Publications by authors named "Arvind Dasari"

77 Publications

Role of immunotherapy in gastro-enteropancreatic neuroendocrine neoplasms (gep-nens): Current advances and future directions.

J Neuroendocrinol 2021 Mar;33(3):e12943

Department of Hematology and Medical Oncology, University Hospitals, Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, USA.

Neuroendocrine neoplasms (NENs) are heterogeneous tumours originating from neuroendocrine cells (Pearse & Polak, Gut, 1971, 12,783). They were once considered as rare tumours, although their annual incidence has increased significantly and now exceeds seven cases in 100 000 in the USA (Dasari, et al., JAMA oncology, 2017, 3, 1335). They are a group of highly diverse neoplasms and can be classified into the spectrum of well-differentiated neuroendocrine tumours to poorly differentiated neuroendocrine carcinomas. This is entirely based on the tumour differentiation and grade (low, intermediate, high), which is determined by the Ki-67/mitotic index. The lower grades (G1/2) of the well-differentiated group are characterised by a relative indolent clinical course and the ability to secrete a variety of peptide hormones (Kloppel, Visceral medicine, 2017, 33, 324). Higher grades and poorly differentiated tumours tend to be more aggressive and have limited therapeutic options (Sorbye et al., Neuroendocrinology, 2019, 108, 54). In the modern era of immuno-oncology, immune checkpoint inhibitors (ICPIs) that target programmed cell death 1 (pembrolizumab, nivolumab), programmed cell death-ligand1 (avelumab, atezolizumab and durvalumab) or cytotoxic T-lymphocyte-associated protein 4 (ipilimumab) have revolutionised the management of many solid tumours. In patients with gastro-enteropancreatic (GEP)-NENs, there is a limited data regarding the role of ICPIs either as a single agent or in combination regimens. Here, we review the current advances for ICPIs and where they fit in the management of GEP-NENs.
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http://dx.doi.org/10.1111/jne.12943DOI Listing
March 2021

Epidemiology, Incidence, and Prevalence of Neuroendocrine Neoplasms: Are There Global Differences?

Curr Oncol Rep 2021 Mar 14;23(4):43. Epub 2021 Mar 14.

Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Purpose Of Review: The purpose of our review is to explore global epidemiologic trends of gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). Specifically, we sought to examine whether there are differences in incidence, prevalence, distribution (by primary tumor site, tumor grade, tumor stage at presentation), and overall survival of GEP NETs between different regions of the world.

Recent Findings: GEP NET incidence rates are rising steadily in North America, Asia, and Europe, though this rise appears to be most profound in North America. The distribution of GEP NETs differs regionally as in North America small intestinal and rectal NETs are most prevalent, in Asia rectal and pancreatic NETs are most prevalent, and in Europe small intestinal and pancreatic NETs are most prevalent. Overall survival for patients with GEP NETs appears to be improving with time. Some of the global increase in GEP NET incidence can be explained by increased health care utilization. This factor alone, however, does not explain the rise completely. Population-based studies utilizing uniform data collection instruments and a standard pathologic grading system are needed to identify other factors which may be contributing to this phenomenon.
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http://dx.doi.org/10.1007/s11912-021-01029-7DOI Listing
March 2021

Moving Beyond the Momentum: Innovative Approaches to Clinical Trial Implementation.

JCO Oncol Pract 2021 Feb 3:OP2000701. Epub 2021 Feb 3.

Smilow Cancer Center, Yale School of Medicine, New Haven, CT.

Despite efforts to enhance enrollment and the merger of national cooperative groups, < 5% of patients with cancer will enroll into a clinical trial. Additionally, clinical trials are affected by a lack of diversity inclusive of minority patients, rural residents, or low-income individuals. COVID-19 further exacerbated known barriers of reduced physician-patient interaction, physician availability, trial activation and enrollment, financial resources, and capacity for conducting research. Based on the cumulative insight of academic and community clinical researchers, we have created a white paper identifying existing challenges in clinical trial conduct and have provided specific recommendations of sustainable modifications to improve efficiency in the activation and conduct of clinical trials with an overarching goal of providing improved access and care to our patients with cancer.
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http://dx.doi.org/10.1200/OP.20.00701DOI Listing
February 2021

FAS and Subsequent Therapies in Pancreatic Neuroendocrine Tumors.

Neuroendocrinology 2021 Jan 12. Epub 2021 Jan 12.

We evaluated outcomes of treatment with 5-fluorouracil (5-FU), doxorubicin, and streptozocin (FAS) in well-differentiated pancreatic neuroendocrine tumors (PanNETs) and its impact on subsequent therapy (everolimus or temozolomide). Advanced PanNET patients treated at our center from 1992 to 2013 were retrospectively reviewed. Patients received bolus 5-FU (400 mg/m2), streptozocin (400 mg/m2) (both IV, days 1-5) and doxorubicin (40 mg/m2 IV, day 1) every 28 days. Overall response rate (ORR) was assessed using RECIST version 1.1. Of 243 eligible patients, 220 were evaluable for ORR, progression-free survival (PFS), and toxicity. Most (90%) had metastatic, nonfunctional PanNETs; 14% had prior therapy. ORR to FAS was 41% (95% confidence interval [CI]: 36-48%). Median follow-up was 61 months. Median PFS was 20 (95% CI: 15-23) months; median overall survival (OS) was 63 (95% CI: 60-71) months. Cox regression analyses suggested improvement with first-line vs subsequent lines of FAS therapy. Main adverse events ≥ grade 3 were neutropenia (10%) and nausea/vomiting (5.5%). Dose reductions were required in 32% of patients. Post-FAS everolimus (n=108; 68% second line) had a median PFS of 10 (95% CI: 8-14) months. Post-FAS temozolomide (n=60; 53% > fourth line) had an ORR of 13% and median PFS of 5.2 (95% CI: 4-12) months. In this largest reported cohort of PanNETs treated with chemotherapy, FAS demonstrated activity without significant safety concerns. FAS did not appear to affect subsequent PFS with everolimus; this sequence is being evaluated prospectively. Responses were noted with subsequent temozolomide-based regimens although PFS was possibly limited by line of therapy.
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http://dx.doi.org/10.1159/000514339DOI Listing
January 2021

Impacts of pembrolizumab therapy on immune phenotype in patients with high-grade neuroendocrine neoplasms.

Cancer Immunol Immunother 2021 Jan 4. Epub 2021 Jan 4.

Department of Medical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.

