0.0103). Patients with left-sided tumours had approximately similar PFS (median 7.4 versus 6.9 months; hazard ratio [HR] 0.92, 95% confidence interval [CI] 0.87-1.03; P = 0.1998) and OS (median 17.4 versus 16.6 months; HR 0.99, 95% CI 0.91-1.07; P = 0.7597) compared with rectal cancer patients., Conclusion: The site of tumour origin within the left side was not prognostic of outcomes. Moreover, neither bevacizumab nor cetuximab impacted, differently, the findings of the comparisons in outcomes between patients with left-sided colon tumours or rectal cancers., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recently, several study designs incorporating treatment effect assessment in biomarker-based subpopulations have been proposed. Most statistical methodologies for such designs focus on the control of type I error rate and power. In this paper, we have developed point estimators for clinical trials that use the two-stage adaptive enrichment threshold design. The design consists of two stages, where in stage 1, patients are recruited in the full population. Stage 1 outcome data are then used to perform interim analysis to decide whether the trial continues to stage 2 with the full population or a subpopulation. The subpopulation is defined based on one of the candidate threshold values of a numerical predictive biomarker. To estimate treatment effect in the selected subpopulation, we have derived unbiased estimators, shrinkage estimators, and estimators that estimate bias and subtract it from the naive estimate. We have recommended one of the unbiased estimators. However, since none of the estimators dominated in all simulation scenarios based on both bias and mean squared error, an alternative strategy would be to use a hybrid estimator where the estimator used depends on the subpopulation selected. This would require a simulation study of plausible scenarios before the trial., (© 2018 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.)

Background: Estimating prognosis on the basis of clinicopathologic factors can inform clinical practice and improve risk stratification for clinical trials. We constructed prognostic nomograms for one-year overall survival and six-month progression-free survival in metastatic colorectal carcinoma by using the ARCAD database., Methods: Data from 22 674 patients in 26 randomized phase III clinical trials since 1997 were used to construct and validate Cox models, stratified by treatment arm within each study. Candidate variables included baseline age, sex, body mass index, performance status, colon vs rectal cancer, prior chemotherapy, number and location of metastatic sites, tumor mutation status (BRAF, KRAS), bilirubin, albumin, white blood cell count, hemoglobin, platelets, absolute neutrophil count, and derived neutrophil-to-lymphocyte ratio. Missing data (<11%) were imputed, continuous variables modeled with splines, and clinically relevant pairwise interactions tested if P values were less than .001. Final models were internally validated via bootstrapping to obtain optimism-corrected calibration and discrimination C-indices, and externally validated on a 10% holdout sample from each trial (n = 2257)., Results: In final models, all included variables were associated with overall survival except for lung metastases, and all but total white cell count associated with progression-free survival. No clinically relevant pairwise interactions were identified. Final nomogram calibration was good (C = 0.68 for overall and C = 0.62 for progression-free survival), as was external validity (concordance between predicted >50% vs < 50% probability) and actual (yes/no) survival (72.8% and 68.2% concordance, respectively, for one-year overall and six-month progression-free survival, between predicted [>50% vs < 50% probability] and actual [yes/no] overall and progression-free survival). Median survival predictions fell within the actual 95% Kaplan-Meier confidence intervals., Conclusions: The nomograms are well calibrated and internally and externally valid. They have the potential to aid prognostication and patient-physician communication and balance risk in colorectal cancer trials.

