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Shen P, Huang KJ, Zhang CZ, Xiao L, Zhang T. Surgery with adjuvant or neoadjuvant treatment vs surgery alone for resectable pancreatic cancer: A network meta-analysis. World J Meta-Anal 2019; 7:309-322. [DOI: 10.13105/wjma.v7.i6.309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 06/04/2019] [Accepted: 06/10/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most common and lethal malignancies worldwide. The common treatment options for resectable pancreatic cancer include surgery alone, neoadjuvant chemotherapy (CT), neoadjuvant chemoradiotherapy (CRT), adjuvant CT, and adjuvant CRT. However, the optimal treatment is still controversial.
AIM To identify the most effective approach for pancreatic cancer using network meta-analysis.
METHODS Eligible studies were searched from PubMed, MEDLINE, EMBASE, Cochrane database, and Google scholar. We searched and included randomized controlled trials reporting on neoadjuvant and adjuvant therapies. For direct comparisons, standard pairwise meta-analysis was performed using the inverse variance DerSimonian-Laird random-effects model. For indirect comparisons, Bayesian network meta-analysis was used to combine direct and indirect evidence. We used relative hazard ratios (HRs) to estimate death difference of different treatments, and relative odds ratios (ORs) for toxic effects. Treatment effects were ranked based on their efficacy for improving survival or reducing toxicity using rankogram. The quality of evidence of estimates from direct comparison and network meta-analysis was evaluated following the GRADE approach.
RESULTS We included 13 high quality trials with 1591 participants in this network meta-analysis. Compared with surgery alone [pooled HR = 0.7, 95% confidence interval (CI): 0.62-0.79] and surgery with adjuvant CRT (pooled HR = 0.6, 95%CI: 0.54-0.72), surgery with adjuvant CT had a higher rate of overall survival. In contrast, standard pairwise meta-analysis showed a statistically significant survival advantage of surgery with adjuvant CT compared with surgery alone (pooled HR = 0.75, 95%CI: 0.63-0.89; P < 0.001). Rankogram showed that surgery with adjuvant CT was most likely to rank the best in terms of overall survival (probability: 94.2%), followed by surgery alone (probability: 5.8%). No significant differences in overall toxicity or haematological toxicity were found between all the therapies. High quality evidence supported surgery with adjuvant CT over surgery alone for increasing overall survival. Moderate quality evidence supported surgery with adjuvant CT over surgery with adjuvant CRT for increasing overall survival.
CONCLUSION Surgery with adjuvant CT prolongs overall survival compared with surgery alone and surgery with adjuvant CRT, suggesting surgery with adjuvant CT is the optimal treatment for resectable pancreatic cancer.
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Affiliation(s)
- Pu Shen
- Department of Anesthesia, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Kai-Jun Huang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Chuan-Zhao Zhang
- Department of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, Guangdong Province, China
| | - Li Xiao
- Department of Anesthesia, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
| | - Tao Zhang
- Department of Anesthesia, the First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, Guangdong Province, China
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Fitzgerald TL, Hunter L, Mosquera C, Jindal C, Biswas T, Zervos E, Efird JT. A simple matrix to predict treatment success and long-term survival among patients undergoing pancreatectomy. HPB (Oxford) 2019; 21:204-211. [PMID: 30087052 DOI: 10.1016/j.hpb.2018.07.010] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Revised: 05/16/2018] [Accepted: 07/09/2018] [Indexed: 02/08/2023]
Abstract
BACKGROUND A more accurate measure of long-term survival among patients who have undergone a successful resection for pancreatic adenocarcinoma may be computed by accounting for time already survived during the initial treatment window. METHODS Patients diagnosed with pancreatic adenocarcinoma, from 2004 through 2013, were identified from the American College of Surgeons National Cancer Database (NCDB). A risk-stratification matrix was constructed including age, histopathologic factors and the use of adjuvant therapy, given successful treatment and survival at 3-month following diagnosis. RESULTS A total of 25,897 patients (50% male, 53% >65 years of age) presented with stage I-III pancreatic cancer. The majority of patients had tumors >2 cm size (82%), grade I/II (65%), lymphatic invasion (LI) (66%), and negative margins (76%). A survival advantage for adjuvant therapy was observed among all patients, independent of their risk-profile. For example, a patient ≤65 years of age, with early stage cancer (size ≤2 cm, grade I/II, -ve LI, -ve margins) who received adjuvant therapy had a 62% probability of being alive beyond three years (95%CI = 59%-66%). In contrast, the survival probability decreased to 53% (95%CI = 59%-66%) without adjuvant therapy. CONCLUSIONS These results provide surgeons and patients with more accurate information regarding long-term survival, as well as the benefit of opting for adjuvant therapy after successful pancreatic surgery.
