Therapeutic Advances in Pancreatic Cancer Paulson, Andrew Scott; Tran Cao, Hop S; Tempero, Margaret A ...
Gastroenterology (New York, N.Y. 1943)
144, Številka:
6
Journal Article
Recenzirano
Despite our improved understanding of pancreatic cancer biology and ability to perform more complex pancreatic cancer surgeries that produce better short-term outcomes, major progress toward ...increasing survival times has been painstakingly slow. Through the often-repeated, dismal survival statistics, it is easy to lose sight of real progress that has been made in pancreatic cancer therapy. It is particularly interesting to observe the extent to which these advances are interdependent and the effects they have had on practice. For example, during the past 5–10 years, we have seen widespread adoption of pancreatic imaging protocols that allow for objectively defined criteria of resectability. This has led to the definition of “borderline resectable pancreatic cancer”—a new clinical category that has affected the design of clinical trials. A major change in our surgical approach has been the move to minimally invasive pancreatectomy, which continues to gain broader acceptance and use, particularly for left-sided lesions. Although many new agents have been developed aimed at putative molecular targets, recent breakthroughs in therapy for advanced disease have arisen from our ability to safely give patients combination cytotoxic chemotherapy. We are now faced with the challenge of combining multidrug, cytotoxic chemotherapies with newer-generation agents. Ultimately, the hope is that drug combinations will be selected based on biomarkers, and strategies for pancreatic cancer therapy will be personalized, which could prolong patients' lives and reduce toxicity. We review the major advances in pancreatic cancer therapy during the last 5 years, and discuss how these have set the stage for greater progress in the near future.
Pancreatic cancer is an aggressive malignancy with a poor prognosis. The disease and its treatment can cause significant nutritional impairments that often adversely impact patient quality of life ...(QOL). The pancreas has both exocrine and endocrine functions and, in the setting of cancer, both systems may be affected. Pancreatic exocrine insufficiency (PEI) manifests as weight loss and steatorrhea, while endocrine insufficiency may result in diabetes mellitus. Surgical resection, a central component of pancreatic cancer treatment, may induce or exacerbate these dysfunctions. Nutritional and metabolic dysfunctions in patients with pancreatic cancer lack characterization, and few guidelines exist for nutritional support in patients after surgical resection. We reviewed publications from the past two decades (1995-2016) addressing the nutritional and metabolic status of patients with pancreatic cancer, grouping them into status at the time of diagnosis, status at the time of resection, and status of nutritional support throughout the diagnosis and treatment of pancreatic cancer. Here, we summarize the results of these investigations and evaluate the effectiveness of various types of nutritional support in patients after pancreatectomy for pancreatic adenocarcinoma (PDAC). We outline the following conservative perioperative strategies to optimize patient outcomes and guide the care of these patients: (1) patients with albumin < 2.5 mg/dL or weight loss > 10% should postpone surgery and begin aggressive nutrition supplementation; (2) patients with albumin < 3 mg/dL or weight loss between 5% and 10% should have nutrition supplementation prior to surgery; (3) enteral nutrition (EN) should be preferred as a nutritional intervention over total parenteral nutrition (TPN) postoperatively; and, (4) a multidisciplinary approach should be used to allow for early detection of symptoms of endocrine and exocrine pancreatic insufficiency alongside implementation of appropriate treatment to improve the patient's quality of life.
Background
Enhanced Recovery After Surgery (ERAS) has been widely applied in liver surgery since the publication of the first ERAS guidelines in 2016. The aim of the present article was to update the ...ERAS guidelines in liver surgery using a modified Delphi method based on a systematic review of the literature.
Methods
A systematic literature review was performed using MEDLINE/PubMed, Embase, and the Cochrane Library. A modified Delphi method including 15 international experts was used. Consensus was judged to be reached when >80% of the experts agreed on the recommended items. Recommendations were based on the Grading of Recommendations, Assessment, Development and Evaluations system.
Results
A total of 7541 manuscripts were screened, and 240 articles were finally included. Twenty-five recommendation items were elaborated. All of them obtained consensus (>80% agreement) after 3 Delphi rounds. Nine items (36%) had a high level of evidence and 16 (64%) a strong recommendation grade. Compared to the first ERAS guidelines published, 3 novel items were introduced: prehabilitation in high-risk patients, preoperative biliary drainage in cholestatic liver, and preoperative smoking and alcohol cessation at least 4 weeks before hepatectomy.
Conclusions
These guidelines based on the best available evidence allow standardization of the perioperative management of patients undergoing liver surgery. Specific studies on hepatectomy in cirrhotic patients following an ERAS program are still needed.