Aortic sarcomas are a very rare condition typically characterized by a deceiving presentation. Making a correct diagnosis is based on the application of an algorithm which allows to identify the primary disease site and to obtain a tissue diagnosis. Surgical aortic resection with adjuvant therapy offers the best palliation, particularly in cases of well-differentiated tumors with no evidence of diffuse metastatic spread., Competing Interests: The authors declare no conflict of interest related to this article., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures., Methods: We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12., Results: After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority)., Conclusions: Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Purpose: The purpose of this study was to evaluate the safety and efficacy of ontuxizumab (MORAb-004), a monoclonal antibody that interferes with endosialin (tumor endothelial marker-1) function, in patients with chemorefractory metastatic colorectal cancer and to identify a responsive patient population based on biomarkers. Experimental Design: This was a randomized, double-blind, placebo-controlled, phase II study. Patients were randomly assigned in a 2:1 ratio to receive weekly intravenous ontuxizumab (8 mg/kg) or placebo plus best supportive care until progression or unacceptable toxicity. Tissue and blood biomarkers were evaluated for their ability to identify a patient population that was responsive to ontuxizumab. Results: A total of 126 patients were enrolled. No significant difference between the ontuxizumab and placebo groups was evident for the primary endpoint of progression-free survival (PFS), with a median PFS of 8.1 weeks in each group (HR, 1.13; 95% confidence interval, 0.76-1.67; P = 0.53). There were no significant differences between groups for overall survival (OS) or overall response rate (ORR). The most common treatment-emergent adverse events (TEAEs) in the ontuxizumab group (vs. the placebo group, respectively) were fatigue (53.7% vs. 47.5%), nausea (39.0% vs. 35.0%), decreased appetite (34.1% vs. 27.5%), and constipation (28.0% vs. 32.5%). The most common grade 3/4 TEAE in the ontuxizumab group versus placebo was back pain (11.0% vs. 0%). No single biomarker clearly identified patients responsive to ontuxizumab. Conclusions: No benefit with ontuxizumab monotherapy compared with placebo for clinical response parameters of PFS, OS, or ORR was demonstrated. Ontuxizumab was well tolerated. Clin Cancer Res; 24(2); 316-25. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Within the field of cancer research, discovery of biomarkers and genetic mutations that are potentially predictive of treatment benefit is motivating a paradigm shift in how cancer clinical trials are conducted. In this review, we provide an overview of the class of trials known as "master protocols," including basket trials, umbrella trials, and platform trials. For each, we describe standardized terminology, provide a motivating example with modeling details and decision rules, and discuss statistical advantages and limitations. We conclude with a discussion of general statistical considerations and challenges encountered across these types of trials.

Purpose Molecular diagnostic testing has become an integral part of the evaluation of patients with metastatic colorectal cancer (CRC). Expanded mutational testing, such as next-generation sequencing (NGS), often identifies mutations with unclear clinical or prognostic implications. One such example is BRAF mutations that occur outside of codon 600 ( non-V600 BRAF mutations). Methods We conducted this multicenter, retrospective cohort study to characterize the clinical, pathologic, and survival implications of non-V600 BRAF mutations in metastatic CRC. We pooled patients in whom non-V600 BRAF mutations were identified from NGS databases at three large molecular genetics reference laboratories. Results A total of 9,643 patients with metastatic CRC underwent NGS testing. We identified 208 patients with non-V600 BRAF mutations, which occurred in 2.2% of all patients tested and accounted for 22% of all BRAF mutations identified. Cancers with non-V600 BRAF mutations, compared with cancers with V600E BRAF ( V600E BRAF) mutations, were found in patients who were significantly younger (58 v 68 years, respectively), fewer female patients (46% v 65%, respectively), and patients who had fewer high-grade tumors (13% v 64%, respectively) or right-sided primary tumors (36% v 81%, respectively). Median overall survival was significantly longer in patients with non-V600 BRAF-mutant metastatic CRC compared with those with both V600E BRAF-mutant and wild-type BRAF metastatic CRC (60.7 v 11.4 v 43.0 months, respectively; P < .001). In multivariable analysis, non-V600 BRAF mutation was independently associated with improved overall survival (hazard ratio, 0.18; P < .001). Conclusion Non-V600 BRAF mutations occur in approximately 2.2% of patients with metastatic CRC and define a clinically distinct subtype of CRC with an excellent prognosis.

Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.

Background: Little is known about anorectal function and quality of life after chemoradiation followed by local excision, which is an alternative to total mesorectal excision for selected patients with early rectal cancer., Objective: The purpose of this study was to prospectively assess anorectal function and health-related quality of life of patients with T2N0 rectal cancer who were treated with an alternative approach., Design: This was a prospective, phase II trial., Settings: The study was multicentric (American College of Surgeons Oncology Group trial Z6041)., Interventions: Patients with stage cT2N0 rectal adenocarcinomas were treated with an oxaliplatin/capecitabine-based chemoradiation regimen followed by local excision., Main Outcome Measures: Anorectal function and quality of life were assessed at enrollment and 1 year postoperatively with the Fecal Incontinence Severity Index, Fecal Incontinence Quality of Life scale, and Functional Assessment of Cancer Therapy-Colorectal Questionnaire. Results were compared, and multivariable analysis was performed to identify predictors of outcome., Results: Seventy-one patients (98%) were evaluated at enrollment and 66 (92%) at 1 year. Compared with baseline, no significant differences were found on Fecal Incontinence Severity Index scores at 1 year. Fecal Incontinence Quality of Life results were significantly worse in the lifestyle (p < 0.001), coping/behavior (p < 0.001), and embarrassment (p = 0.002) domains. There were no differences in the Functional Assessment of Cancer Therapy overall score, but the physical well-being subscale was significantly worse and emotional well-being was improved after surgery. Treatment with the original chemoradiation regimen predicted worse depression/self-perception and embarrassment scores in the Fecal Incontinence Quality of Life, and male sex was predictive of worse scores in the Functional Assessment of Cancer Therapy overall score and trial outcome index., Limitations: Small sample size, relatively short follow-up, and absence of information before cancer diagnosis were study limitations., Conclusions: Chemoradiation followed by local excision had minimal impact on anorectal function 1 year after surgery. Overall quality of life remained stable, with mixed effects on different subscales. This information should be used to counsel patients about expected outcomes.