High grade neuroendocrine neoplasms (G3 NENs) are rare aggressive tumors with limited treatment options. Twenty-one previously treated patients with metastatic extra-pulmonary G3 NENs were treated with pembrolizumab. Baseline tumor samples were assessed for PD-L1 and tumor infiltrating lymphocytes (TIL). Peripheral blood samples drawn pre-treatment, prior to cycle three, and at disease progression were analyzed by flow cytometry. One patient achieved partial response, two had stable disease, and 18 exhibited progressive disease. The partially responding patient did not progress after 392 days, and the median progression-free survival (PFS) was 59 days. Longer PFS correlated independently with higher pre-treatment peripheral blood T-cell counts and lower pre-treatment activation state (CD69 expression) of naïve T cells and NK cells. Peripheral T-cell viability was reduced in patients with greater TILs. Post-treatment, T cells had reduced numbers of CD4 cells, reduced PD-1 expression, increased activation of effector (CD62L) cells, and increased expression of TIGIT. Baseline TIGIT expression on peripheral T cells also correlated positively with Ki67 in tumor. Patients with higher baseline T-cell expression of TIM-3 had shorter PFS. Despite limited activity of pembrolizumab, this study highlights the immune phenotype in this rare tumor type before and after treatment. High baseline peripheral T-cell count and reduced activation of T and NK cell subsets were associated with improved outcomes. Furthermore, increased post-treatment TIGIT and elevated baseline TIM-3 expression suggest that these may limit the efficacy of pembrolizumab, providing a rationale for combination immunotherapy (PD-1 with TIGIT and/or TIM-3 antibodies) to treat extra-pulmonary G3 NENs.
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http://dx.doi.org/10.1007/s00262-020-02811-5DOI Listing
January 2021

Epidemiology and Molecular-Pathologic Characteristics of CpG Island Methylator Phenotype (CIMP) in Colorectal Cancer.

Clin Colorectal Cancer 2020 Oct 12. Epub 2020 Oct 12.

Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: CpG island methylator phenotype (CIMP) forms a distinct epigenetic phenotype in colorectal cancer (CRC). Though associated with distinct clinicopathologic characteristics, limited evidence exists of the association of CIMP with patient's reported lifestyle factors and tumor molecular characteristics. We assessed the associations of these characteristics in a pooled analysis of CRC patients.

Patients And Methods: We pooled data from 3 CRC patient cohorts: Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC), biomarker-based protocol (Integromics), and The Cancer Genome Atlas (TCGA). CIMP was measured using the classical 6-gene methylated-in-tumor (MINT) marker panel (MINT1, MINT2, MINT31, p14, p16, and MLH1) in ATTACC and genome-wide human methylation arrays in Integromics and TCGA, respectively. CIMP-High (CIMP-H) was defined as ≥ 3 of 6 methylated markers in ATTACC. In TCGA and Integromics, CIMP-H group was defined on the basis of clusters of methylation profiles and high levels of methylation in tumor samples. Baseline comparisons of characteristics across CIMP groups (CIMP-H vs. CIMP-0) were performed by Student t test or chi-square test for continuous or categorical variables, respectively. Further logistic regression analyses were performed to compute the odds ratio (OR) of these associations.

Results: Pooled prevalence of CIMP-H was 22% across 3 data sets. CIMP-H CRC tumors were associated with older age at diagnosis (OR, 1.02; 95% confidence interval [CI], 1.01, 1.03), microsatellite instability-high (MSI-H) status (OR, 9.15; 95% CI, 4.45, 18.81), BRAF mutation (OR, 7.70; 95% CI, 4.98, 11.87), right-sided tumor location (OR, 2.40; 95% CI, 1.78, 3.22), poor differentiation (OR, 2.94; 95% CI, 1.95, 4.45), and mucinous histology (OR, 2.47; 95% CI, 1.77, 3.47), as reported previously in the literature. CIMP-H tumors were also found to be associated with self-reported history of alcohol consumption (OR, ever vs. never, 1.58; 95% CI, 1.07, 2.34). Pathologically, CIMP-H tumors were associated with the presence of intraepithelial lymphocytes (OR, 3.31; 95% CI, 1.41, 7.80) among patients in the Integromics cohort.

Conclusion: CIMP-H tumors were associated with history of alcohol consumption and presence of intraepithelial lymphocytes. In addition, we confirmed the previously known association of CIMP with age, MSI-H status, BRAF mutation, sidedness, and mucinous histology. Molecular pathologic epidemiology associations help us explore the underlying association of lifestyle and clinical factors with molecular subsets like CIMP and help guide cancer prevention and treatment strategies.
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http://dx.doi.org/10.1016/j.clcc.2020.09.007DOI Listing
October 2020

Alteration of FBXW7 is Associated with Worse Survival in Patients Undergoing Resection of Colorectal Liver Metastases.

J Gastrointest Surg 2021 Jan 17;25(1):186-194. Epub 2020 Nov 17.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1484, Houston, TX, 77030, USA.

Background: For patients undergoing resection of colorectal liver metastases (CLMs), the prognostic role of somatic gene alterations is increasingly recognized. F-box/WD repeat-containing protein 7 (FBXW7) is a tumor suppressor gene found in approximately 10% of patients with colorectal cancer. The aim of this study is to assess the association of FBXW7 with overall survival after CLM resection.

Methods: Patients who underwent initial CLM resection during 2001-2016 and had genetic sequencing data were studied. Risk factors for overall survival (OS) were evaluated with Cox proportional hazards models using backward elimination.

Results: Of 2045 patients who underwent CLM resection during the study period, 476 were included. The majority (90.5%) underwent prehepatectomy chemotherapy. A total of 27 patients (5.7%) had FBXW7 alteration, along with 240 (50.4%) RAS, 337 (70.8%) TP53, 51 (10.7%) SMAD4, and 27 (5.7%) BRAF. Cox proportional hazards model analyses including 5 somatic gene alteration status and 12 clinicopathologic factors revealed FBXW7(hazard ratio [HR] 1.99, P = 0.015), BRAF (HR 2.47, P = 0.023), RAS (HR 2.42, P < 0.001), TP53 (HR 2.00, P < 0.001), and SMAD4 alterations (HR 1.90, P = 0.004) as significantly associated with OS, together with three clinicopathologic factors, prehepatectomy chemotherapy > 6 cycles (HR 1.51, P = 0.021), number of CLM (HR 1.05, P = 0.007), and largest liver metastasis diameter (HR 1.07, P = 0.023). The covariate-adjusted 5-year OS was significantly lower in patients with FBXW7 alteration than in patients with FBXW7 wild-type (40.4% vs.59.4%, P = 0.015).

Conclusions: FBXW7 alterations are associated with worse survival after CLM resection. The information on multiple somatic gene alterations is imperative for risk stratification and patient selection for CLM resection.
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http://dx.doi.org/10.1007/s11605-020-04866-2DOI Listing
January 2021

Targeted Therapies in the Management of Well-Differentiated Digestive and Lung Neuroendocrine Neoplasms.

Curr Treat Options Oncol 2020 Oct 7;21(12):96. Epub 2020 Oct 7.

Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

Opinion Statement: Ongoing advances in our understanding of neuroendocrine tumor (NET) biology, genetics, and immunology, will continue to expand the availability of targeted therapies, thus improving the outcomes of patients. Well-differentiated neuroendocrine tumors (NETs) are grouped into pancreatic and non-pancreatic NETs (includes GI and thoracic NETs) for treatment considerations (Fig. 1). For panNETs, initial therapy is driven by the need of radiographic response, and targeted agents are typically reserved for second and third line based on the toxicity profile. Treatment options for non-pancreatic NETs are also expanding and while SSAs are the typical first-line option, everolimus and PRRT both remain approved therapies for future lines, and VEGF TKIs are showing promising results in research settings. Sequencing these agents and best time to incorporate peptide receptor radio therapy into the management algorithm remains an unmet need.
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http://dx.doi.org/10.1007/s11864-020-00794-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592099PMC
October 2020

Identification of Actionable Fusions as an Anti-EGFR Resistance Mechanism Using a Circulating Tumor DNA Assay.

