Pancreatic cancer–Palliative therapy: chemotherapy

Single-agent Gemcitabine has been the standard treatment for advanced pancreatic adenocarcinoma in the past years. Due to the aggressive and often chemotherapy-refractory character of this malignancy, systemic treatment options still remain limited. Many combination therapies have been evaluated in clinical trials to improve survival over Gemcitabine alone, until recently without satisfying results. Based on the positive results of a recent randomized trial, the combination of Gemcitabine and Capecitabine might become a new standard as first-line treatment for advanced pancreatic cancer. The clinical advantage of Erlotinib as a novel targeted agent in combination with Gemcitabine seems to be only marginal. Due to the small number of studies, there is still no standard of care in second-line therapy, but Oxaliplatin seems to be an active treatment option in Gemcitabine refractory disease. This article will review the development of cytotoxic antitumoral treatment for advanced pancreatic adenocarcinoma (locally advanced, irresectable and/or metastatic disease) including monotherapies and newer approaches with combination therapies.     

Pancreatic cancer–Palliative therapy: stenting

Pancreatic cancer remains a common and very lethal malignancy with a median survival of approximately 6 months. Surgical resection offers the only potentially curative approach but many patients (80% or more) are ineligible for this kind of therapy, because of age, comorbidities, or locally advanced or metastatic disease that does not benefit from resection. Thus, for many patients with pancreatic cancer treatment remains palliative and endoscopic therapy to relieve bile duct or gastric outlet obstruction becomes of special importance. Although both surgical and non surgical palliative procedures can relieve biliary and duodenal obstruction particularly endoscopic treatment with plastic prostheses or self expanding metal stents was shown to be not only highly effective but also to be burdened with only few complications. The present article summarizes the palliative endoscopic treatment in patients with non resectable pancreatic cancer.     

Pancreatic cancer–Curative resection

Resecting pancreatic cancer is the only chance for cure for this devastating disease [1–3]. It increases survival significantly and may also contribute to a better quality of life [4]. While median survival for patients with unresect-able pancreatic cancer is only about 4–8 months, resective surgery improves prognosis to a median survival of 14–20 months and 5-year survival rates of up to 25% [1, 5]. A few     

Pancreatic cancer–Laparoscopic resection

Objective: To assess current role of laparoscopic resection for pancreatic cancer, so as to improve the surgical management of pancreatic cancer. Methods: A comprehensive review of articles from PubMed was carried out. Results: Cur- rently, the advantages of a complete laparoscopic pancreatoduodenectomy (LPD) are still outweighed by the morbidity associ- ated with the procedure. However, laparoscopic distal pancreatectomy (LDP) offers patients benefits in terms of postoperative recovery and the length of hospital stay with similar morbidity and mortality to open surgery. Hand-assisted laparoscopic sur- gery can help to overcome the limitation of a complete laparoscopic surgery while maintaining a minimally invasive approach. Conclusion: Current literature suggests that laparoscopic resection of pancreatic cancer is feasible and safe in experienced hands. The hand-assisted laparoscopic surgery shows a promising future in pancreatic cancer surgery.     

Pancreatic cancer–Outlook: gene therapy

Gene therapy offers an elegant alternative to toxic chemotherapy regimens, mostly without severe side effects. Cancer gene therapy was among the first applications. Following the enthusiasm in the early nineties, a more rationale view is the recent way to look at it. This tutorial review looks upon the tools of gene therapy and the principle elements (vector, promoter, targeting, therapeutic gene). The principles of gene therapy such as gene directed enzyme prodrug therapy (GDEPT) and gene directed tumor vaccination are explained. Further, published protocols and clinical studies for pancreatic carcinoma gene therapy are reviewed. Finally, an outlook is given on the latest developments, some of them beyond conventional gene therapy.     

Pancreatic cancer–Neoadjuvant therapy

In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses multimodality therapy for patients with pancreatic cancer. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma. However only 10%–20% of patients present with tumors that are amenable to resection, and even after resection of localized cancers, long term survival is rare. The addition of chemoradiation therapy significantly increases median survival. To achieve long-term success in treating this disease it is therefore increasingly important to identify effective neoadjuvant/adjuvant multimodality therapies. Preoperative chemoradiation for potentially resectable pancreatic cancer has the following advantages: (1) neoadjuvant treatment would eliminate the delay of adjuvant treatment due to postoperative complications; (2) neoadjuvant treatment could avoid unnecessary surgery for patients with metastatic disease evident on restaging after neoadjuvant therapy; (3) downstaging after neoadjuvant therapy may increase the likelihood for negative surgical margins; and (4) neoadjuvant treatment could prevent peritoneal tumor cell implantation and dissemination caused during surgery. This review systematically summarizes the current status, controversies, and prospects of neoadjuvant treatment of pancreatic cancer.     