Background: The Oncotype DX colon cancer assay is a validated predictor of recurrence risk in patients with resected stage II colon cancer. We previously reported that Oncotype DX led to a change in treatment recommendations for 45% of patients with T3 mismatch repair proficient (MMR-P) stage II tumors in a prospective study. In the present study, we report the assay's influence on patient treatment decisions, physician confidence, concordance between physicians and patients, and patient decisional conflict., Patients and Methods: Consecutive patients with resected stage IIA colon cancer were enrolled. The tumor specimens were assessed using a 12-gene assay (reverse transcription-polymerase chain reaction) and by immunohistochemistry for MMR. Before and after receiving the results, the patients completed surveys that included their treatment preference, their current and preferred roles in treatment decision-making, and indicators of decisional conflict. Physicians completed similar pre- and postassay surveys., Results: Of 221 patients enrolled, 139 T3 MMR-P patients were evaluable for the patient-reported analyses and 150 patients were evaluable for the physician-reported analyses. Before the assay, 46% of the patients chose observation, 3% 5-fluorouracil, 7% oxaliplatin, 4% other, and 41% were undecided. After the assay, 75% chose observation, 12% 5-fluorouracil, 11% oxaliplatin, and 2% other. After the assay, 94% of the defined treatment decisions were concordant between patients and physicians compared with 60% before the assay. Physicians reported the assay influenced their treatment decisions and increased confidence in their treatment recommendations for 69% and 84% of patients, respectively. Most patients (86%) reported that the assay influenced their treatment decisions. Patient decisional conflict was significantly lower after learning the assay results (P < .001)., Conclusion: In the present prospective study, knowledge of the 12-gene assay results influenced treatment decisions for most patients and physicians, increased physician confidence, improved the concordance between patients and physicians, and decreased patient decisional conflict., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Traditionally, site of disease and anatomic staging have been used to define patient populations to be studied in individual cancer clinical trials. In the past decade, however, oncology has become increasingly understood on a cellular and molecular level, with many cancer subtypes being described as a function of biomarkers or tumor genetic mutations. With these changes in the science of oncology have come changes to the way we design and perform clinical trials. Increasingly common are trials tailored to detect enhanced efficacy in a patient subpopulation, e.g. patients with a known biomarker value or whose tumors harbor a specific genetic mutation. Here, we provide an overview of traditional and newer biomarker-based trial designs, and highlight lessons learned through implementation of several ongoing and recently completed trials., Competing Interests: STATEMENT The authors have no conflicts of interest to disclose, (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

In recent years, cancers once viewed as relatively homogeneous in terms of organ location and treatment strategy are now better understood to be increasingly heterogeneous across biomarker and genetically defined patient subgroups. This has produced a shift toward development of biomarker-targeted agents during a time when funding for cancer research has been limited; as a result, the need for improved operational efficiency in studying many agent-and-target combinations in parallel has emerged. Platform trials, basket trials, and umbrella trials are new approaches to clinical research driven by this need for enhanced efficiency in the modern era of increasingly specific cancer subpopulations and decreased resources to study treatments for individual cancer subtypes in a traditional way. In this review, we provide an overview of these new types of clinical trial designs, including discussions of motivation for their use, recommended terminology, examples, and challenges encountered in their application.

The Adjuvant Colon Cancer End Points (ACCENT) Collaborative Group was formed 15 years ago to address scientific questions in early stage colon cancer that could best be answered by pooling individual patient data across many randomized clinical trials. Today, the ACCENT database contains detailed information collected from over 40,000 patients enrolled onto 27 major adjuvant colon cancer trials conducted between 1977 and 2009. Since its inception, the ACCENT group has led many sophisticated analyses addressing a variety of clinical questions, such as the long-term survivorship of colon cancer patients by treatment, the time course of oxaliplatin benefit, and support for the use of disease-free survival (DFS) as a surrogate endpoint for overall survival (OS), among many others. Here, we provide an updated overview of recent important results and future directions of the ACCENT collaboration.

