Managing Metastatic Extrapulmonary Neuroendocrine Carcinoma After First-Line Treatment.

PURPOSE OF REVIEW: Extrapulmonary neuroendocrine carcinoma (EP-NEC) is a rare, aggressive malignancy that can arise from any organ and frequently presents with distant metastases. Advanced disease has a poor prognosis with median overall survival (OS) rarely exceeding 1 year even with systemic therapy. The management paradigm of advanced/metastatic EP-NEC has been extrapolated from small cell lung cancer (SCLC) and commonly consists of 1st line therapy with etoposide and platinum (cisplatin or carboplatin), followed by alternative cytotoxic regimens at the time of progression. Only a minority of patients are able to receive 2nd line therapy, and cytotoxics derived from the SCLC paradigm such as topotecan or lurbinectedin have very limited activity. We aimed to evaluate emerging therapeutic options in the 2nd and later lines and survey potential future developments in this space. RECENT FINDINGS: After a long period of stagnation in treatment options and outcomes, more promising regimens are gradually being utilized in the 2nd line setting including systemic therapy combinations such as FOLFIRI, FOLFOX, modified FOLFIRINOX, CAPTEM, and, more recently, novel checkpoint inhibitors such as nivolumab and ipilimumab. Simultaneously, advances in the understanding of disease biology are helping to refine patient selection and identify commonalities between NEC and their sites of origin which may eventually lead to additional targeted therapy options. While many questions remain, contemporary developments give grounds for optimism that improved outcomes for EP-NEC will soon be within reach.

Treatment landscape of advanced high-grade neuroendocrine neoplasms.

Grade 3 neuroendocrine neoplasms (NEN G3) are high-grade (Ki-67 index >20%) neuroendocrine malignancies that comprise both rapidly proliferating, well-differentiated neuroendocrine tumors (NET G3) and poorly differentiated neuroendocrine carcinomas (NEC). The phenotypic differences between NET G3 and NEC stem from differences in their underlying genomic alterations. As a result of these differences, NET G3 is molecularly, radiologically, and prognostically distinct from NEC. The optimal management of NET G3 and NEC is currently being refined through clinical trials that focus on NET G3 and NEC as separate entities. This review aims to summarize the current understanding of NEN G3 by distinguishing between NET G3 and NEC and describing the clinical implications associated with each.

Survival and Incidence Patterns of Pancreatic Neuroendocrine Tumors Over the Last 2 Decades: A SEER Database Analysis.

BACKGROUND: Pancreatic neuroendocrine tumors (pNETs) are rare cancers with outcomes determined by multiple factors including grade, stage, and clinical presentation. In this study, we aimed to determine the prognosis of patients with pNETs using a large population-based database. MATERIALS AND METHODS: In this population-based study, we identified patients with pNETs from the SEER 18 registry (2000-2016) using a combination of ICD-O-3 and histology codes. We calculated age-adjusted incidence rates using SEER*Stat 8.3.5. In addition, we analyzed overall survival (OS) using the Kaplan-Meier method, and investigated prognostic factors using a multivariable Cox proportional hazards model. RESULTS: A total of 8944 pNETs patients were identified. Annual incidence rates increased from 0.27 to 1.00 per 100 000. This was largely explained by an increase in number of patients diagnosed with localized disease in more recent years (2012-2016). Median OS was 68 months (95% CI [64, 73]) and 5-year OS rates in localized, regional, and metastatic disease were 83%, 67%, and 28%, respectively. There was a significant improvement in OS for patients diagnosed between 2009 and 2016 (median OS 85 months) compared with those diagnosed between 2000 and 2008 (median OS 46 months) (HR 0.66; 95% CI [0.62, 0.70]). This improvement in OS was consistent across all stages. CONCLUSIONS AND RELEVANCE: This study shows a steady increase pNETs incidence with notable stage migration to earlier stages in recent years. This increase in incidence is accompanied by a significant improvement in survival across different disease stages.

The Role of Systemic Therapy in Resectable Colorectal Liver Metastases: Systematic Review and Network Meta-Analysis.