Pancreatic cancer–Adjuvant therapy

Pancreatic cancer ranks tenth in terms of newly diagnosed cases, but just 10%–15% of these patients can undergo resection. Survival after curative surgery is dismal, as recurrences occur either locally or in the liver. Adjuvant treatment with either chemotherapy or chemoradiation (with or without maintenance chemotherapy) has been employed, to improve the poor prognosis. Justification for the use of chemoradiation, with follow on chemotherapy, is based on the results of an underpowered 1987 GITSG study, which closed prematurely and compared intervention to observation. There has been no survival advantage demonstrated in the one randomized controlled trial that examined chemoradiation compared to chemotherapy. There is a clear cut survival advantage however with chemotherapy compared to observation, based on the results from two large randomized controlled trials, and supported by an individual patient data meta-analysis. The standard of care for adjuvant therapy based on level I evidence (from the ESPAC-1 trial) is post operative chemotherapy using 5-Fluorouracil with folinic acid providing a best estimate of 29% five years survival.     

Pancreatic cancer–Outlook: targeted therapy

Pancreatic cancer is a devastating disease characterized by almost identical incidence and mortality rates. Since this tumour is mostly diagnosed in an advanced stage there is usually no option for a curative surgical resection. In addition, pancreatic cancers known to be resistant to conventional treatment modalities such as chemotherapy and radiotherapy. Therefore, novel strategies for targeting these tumors are urgently needed. The increasing knowledge on the underlying pathogenetic mechanisms has led to the identification of surface receptor molecules that initiate intracellular signalling cascades upon ligand binding, thus leading to tumor progression. Targeting these receptors or their secreted ligands is therefore an attractive new approach for cancer therapy. The epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR) are transmembrane tyrosine kinase receptors which can be targeted by various compounds such as antibodies or small molecule inhibitors. In addition, various molecules targeting proteins secreted by pancreatic cancers such as matrix metalloproteinases (MMP’s) or intracellular oncogenic signalling components such as the farnesyltransferase have been proposed as potential new approaches for targeted cancer therapy. The use of these agents alone or in combination with conventional therapeutic regimens is currently being evaluated and shows first promising results for pancreatic cancer therapy.     

Pancreatic cancer–Diagnostics: PET

Important challenges for imaging of pancreatic cancer are the late presentation of the disease and the fact that therapeutic management is of limited success. Surgery continues to be the only treatment that offers potential cure. Therefore, defining whether the patient has an operable tumor remains the ultimate aim of imaging in pancreatic cancer. PET and PET/ CT with fluorodeoxyglucose (FDG) are of value in differential diagnosis between pancreatitis and carcinoma and for the detection of remote metastases, but relatively inefficient in the detection of nodal disease. The detection of recurrent disease is of little clinical consequence. FDG-PET may be considered as a prognostic marker for patient survival or therapy response, but evidence for these applications is lacking. Future applications will broaden the spectrum of tracers applied using molecules for the assessment of proliferation and detection of receptors.     

Pancreatic cancer–Pathology

IntroductionsPancreatic ductal adenocarcinoma (frequently simply being referred to as “pancreatic cancer”) represents the most frequent neoplasm of the pancreas, accounting for 85% to 90% of all pancreatic tumors [1, 2]. According to the definition of the World Health Organization [1], it “prob-ably arises from and is phenotypically similar to pancre     

Pancreatic cancer–Endosonography

EUS is the most sensitive imaging procedure for the detection of small solid pancreatic masses and is accurate in determining vascular invasion of the portal venous system. Even compared to the new CT-techniques EUS provides excellent results in preoperative staging of solid pancreatic tumors. Compared to helical CT-techniques EUS is less accurate in detecting tumor involvement of superior mesenteric artery. EUS staging and EUS-guided FNA can be performed in a single-step procedure, to establish the diagnosis of cancer. There is no known negative impact of tumor cell seeding due to EUS-FNA. Without FNA EUS and additional methods are not able to reliably distinguish between inflammatory and malignant masses.     

Pancreatic cancer–Molecular alterations

Pancreatic ductal adenocarcinoma is a dismal disease with a median survival below 6 months and a 5 year survival rate below 1%. High mortality is due to early lymphatic and hematogenic dissemination. Effective therapies for local advanced or metastatic tumors are missing and curative resected patients relapse in over 80% of the cases. Together this findings reflects the aggressive biology of the disease. Here we describe molecular mechanisms leading to unrestrained proliferation, insensitivity to growth inhibitory signals, evasion of apoptosis, limitless replicative potential, tissue invasion, metastasis and sustained angiogenesis.     

