Allan Andresson Lima Pereira

Refractory carcinoid syndrome: a review of treatment options

Carcinoid syndrome (CSy) is a constellation of symptoms that may commonly present in patients with well differentiated neuroendocrine tumors (NETs), with somatostatin analogs (SSAs) being the first-line option for symptom management. However, symptomatic progression eventually occurs and in this scenario of a refractory CSy; several treatment options have been studied such as dose escalation of SSA, interferon and liver-directed therapies. Nevertheless, recent phase III trials have contributed to the understanding and management of this condition. We performed a comprehensive review of interventional studies examining refractory CSy to provide the evidence for current treatment options and propose a treatment sequence.

The impact of complete chemotherapy stop on the overall survival of patients with advanced colorectal cancer in first-line setting: A meta-analysis of randomized trials.

Background. The impact of the duration of chemotherapy on the overall survival of patients with metastatic colorectal cancer (mCRC) is controversial and studies have failed to define a clear standard. Methods. We searched medical literature databases and oncology conferences proceedings for randomized controlled trials (RCT) that compared the overall survival of mCRC patients who received continuous first-line chemotherapy until disease progression versus those who were offered complete treatment stop after a fixed number of cycles. Studies including targeted agents were also included. A meta-analysis of reported hazard ratios (HRs) for survival was performed. Results. We retrieved 240 trials, of which six were eligible and five were included in the pooled analysis of overall survival (N = 3061). The overall survival between continuously delivered chemotherapy and complete stop was not statistically different (HR = 0.93, 95% CI 0.85–1.02; p = 0.12; I² = 5%). The results are similar when we analyzed separately the trials performing randomization before versus after induction therapy. The median chemotherapy free interval in the complete stop group was 3.9 months (3.6–4.3 months). Chemotherapy administered until progression was associated with more adverse effects and impaired quality of life. Conclusion. Compared with first-line continuous chemotherapy administered until disease progression, complete treatment stop did not have a detrimental impact on the overall survival of patients with mCRC. Identification of predictive biomarkers could help clinicians to select the patients who would benefit from continuous cancer-directed therapies.

Clinical utility of circulating cell-free DNA in advanced colorectal cancer

Background Circulating cell-free DNA (cfDNA) isolated from the plasma of cancer patients (pts) has been shown to reflect the genomic mutation profile of the tumor. However, physician and patient assessment of clinical utility of these assays in patients with metastatic colorectal cancer (mCRC) has not been previously described. Methods Patients were prospectively consented to a prospective genomic matching protocol (Assessment of Targeted Therapies Against Colorectal Cancer [ATTACC]), with collection of blood for cfDNA extraction and sequencing of a 54-gene panel in a CLIA-certified lab. Formalin-fixed, paraffin-embedded (FFPE) tissue from prior resections or biopsies underwent 50-gene sequencing. Results from both assays were returned to the treating physicians for patient care and clinical trial selection. Follow-up surveys of treating physicians and chart reviews assessed clinical utility. Results 128 mCRC pts were enrolled between 6/2014 and 1/2015. Results were returned in median of 13 and 26 days for cfDNA and FFPE sequencing, respectively. With cfDNA sequencing, 78% (100/128) of samples had a detectable somatic genomic alteration. 50% of cfDNA cases had potentially actionable alterations, and 60% of these could be genomically matched to at least one clinical trial in our institution. 50% (15/30) of these pts enrolled onto an identified matched trial. Physicians reported that the cfDNA testing improved the quality of care they could provide in 73% of the cases, and that 89% of pts reported greater satisfaction with the efforts to personalize experimental therapeutic agents. Conclusions cfDNA sequencing can provide timely information on potentially actionable mutations and amplifications, thereby facilitating clinical trial enrollment and improving the perceived quality of care.

Systematic Reviews and Meta-Analyses of Oncology Studies

This chapter is intended principally for practicing clinicians who want to understand the concepts of and reasons for conducting systematic reviews and meta-analyses in oncology. Although there are a few striking examples of cancer treatments that really do work extremely well, most claims for efficacy turn out to be limited. Uncertainties coming from results obtained by different clinical studies need to be interpreted. Systematic reviews can define whether scientific findings are consistent and can be generalized across populations and treatment variations, or whether findings vary significantly by particular subsets. Meta-analyses can increase the power and precision of estimates of treatment effects and exposure risks. Explicit methods should be used to limit bias and improve the reliability and accuracy of conclusions. In the field of clinical oncology, there are several reasons for conducting a systematic review with meta-analyses. Here we discuss how to perform and interpret these studies, and present the main statistical concepts with examples from the literature.

Efficacy and Safety of Docetaxel in Elderly Patients With Metastatic Castration-Resistant Prostate Cancer