BACKGROUND: Despite multiple randomized trials, the role of perioperative chemotherapy in colorectal cancer liver metastasis (CRLM) is still under debate. In this systematic review and network meta-analysis (NMA), we aim to evaluate the efficacy of perioperative systemic therapies for patients with CRLM. METHODS: We searched various databases for abstracts and full-text articles published from database inception through May 2021.We included randomized controlled trials (RCTs) comparing the addition of perioperative (post, pre, or both) systemic therapies to surgery alone in patients with CRLM. The outcomes were compared according to the chemotherapy regimen using a random effects model. Outcomes of interest included disease-free survival (DFS) and overall survival (OS). RESULTS: Seven RCTs with a total of 1504 patients with CRLM were included. Six studies included post-operative treatment and one evaluated perioperative (pre- and postoperative) therapy. Fluoropyrimidine-based chemotherapy was the most used systemic therapy. NMA showed benefit of adding perioperative therapy to surgery in terms of DFS (HR 0.73, 95% CI 0.63 to 0.84). However, these findings did not translate into a statistically significant OS benefit (HR 0.88, 95% CI 0.74 to 1.05). NMA did not show any advantage of one regimen over another including oxaliplatin or irinotecan. CONCLUSIONS: This systematic review and NMA of 7 RCTs found that the addition of perioperative systemic treatment for resectable CRLM could improve disease-free survival but not overall survival. Based on the findings, addition of perioperative treatment in resectable CRLM should be individualized weighing the risks and benefits.

A pilot study of Pan-FGFR inhibitor ponatinib in patients with FGFR-altered advanced cholangiocarcinoma.

Background Biliary tract cancers (BTC) are rare, chemo resistant and are associated with a poor prognosis. Preclinical and early clinical work had demonstrated interesting anti-tumor activity from targeting fibroblast growth factor receptor (FGFR) pathway. We hypothesized that ponatinib, a multi-targeted tyrosine kinase inhibitor with activity against FGFR, would be active in BTC patients with FGFR alterations. Methods This was a multi-center, single institution pilot study of ponatinib in patients with advanced, refractory BTC with FGFR alterations. The primary end point was overall response rate, with secondary points of overall survival (OS), progression-free survival (PFS) and Health Related Quality of Life (HRQoL) assessment. Results Twelve patients were enrolled prior to early termination of the trial. Partial responses were observed in 1 from 12 patients. Median PFS was 2.4 months and median OS was 15.7 months. All observed toxicities were manageable and reversible. Toxicities were mild, with lymphopenia (75%), rash (63%) and fatigue (50%) being the most frequent. No significant detriment in global QoL was observed. Conclusions Ponatinib as a single agent in FGFR altered BTC is tolerable with limited clinical activity. This is the first report of prospective assessment of FGFR inhibition in BTC using ponatinib, and the first study to report its effect on HRQoL. Further development of ponatinib will involve correlative studies to better refine patient selection, focus on combinations with other molecular targeted agents, conventional cytotoxic chemotherapy, and studies to better understand mechanisms of treatment resistance.

The treatment landscape for gastroesophageal adenocarcinomas.

The treatment landscape for gastroesophageal adenocarcinomas has significantly changed over the last year. The addition of nivolumab to first-line chemotherapy has led to survival benefit in patients who have metastatic gastroesophageal adenocarcinoma with a programmed death ligand 1 combined positive score of 5 or greater. Similarly, in patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive gastroesophageal adenocarcinoma, the addition of pembrolizumab to chemotherapy and trastuzumab has significantly improved efficacy. Furthermore, a phase 2 study revealed that trastuzumab deruxtecan, a new antibody-drug conjugate, significantly improved survival in comparison with chemotherapy among patients with HER2-positive gastric cancer in the refractory setting, and it produced a signal of efficacy in the second-line setting. Chemoimmunotherapy combinations are now considered the standard of care for a significant number of patients with gastroesophageal adenocarcinomas.

Treatment Outcomes of Well-Differentiated High-Grade Neuroendocrine Tumors.