JCO Precis Oncol 2019 3;3. Epub 2019 Oct 3.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Gene fusions are established oncogenic drivers and emerging therapeutic targets in advanced colorectal cancer. This study aimed to detail the frequencies and clinicopathological features of gene fusions in colorectal cancer using a circulating tumor DNA assay.

Methods: Circulating tumor DNA samples in patients with advanced colorectal cancer were analyzed at 4,581 unique time points using a validated plasma-based multigene assay that includes assessment of fusions in , , , , , and Associations between fusions and clinicopathological features were measured using Fisher's exact test. Relative frequencies of genomic alterations were compared between fusion-present and fusion-absent cases using an unpaired test.

Results: Forty-four unique fusions were identified in 40 (1.1%) of the 3,808 patients with circulating tumor DNA detected: (n = 6; 36% of all fusions detected), (n = 2; 27%), (n = 10, 23%), (n = 3; 7%), (n = 2; 5%), and (n = 1; 2%). Relative to nonfusion variants detected, fusions were more likely to be subclonal (odds ratio, 8.2; 95% CI, 2.94 to 23.00; < .001). Mutations associated with a previously reported anti-epidermal growth factor receptor (anti-EGFR) therapy resistance signature (subclonal and mutations) were found with fusions in (10 of 12 patients), (nine of 16 patients), and (seven of 10 patients). For the 27 patients with available clinical histories, 21 (78%) had EGFR monoclonal antibody treatment before fusion detection.

Conclusion: Diverse and potentially actionable fusions can be detected using a circulating tumor DNA assay in patients with advanced colorectal cancer. Distribution of coexisting subclonal mutations in , , and in a subset of the patients with fusion-present colorectal cancer suggests that these fusions may arise as a novel mechanism of resistance to anti-EGFR therapies in patients with metastatic colorectal cancer.
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http://dx.doi.org/10.1200/PO.19.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526699PMC
October 2019

Tumor Sidedness, Recurrence, and Survival After Curative Resection of Localized Colon Cancer.

Clin Colorectal Cancer 2021 Mar 31;20(1):e53-e60. Epub 2020 Aug 31.

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Health Services Research, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: Right-sided primary tumor location is associated with worse prognosis in metastatic colon cancer, but the effect of sidedness on recurrence and prognosis for non-metastatic disease is less understood. The purpose of this study was to examine the relationship between sidedness, recurrence, and survival among patients with localized colon cancer.

Patients And Methods: Consecutive patients who underwent curative resection of colon cancer (2006-2013) were identified from a prospective database and retrospectively analyzed. Risk for recurrence, overall survival, and survival after recurrence (SAR) were compared between left- and right-sided tumors using the log-rank test, and multivariable Cox proportional hazards regression.

Results: We evaluated 673 patients (347 right-sided). There was no difference in overall recurrence rates (adjusted hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.54-1.55; P = .75) or overall survival (HR, 1.22; 95% CI, 0.75-1.97; P = .42) between right- and left-sided primary tumors. However, right-sided tumors were more likely to develop multi-focal and poor prognostic site recurrence (P = .04). Among the 71 patients who developed recurrence, those with right-sided tumors had significantly lower SAR (HR, 3.88; 95% CI, 1.42-10.62; P = .008).

Conclusions: Among patients with colon cancer who underwent curative resection, tumor sidedness was not associated with recurrence risk. However, among patients who developed recurrence, right-sidedness was associated with unique recurrence patterns and inferior SAR. For patients presenting with localized disease, treatment stratification should not be based on tumor sidedness alone.
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http://dx.doi.org/10.1016/j.clcc.2020.08.007DOI Listing
March 2021

Sex Representation in Clinical Trials Associated with FDA Cancer Drug Approvals Differs Between Solid and Hematologic Malignancies.

Oncologist 2021 Feb 7;26(2):107-114. Epub 2020 Oct 7.

Medical Oncology, BC Cancer, Vancouver, British Columbia, Canada.

Background: Proportionate female representation in health research is necessary for scientific rigor and health equity. We aimed to assess the representation of women in clinical trials leading to U.S. Food and Drug Administration (FDA) cancer drug approvals.

Materials And Methods: Trials supporting FDA cancer drug approvals between July 2008 and June 2018 were sourced from PubMed and ClinicalTrials.gov. The ratio of female to male trial enrollment was compared with cancer incidence and mortality in the U.S. using International Agency for Research on Cancer data. Reproductive tract and breast cancers were excluded. Odds ratios (ORs) and 95% confidence intervals (CIs) comparing trial enrollment with population incidence and mortality were calculated.

Results: A total of 186 trials leading to 170 FDA cancer drug approvals showed slight female underrepresentation compared with overall cancer incidence in the U.S. (OR, 0.97; 95% CI, 0.95-0.98, p < .0001). Female enrollment for drugs approved between 2008-2013 and 2014-2018 was unchanged (OR, 1.02; 95% CI, 0.99-1.05, p = .25). There was slight female underrepresentation in hematological trials (OR, 0.95; 95% CI, 0.91-0.998; p = .040 for leukemia; OR, 0.95; 95% CI, 0.90-0.997; p = .040 for lymphoma) and significant female underrepresentation in colorectal (OR, 0.72; 95% CI, 0.69-0.76; p < .0001), pancreas (OR, 0.85; 95% CI, 0.78-0.93; p = .0004), lung (OR, 0.77; 95% CI, 0.75-0.80; p < .0001), kidney (OR, 0.63; 95% CI, 0.60-0.67; p < .0001), and thyroid cancer trials (OR, 0.26; 95% CI, 0.23-0.28; p < .0001) compared with U.S. incidence.

Conclusion: Female underrepresentation has persisted within solid organ tumor trials but is less notable in hematologic trials. Additional work is required to identify drivers of such disparity.

Implications For Practice: Adequate gender representation in clinical trials is a matter of health equity. This study demonstrates that women remain underrepresented in trials across hematological and solid organ trials compared with cancer incidence and mortality in women, with the disparity worse in a number of solid organ tumor types. There are thus still significant improvements to be made regarding adequate representation of women in trials. Studies exploring the reasons for ongoing disparity in gender representation are warranted to help clinicians to rectify this.
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http://dx.doi.org/10.1002/onco.13534DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7873318PMC
February 2021

Atypical, Non-V600 BRAF Mutations as a Potential Mechanism of Resistance to EGFR Inhibition in Metastatic Colorectal Cancer.

JCO Precis Oncol 2019 5;3. Epub 2019 Aug 5.