Purpose Limited data are available about the tolerability and clinical outcomes of elderly patients with metastatic castration-resistant prostate cancer (mCRPC) who are treated with docetaxel. We evaluated the efficacy and safety of docetaxel as first-line chemotherapy for patients with mCRPC who were treated in our institution. Materials and Methods We retrospectively identified patients with mCRPC and a Karnosfky performance status of 60% or greater treated with docetaxel on any schedule as first-line chemotherapy between 2008 and 2013. The primary end point was a comparison of median overall survival (OS) according to age in this population. Secondary end points were comparisons of the rates of severe toxicities, prostate-specific antigen (PSA) decline of 50% or greater, and time to progression (TTP). Results were stratified by three age groups: younger than 65 years, 65 to 74 years, and 75 years or older. Results Among the 197 patients included, 68 (34%) were younger than 65 years, 85 (43%) were 65 to 74 years, and 44 (22%) were 75 years or older. The mean number of comorbidities was not different among groups (1.19 v 1.32 v 1.43; P = .54). Patients younger than 65 years received a higher cumulative dose of docetaxel (450 mg/m2 v 382 mg/m2 v 300 mg/m2; P = .004). The rates of PSA decline of 50% or greater (41% v 47% v 36.4%; P = .51) and the median TTP (5.13 v 5.13 v 4.7 months; P = .15) were comparable among all groups. The median OS was longer in the group of patients younger than age 65 years (19.6 v 12.4 v 12.3 months; P = .012). Rates of any grade 3 or higher adverse event were not different among groups (63.2% v 71.8% v 54.5%; P = .14). Conclusion Administration of docetaxel in elderly patients who had good performance status was well tolerated. Rates of PSA decline and TTP were similar to those of younger patients, but median survival was lower.

Performance status (PS) in advanced germ cell tumors (aGCT): Clinical and prognostic value of an underreported important variable.

e16537Background: Although PS is a strong marker of adverse outcomes in most metastatic solid tumors, data of PS status are lacking in GCT, especially using validated scales such as Eastern Coopera...

Correction to: Accelerating Therapeutic Development through Innovative Trial Design in Colorectal Cancer

In the original version of this article, which published in Volume 19, Issue 2 (February 2018), the third author’s name was captured incorrectly. The proper name is now provided.

Prognostic Implications of Mucinous Differentiation in Metastatic Colorectal Carcinoma Can Be Explained by Distinct Molecular and Clinicopathologic Characteristics

Micro‐Abstract Mucinous colorectal cancer (CRC) is a unique histologic subtype that remains poorly defined. We aimed to better characterize this subtype of CRC and identified an increased frequency of mutations in GNAS, ERBB2, BRAF, KRAS, and SMAD4 with the mucinous histologic subtype, in addition to increased consensus molecular subtype (CMS) 1 (microsatellite instability immune) and decreased CMS2 (canonical) prevalence. Adverse clinical features included microsatellite instability and synchronous metastatic disease at presentation. Even after controlling for clinical and mutation differences, the mucinous histologic subtype was associated with worse overall survival. Background The mucinous histologic subtype accounts for 5% to 20% of colorectal cancer (CRC) cases but remains poorly characterized. The present study characterized the baseline characteristics, mutational profile, and clinical outcomes of patients diagnosed with mucinous CRC. Materials and Methods We identified 1877 patients with metastatic CRC with available histologic findings and molecular profiling and summarized the baseline clinical and pathologic characteristics and overall survival (OS) stratified by the histologic type. The data from separate cohorts with consensus molecular subtype (CMS) and CpG island methylator information were also summarized. Results The mucinous histologic type was found in 277 of the 1877 patients (14.8%) and was associated with an increased prevalence of microsatellite instability (P < .001) and a right‐sided primary (P < .001). An increased frequency of CMS1 (microsatellite instability immune) and lower rates of CMS2 (canonical) were identified, with mucinous compared with nonmucinous adenocarcinoma (P < .0001). Mutations in SMAD4 (P < .001), GNAS (P < .001), ERBB2 (P = .02), BRAF (P < .001), and KRAS (P < .001) occurred at greater frequencies in the mucinous CRC cases, and TP53 (P < .001), APC (P < .001), and NRAS mutations (P = .03) were less common. Univariate (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.17‐1.63; P < .001) and multivariate analysis (HR, 1.36; 95% CI, 1.12‐1.64; P = .002) demonstrated that the mucinous histologic type is associated with worse OS. The features associated with the mucinous histologic subtype were independent predictors for shorter OS, including BRAF (HR, 1.74; 95% CI, 1.35‐2.25; P < .001) and KRAS (HR, 1.42; 95% CI, 1.22‐1.65; P < .001) mutations, right‐sided location (HR, 1.20; 95% CI, 1.04‐1.39; P = .01), and synchronous metastases (HR, 2.92; 95% CI, 2.49‐3.42; P < .001). Conclusion Compared with nonmucinous adenocarcinoma, the mucinous histologic type is associated with a worse prognosis, even when controlling for known prognostic features. This unique biologic behavior should be considered in the treatment and prognostic assessment of patients with CRC.

Association between KRAS mutation and lung metastasis in advanced colorectal cancer.

494 Background: The role of KRAS status in the time-dependent pattern of metastasis in colorectal cancer (CRC) patients has been reported but not validated in independent series of unresectable metastatic CRC. We aimed to determine its potential value as a predictive factor for development of lung metastasis. Methods: We retrospectively evaluated data from MD Anderson Cancer Center from 494 patients diagnosed with metastatic CRC with KRAS mutation testing (codons 12, 13, 61) by Sanger sequencing or mass spectroscopy genotyping in 2008 through 2010. Medical records and image reports were assessed to determine date of lung metastasis diagnosis, pattern of lung involvement and presence of thoracic lymph nodal metastasis. Time-to-lung metastasis (TTLM), lung-metastasis-free survival (LMFS) and overall survival (OS) were calculated from the time of diagnosis of first metastasis in any site according to the Kaplan-Meier method and were compared by log-rank test. Results: We included 494 patients (41% female) wi...