INTRODUCTION: Recent classification of neuroendocrine neoplasms has defined well-differentiated high-grade neuroendocrine tumors (NET G3) as a distinct entity from poorly differentiated neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aimed to evaluate metastatic NET G3 response to different treatment regimens. MATERIALS AND METHODS: This was a retrospective study of patients with NET G3 within the Mayo Clinic database. Patients' demographics along with treatment characteristics, responses, and survival were assessed. Primary endpoints were progression-free survival (PFS) and overall survival. Secondary endpoints were objective response rate (ORR) and disease control rate (DCR). RESULTS: Treatment data was available in 30 patients with median age of 59.5 years at diagnosis. The primary tumor was mostly pancreatic (73.3%). Ki-67 index was ≥55% in 26.7% of cases. Treatments included capecitabine + temozolomide (CAPTEM) (n = 20), lutetium 177 DOTATATE (PRRT; n = 10), Platinum-etoposide (EP; n = 8), FOLFOX (n = 7), and everolimus (n = 2). CAPTEM exhibited ORR 35%, DCR 65%, and median PFS 9.4 months (95% confidence interval, 2.96-16.07). Both EP and FOLFOX showed similar radiographic response rates with ORR 25.0% and 28.6%; however, median PFS durations were quite distinct at 2.94 and 13.04 months, respectively. PRRT had ORR of 20%, DCR of 70%, and median PFS of 9.13 months. CONCLUSION: Among patients with NET G3, CAPTEM was the most commonly used treatment with clinically meaningful efficacy and disease control. FOLFOX or PRRT are other potentially active treatment options. EP has some activity in NET G3, but responses appear to be short-lived. Prospective studies evaluating different treatments effects in patients with NET G3 are needed to determine an optimal treatment strategy. IMPLICATIONS FOR PRACTICE: High-grade well-differentiated neuroendocrine tumors (NET G3) are considered a different entity from low-grade NET and neuroendocrine carcinoma in terms of prognosis and management. The oral combination of capecitabine and temozolomide is considered a good option in the management of metastatic NET G3 and may be preferred. FOLFOX is another systemic option with reasonable efficacy. Similar to other well-differentiated neuroendocrine tumors, peptide receptor radionuclide therapy seems to have some efficacy in these tumors.

Causes of Death Following Nonmetastatic Colorectal Cancer Diagnosis in the U.S.: A Population-Based Analysis.

INTRODUCTION: Because of the improved colorectal cancer (CRC) survival in the U.S., patients may live long enough after CRC diagnosis to the point where non-cancer-related comorbidities may considerably impact their overall survival. In this study, we perform a long-term analysis of causes of death (CODs) following nonmetastatic CRC with respect to different demographic and tumor-related criteria. MATERIALS AND METHODS: We gained access to the Surveillance, Epidemiology, and End Results data to review patients diagnosed with nonmetastatic CRC during 2000-2015. We calculated standardized mortality ratios (SMRs) for each COD following CRC. SMRs represented the change of risk of a specific COD following CRC diagnoses when compared with the risk in the general U.S. RESULTS: We reviewed 302,345 patients, of whom 112,008 died during the study period. More deaths (68.3%) occurred within 5 years following nonmetastatic CRC diagnosis, with 76,486 deaths. CRC was the most common COD (51.4%) within 5 years of diagnosis followed by heart disease (15.2%) and other cancers (8.4%). As time passed after diagnosis, the number of CRC deaths decreased, and other noncancer causes increased to the point that after 10 years only 10.4% of deaths were attributed to CRC, 15.3% were attributed to other cancers, and 34.2% were secondary to heart disease. CONCLUSION: Following nonmetastatic CRC diagnosis, most deaths remain secondary to CRC. Other causes, including other cancers and cardiovascular disease, represent a significant number of deaths, especially in the 5 years following initial CRC diagnosis. Our findings help guide counseling patients with CRC regarding future health risks. IMPLICATIONS FOR PRACTICE: Most common causes of death following nonmetastatic colorectal cancer (CRC) are heart diseases, other cancers, chronic obstructive pulmonary disease, and cerebrovascular diseases. Physicians should counsel patients regarding survivorship with cancer screening and focus on prevention of noncancer deaths. These findings should be considered by physicians who give care for survivors of nonmetastatic CRC.

Circulating Tumor DNA-Based Testing and Actionable Findings in Patients with Advanced and Metastatic Pancreatic Adenocarcinoma.