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Affiliation(s)
| | - Lucas Hunter
- Department of Surgical Oncology, Brody School of Medicine, Greenville, NC, USA
| | - Catalina Mosquera
- Department of Surgical Oncology, Brody School of Medicine, Greenville, NC, USA; Vidant Cancer Care, Greenville, NC, USA
| | - Charulata Jindal
- Centre for Clinical Epidemiology and Biostatistics (CCEB), School of Medicine and Public Health, The University of Newcastle (UoN), Newcastle, 2308, Australia
| | - Tithi Biswas
- Department of Radiation Oncology, University Hospitals, Case Western Reserve University, Cleveland, OH, USA
| | | | - Jimmy T Efird
- Centre for Clinical Epidemiology and Biostatistics (CCEB), School of Medicine and Public Health, The University of Newcastle (UoN), Newcastle, 2308, Australia.
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Samawi HH, Yin Y, Lim HJ, Cheung WY. Primary Care Versus Oncology-Based Surveillance Following Adjuvant Chemotherapy in Resected Pancreatic Cancer. J Gastrointest Cancer 2018; 49:429-436. [PMID: 28674913 DOI: 10.1007/s12029-017-9988-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
INTRODUCTION High level evidence to guide surveillance following curative intent treatment for pancreatic cancer is lacking and this has likely resulted in wide variations in practice. We aim to describe patterns of surveillance and evaluate their impact on outcomes. METHODS A total of 147 adult patients who received at least one cycle of adjuvant gemcitabine or 5-fluorouracil-based chemotherapy at any one of five British Columbia Cancer Agency centers between 2001 and 2015 were included. Surveillance strategies were classified into two categories: discharged to primary care physicians (PCPs) or follow-up at cancer centers (CC) that included regular clinical assessments, laboratory testing, and/or diagnostic imaging. RESULTS Median age at diagnosis was 64 (range 38-85) years and 48% were men. More patients were followed by CC than by PCPs (66 vs. 44%). Among the measured prognostic factors, only patients with advanced tumor stage (T3/4) were more likely to be followed by cancer specialists (78 vs. 62%, P = 0.03), while other patient and disease characteristics were balanced between the two groups. In the entire cohort, 100 (68%) patients had a documented recurrence. Patients followed by CC were more likely to receive palliative chemotherapy at recurrence than those followed by PCPs (58 vs. 34%, respectively, P = 0.03). The median overall survival (OS) was 2.82 (95% CI 2.17-3.32) years in the CC group and 3.35 (95% CI 2.85-5.06) years in the PCP group while the median relapse-free survival (RFS) was 1.4 (95% CI 1.37-1.77) and 2.4 (95% CI 2.07-4.59) years, respectively. On multivariate analysis, there was no significant difference in OS between CC and PCP-based surveillance (HR 1.23; 95% CI 0.74-2.04, P = 0.40); however, RFS favored the PCP group (HR 1.62; 95% CI 1.01-2.56, P = 0.04, for the CC group). CONCLUSION In this population-based analysis, surveillance tests and imaging performed by CC detected recurrences earlier when compared to follow-up by PCPs, but this did not result in OS differences. Patients with more advanced tumors were more likely to be seen at CC. PCPs may play a larger role in the follow-up care of selected low risk patients with resected pancreatic cancer.