Pancreatic cancer–Diagnostics: CT, MRI

IntroductionThe introduction of modern imaging and fast imaging processing has tremendously improved detection and staging of pancreatic cancer. Besides progress in surgical techniques and handling the advances of both computerized tomography (CT) and magnetic resonance imaging (MRI) have remarkably contributed to higher resection     

Pancreatic cancer–Staging laparoscopy

Objective: Accurate staging of patients with pancreatic cancer is crucial to clarify whether meaningful resection is indeed possible. Staging laparoscopy has been suggested as a tool for staging which may spare up to two-fifth of these patients from undergoing nontherapeutic laparotomy. A controversy exists, however, as to whether the procedure should be used routinely or selectively in these patients with no evidence of metastasis on noninvasive staging. This review aims to evaluate the available literature critically, identify its limitations and address the existing controversies. Methods: The current available English literature was reviewed on this topic. Results: A direct and conclusive comparison of the controversial literature is difficult because of inconsistent use of high-quality CT scans, different study designs and dissimilarity of judgment for non-resectability among patients staged by laparoscopy. However, recent studies reveal that not more than 14% of the patients benefit from diagnostic laparoscopy when a dual-contrast thin cut and 3-D digital reformatting CT scan has been performed previously. Conclusion: We conclude that routine use of diagnostic laparoscopy does not appear warranted in all patients with pancreatic cancer, especially for patients with early-staged pancreatic cancer or non-pancreatic periampullary cancers, because diagnostic laparoscopy is costly and ultrasonography is largely operator-dependent. Rather, selective use is appropriate, especially in patients with a large primary tumor, a tumor in the body or tail of the pancreas, equivocal findings of metastasis on CT, the presence of ascites, severe weight loss, hypoalbuminemia, and a markedly elevated CA 19–9.     

Pancreatic cancer–Surgery for recurrent disease

Recurrence of pancreatic ductal adenocarcinoma (PDAC) after a resection with curative intent is inevitable in the majority of cases. Approximately three-quarters of patients ultimately die from metastatic, local, or combined tumor recurrence [1–3]. This may be due to the insuf     

Intravesical bacillus Calmette–Guerin therapy after second transurethral resection for primary T1 bladder cancer

Background

To evaluate the effect of intravesical bacillus Calmette–Guerin (BCG) instillation therapy after second transurethral resection (TUR) on primary T1 bladder cancer.

Methods

The subjects were 180 patients diagnosed with T1 bladder cancer at our university and at affiliated hospitals between January 1990 and December 2015. Tumor residual rate, intravesical recurrence rate, and risk factors for intravesical recurrence were investigated.

Results

The median follow-up period was 26 (1–175) months. Of the 180 patients, 78 (43%) underwent a second TUR. Residual tumors were detected in 42 patients (53.8%), and no up-staging cases were observed. Within the whole group, 42 patients were treated with intravesical BCG therapy following a second TUR (group 1), 36 were treated with second TUR alone (group 2), 28 were treated with intravesical BCG therapy alone (group 3), and 74 were treated without second TUR or intravesical BCG therapy (group 4). The 1- and 5-year recurrence-free survival rates of the four groups were 80.7 and 59.7% (group 1), 69.0 and 26.3% (group 2), 76.3 and 56.6% (group 3), 64.6 and 48.6% (group 4), respectively. There was no significant difference between group 1 and group 3 (p?=?0.401). Intravesical BCG therapy was the only factor preventing intravesical recurrence (p?=?0.013).

Conclusions

Intravesical BCG therapy alone showed a significant preventive effect with regard to intravesical recurrence. In our cohort, however, second TUR did not improve recurrence-free survival in those individuals who underwent BCG instillation.

     

Multimodality therapy in inflammatory breast cancer: Is there a place for surgery?

Background:In many centres surgery is used as part of a combinedmodality approach to the treatment of inflammatory breast cancer (IBC).Nevertheless, its value is controversial given the high risk of metastaticrelapse and poor overall prognosis. We have reviewed patients with true IBCprospectively treated at the Royal Marsden Hospital in chemotherapy trials toassess further the role of surgery as part of combined modality treatment. Patients and methods:Fifty-four patients who had responsive orstable disease to primary chemotherapy went on to have either radiotherapyalone (n = 35) or surgery plus radiotherapy (n = 19); thedecision on surgery was based partly on clinician preference and partly onclinical response. Results:The 35 patients undergoing radiotherapy alone had amedian progression-free survival (PFS) of 16 months and median overallsurvival (OS) of 35 months. Twenty-four patients (69%) have relapsedwith a total of twelve (34%) relapsing locally. In comparison, the 19patients receiving both surgery and radiotherapy had a PFS of 20 months, anda median OS of 35 months. Fifteen patients (79%) have relapsed, eight(42%) of these locally. None of these differences were statisticallysignificant. Conclusions:These results do not suggest a clinical advantage forsurgery in addition to chemotherapy and radiotherapy for patients with IBC.They support the need for a prospective randomised trial to address thisquestion.     

Pancreatic cancer: promise for personalised medicine?

Sleeping Beauty (SB) is a genetically engineered insertional mutagenesis system. Its ability to rapidly induce cancer in SB-transgenic mice as well as the ease of identification of the mutated genes suggest important roles for SB in the discovery of novel cancer genes as well as the generation of models of human cancers where none currently exist. The range of SB-related tumors extends from haematopoietic to solid cancers such as hepatocellular carcinoma. This review follows the refinement of SB for different cancers and assesses its potential as a model for all cancers and a tool for cancer gene discovery.