PURPOSE: Recent advances in molecular diagnostic technologies allow for the evaluation of solid tumor malignancies through noninvasive blood sampling, including circulating tumor DNA profiling (ctDNA). Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, often because of late presentation of disease. Diagnosis is often made using endoscopic ultrasound or endoscopic retrograde cholangiopancreatography, which often does not yield enough tissue for next-generation sequencing. With this study, we sought to characterize the ctDNA genomic alteration landscape in patients with advanced PDAC with a focus on actionable findings. MATERIALS AND METHODS: From December 2014 through October 2019, 357 samples collected from 282 patients with PDAC at Mayo Clinic underwent ctDNA testing using a clinically available assay. The majority of samples were tested using the 73-gene panel which includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. Clinical data and outcome variables were available for 165 patients; with 104 patients at initial presentation. RESULTS: All patients included in this study had locally advanced or metastatic PDAC. Samples having at least one alteration, when variants of unknown significance (VUS) were excluded, numbered 266 (75%). After excluding VUS, therapeutically relevant alterations were observed in 170 (48%) of the total 357 cohort, including KRAS (G12C), EGFR, ATM, MYC, BRCA, PIK3CA, and BRAF mutations. KRAS, SMAD, CCND2, or TP53 alterations were seen in higher frequency in patients with advanced disease. CONCLUSION: Our study is the largest cohort to date that demonstrates the feasibility of ctDNA testing in PDAC. We provide a benchmark landscape upon which the field can continue to grow. Future applications may include use of ctDNA to guide treatment and serial monitoring of ctDNA during disease course to identify novel therapeutic targets for improved prognosis. IMPLICATIONS FOR PRACTICE: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis often due to late presentation of disease. Biopsy tissue sampling is invasive and samples are often inadequate, requiring repeated invasive procedures and delays in treatment. Noninvasive methods to identify PDAC early in its course may improve prognosis in PDAC. Using ctDNA, targetable genes can be identified and used for treatment.

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia: DIPNECH.

PURPOSE OF REVIEW: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is a rare premalignant condition. Over the past decade, there has been increased recognition and reporting of DIPNECH in the literature. Currently, our understanding is that DIPNECH has a predilection to nonsmoking females around their sixth decade of life. The patients usually present with chronic cough, dyspnea, and computed tomography (CT) showing multifocal pulmonary nodules with associated mosaic attenuation. The clinic history is largely driven by constrictive obliterative bronchiolitis, which typically has an indolent course with progressive respiratory decline and difficult to treat symptoms. RECENT FINDINGS: DIPNECH has been found to be associated with carcinoid tumors. Recent data has found that symptomatic DIPNECH patients respond to somatostatin analog (SSA). SSAs provide improvement in symptoms and pulmonary function tests. According to small studies and case series SSAs can be used in conjunction with steroids and bronchodilators for the treatment of respiratory symptoms. SUMMARY: DINPNECH is a premalignant condition that can transform into carcinoid tumors. Although the recent data suggest the potential efficacy of SSA, further studies are needed to validate such results in prospective fashion in addition to investigating other therapeutic agents.

Management of well-differentiated neuroendocrine tumors.

Neuroendocrine tumors (NETs) are a heterogeneous group of epithelial neoplasms with predominantly neural and endocrine differentiation that have the ability to produce peptide hormones and other biologically active substances. The histologic characterization of NETs based on differentiation and grading is crucial to determining prognosis and treatment. Surgery still offers the best chance of cure for patients with NETs, and tumor resection is the preferred approach when possible. For locally advanced or metastatic disease, approaches to treatment can vary widely depending on the extent of disease and goals of therapy. A better understanding of the biology of NETs acquired over the last decade has facilitated the development of targeted therapies, such as everolimus and a variety of tyrosine kinase inhibitors. Furthermore, the field of theranostics has led to dramatic improvements in our diagnostic and treatment abilities. Chemotherapy has a role in the treatment of NETs, evidenced by the benefit shown with the combination of temozolomide and capecitabine to treat pancreatic NETs. Somatostatin analogues are a mainstay of treatment because they reduce secretory products and have antiproliferative effects on NET cells. In this work, we aim to review the landscape for the diagnosis and treatment of well-differentiated NETs.

Causes of death after breast cancer diagnosis: A US population-based analysis.

