Neoadjuvant Therapy in Pancreatic Cancer
ABSTRACT Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. Surgical resection offers the only hope of cure, though the addition of chemoradiation in the adjuvant setting has been shown to improve survival over surgery alone. Many patients are unable to receive adjuvant therapy due to prolonged postoperative recovery. For this reason, administration of chemoradiation preoperatively (neoadjuvant) has been proposed as an alternative to postoperative treatment. In patients with resectable disease, neoadjuvant therapy results in similar survivals compared to postoperative therapy, with a greater proportion of patients able to complete treatment. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging and increasing the likelihood of a margin-negative resection. This article reviews the use of neoadjuvant therapy in the treatment of pancreatic cancer.
- SourceAvailable from: Oliver Jäkel
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- "The idea to bring locally advanced tumors into a resectable status has been addressed explicitly in several studies [17,19-24]. There is evidence that the rate of margin-free resection can be increased by preoperative chemoradiation ; however, no randomized trials have confirmed this hypothesis. "
ABSTRACT: Treatment options for patients with locally advanced pancreatic cancer include surgery, chemotherapy as well as radiotherapy. In many cases, surgical resection is not possible, and therefore treatment alternatives have to be performed. Chemoradiation has been established as a convincing treatment alternative for locally advanced pancreatic cancer. Carbon ions offer physical and biological characteristics. Due to their inverted dose profile and the high local dose deposition within the Bragg peak precise dose application and sparing of normal tissue is possible. Moreover, in comparison to photons, carbon ions offer an increased relative biological effectiveness (RBE), which can be calculated between 1.16 and 2.46 depending on the pancreatic cancer cell line as well as the endpoint analyzed. Japanese Data on the evaluation of carbon ion radiation therapy showed promising results for patients with pancreatic cancer.Methods and design: The present PHOENIX-01 trial evaluates carbon ion radiotherapy using the active rasterscanning technique in patients with advanced pancreatic cancer in combination with weekly gemcitabine and adjuvant gemcitabine. Primary endpoint is toxicity, secondary endpoints are overall survival, progression-free survival and response. The physical and biological properties of the carbon ion beam promise to improve the therapeutic ratio in patients with pancreatic cancer: Due to the inverted dose profile dose deposition in the entry channel of the beam leads to sparing of normal tissue; the Bragg peak can be directed into the defined target volume, and the sharp dose fall-off thereafter again spares normal tissue behind the target volume. The higher RBE of carbon ions, which has been shown also for pancreatic cancer cell lines in the preclinical setting, is likely to contribute to an increase in local control, and perhaps in OS. Early data from Japanese centers have shown promising results. In conclusion, this is the first trial to evaluate actively delivered carbon ion beams in patients with locally advanced pancreatic cancer within a dose-escalation strategy.Trial registration: NCT01795274.BMC Cancer 09/2013; 13(1):419. DOI:10.1186/1471-2407-13-419 · 3.32 Impact Factor
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ABSTRACT: Pancreatic cancer, a lethal malignancy is difficult to diagnose and is associated with poor prognosis due to distal dissemination of the cancer to organs such as the liver, spleen and gastrointestinal tract. Epidermal growth factor receptor (EGFR), a member of ErbB family of growth factor receptors, is over-expressed in pancreatic cancer and is an important indicator of poor prognosis and therapeutic outcomes. Cetyltriethylammonium bromide (CTAB)-modified positively-charged poly(ethylene oxide)-poly(epsilon-caprolactone) (PEO-PCL) nanoparticles loaded with both EGFR-silencing siRNA and paclitaxel (PTX) were prepared and characterized by determining particle size and surface charge found to be approximately 260 nm and 10 mV respectively. When 1 nM siRNA was loaded on 2 mg of CTAB-modified PEO-PCL nanoparticles, the loading capacity and efficiency were 6.5 μg/2 mg and 97%, respectively. Human pancreatic adenocarcinoma (Panc-1) cells were incubated for 3 hours with PEO-modified PCL nanoparticles loaded with siGLO siRNA and OregonGreen®-labeled PTX and viewed under a fluorescence microscope to confirm nanoparticle uptake and distribution in the cells. The baseline EGFR expression in Panc-1 cells was confirmed by Western blot and immunocytometric analysis. The EGFR silencing efficacy studies using aqueous solution and nanoparticle formulations was examined with RT-PCR and Western blot analysis. These studies were carried out by extracting RNA and protein from Panc-1 cells treated with EGFR silencing siRNA- and scrambled siRNA-loaded CTAB-modified-PEO-PCL nanoparticles. For the Western blot and PCR EGFR band intensity was the least for protein extracted from cells treated with EGFR siRNA loaded nanoparticles compared to band intensity from protein extracted from both untreated cells and cells treated with scrambled siRNA loaded nanoparticles. The results of an MTS assay showed that PTX loaded CTAB-modified-PEO-PCL nanoparticles had a 3-fold lower IC50 value of 100nM compared to PTX in solutions, which had an IC50 of 300nM. Similarly siRNA loaded CTAB-modified PEO-PCL nanoparticles showed a greater reduction in percent cell viability compared to siRNA in solution. And finally combination of EGFR siRNA + PTX loaded CTAB-modified PEO-PCL nanoparticles showed greater reduction in percent cell viability compared to using either alone or PTX loaded nanoparticles, scrambled siRNA loaded nanoparticles and combination of scrambled siRNA + PTX loaded nanoparticles. Lastly, both quantitative and qualitative apoptosis studies were carried out using treated and untreated Panc-1 cells. Caspase 3/7 assay was performed to quantitatively determine that maximum apoptosis occurs in cells incubated with a combination of EGFR siRNA and PTX loaded nanoparticles. Qualitative TUNEL assay was performed to evaluate the enhancement in apoptotic cell death due to combination therapy. In comparison to the other treatments combination of EGFR siRNA + PTX loaded nanoparticles showed the most apoptotic cells based on the brown stained nuclei.
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ABSTRACT: Patients with borderline resectable pancreatic cancer are at high risk of having positive surgical margins due to involvement of the tumor with adjacent vasculature. This article reviews the management of this subset of pancreatic cancer patients. The authors review the current definitions of borderline resectable pancreatic cancer and how it is diagnosed and staged. The history, current approaches, and future directions in neoadjuvant therapy for borderline resectable pancreatic cancer are also reviewed with emphasis on various chemotherapy regimens that have been used. The application of intensity-modulated radiation therapy and image-guided radiation therapy that accounts for respiratory motion to targeting the gross tumor volume in the pancreas are discussed, and the promise of integrating targeted therapies in neoadjuvant treatment programs is highlighted. The use of neoadjuvant treatment programs that employ gemcitabine-based chemotherapy regimens followed by chemoradiation increases the likelihood of subsequent margin-negative resection in borderline resectable pancreatic cancer. There has been progress in the imaging, staging, surgical technique, and the use of chemotherapy and chemoradiotherapy in the management of borderline resectable pancreatic cancer. Patients can benefit from multidisciplinary management at high-volume pancreatic cancer treatment centers.Cancer control: journal of the Moffitt Cancer Center 11/2008; 15(4):295-307. · 2.66 Impact Factor