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Affiliation(s)
- Haider H Samawi
- Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Yaling Yin
- Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Howard J Lim
- Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Winson Y Cheung
- Section of Medical Oncology, Tom Baker Cancer Centre, 1331 29 St NW, Calgary, AB, T2N 4N2, Canada.
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Kyrochristos ID, Ziogas DE, Glantzounis GK, Roukos DH. Molecular landscape of pancreatic cancer: challenges and clinical implications. Future Oncol 2017; 13:2741-2744. [PMID: 29182377 DOI: 10.2217/fon-2017-0335] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 07/20/2017] [Indexed: 01/23/2023] Open
Affiliation(s)
- Ioannis D Kyrochristos
- Centre for Biosystems & Genome Network Medicine, Ioannina University, Ioannina 45110, Greece
- Department of Surgery, Ioannina University Hospital, Ioannina 45500, Greece
| | - Demosthenes E Ziogas
- Centre for Biosystems & Genome Network Medicine, Ioannina University, Ioannina 45110, Greece
- Department of Surgery, 'G Hatzikosta' General Hospital, Ioannina 45001, Greece
| | | | - Dimitrios H Roukos
- Centre for Biosystems & Genome Network Medicine, Ioannina University, Ioannina 45110, Greece
- Department of Surgery, Ioannina University Hospital, Ioannina 45500, Greece
- Biomedical Research Foundation of the Academy of Athens (BRFAA), Athens 11527, Greece
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Lau SC, Cheung WY. Evolving treatment landscape for early and advanced pancreatic cancer. World J Gastrointest Oncol 2017; 9:281-292. [PMID: 28808501 PMCID: PMC5534396 DOI: 10.4251/wjgo.v9.i7.281] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 03/21/2017] [Accepted: 04/19/2017] [Indexed: 02/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is an infrequent cancer with a high disease related mortality rate, even in the context of early stage disease. Until recently, the rate of death from pancreatic cancer has remained largely similar whereby gemcitabine monotherapy was the mainstay of systemic treatment for most stages of disease. With the discovery of active multi-agent chemotherapy regimens, namely FOLFIRINOX and gemcitabine plus nab-paclitaxel, the treatment landscape of pancreatic cancer is slowly evolving. FOLFIRINOX and gemcitabine plus nab-paclitaxel are now considered standard first line treatment options in metastatic pancreatic cancer. Studies are ongoing to investigate the utility of these same regimens in the adjuvant setting. The potential of these treatments to downstage disease is also being actively examined in the locally advanced context since neoadjuvant approaches may improve resection rates and surgical outcomes. As more emerging data become available, the management of pancreatic cancer is anticipated to change significantly in the coming years.
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Ronco C, Millet A, Plaisant M, Abbe P, Hamouda-Tekaya N, Rocchi S, Benhida R. Structure activity relationship and optimization of N-(3-(2-aminothiazol-4-yl)aryl)benzenesulfonamides as anti-cancer compounds against sensitive and resistant cells. Bioorg Med Chem Lett 2017; 27:2192-2196. [PMID: 28372910 DOI: 10.1016/j.bmcl.2017.03.054] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Revised: 03/20/2017] [Accepted: 03/21/2017] [Indexed: 12/18/2022]
Abstract
We recently described a new family of bioactive molecules with interesting anti-cancer activities: the N-(4-(3-aminophenyl)thiazol-2-yl)acetamides. The lead compound of the series (1) displays significant anti-proliferative and cytotoxic activities against a panel of cancer cell lines, either sensitive or resistant to standard treatments. This molecule also shows a good pharmacological profile and high in vivo potency towards mice xenografts, without signs of toxicity on the animals. In the present article, we disclose the structure-activity relationships of this lead compound, which have provided clear information about the replacement of the acetamide function and the substitution pattern of the benzenesulfonamide ring. An improved high-yielding synthetic procedure towards these compounds has also been developed. Our drug design resulted in potency enhancement of 1, our new optimized lead compound being 19. These findings are of great interest to further improve this scaffold for the development of future clinical candidates.