BACKGROUND: The focus on noncancer causes of death in patients with breast cancer (BC) remains superficial. The objective of the current study was to assess and quantify causes of death after BC diagnosis. METHODS: In total, 754,270 women with BC in the United States who were diagnosed during 2000 through 2015 and retrieved from the Surveillance, Epidemiology, and End Results (SEER) program were studied. Standardized mortality ratios (SMRs) for causes of death were calculated. RESULTS: Of the included patients, 183,002 (24.3%) died during the follow-up period. The greatest proportion of deaths (46.2%) occurred within 1 to 5 years after diagnosis. Most deaths occurred from BC itself or from other cancers, and the number of BC deaths decreased as more years passed after diagnosis. The most common noncancer causes of death within <10 years after diagnosis were heart diseases followed by cerebrovascular diseases. However, >10 years after diagnosis, the most common noncancer causes of death were heart diseases followed by Alzheimer disease. Patients had a statistically significant higher risk of death from chronic liver diseases within 5 to 10 years after diagnosis compared with the general population (SMR, 1.23; 95% CI, 1.09-1.38) and had statistically significant higher risks of death from Alzheimer disease (SMR, 1.21; 95% CI, 1.14-1.29) and from diseases of the heart (SMR, 1.06; 95% CI, 1.02-1.09) >10 years after diagnosis. CONCLUSIONS: Although BC remains the most common cause of death after BC diagnosis, other non-BC causes of death (mainly heart and cerebrovascular diseases) represent a significant number of deaths among patients with BC. These findings provide important insight into how BC survivors should be counselled regarding future health risks.

Choosing a Reduced-Intensity Conditioning Regimen for Allogeneic Stem Cell Transplantation, Fludarabine/Busulfan versus Fludarabine Melphalan: A Systematic Review and Meta-Analysis.

Fludarabine with busulfan (FB) or melphalan (FM) are 2 more commonly used reduced-intensity conditioning (RIC) regimens for allogeneic stem cell transplantation (HCT).We present a systematic review and meta-analysis of studies comparing these 2 RIC regimens. We searched electronic databases from inception through November 1, 2017 for literature searches to identify relevant studies. A DerSimonian random effects model was used to measure efficacy outcomes; hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) are reported. Seven studies, including a total of 1955 patients, met criteria for inclusion, of which 6 were included in the overall pooled analysis because of repetition of some patients in 2 studies. Three studies were included in the subgroup analysis of acute myelogenous leukemia (AML)/myelodysplastic syndrome (MDS) and 2 in the subgroup analysis of lymphoid malignancies. Overall survival (OS) and progression-free survival were not statistically significantly different between the 2 RIC regimens in analysis of all studies. However, OS was better with FM in subgroup analysis of AML/MDS studies (HR, .83; 95% CI, .73 to .95). Nonrelapse mortality was lower with FB (HR, .64; 95% CI, .46 to .89), whereas relapse was lower with FM (HR, 1.52; 95% CI, 1.13 to 2.06) in the analysis of all studies. This meta-analysis shows that FB and FM are associated with a similar OS in patients undergoing HCT. Relapse rates are lower with FM but at the cost of higher nonrelapse mortality.

High-Dose Chemotherapy with Early Autologous Stem Cell Transplantation Compared to Standard Dose Chemotherapy or Delayed Transplantation in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis.

Autologous stem cell transplantation (SCT) is the standard of care for all transplantation-eligible patients diagnosed with multiple myeloma (MM). Various studies have compared clinical outcomes with frontline SCT ("early SCT") versus standard-dose therapy (SDT) alone, with or without salvage SCT ("SDT/late SCT"). In this meta-analysis, we compare overall survival (OS) and progression-free survival (PFS) outcomes between these 2 treatment approaches. Twelve studies were identified, including a total of 3633 patients, of whom 1811 received early SCT and 1822 received SDT/late SCT. In our analysis of all 12 studies, OS was not significantly different between the 2 groups (hazard ratio [HR], .86; 95% confidence interval [CI], .70 to 1.04), but PFS was better with early SCT (HR, .67; 95% CI, .54 to .82). In a subgroup analysis of 3 studies in which novel agents were used for induction, OS again was similar in the 2 groups, and PFS was favorable with early SCT (HR, .50; 95% CI, .36 to .70). This analysis shows that over the years, early SCT has been associated with prolonged PFS, but this did not consequently translate into prolonged OS in patients with newly diagnosed MM. The benefit of early SCT in terms of OS is less clear in the era of novel agents, given the limited follow-up of these studies.