The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Atypical, non-V600 BRAF () mutations represent a rare molecular subtype of metastatic colorectal cancer (mCRC). Preclinical data are used to categorize mutations into class II (intermediate to high levels of kinase activity, independent) and III (low kinase activity level, dependent). The clinical impact of these mutations on anti-EGFR treatment efficacy is unknown.

Patients And Methods: Data from 2,084 patients with mCRC at a single institution and from an external cohort of 5,257 circulating tumor DNA (ctDNA) samples were retrospectively analyzed. Overall survival (OS) was calculated using Kaplan-Meier and log-rank tests. Statistical tests were two-sided.

Results: BRAF mutations were harbored by 257 patients, including 36 with mutations: 22 class III, 10 class II, four unclassified. For patients with mCRC, median OS was 36.1 months, without a difference between classes, and median OS was 21.0 months for patients with mCRC. In contrast to right-sided predominance of tumors with mutation, 53% of patients with mCRC had left-sided primary tumors. Concurrent mutations were noted in 33% of patients with mCRC, and 67% of patients had microsatellite stable disease. Among patients with wild-type mCRC who received anti-EGFR antibodies (monotherapy, n = 1; combination therapy, n = 10), no responses to anti-EGFR therapy were reported, and six patients (four with class III mutations, one with class II, and one unclassified) achieved stable disease as best response. Median time receiving therapy was 4 months (range, 1 to 16). In the ctDNA cohort, there was an increased prevalence of mutations and subclonal mutations ( < .001 for both) among predicted anti-EGFR exposed compared with nonexposed patients.

Conclusion: Efficacy of anti-EGFR therapy is limited in class II and III mCRC. Detection of mutations in ctDNA after EGFR inhibition may represent a novel mechanism of resistance.
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http://dx.doi.org/10.1200/PO.19.00102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446507PMC
August 2019

Representativeness of Black Patients in Cancer Clinical Trials Sponsored by the National Cancer Institute Compared With Pharmaceutical Companies.

JNCI Cancer Spectr 2020 Aug 24;4(4):pkaa034. Epub 2020 Apr 24.

Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA.

Background: Many clinical trials supporting new drug applications underrepresent minority patients. Trials conducted by the National Cancer Institute's National Clinical Trial's Network (NCTN) have greater outreach to community sites, potentially allowing better representation. We compared the representation of Black patients in pharmaceutical company-sponsored cancer clinical trials with NCTN trials and with the US cancer population.

Methods: We established a large cohort of study publications representing the results of trials that supported new US Food and Drug Administration drug approvals from 2008 to 2018. NCTN trial data were from the SWOG Cancer Research Network. US cancer population rates were estimated using Surveillance, Epidemiology, and End Results survey data. We compared the proportion of Black patients by enrollment year for each cancer type and overall. Tests of proportions were used. All statistical tests were 2-sided.

Results: A total 358 trials (pharmaceutical company-sponsored trials, 85; SWOG trials, 273) comprised of 93 825 patients (pharmaceutical company-sponsored trials, 46 313; SWOG trials, 47 512) for 15 cancer types were analyzed. Overall, the proportion of Black patients was 2.9% for pharmaceutical company-sponsored trials, 9.0% for SWOG trials, and 12.1% for the US cancer population ( < .001 for each pairwise comparison). These findings were generally consistent across individual cancer types.

Conclusions: The poor representation of Black patients in pharmaceutical company-sponsored trials supporting new drug applications could result in the use of new drugs with little data about efficacy or side effects in this key population. Moreover, because pharmaceutical company-sponsored trials test the newest available therapies, limited access to these trials represents a disparity in access to potential breakthrough therapies.
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http://dx.doi.org/10.1093/jncics/pkaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368466PMC
August 2020

FOLFOXIRI Versus Doublet Regimens in Right-Sided Metastatic Colorectal Cancer: Focus on Subsequent Therapies and Impact on Overall Survival.

Clin Colorectal Cancer 2020 Dec 5;19(4):248-255.e6. Epub 2020 Jun 5.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Introduction: It has been determined that right-sided metastatic colorectal cancer (mCRC) has a worse prognosis for overall survival (OS). Currently, there is no consensus on the best systemic regimen for treatment-naive right-sided tumors. We compared the impact of subsequent therapies on OS of patients treated with FOLFOXIRI (leucovorin, 5-fluorouracil, oxaliplatin, irinotecan) versus doublet regimens.

Patients And Methods: Data of patients with treatment-naive right-sided mCRC who received FOLFOXIRI or doublet regimens between January 2001 to December 2018 were retrospectively analyzed. OS was compared between the two groups, and prognostic factors were assessed by multivariate analysis.

Results: A total of 196 patients were selected; 33 patients received FOLFOXIRI and 163 patients doublet therapy. Median follow-up was 82.3 months. The FOLFOXIRI cohort received fewer subsequent lines of therapies (61% vs. 78%, P = .043). The greater the number of subsequent lines of therapy, the lower the risk of death (hazard ratio [95% confidence interval] 0.67 [0.46-0.99], 0.62 [0.45-0.86], and 0.56 [0.39-0.81] for > 1, > 2, and > 3 lines, respectively). By multivariate analysis, metastasectomy and bevacizumab with subsequent lines of therapy were the variables with greatest positive impact on OS (respectively, hazard ratio [95% confidence interval] 0.54 [0.38-0.78] and 0.61 [0.44-0.84]).

Conclusion: Patients with treatment-naive right-sided mCRC who received front-line FOLFOXIRI had a lower number of subsequent therapies than patients who received doublet regimens. Our findings highlight the relevance of the continuum of care in mCRC, regardless of the first-line regimen, and the importance of careful selection of patients for the FOLFOXIRI regimen.
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http://dx.doi.org/10.1016/j.clcc.2020.05.010DOI Listing
December 2020

ctDNA applications and integration in colorectal cancer: an NCI Colon and Rectal-Anal Task Forces whitepaper.

Nat Rev Clin Oncol 2020 12 6;17(12):757-770. Epub 2020 Jul 6.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

An increasing number of studies are describing potential uses of circulating tumour DNA (ctDNA) in the care of patients with colorectal cancer. Owing to this rapidly developing area of research, the Colon and Rectal-Anal Task Forces of the United States National Cancer Institute convened a panel of multidisciplinary experts to summarize current data on the utility of ctDNA in the management of colorectal cancer and to provide guidance in promoting the efficient development and integration of this technology into clinical care. The panel focused on four key areas in which ctDNA has the potential to change clinical practice, including the detection of minimal residual disease, the management of patients with rectal cancer, monitoring responses to therapy, and tracking clonal dynamics in response to targeted therapies and other systemic treatments. The panel also provides general guidelines with relevance for ctDNA-related research efforts, irrespective of indication.
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http://dx.doi.org/10.1038/s41571-020-0392-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790747PMC
December 2020

Pathologic Response and Postoperative Complications After Short-course Radiation Therapy and Chemotherapy for Patients With Rectal Adenocarcinoma.

Clin Colorectal Cancer 2020 06 8;19(2):116-122. Epub 2020 Feb 8.

Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: The role of neoadjuvant short-course radiation therapy (SCRT) in treating rectal adenocarcinoma is a topic of ongoing debate. Growing interest in total neoadjuvant therapy has spurred discussion on the optimal sequence of preoperative SCRT and chemotherapy.

Patients And Methods: All patients receiving SCRT (5 Gy × 5 fractions) were identified. Details about preoperative treatments, radiation toxicities, and postoperative complications were collected. Patients were divided into 2 groups: those who underwent surgery within 14 days of completing SCRT and those with a longer delay. Outcomes compared included extent of pathologic response, margin-negative resection rate, acute radiation toxicities, and postoperative complications.

Results: Fifty-seven patients with locally advanced or metastatic rectal cancer received SCRT between 2008 and 2018. Thirty-nine of 57 patients underwent definitive pelvic surgery with total mesorectal excision. There were no significant differences in tumor downstaging, radial margin status, or percent tumor viability between patients with immediate surgery versus delayed surgery. The delay group had higher rates of nodal downstaging (64.7% vs. 18.2%; P = .003). There were no differences in total or grade 3+ gastrointestinal radiation toxicity, postoperative complications, reoperation, readmission, and mortality between the 2 groups.

Conclusions: Though not yet common in the United States, SCRT has compared favorably with long course chemoradiation in multiple trials. Moreover, it is associated with greater efficiency and less disruption to chemotherapy. Our data show similar response and toxicity outcomes between the immediate and delay groups, suggesting SCRT is well-tolerated regardless of treatment sequence. Recently completed prospective trials may reveal the optimal preoperative treatment sequence.
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http://dx.doi.org/10.1016/j.clcc.2020.02.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370689PMC
June 2020

Pembrolizumab monotherapy in patients with previously treated metastatic high-grade neuroendocrine neoplasms: joint analysis of two prospective, non-randomised trials.

Br J Cancer 2020 04 10;122(9):1309-1314. Epub 2020 Mar 10.

H. Lee Moffitt Cancer Center, Tampa, FL, United States.

Background: Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs.

Methods: Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint.

Results: Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups (p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related.

Conclusions: Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered.

Clinical Trial Registration Number: NCT02939651 (10/20/2016).
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http://dx.doi.org/10.1038/s41416-020-0775-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7188798PMC
April 2020

Patient-reported Symptom Outcomes and Microsatellite Instability in Patients With Metastatic Colorectal Cancer.

Clin Colorectal Cancer 2020 03 23;19(1):48-56.e2. Epub 2019 Oct 23.

Department of Symptom Research, The University of Texas MD Anderson Cancer Center, Houston, TX. Electronic address:

Background: The survival of patients with metastatic colorectal cancer (mCRC) is influenced by the genetic and epigenetic changes that might influence the patient experience of symptom burden. Understanding the association of molecular changes with the symptom burden could help clinicians gain insight into the molecular basis of symptom burden and improve treatment tolerance. To date, no studies have compared the patient-reported symptom burden with these molecular subsets among patients with mCRC.

Patients And Methods: We recruited patients with mCRC that was refractory to ≥ 1 line of therapy who had been enrolled in the Assessment of Targeted Therapies Against Colorectal Cancer trial at The University of Texas MD Anderson Cancer Center. All patients completed a baseline gastrointestinal symptom inventory (MD Anderson Symptom Inventory, gastrointestinal). The symptom burden across key demographic variables and molecular changes, including CRC-associated mutations, microsatellite instability (MSI) status, and the CpG island methylator phenotype (CIMP) were compared using χ tests. Association of the symptom burden with overall survival was examined using Cox regression models.

Results: Patients with an MSI-high (MSI-H) phenotype reported greater pain (odds ratio [OR], 3.06; 95% confidence interval [CI], 1.61-5.84), fatigue (OR, 2.78; 95% CI, 1.41-5.49), sleep (OR, 2.52; 95% CI, 1.32-4.08); and drowsiness (OR, 2.51; 95% CI, 1.32-4.78) compared with microsatellite stable patients. Patients with an MSI-H phenotype also had greater odds of overall symptom burden (OR, 2.48; 95% CI, 1.29-4.74) compared with microsatellite stable patients. The CIMP-high patients experienced greater odds of pain compared with the CIMP-negative patients (OR, 1.72; 95% CI, 1.06-2.80). A greater overall symptom burden was associated with poor overall survival (hazard ratio, 1.42; 95% CI, 0.98-2.06]), although the difference was not significant (P = .06).

Conclusion: Correlation of MSI-H-associated tumor features with the symptom burden could help provide a better understanding of underlying mechanisms associated with our findings.
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http://dx.doi.org/10.1016/j.clcc.2019.10.006DOI Listing
March 2020

Direct costs of carcinoid syndrome diarrhea among adults in the United States.

World J Gastroenterol 2019 Dec;25(47):6857-6865

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, United States.

Background: The burden of carcinoid syndrome (CS) among patients with neuroendocrine tumors is substantial and has been shown to result in increased healthcare resource use and costs. The incremental burden of CS diarrhea (CSD) is less well understood, particularly among working age adults who make up a large proportion of the population of patients with CS.

Aim: To estimate the direct medical costs of CSD to a self-insured employer in the United States.

Methods: CS patients with and without CSD were identified in the IBM MarketScan Database, including the Medicare Supplemental Coordination of Benefits database. Eligible patients had ≥ 1 medical claim for CS with continuous health plan enrollment for ≥ 12 mo prior to their first CS diagnosis and for ≥ 30 d after, no claims for acromegaly, and no clinical trial participation during the study period (2014-2016). Baseline demographic and clinical characteristics, including comorbidities and treatment, were analyzed using descriptive statistics. Measures of healthcare resource use and costs were compared between patients with and without CSD, including Emergency Department (ED) visits, hospital admissions and length of stay, physician office visits, outpatient services, and prescription claims, using univariate and multivariate analyses to evaluate associations of CSD with healthcare resource use and costs, controlling for baseline characteristics.

Results: Overall, 6855 patients with CS were identified of which 4,043 were eligible for the analysis (1352 with CSD, 2691 with CS only). Baseline demographic and clinical characteristics were similar between groups with the exception of age, underlying tumor type, and health insurance plan. Patients with CSD were older, had more comorbidities, and received more somatostatin analog therapy at baseline. Patients with CSD required greater use of healthcare resources and incurred higher costs than their peers without CSD, including hospitalizations (44% 25%) and ED visits (55% 31%). The total adjusted annual healthcare costs per patient were 50% higher (+ $23865) among those with CSD, driven by outpatient services (+ 56%), prescriptions (+ 48%), ED visits (+ 26%), physician office visits (+ 21%), and hospital admissions (+ 11%).

Conclusion: The economic burden of CSD is greater than that of CS alone among insured working age adults in the United States, which may benefit from timely diagnosis and management.
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http://dx.doi.org/10.3748/wjg.v25.i47.6857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6931008PMC
December 2019

Geographic and demographic features of neuroendocrine tumors in the United States of America: A population-based study.

Cancer 2020 02 12;126(4):792-799. Epub 2019 Nov 12.