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Affiliation(s)
- Cyril Ronco
- Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR7272, 06108 Nice, France
| | - Antoine Millet
- Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR7272, 06108 Nice, France
| | - Magali Plaisant
- Université Côte d'Azur, INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée au mélanome, 151 Route de Saint-Antoine, 06200 Nice, France
| | - Patricia Abbe
- Université Côte d'Azur, INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée au mélanome, 151 Route de Saint-Antoine, 06200 Nice, France
| | - Nedra Hamouda-Tekaya
- Université Côte d'Azur, INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée au mélanome, 151 Route de Saint-Antoine, 06200 Nice, France
| | - Stéphane Rocchi
- Université Côte d'Azur, INSERM, U1065, Centre Méditerranéen de Médecine Moléculaire (C3M), Equipe Biologie et Pathologie des cellules mélanocytaires: de la pigmentation cutanée au mélanome, 151 Route de Saint-Antoine, 06200 Nice, France
| | - Rachid Benhida
- Université Côte d'Azur, CNRS, Institut de Chimie de Nice UMR7272, 06108 Nice, France.
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Prognostic Implications of Expression Profiling for Gemcitabine-Related Genes (hENT1, dCK, RRM1, RRM2) in Patients With Resectable Pancreatic Adenocarcinoma Receiving Adjuvant Chemotherapy. Pancreas 2017; 46:684-689. [PMID: 28196013 DOI: 10.1097/mpa.0000000000000807] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES The aim of this study was to examine the relevance of expression profiling of 4 genes involved in the action of gemcitabine among patients with pancreatic ductal-cell adenocarcinoma (PDAC). METHODS A group of 100 patients who underwent pancreatic resections for PDAC and received adjuvant chemotherapy with gemcitabine between 2007 and 2010 was identified. Expression of mRNAs for human equilibrative nucleoside transporter 1 (hENT1), ribonucleotide reductase subunits (RRM1, RRM2), and deoxycytidine kinase (dCK) was examined by quantitative real-time polymerase chain reaction, normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH), and dichotomized into groups of low and moderate/high expression levels grouped by tertiles. RESULTS Significantly better median survival times were found for high/moderate expression levels of hENT1 (27.9 vs 12.4 months, P = 0.001) and dCK (19.7 vs 10.5 months, P = 0.003), as well as low expression of RRM1 (23.4 vs 11.4 months, P = 0.027). A Cox proportional hazards model identified low expression of hENT1 (hazard ratio [HR], 3.38; 95% confidence intervals [CI], 2.28-10.50) and dCK (HR, 2.24; 95% CI, 1.63-3.39), and high/moderate levels of RRM1 (HR, 1.65; 95% CI, 1.23-2.45) as negative prognostic factors. CONCLUSIONS Expression of hENT, RRM1, and dCK genes provides important prognostic information for PDAC patients treated with adjuvant gemcitabine.
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Silvestris N, Brunetti O, Vasile E, Cellini F, Cataldo I, Pusceddu V, Cattaneo M, Partelli S, Scartozzi M, Aprile G, Casadei Gardini A, Morganti AG, Valentini V, Scarpa A, Falconi M, Calabrese A, Lorusso V, Reni M, Cascinu S. Multimodal treatment of resectable pancreatic ductal adenocarcinoma. Crit Rev Oncol Hematol 2017; 111:152-165. [PMID: 28259290 DOI: 10.1016/j.critrevonc.2017.01.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 01/11/2017] [Accepted: 01/24/2017] [Indexed: 01/17/2023] Open
Abstract
After a timing preoperative staging, treatment of resectable pancreatic adenocarcinoma (PDAC) includes surgery and adjuvant therapies, the former representing the initial therapeutic option and the latter aiming to reduce the incidence of both distant metastases (chemotherapy) and locoregional failures (chemoradiotherapy). Herein, we provide a critical overview on the role of multimodal treatment in PDAC and on new opportunities related to current more active poli-chemotherapy regimens, targeted therapies, and the more recent immunotherapy approaches. Moreover, an analysis of pathological markers and clinical features able to help clinicians in the selection of the best therapeutic strategy will be discussed. Lastly, the role of neoadjuvant treatment of initially resectable disease will be considered mostly in patients whose malignancy shows morphological but not clinical or biological criteria of resectability. Depending on the results of these investigational studies, today a multidisciplinary approach can offer the best address therapy for these patients.