A Systematic Review and Network Meta-Analysis of Regorafenib and TAS-102 in Refractory Metastatic Colorectal Cancer.

BACKGROUND: Regorafenib at different dosing strategies and TAS-102 are treatment options for refractory metastatic colorectal cancer (mCRC). We aimed to evaluate the comparative effectiveness evidence supporting these different strategies. MATERIALS AND METHODS: We searched different databases for randomized controlled trials evaluating TAS-102 or regorafenib in patients with refractory mCRC who failed prior oxaliplatin, irinotecan, and fluoropyrimidine. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the DerSimonian random effects model. We conducted network meta-analysis based on White's multivariate meta-regression to pool evidence from direct and indirect comparisons. RESULTS: Six trials at low risk of bias (2,445 patients) were included. Direct comparisons showed that Rego 160 and TAS-102 as monotherapy were superior to best-supportive care (BSC) in terms of PFS (Rego 160: hazard ratio [HR], 0.4; 95% confidence ratio [CI], 0.26-0.63; TAS-102: HR, 0.46 CI, 0.40-0.52) and OS (Rego 160: HR, 0.67; CI, 0.48-0.93; TAS-102: HR, 0.67; CI, 0.57-0.80). Network analysis showed no statistically difference in PFS or OS between Rego 160 and TAS-102. Rego 80+ was superior to BSC in terms of OS (HR, 0.44; CI, 0.23-0.84) and PFS (HR, 0.37; CI, 0.21-0.66). Rego 80+ was associated with statistically nonsignificant improvement in OS and PFS compared with TAS-102 and Rego 160. CONCLUSION: Regorafenib 160 and TAS-102 appear to have similar efficacy. Rego 80+ is shown to be superior to BSC. A trend for improved OS was observed with Rego 80+ versus Rego 160 or TAS 102. IMPLICATIONS FOR PRACTICE: Regorafenib at a dose of 160 mg and TAS-102 appear to have similar efficacy in patients with refractory metastatic colorectal cancer. Regorafenib with a dose escalation strategy is superior to best-supportive care. Given its tolerability and the observed trend in survival benefit compared with regorafenib 160, dose escalation strategy of regorafenib (80+) may be the preferred option in this setting.

Impact of prior malignancies on outcome of colorectal cancer; revisiting clinical trial eligibility criteria.

BACKGROUND: Most clinical trials on colorectal cancer (CRC) exclude cases who have history of a prior malignancy. However, no prior research studied this history's actual impact on the survival of CRC. In the paper, we study the effects of having a malignancy preceding CRC diagnosis on its survival outcomes. METHODS: CRC patients diagnosed during 1973-2008 were reviewed using the SEER 18 database. We calculated overall survival and cancer-specific survival of subsequent CRC, and more specifically stage IV CRC, using Kaplan-Meier test and adjusted Cox models. RESULTS: A total 550,325 CRC patients were reviewed, of whom 31,663 had history of a prior malignancy. The most commonly reported sites of a prior malignancy were: prostate, breast, urinary bladder, lung, and endometrium. Patients with history of a prior non-leukemic malignancy or history of a prior leukemia were found to have worse overall survival (HR = 1.165 95%CI = 1.148-1.183, P < 0.001) and (HR = 1.825 95%CI = 1.691-1.970, P < 0.001), respectively. However, CRC patients with history of a prior non-leukemic malignancy showed an improved colorectal cancer-specific survival (HR = .930 95%CI = .909-.952, P < 0.001). Analysis of stage IV CRC patients showed that patients with history of any non-leukemic malignancy did not have a significant change in overall survival. Whereas, patients with a prior leukemia showed a worse overall survival (HR = 1.535, 95%CI = 1.303-1.809, P < 0.001). When analyzed separately, right CRC and left CRC showed similar survival patterns. CONCLUSION: A prior malignancy before CRC -in general- can be associated with worse clinical survival outcomes. These worse outcomes are not observed in stage IV CRC. Considering these results when including/excluding stage IV CRC patients with prior malignancies in clinical trials may play help improve their generalizability.