Ambient ionization mass spectrometry has been widely applied to image lipids and metabolites in primary cancer tissues with the purpose of detecting and understanding metabolic changes associated ...with cancer development and progression. Here, we report the use of desorption electrospray ionization mass spectrometry (DESI-MS) to image metastatic breast and thyroid cancer in human lymph node tissues. Our results show clear alterations in lipid and metabolite distributions detected in the mass spectra profiles from 42 samples of metastatic thyroid tumors, metastatic breast tumors, and normal lymph node tissues. 2D DESI-MS ion images of selected molecular species allowed discrimination and visualization of specific histologic features within tissue sections, including regions of metastatic cancer, adjacent normal lymph node, and fibrosis or adipose tissues, which strongly correlated with pathologic findings. In thyroid cancer metastasis, increased relative abundances of ceramides and glycerophosphoinisitols were observed. In breast cancer metastasis, increased relative abundances of various fatty acids and specific glycerophospholipids were seen. Trends in the alterations in fatty acyl chain composition of lipid species were also observed through detailed mass spectra evaluation and chemical identification of molecular species. The results obtained demonstrate DESI-MSI as a potential clinical tool for the detection of breast and thyroid cancer metastasis in lymph nodes, although further validation is needed.
Graphical Abstract
Desorption electrospray ionization mass spectrometry imaging is used to differentiate metastatic cancer from adjacent lymph node tissue
Background
While surgery is a mainstay of curative-intent treatment for patients with intrahepatic cholangiocarcinoma (IHC), the role of neoadjuvant therapy (NT) has not been well-established. We ...sought to describe trends in NT utilization, characterize associated factors, and evaluate association with overall survival (OS).
Methods
Retrospective cohort study of 4456 surgically resected IHC patients within National Cancer Data Base (2006–2016). NT included chemotherapy alone and/or (chemo)radiation. Descriptive statistics used to describe the cohort. Multivariable hierarchical logistic regression models were used to examine factors associated with NT administration. Analyses conducted comparing OS among upfront surgery patients and NT patients using propensity matching using nearest-neighbor methodology and adjustment using inverse probability of treatment weighting (IPTW). Association between NT and risk of death evaluated using multivariable Cox shared frailty modeling.
Results
Utilization of NT did not significantly increase over time (11%-2006 to 16%-2016, trend test
p
= 0.07) but did increase among patients with clinical nodal involvement (cN+, 13% to 36%,
p
= 0.002). Factors associated with NT use include cN+ disease (odds ratio OR 1.68, 95% confidence interval CI 1.31–2.15) and advanced clinical T stage: T2 (OR 1.65, 95% CI 1.33–2.06); T3 (OR 1.51, 95% CI 1.13–2.02). After propensity matching, NT associated with a 23% decreased risk of death relative to upfront surgery (hazard ratio HR 0.77, 95% CI 0.61–0.97). Findings were similar after IPTW (HR 0.83, 95% CI 0.78–0.88).
Conclusions
NT is increasingly used for the management of IHC patients with characteristics indicating aggressive tumor biology and is associated with decreased risk of death. These data suggest need for prospective studies of NT in management of patients with potentially resectable IHC.
IMPORTANCE: The incidence of squamous cell carcinoma of the anal canal (SCCAC) is increasing. Although standard management of SCCAC includes the use of concurrent chemotherapy and radiotherapy ...(chemoradiotherapy), data are lacking on potentially less morbid, alternative management strategies, such as local excision, among patients with node-negative T1 disease. OBJECTIVES: To examine the use of local excision among patients with T1 SCCAC and to compare overall survival relative to those who received standard treatment with chemoradiotherapy. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study assessed 2243 patients in the National Cancer Database (2004-2012) between 18 and 80 years of age with T1N0M0 SCCAC. The association between the type of treatment received and overall risk of death was evaluated using multivariable Cox proportional hazards regression models. Data analysis was performed from June 29, 2016, to April 17, 2017. MAIN OUTCOMES AND MEASURES: Overall survival. RESULTS: Among 2243 patients with T1N0 SCCAC, 503 (22.4%) were treated with local excision alone (mean SD age, 54.5 12.1 years; 240 47.7% male; 419 83.3% white) and 1740 with chemoradiotherapy (mean SD age, 57.0 10.6 years; 562 32.3% male; 1547 88.9% white). Among those treated with chemoradiotherapy, 12 patients underwent a subsequent abdominoperineal resection. There was a statistically significant increase in the use of local excision during the study period (34 17.3% in 2004 to 68 30.8% in 2012; trend test, P < .001). This increase in use was observed among patients with primary tumors that measured 1 cm or smaller and greater than 1 cm to 2 cm or smaller (trend test, P < .001 for both). Overall survival at 5 years was not significantly different for the 2 management strategies (85.3% in the local excision cohort and 86.8% in the chemoradiotherapy cohort; log-rank test, P = .93). Overall risk of death was not significantly different for local excision alone relative to that for treatment with chemoradiotherapy (hazard ratio, 1.06; 95% CI, 0.78-1.44). These findings were robust when stratified by tumor size and when patients who underwent abdominoperineal resection after chemoradiotherapy were excluded. CONCLUSIONS AND RELEVANCE: The use of local excision alone for the management of T1N0 SCCAC has significantly increased over time, with no clear decrement in overall survival. Because local excision may represent a lower-cost, less morbid treatment option for select patients with SCCAC, future studies are needed to better delineate its role and efficacy relative to the current standard of chemoradiotherapy.