Background: Adjuvant! Online is a tool used for clinical decision making in patients with early stage colon cancer. As details of the tool's construction are not published, the ability of Adjuvant! Online to accurately predict outcomes for older patients (age 70+) with node positive colon cancer receiving adjuvant chemotherapy is unclear., Methods: Individual data from older patients with stage III colon cancer who enrolled into multiple trials within the ACCENT database were entered into the Adjuvant! Online program to obtain predicted probabilities of 5-year overall survival (OS) and recurrence-free survival (RFS). Median predictions were compared with known rates. As co-morbidities were not known for ACCENT patients, but required for calculator entry, patients were assumed to have either "minor" or "average for age" co-morbidities., Results: 2967 older patients from 10 randomized studies were included. When "minor" co-morbidities were assumed, the median predicted 5-year OS rate of 64% nearly matched the actual rate of 65%; when "average for age" co-morbidities were assumed, the median prediction dropped to 58%, outside the CI for the actual rate. On the other hand, assuming "minor" co-morbidities gave a median 5-year RFS prediction of 62%, outside the 95% CI for the actual rate of 58%, while assuming "average for age" co-morbidities yielded a better median prediction of 57%., Conclusion: Adjuvant! Online is reasonably accurate overall for predicting outcomes in older trial patients with stage III colon cancer, though accuracy may differ between 5-year RFS and 5-year OS predictions when a fixed degree of co-morbidities is assumed., Competing Interests: AND CONFLICT OF INTEREST STATEMENTS The authors have declared no conflicts of interest., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Factors associated with early mortality after surgery and treatment with adjuvant chemotherapy in colon cancer are poorly understood. We aimed to characterize the determinants of early mortality in a large cohort of colon cancer trial participants., Methods: A pooled analysis of 37,568 patients in 25 randomized trials of adjuvant systemic therapy was conducted. Multivariable logistic regression models with several definitions of early mortality (30, 60, and 90 days, and 6 months) were constructed, adjusting for clinically and statistically significant variables. A nomogram for 6-month mortality was developed and validated., Results: Median age among patients was 61 years, patient demographics included 54% men and 90% White, 29% and 71% had stage II and III disease, respectively, and 79%, 20%, and 1% had an Eastern Cooperative Oncology Group performance status (PS) of 0, 1, and ≥ 2, respectively. Early mortality was low: 0.3% at 30 days, 0.6% at 60 days, 0.8% at 90 days, and 1.4% at 6 months. Of those patients who died by 6 months post-random assignment, 40% had documented disease recurrence prior to death. Early disease recurrence was associated with a markedly increased risk of death during the first 6 months post-treatment (hazard ratio, 82.6; 95%CI, 66.9 to 102.1). In prognostic analyses, advanced age, male sex, poorer PS, increasing ratio of positive to examined lymph nodes, earlier decade of enrollment, and higher tumor stage and grade predicted a greater likelihood of early mortality, whereas treatment received was not strongly predictive. A multivariable model for 6-month mortality showed strong optimism-adjusted discrimination (concordance index, 0.73) and calibration., Conclusion: Early mortality was infrequent but more prevalent in patients with advanced age and a PS of ≥ 2, underscoring the need to carefully consider the risk-to-benefit ratio when making treatment decisions in these subgroups., (© 2016 by American Society of Clinical Oncology.)

Purpose: Fluorouracil plus leucovorin (FU + LV) adjuvant chemotherapy reduced the risk of recurrence and death across all time points in a pooled analysis of 20,898 patients with colon cancer from 18 randomized studies. The impact of oxaliplatin added to FU + LV on the time course of recurrence and survival remains unknown., Patients and Methods: A total of 12,233 patients enrolled to the randomized trials C-07, C-08, N0147, MOSAIC (Adjuvant Treatment of Colon Cancer), and XELOXA (Adjuvant XELOX) were pooled to examine the impact of oxaliplatin and tumor-specific factors on the time course of recurrence and death. For each end point, continuous-time risk was modeled over 6 years post treatment in all oxaliplatin-treated patients and patients concurrently randomized to FU + LV with or without oxaliplatin; the latter analyses supported time-dependent treatment comparisons., Results: Addition of oxaliplatin significantly reduced the risk of recurrence within the first 14 months post treatment for patients with stage II disease and within the first 4 years for patients with stage III disease. Oxaliplatin also significantly reduced risk of death from 2 to 6 years post treatment for patients with stage III disease, with no differences in timing of outcomes between treatment groups (ie, oxaliplatin did not simply postpone recurrence or death compared with FU + LV alone). Patients with stage II disease receiving oxaliplatin did not exhibit a significant reduction in risk of death in the first 6 years post treatment. Recurrence risk peaked near 14 months for both treatments, and risk of recurrence and death increased with increased tumor and nodal burden., Conclusions: These analyses support the addition of oxaliplatin to fluoropyrimidine-based adjuvant therapy in patients with stage III disease and underscore the need for adequate surveillance of patients with colon cancer during the first 3 years after adjuvant therapy., Competing Interests: Authors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)