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Affiliation(s)
- Nicola Silvestris
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy.
| | - Oronzo Brunetti
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy.
| | - Enrico Vasile
- Department of Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy.
| | - Francesco Cellini
- Radiation Oncology Department, Gemelli ART, Università Cattolica del Sacro Cuore, Roma, Italy.
| | - Ivana Cataldo
- ARC-NET Research Centre, University of Verona, Verona, Italy.
| | | | - Monica Cattaneo
- Department of Medical Oncology, University and General Hospital, Udine, Italy.
| | - Stefano Partelli
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy.
| | - Mario Scartozzi
- Medical Oncology Unit, University of Cagliari, Cagliari, Italy.
| | - Giuseppe Aprile
- Department of Medical Oncology, University and General Hospital, Udine, Italy; Department of Medical Oncology, General Hospital of Vicenza, Vicenza, Italy.
| | | | - Alessio Giuseppe Morganti
- Radiation Oncology Center, Dept. of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy.
| | - Vincenzo Valentini
- Radiation Oncology Department, Gemelli ART, Università Cattolica del Sacro Cuore, Roma, Italy.
| | - Aldo Scarpa
- ARC-NET Research Centre, University of Verona, Verona, Italy.
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy.
| | - Angela Calabrese
- Radiology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy.
| | - Vito Lorusso
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy.
| | - Michele Reni
- Medical Oncology Department, IRCCS San Raffaele Scientific Institute, Milan, Italy.
| | - Stefano Cascinu
- Modena Cancer Center, Policlinico di Modena Università di Modena e Reggio Emilia, Italy.
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Chemoradiotherapy for locally advanced pancreatic cancer patients: is it still an open question? Contemp Oncol (Pozn) 2016; 20:102-8. [PMID: 27358587 PMCID: PMC4925731 DOI: 10.5114/wo.2016.60066] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 03/19/2015] [Indexed: 12/15/2022] Open
Abstract
Operable pancreatic cancer is characterized by a high risk of recurrence. Efforts are made to incorporate new therapies. Throughout the world there is a lack of uniform recommendations concerning the adjuvant treatment of pancreatic cancer patients, due to confusing evidence-based data. The patients recruited to clinical trials differ from the population of patients treated in everyday practice. These differences have an influence on tolerance of treatment, toxicity and results of therapy. The decision on administration of adjuvant treatment is made individually and differs from center to center. A review of the literature concerning both results and tolerance of postoperative chemoradiotherapy of pancreatic cancer patients is presented.
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10
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GONG JUN, TULI RICHARD, SHINDE ARVIND, HENDIFAR ANDREWE. Meta-analyses of treatment standards for pancreatic cancer. Mol Clin Oncol 2016; 4:315-325. [PMID: 26998283 PMCID: PMC4774516 DOI: 10.3892/mco.2015.716] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 11/23/2015] [Indexed: 01/05/2023] Open
Abstract
Pancreatic cancer is the most lethal common cancer with an estimated 5-year survival rate of 6-7% (across all stages). The only potential curative therapy is surgical resection in those with localized disease. Adjuvant (postoperative) therapy confers a survival advantage over postoperative observation alone. Neoadjuvant (preoperative) therapy offers the potential to downstage initially unresectable tumors for resection, sterilize resection margins and decrease locoregional recurrence, and identify a subset of patients with aggressive disease for whom surgery will not be beneficial. Induction chemotherapy followed by consolidation chemoradiation is another recommended approach in those with locally advanced disease. For those who cannot be downstaged, cannot tolerate surgery, or were diagnosed with metastatic disease, treatment remains palliative with chemotherapy being a critical component of this approach. Recently, intensive combination chemotherapy has been shown to improve survival rates in comparison to gemcitabine alone in advanced disease. The past few decades have afforded an accumulation of high-level evidence regarding neoadjuvant, adjuvant and palliative therapies in pancreatic cancer. There are numerous reviews discussing recent retrospective studies, prospective studies and randomized controlled trials in each of these areas. However, reviews of optimal and recommended treatment strategies across all stages of pancreatic cancer that focus on the highest levels of hierarchical evidence, such as meta-analyses, are limited. The discussion of novel therapeutics is beyond the scope of this review. However, an extensive and the most current collection of meta-analyses of first-line systemic and locoregional treatment options for all stages of pancreatic cancer to date has been accumulated.