An understanding of signaling pathways has not been fully incorporated into prognostication and therapeutic options. We evaluated the hypothesis that information about cancer-related signaling ...pathways can improve prognostic stratification and explain some of the clinical heterogeneity in patients with metastatic colorectal cancer.
We analyzed prognostic relevance of signaling pathways in patients undergoing resection of colorectal liver metastases (CLM) from 2004–2017, and clinical actionability of gene alterations in 7 signaling pathways: p53, Wnt, RTK-RAS, PI3K, TGFβ, Notch, and cell cycle. To assess the wide applicability, the results were validated in an external retrospective cohort including patients with unresectable metastatic colorectal cancer.
Of 579 patients, the numbers of patients with pathway alterations were as follows: p53, n = 420 (72.5%); Wnt, 340 (58.7%); RTK-RAS, 333 (57.5%); PI3K, 110 (19.0%); TGFβ, 65 (11.2%); Notch, 41 (7.1%); and cell cycle, 15 (2.6%). More than 80% of alterations in each pathway occurred in a single predominant gene TP53, APC, KRAS, PIK3CA, FBXW7, and RB1 in p53, Wnt, RTK-RAS, PI3K, Notch, and cell cycle pathways, respectively. Alterations of 4 pathways (p53, RTK-RAS, TGFβ, and Notch) and corresponding predominant genes (TP53, RAS/BRAF, SMAD4, and FBXW7) were significantly associated with worse overall survival (OS), and alterations of Wnt pathway (APC) were associated with better OS in the median follow-up duration of 3.8 years. Similarly, in the external cohort, alterations of p53 (TP53) and RTK-RAS (RAS/BRAF) were significantly associated with worse OS, whereas alteration of Wnt (APC) was associated with better OS in the median follow-up duration of 2.6 years.
Genomic sequencing provides insights into clinical heterogeneity and permits finer prognostic stratification in patients with metastatic colorectal cancer.
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Liquid biopsies are increasingly tested in patients with colorectal cancer to assess tumor burden, response to therapy, and prognosis. The significance of liquid biopsy results after resection of ...colorectal liver metastases (CLMs) is not well-defined.
Sixty-three patients undergoing CLM resection between 2016 and 2018 had plasma drawn postoperatively for liquid biopsy evaluation. Next-generation sequencing analysis was performed to detect somatic mutations in 70 genes.
Liquid biopsy after CLM resection was positive in 42 of 63 patients (67%). Eleven patients (18%) had 1 gene mutation, 14 patients (22%) had 2 to 3 mutations, and 17 patients (27%) had 4 or more mutations. The most common mutation was APC, detected in 32 patients (76%), followed by TP53 (74%) and KRAS (38%). Two-year overall survival rate from date of liver resection was significantly worse among patients with a positive liquid biopsy (70% vs 100%; p = 0.005), particularly for those with 4 or more gene mutations detected, whose 2-year overall survival rate was 41%. Sixteen of the 63 patients underwent serial liquid biopsies, resulting in 100 liquid biopsies with matched serum CEA and CT scan results. Metastases were identified in 74 CT scans, which correlated with positive liquid biopsy in 77% of samples (p < 0.001) and CEA > 3 ng/mL in 45% of samples (p < 0.22).
Liquid biopsy results provide information about disease burden and prognosis that is complementary to serum CEA and CT imaging. A positive liquid biopsy after CLM resection is associated with worse overall survival, particularly when multiple gene mutations are detected.
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