Division of Hematology and Oncology, Roswell Park Comprehensive Cancer Center, University at Buffalo School of Medicine, Buffalo, New York.

Background: The incidence of neuroendocrine tumors (NETs) is rapidly rising. There are very few studies investigating the role of sociodemographic factors in NETs. This study was aimed at examining how geographic and sociodemographic characteristics shape outcomes in the NET population.

Methods: A retrospective analysis using the Surveillance, Epidemiology, and End Results database was performed, and the NET patient population from 1973 to 2015 was studied. Univariate and multivariable analyses were performed to evaluate patients' disease-specific survival (DSS) and overall survival (OS). Geographic and sociodemographic factors, including the location of residence (urban area [UA] vs rural area [RA]), sex, race, insurance status, and marital status, were included in the analysis.

Results: A total of 53,034 patients (5517 in RAs and 47,517 in UAs) were included in the analysis. The incidence of NETs was found to be rising in both RAs and UAs but more rapidly in RAs (with the highest incidence in 2006-2015: 5.93 per 100,000 in RAs vs 4.10 per 100,000 in UAs). Patients from RAs presented at advanced stages in comparison with patients from UAs (regional, 18% vs 16%; distant, 15% vs 13%; P < .01). In the multivariable model, RA patients had a trend toward poorer OS (hazard ratio, 1.05; P = .053) in comparison with UA patients. The multivariable analysis showed significantly worse DSS and OS for uninsured, single, and male patients in comparison with insured, married, and female patients, respectively.

Conclusions: This study has identified sociodemographic disparities in NET outcomes. Access to health care could be a potential contributing factor, although differences in environmental exposure, health behavior, and tumor biology could also be responsible.
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http://dx.doi.org/10.1002/cncr.32607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870292PMC
February 2020

Racial Differences in the Incidence and Survival of Patients With Neuroendocrine Tumors.

Pancreas 2019 Nov/Dec;48(10):1373-1379

Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Objectives: The incidence of neuroendocrine tumors (NETs) has been steadily increasing. Racial differences in the incidence and survival are mostly unknown. This study examines the racial differences and the underlying causes.

Methods: We conducted a retrospective, population-based study using datasets from Surveillance, Epidemiology, and End Results (SEER) cancer registry and SEER data linked with Medicare claims (SEER-Medicare). We examined the incidence rates and the effects of patient demographics, clinical characteristics, and socioeconomic factors on survival.

Results: Of the 15,786 and 1731 cases from SEER and SEER-Medicare, 1991 and 163 were blacks, respectively. We found that blacks had higher NET incidence for all stages, with the largest difference noted in the local stage (4.3 vs 2.6 per 100,000 in whites). We found worse survival for distant-stage black patients, although they more often had clinical factors typically associated with better prognosis in NETs. However, they were also found to have significant unfavorable differences in socioeconomic and sociodemographic factors.

Conclusions: Blacks have higher incidence of NETs and worse survival compared with other races, especially whites. The influences of neighborhood socioeconomic, sociodemographic, and marital status suggest that social determinants, support mechanisms, and access to health care may be contributing factors.
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http://dx.doi.org/10.1097/MPA.0000000000001431DOI Listing
September 2020

Who Should Get Lateral Pelvic Lymph Node Dissection After Neoadjuvant Chemoradiation?

Dis Colon Rectum 2019 10;62(10):1158-1166

Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Despite the use of neoadjuvant chemoradiation and total mesorectal excision for rectal cancer, lateral pelvic lymph node recurrence is still an important problem.

Objective: This study aimed to determine the indication for lateral pelvic lymph node dissection in post neoadjuvant chemoradiation rectal cancer.

Design: This is a retrospective analysis of a prospectively collected institutional database.

Settings: This study was conducted at a tertiary care cancer center from January 2006 through December 2017.

Patients: Patients who had rectal cancer with suspected lateral pelvic lymph node metastasis, who underwent total mesorectal excision with lateral pelvic lymph node dissection, were included.

Main Outcome Measures: The primary outcome measured was pathologic lateral pelvic lymph node positivity.

Interventions: The associations between lateral pelvic lymph node size on post-neoadjuvant chemoradiation imaging and pathologic lateral pelvic lymph node positivity and recurrence outcomes were evaluated.

Results: A total of 64 patients were analyzed. The mean lateral pelvic lymph node size before and after neoadjuvant chemoradiation was 12.6 ± 9.5 mm and 8.5 ± 5.4 mm. The minimum size of positive lateral pelvic lymph node was 5 mm on post neoadjuvant chemoradiation imaging. Among 13 (20.3%) patients who had a <5 mm lateral pelvic lymph node after neoadjuvant chemoradiation, none were pathologically positive. Among 51 (79.7%) patients who had a ≥5 mm lateral pelvic lymph node after neoadjuvant chemoradiation, 33 patients (64.7%) were pathologically positive. Five-year overall survival and disease-specific survival were higher in the histologic lateral pelvic lymph node negative group than in the lateral pelvic lymph node positive group (overall survival 79.6% vs 61.8%, p = 0.122; disease-specific survival 84.5% vs 66.2%, p= 0.088). After a median 39 months of follow-up, there were no patients in the <5 mm group who died of cancer. There were no lateral compartment recurrences in the entire cohort.

Limitations: Being a single-center retrospective study may limit generalizability.

Conclusions: Post-neoadjuvant chemoradiation lateral pelvic lymph node size ≥5 mm was strongly associated with pathologic positivity. No patients with size <5 mm had pathologically positive lymph nodes. Following lateral pelvic lymph node dissection, no patients with a positive lateral pelvic lymph node developed lateral compartment recurrence. Therefore, patients who have rectal cancer with clinical evidence of lateral pelvic lymph node metastasis and post-neoadjuvant chemoradiation lateral pelvic lymph node size ≥5 mm should be considered for lateral pelvic lymph node dissection at the time of total mesorectal excision. See Video Abstract at http://links.lww.com/DCR/B3. ¿QUIéN DEBE RECIBIR LINFADENECTOMíA PéLVICA LATERAL DESPUéS DE LA QUIMIORRADIACIóN NEOADYUVANTE?: A pesar del uso de quimiorradiación neoadyuvante y la escisión total de mesorectao para el cáncer de recto, la recurrencia en los ganglios linfáticos pélvicos laterales sigue siendo un problema importante.

Objetivo: Determinar la indicación para la disección de los ganglios linfáticos pélvicos laterales en el cáncer rectal post quimiorradiación neoadyuvante. DISEÑO:: Análisis retrospectivo de la base de datos institucional prospectivamente recopilada.

Escenario: Centro de cáncer de atención terciaria, de enero de 2006 hasta diciembre de 2017.

Pacientes: Pacientes con cáncer de recto con sospecha de metástasis en los ganglios linfáticos pélvicos laterales, que se sometieron a escisión total mesorectal con disección de los ganglios linfáticos pélvicos laterales.

Principales Medidas De Resultados: Positividad de ganglios linfáticos pélvicos laterales en histopatología.