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Affiliation(s)
- JUN GONG
- Department of Internal Medicine, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - RICHARD TULI
- Department of Radiation Oncology, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - ARVIND SHINDE
- Department of Hematology and Oncology, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - ANDREW E. HENDIFAR
- Gastrointestinal and Neuroendocrine Malignancies, Samuel Oschin Cancer Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Mohammed A, Janakiram NB, Pant S, Rao CV. Molecular Targeted Intervention for Pancreatic Cancer. Cancers (Basel) 2015; 7:1499-542. [PMID: 26266422 PMCID: PMC4586783 DOI: 10.3390/cancers7030850] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2015] [Revised: 07/24/2015] [Accepted: 08/04/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) remains one of the worst cancers, with almost uniform lethality. PC risk is associated with westernized diet, tobacco, alcohol, obesity, chronic pancreatitis, and family history of pancreatic cancer. New targeted agents and the use of various therapeutic combinations have yet to provide adequate treatments for patients with advanced cancer. To design better preventive and/or treatment strategies against PC, knowledge of PC pathogenesis at the molecular level is vital. With the advent of genetically modified animals, significant advances have been made in understanding the molecular biology and pathogenesis of PC. Currently, several clinical trials and preclinical evaluations are underway to investigate novel agents that target signaling defects in PC. An important consideration in evaluating novel drugs is determining whether an agent can reach the target in concentrations effective to treat the disease. Recently, we have reported evidence for chemoprevention of PC. Here, we provide a comprehensive review of current updates on molecularly targeted interventions, as well as dietary, phytochemical, immunoregulatory, and microenvironment-based approaches for the development of novel therapeutic and preventive regimens. Special attention is given to prevention and treatment in preclinical genetically engineered mouse studies and human clinical studies.
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Affiliation(s)
- Altaf Mohammed
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Naveena B Janakiram
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Shubham Pant
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, PC Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
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12
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Hartley ML, Bade NA, Prins PA, Ampie L, Marshall JL. Pancreatic cancer, treatment options, and GI-4000. Hum Vaccin Immunother 2015; 11:931-7. [PMID: 25933185 PMCID: PMC4514241 DOI: 10.1080/21645515.2015.1011017] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Revised: 11/10/2014] [Accepted: 11/14/2014] [Indexed: 12/13/2022] Open
Abstract
Although pancreatic cancer is but the eleventh most prevalent cancer in the US, it is predicted that of all the patients newly diagnosed with this disease in 2014, only 27% will still be alive at the end of the first year, which is reduced to 6% after 5 years. The choice of chemotherapy in the treatment of pancreatic cancer is dependent on disease stage and patient performance status but, in general, the most widely used approved regimens include 5-fluorouracil (5-FU) combinations and gemcitabine combinations. Recent therapeutic strategies have resulted in an improvement in survival of patients with pancreatic cancer but the magnitude of change is disappointing and vast improvements are still needed. The goal of immunotherapy is to enhance and guide the body's immune system to recognize tumor-specific antigens and mount an attack against the disease. Among newer immune therapies, GI-4000 consists of 4 different targeted molecular immunogens, each containing a different Ras protein (antigen) encoded by the most commonly found mutant RAS genes in solid tumors-RAS mutations exist in over 90% of pancreatic ductal adenocarcinomas. We will review pancreatic cancer epidemiology and its current treatment options, and consider the prospects of immunotherapy, focusing on GI-4000. We discuss the potential mechanism of action of GI-4000, and the performance of this vaccination series thus far in early phase clinical trials.