Management of Well-Differentiated High-Grade (G3) Neuroendocrine Tumors.

OPINION STATEMENT: In 2017, the World Health Organization (WHO) classification for pancreatic NET was updated to include a new category of well-differentiated high-grade (Ki 67 > 20%) pancreatic tumors (NET G3), distinct from high-grade poorly differentiated neuroendocrine carcinoma (NEC). NET G3 are considered a molecularly, radiologically, and prognostically distinct entity compared to NEC and NET G1/G2. The optimal first-line management in NET G3 and sequencing therapies remains a challenge awaiting future trials taking into consideration the unique characteristics of this category. In this review, we aim to summarize the current evidence in the management of NET G3.

CanStem111P trial: a Phase III study of napabucasin plus nab-paclitaxel with gemcitabine.

Napabucasin (also known as BBI-608 or BBI608) is an investigational, oral agent hypothesized to inhibit multiple oncogenic pathways. In this article, we describe the design and rationale for the CanStem111P clinical trial, a multicenter, randomized, open-label, Phase III study designed to determine the efficacy and safety of combining napabucasin with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma (NCT02993731). Patients were randomized in a 1:1 fashion to receive weekly gemcitabine and nab-paclitaxel with or without napabucasin. The results of this study will help define the role of this novel agent in the management of advanced pancreatic cancer.

A clinical trial protocol paper discussing the BRIGHTER study.

Napabucasin is a novel oral first-in-class cancer stemness inhibitor. Preclinical and early phase clinical trials showed promising antitumor efficacy signals for napabucasin in a variety of malignancies. In this article, we describe the design and rationale for the now completed BRIGHTER trial, a multicenter, randomized, placebo-controlled, Phase III study designed to determine the efficacy and safety of combining napabucasin with paclitaxel in previously treated patients with advanced gastric and gastroesophageal junction adenocarcinoma (NCT02178956). Patients were randomized in a 1:1 fashion to receive weekly paclitaxel with either napabucasin or placebo. The study failed to achieve its primary end point of overall survival in the intention to treat population. Ongoing analysis of the secondary end points includes progression-free survival, objective response rate, disease control rate, the safety of the combination therapy and evaluation of efficacy in the biomarker-positive subpopulation.

Second-line treatment in patients with pancreatic ductal adenocarcinoma: A meta-analysis.

BACKGROUND: There are limited therapeutic options for treatment-refractory pancreatic ductal adenocarcinoma (PDAC), with a paucity of data to support the best option after progression on gemcitabine-based regimens. The authors performed a meta-analysis to determine the effectiveness of adding oxaliplatin (OX) or various irinotecan formulations to a fluoropyrimidine (FP) after first-line treatment progression in patients with PDAC. METHODS: Different databases, including PubMed, EMBASE, and Cochrane, were searched to identify randomized controlled trials comparing FP monotherapy versus FP combination therapy that included either oxaliplatin (FPOX) or various irinotecan formulations (FPIRI) in patients with PDAC who progressed after first-line treatment. Secondary analyses were planned to assess the effectiveness of FPOX and FPIRI compared with FP. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). RESULTS: Five studies with 895 patients were identified. Patients randomized to receive FPIRI/FPOX had a significantly improved PFS and a trend toward improved OS compared with those who received FP monotherapy. When comparing FPIRI with FP, there was an improvement in both PFS (hazard ratio, 0.64; 95% confidence interval, 0.47-0.87; P = .005) and OS (hazard ratio, 0.70; 95% confidence interval, 0.55-0.89; P = .004) in patients who received the combination. Conversely, FPOX produced only a modest improvement in PFS with no improvement in OS. CONCLUSIONS: Combination chemotherapy with OX or various IRI formulations appears to improve PFS compared with single-agent FP. FPIRI, but not FPOX, appears to confer an OS advantage. The combination of FP with irinotecan formulations appears to be the appropriate next line of treatment upon progression after gemcitabine-based chemotherapy regimens. Cancer 2017;123:4680-4686. © 2017 American Cancer Society.