Intervenciones: Se evaluaron las asociaciones entre el tamaño de los ganglios linfáticos pélvicos laterales en imagenología postquimiorradiación neoadyuvante y la positividad y recurrencia en los ganglios linfáticos pélvicos laterales en histopatología.

Resultados: Se analizaron un total de 64 pacientes. La media del tamaño de los ganglios linfáticos pélvicos laterales antes y después de la quimiorradiación neoadyuvante fue de 12.6 ± 9.5 mm y 8.5 ± 5.4 mm, respectivamente. El tamaño mínimo de los ganglios linfáticos pélvicos laterales positivos fue de 5 mm en las imágenes postquimiorradiación neoadyuvante. Entre 13 (20.3%) pacientes que tenían <5 mm de ganglio linfático lateral pélvico después de la quimiorradiación neoadyuvante; ninguno fue positivo en histopatología. Entre 51 (79.7%) pacientes con ganglio linfático pélvico lateral ≥ 5 mm después de la quimiorradiación neoadyuvante; 33 pacientes (64.7%) fueron positivos en histopatología. La supervivencia general a 5 años y la supervivencia específica de la enfermedad fueron mayores en el grupo histológico de ganglio linfático pélvico lateral negativo que en el grupo de ganglio linfático pélvico lateral positivo (Supervivencia general 79.6% vs 61.8%, p = 0.122; Supervivencia específica de la enfermedad 84.5% vs 66.2%, p = 0.088). Después de una mediana de seguimiento de 39 meses, no hubo pacientes en el grupo de <5 mm que hayan fallecido por cáncer. No hubo recurrencias en el compartimento lateral en toda la cohorte.

Limitaciones: Al ser un estudio retrospectivo en un solo centro puede limitar la generalización.

Conclusiones: El tamaño de los ganglios linfáticos pélvicos laterales postquimiorradiación neoadyuvante ≥ 5 mm se asoció fuertemente con la positividad histopatológica. Ningún paciente con tamaño <5 mm tuvo ganglios linfáticos histopatológicamente positivos. Después de la disección de los ganglios linfáticos pélvicos laterales, ningún paciente con ganglios linfáticos pélvicos laterales positivos desarrolló recurrencia del compartimiento lateral. Por lo tanto, los pacientes con cáncer rectal con evidencia clínica de metástasis en los ganglios linfáticos pélvicos laterales y tamaño de ganglios linfáticos pélvicos laterales postquimiorradiación neoadyuvante ≥ 5 mm deben considerarse para disección de los ganglios linfáticos pélvicos laterales en el momento de la escisión total de mesorrecto. Vea el Abstract en video en http://links.lww.com/DCR/B3.
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http://dx.doi.org/10.1097/DCR.0000000000001465DOI Listing
October 2019

Work productivity burden and indirect costs associated with carcinoid syndrome diarrhea.

Expert Rev Pharmacoecon Outcomes Res 2020 Oct 26;20(5):507-511. Epub 2019 Aug 26.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX, USA.

: We estimated the indirect costs of work productivity burden from carcinoid syndrome diarrhea (CSD) among employed, insured adults in the United States. : Retrospective cohort study of patients ≥18 years old with CS who did and did not have CSD (2014-2016). Eligible patients had continuous health plan enrollment for ≥12 months prior to their first CS claim and for ≥30 days after. Univariate analyses of clinical and work productivity outcomes and indirect costs were conducted. Multivariate analyses examined associations of CSD with work productivity measures, controlling for baseline characteristics. : A total of 1,880 patients with CS were eligible, including 577 with CSD and 1,303 with CS only. Baseline characteristics were generally similar. Patients with CSD missed half of eligible workdays (median 56%, 146/260); those with CS-only missed one-third (38%, 100/260). Work productivity was lower and the associated costs were higher in the presence of CSD. Patients with CSD had more absenteeism, short-term disability, and lost workdays which translated into incremental mean costs of $16,679 greater than those with CS only. : Indirect costs related to work productivity losses among adults with CSD are significant, which further add to the burden of CSD to society.
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http://dx.doi.org/10.1080/14737167.2019.1660646DOI Listing
October 2020

Disparity of Race Reporting and Representation in Clinical Trials Leading to Cancer Drug Approvals From 2008 to 2018.

JAMA Oncol 2019 Aug 15:e191870. Epub 2019 Aug 15.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.

Importance: Representative racial/ethnic participation in research, especially in clinical trials that establish standards of care, is necessary to minimize disparities in outcomes and to uphold societal equity in health care.

Objective: To evaluate the frequency of race reporting and proportional race representation in trials supporting US Food and Drug Administration (FDA) oncology drug approvals.

Design, Setting, And Participants: Database study of all reported trials supporting FDA oncology drug approvals granted between July 2008 and June 2018. Primary reports of trials were obtained from PubMed and ClinicalTrials.gov. Food and Drug Administration approvals were identified using the FDA archives. The US population-based cancer estimates by race were calculated using National Cancer Institute-Surveillance, Epidemiology, and End Results and US Census databases.

Main Outcomes And Measures: Primary outcomes were the proportion of trials reporting race and the proportion of patients by race participating in trials. Secondary outcomes included race subgroup analyses reporting and gaps between race proportion in trials and the US population. Descriptive statistics, Fisher exact, and χ2 tests were used to analyze the data. Proportions and odds ratios (OR) with 95% CIs were reported.

Results: Among 230 trials with a total of 112 293 participants, 145 (63.0%) reported on at least 1 race, 18 (7.8%) documented the 4 major races in the United States (white, Asian, black, and Hispanic), and 58 (25.2%) reported race subgroup analyses. Reporting on white, Asian, black, and Hispanic races was included in 144 (62.6%), 110 (47.8%), 88 (38.2%), and 23 (10.0%) trials, respectively. Between July 2008 and June 2013 vs July 2013 and June 2018, the number of trials reporting race (45 [56.6%] vs 100 [67.1%]; OR, 1.63; 95% CI, 0.93-2.87; P = .09) and race subgroup analysis (13 [16.1%] vs 45 [30.2%]; OR, 2.26, 95% CI, 1.16-4.67; P = .03) changed minimally and varied across races. Whites, Asians, blacks, and Hispanics represented 76.3%, 18.3%, 3.1% and 6.1% of trial participants, respectively, and the proportion for each race enrolled over time changed nominally (blacks, 3.6% vs 2.9% and Hispanics, 5.3% vs 6.7%) from July 2008 to June 2013 vs July 2013 to June 2018. Compared with their proportion of US cancer incidence, blacks (22% of expected) and Hispanics (44% of expected) were underrepresented compared with whites (98% of expected) and Asians (438% of expected).

Conclusions And Relevance: Race and race subgroup analysis reporting occurs infrequently, and black and Hispanic races are consistently underrepresented compared with their burden of cancer incidence in landmark trials that led to FDA oncology drug approvals. Enhanced minority engagement is needed in trials to ensure the validity of results and reliable benefits to all.
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http://dx.doi.org/10.1001/jamaoncol.2019.1870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696743PMC
August 2019

Signet ring cell colorectal cancer: genomic insights into a rare subpopulation of colorectal adenocarcinoma.