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Affiliation(s)
- Marion L Hartley
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
| | - Najeebah A Bade
- The Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
| | - Petra A Prins
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
| | - Leonel Ampie
- The Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
| | - John L Marshall
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University; Washington, DC USA
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Zhang X, Huang HJ, Feng D, Yang DJ, Wang CM, Cai QP. Is concomitant radiotherapy necessary with gemcitabine-based chemotherapy in pancreatic cancer? World J Gastroenterol 2014; 20:17648-17655. [PMID: 25516680 PMCID: PMC4265627 DOI: 10.3748/wjg.v20.i46.17648] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2014] [Revised: 06/05/2014] [Accepted: 07/30/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To evaluate the efficacy and safety of gemcitabine (GEM) plus radiotherapy compared with GEM alone for pancreatic cancer (PC).
METHODS: A systematic search for eligible studies comparing gemcitabine plus radiotherapy with gemcitabine alone for PC was performed using MEDLINE, EMBASE, and the Cochrane Library. A quality assessment was performed in each study. Meta-analyses were performed to study the pooled effects of relative risk with 95% confidence interval (CI).
RESULTS: A total of 336 participants from four original studies were included. Gemcitabine plus radiotherapy resulted in comparable overall survival (HR = 0.84, 95%CI: 0.53-1.34, P = 0.48) and progress free survival (HR = 0.99, 95%CI: 0.97-1.01, P = 0.36) to gemcitabine alone. Moreover, concomitant radiotherapy was associated with a significantly higher incidence of severe (grade 3 or greater) toxicities, mainly anemia, leukocytopenia, thrombocytopenia, anorexia, nausea/vomiting, and asthenia/fatigue.
CONCLUSION: Radiotherapy is not beneficial with gemcitabine-based chemotherapy for PC. Further exploration for better radiotherapy approaches and therapeutic regimens for the treatment of PC is warranted.
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Hartley ML, Bade NA, Prins PA, Ampie L, Marshall JL. Pancreatic cancer, treatment options, and GI-4000. Hum Vaccin Immunother 2014; 10:3347-53. [PMID: 25585100 PMCID: PMC4514054 DOI: 10.1080/21645515.2014.1004017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2014] [Revised: 11/10/2014] [Accepted: 11/14/2014] [Indexed: 12/13/2022] Open
Abstract
Although pancreatic cancer is but the eleventh most prevalent cancer in the US, it is predicted that of all the patients newly diagnosed with this disease in 2014, only 27% will still be alive at the end of the first year and only 6% will make it past 5 years. The choice of chemotherapy in the treatment of pancreatic cancer is dependent on disease stage and patient performance status but, in general, the most widely used approved regimens include 5-fluorouracil (5-FU) combinations and gemcitabine combinations. Recent therapeutic strategies have resulted in an improvement in survival of patients with pancreatic cancer but the magnitude of change is disappointing and vast improvements are still needed. The goal of immunotherapy is to enhance and guide the body's immune system to recognize tumor-specific antigens and mount an attack against the disease. Among newer immune therapies, GI-4000 consists of 4 different targeted molecular immunogens, each containing a different Ras protein (antigen) encoded by the most commonly found mutant RAS genes in solid tumors--RAS mutations exist in over 90% of pancreatic ductal adenocarcinomas. We will review pancreatic cancer epidemiology and its current treatment options, and consider the prospects of immunotherapy, focusing on GI-4000. We discuss the potential mechanism of action of GI-4000, and the performance of this vaccination series thus far in early phase clinical trials.
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Affiliation(s)
- Marion L Hartley
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington DC USA
| | - Najeebah A Bade
- The Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington DC USA
| | - Petra A Prins
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington DC USA
| | - Leonel Ampie
- The Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington DC USA
| | - John L Marshall
- The Ruesch Center for the Cure of GI Cancers at the Georgetown Lombardi Comprehensive Cancer Center; Georgetown University Medical Center; Washington DC USA
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