Br J Cancer 2019 09 13;121(6):505-510. Epub 2019 Aug 13.

Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: Signet ring cell carcinoma (SRCC) is a rare subtype of colorectal cancer (CRC). The aim of this study was to characterise the genomic alterations and outcomes of SRCC.

Methods: Medical records of metastatic CRC (mCRC) patients whose tumours were evaluated by NGS analysis were reviewed. SC-mCRC were classified into two groups: SRCC (>50% signet ring cells) and adenocarcinoma (AC) with SC component (≤50% signet ring cells).

Results: Six hundred and sixty-five mCRC patients were included. Of the 93 mCRC cases with SC features, 63 had slides for review. Of those 63 cases, 35 were confirmed SRCC, and 28 were AC with SC component. Compared with AC group, KRAS and PIK3CA mutations (mts) were found in only 11% (OR: 0.13) and 3% (OR: 0.15) of SRCC cases, respectively. In contrast to the 44% rate of APC mts in AC group, only 3% of SRCC patients had APC mts (OR = 0.04).

Conclusions: SRCC has distinct molecular features, including low rates of KRAS, PIK3CA and APC mts. Further study to identify activation pathways and potential therapeutic targets are needed.
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http://dx.doi.org/10.1038/s41416-019-0548-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738104PMC
September 2019

Living With Neuroendocrine Tumors: Assessment of Quality of Life Through a Mobile Application.

JCO Clin Cancer Inform 2019 07;3:1-10

MD Anderson Cancer Center, Houston, TX.

Purpose: To understand the quality of life (QoL) for patients with neuroendocrine tumors (NETs) through comparison of QoL questionnaires and symptom tracking as well as journaling via the Carcinoid NETs Health Storylines mobile application (app).

Patients And Methods: This was a 12-week prospective, observational study of US patients with NET who were taking long-acting somatostatin analogs. National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) and European Organisation for Research and Treatment of Cancer (EORTC) questionnaires were administered three times. Patients also monitored symptoms, mood, bowel movements, food, activity, and sleep, and they journaled in their app, which was coded by theme and sentiment for qualitative analysis.

Results: Of the 120 patients with NET, 78% were women (mean age, 57 years); 76% had gastroenteropancreatic NETs, and 88% had metastases. Lanreotide depot and octreotide long-acting release (LAR) were used by 41% and 59%, respectively. The most common symptoms at baseline were fatigue (76.7%), diarrhea (62.5%), abdominal discomfort (64.1%), and trouble sleeping (57.5%). The majority completed five of six survey assessments (median, 5; mean, 5.1) and tracked four symptoms in the app (median, 4; mean, 5.5); the average frequency was 41.6 days for each symptom (median, 43; mean, 41.6; range, 1 to 84 days [12 weeks]). Without treatment change, most EORTC-assessed physical symptoms decreased from baseline to midpoint (eg, 59.3% at baseline 33% at midpoint reported "quite a bit" or "very much" diarrhea; = .002). App-based symptom tracking revealed large day-to-day variation, but weekly averages correlated well with survey scores. Journal entries showed that more patients made predominantly negative unsolicited entries about their injection experience with octreotide LAR compared with lanreotide (13 of 17 two of 13; < .001).

Conclusion: Patients with NET experience a large symptom burden that varies daily. A decrease in physical symptoms on QoL surveys suggests an effect from daily app-based monitoring or journaling, which may reduce recall bias and benefit the patient's experience of symptoms.
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http://dx.doi.org/10.1200/CCI.19.00025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6873920PMC
July 2019

Can Circulating Tumor DNA in Early-Stage Colorectal Cancer Be More Than a Prognostic Biomarker?

JAMA Oncol 2019 May 9. Epub 2019 May 9.

The University of Texas MD Anderson Cancer Center, Houston.

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http://dx.doi.org/10.1001/jamaoncol.2019.0503DOI Listing
May 2019

National Cancer Institute (NCI) state of the science: Targeted radiosensitizers in colorectal cancer.

Cancer 2019 08 24;125(16):2732-2746. Epub 2019 Apr 24.

Clinical Radiation Oncology Branch, Radiation Research Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Colorectal cancer (CRC) represents a major public health problem as the second leading cause of cancer-related mortality in the United States. Of an estimated 140,000 newly diagnosed CRC cases in 2018, roughly one-third of these patients will have a primary tumor located in the distal large bowel or rectum. The current standard-of-care approach includes curative-intent surgery, often after preoperative (neoadjuvant) radiotherapy (RT), to increase rates of tumor down-staging, clinical and pathologic response, as well as improving surgical resection quality. However, despite advancements in surgical techniques, as well as sharpened precision of dosimetry offered by contemporary RT delivery platforms, the oncology community continues to face challenges related to disease relapse. Ongoing investigations are aimed at testing novel radiosensitizing agents and treatments that might exploit the systemic antitumor effects of RT using immunotherapies. If successful, these treatments may usher in a new curative paradigm for rectal cancers, such that surgical interventions may be avoided. Importantly, this disease offers an opportunity to correlate matched paired biopsies, radiographic response, and molecular mechanisms of treatment sensitivity and resistance with clinical outcomes. Herein, the authors highlight the available evidence from preclinical models and early-phase studies, with an emphasis on promising developmental therapeutics undergoing prospective validation in larger scale clinical trials. This review by the National Cancer Institute's Radiation Research Program Colorectal Cancer Working Group provides an updated, comprehensive examination of the continuously evolving state of the science regarding radiosensitizer drug development in the curative treatment of CRC.
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http://dx.doi.org/10.1002/cncr.32150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663584PMC
August 2019

Loss of Menin Expression by Immunohistochemistry in Pancreatic Neuroendocrine Tumors: Comparison Between Primary and Metastatic Tumors.

Pancreas 2019 04;48(4):510-513

From the Departments of Pathology.

Objectives: Molecular characterization of sporadic pancreatic neuroendocrine tumors (PanNETs) demonstrates frequent alterations in MEN1. As the role of menin immunohistochemistry as a potential biomarker is being developed, knowledge of whether the pattern of menin expression is the same in primary tumors and distant metastases may help in patient care. Therefore, we compared patterns of menin expression in matched primary tumors and metastases.

Methods: We evaluated loss of menin nuclear expression by immunohistochemistry in 44 matched samples of primary and metastatic PanNETs and concordance in staining pattern between primary and metastatic tumors.

Results: Menin nuclear expression was lost in 18 (41%) of 44 primary tumors and 17 (39%) of 44 metastases. Concordant loss of menin expression was observed in 41 cases (93%); discordance was observed in 3 cases (7%; 95% confidence interval, 1.4%-18.7%), including 2 with loss in the primary tumor but not the metastasis.

Conclusions: The concordance of menin staining between primary tumor and metastasis in most cases suggests that menin loss is an early event in PanNET tumorigenesis. The discordant expression observed in a small subset may be a source of menin-directed therapy failure; thus, repeat assessment of metastases may be helpful for treatment selection.
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http://dx.doi.org/10.1097/MPA.0000000000001274DOI Listing
April 2019