Treatment of locally advanced pancreatic cancer: the role of radiation therapy

Pancreatic cancer remains associated with an extremely poor prognosis. Surgical resection can be curative, but the majority of patients present with locally advanced or metastatic disease. Treatment for patients with locally advanced disease is controversial. Therapeutic options include systemic therapy alone, concurrent chemoradiation, or induction chemotherapy followed by chemoradiation. We review the evidence to date regarding the treatment of locally advanced pancreatic cancer (LAPC), as well as evolving strategies including the emerging role of targeted therapies. We propose that if radiation is used for patients with LAPC, it should be delivered with concurrent chemotherapy and following a period of induction chemotherapy.     

Combinational therapy: New hope for pancreatic cancer?

Pancreatic cancer is a devastating disease with a low overall survival rate. Chemotherapy is the most common treatment for patients presenting with advanced pancreatic cancer. Gemcitabine achieves a modest improvement in overall survival and is the gold standard for advanced pancreatic cancer treatment. Capecitabine and S-1, derivatives of 5-fluorouracil (5-FU), offers minimal clinical benefits. Folfirinox represents a new and aggressive regimen that might benefit patients of metastatic pancreatic cancer with good performance status. Other chemotherapy drugs such as platinums and irinotecan do not provide significant improvement in overall survival, but have been used as part of combinational therapies. Comparing to systemically delivered chemotherapy, regional intra-arterial chemotherapy achieves higher local drug concentration in tumors with lower systemic drug toxicity, and may serve as a better treatment regimen. Although there have been progress made in chemotherapeutic strategies against pancreatic cancer, the overall survival is not significantly improved in the last decade. Recently, development of chemotherapy in combination with molecular targeted therapies holds great promise in pancreatic cancer treatment, especially in patients with metastatic disease. Growing bodies of preclinical and clinical evidences indicate that the combination of conventional modalities with specific molecular targeted therapy increase the efficacy of the monotherapy without an increase in toxicity. In this review, we summarized the current regimens of chemotherapy and molecular targeted therapy for advanced pancreatic cancer and highlighted the novel combinational treatments tested in recent clinical trials.     

Multimodale kurative/neoadjuvante Therapie beim Pankreaskarzinom

In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses curative multimodality therapy for patients with pancreatic cancer. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma. However, only a few patients present with tumors that are amenable to resection, end even after resection of localized cancers, long-term survival is poor. 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.     

Current status of adjuvant therapy for pancreatic cancer

In this article, we review the rationale for and outcomes associated with the use of adjuvant and neoadjuvant therapy for resectable and borderline resectable cancer of the pancreatic head and uncinate process. Localized pancreatic cancer is a systemic disease that requires nonoperative therapies to minimize the local and systemic recurrences that almost invariably occur in the absence of such therapy, even following complete surgical resection. A well-defined role exists for the systemic administration of gemcitabine or 5-fluorouracil in the postoperative setting. Although the survival benefit associated with adjuvant chemoradiation has not been as rigorously defined, its use is supported by extensive historic experience; chemoradiation should be considered particularly for patients at high risk for local recurrence. Delivery of chemotherapy and/or chemoradiation prior to surgery has multiple potential advantages, although the superiority of neoadjuvant therapy over standard postoperative therapy has yet to be demonstrated. Neoadjuvant therapy may be particularly beneficial among patients with borderline resectable cancers. Although the existing literature is confusing, and indeed controversial, available evidence suggests that systemic chemotherapy and/or chemoradiation should be offered to all patients with pancreatic cancer who undergo potentially curative resection. Well-designed prospective trials are needed to define the optimal adjuvant or neoadjuvant therapy strategy for these patients.     

胰腺癌:新辅助治疗

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.     

胰腺癌:新辅助治疗

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.     

Liver-Directed Therapies: Does It Make Sense in the Current Therapeutic Strategy for Patients With Confined Liver Colorectal Metastases?

Nearly half of patients with colorectal cancer will have metastases in the course of their disease and the liver appears to be the most common location for metastases. For patients with confined hepatic colorectal metastases, complete surgical resection is the only chance for cure, with a 5-year postoperative survival rate between 35% and 50%. Over the past 5 years, combinations of chemotherapy with targeted therapies have succeeded in inducing tumoral response and have made curative surgery of initially unresectable liver metastases possible. However despite optimal preoperative treatment, disease in the majority of patients remains unresectable. For patients with liver-limited or liver-dominant metastatic colorectal cancer (mCRC), the current challenges are to explore different locoregional treatments to improve local control, overall survival (OS), and curative resection. In this way, liver-directed therapy, which is defined by injection, infusion, or embolization of chemotherapy or loaded radionuclide (with radioactive yttrium-90) microspheres into the arterial liver vasculature, has been an appealing investigational method for patients with liver-confined mCRC, in whom it has yielded reproducibly higher response rates (RRs) than conventional intravenous therapy. In this article, we propose to review, compare, and discuss the clinical benefit, the current indications, and the optimal use of liver-directed therapies for patients with liver-dominant mCRC.     

Targeted therapies in colorectal cancer: surgical considerations

Colorectal cancer (CRC) is a leading worldwide health concern that is responsible for thousands of deaths each year. The primary source of mortality for patients with CRC is the development and subsequent progression of metastatic disease. The most common site for distant metastatic disease is the liver. Although patients with metastatic disease to the liver have several effective treatment options, the only one for cure remains surgical resection of the liver metastases. Historically, most patients with liver metastases have had unresectable disease, and only a small percentage of patients have undergone complete curative resection. However, improved systemic therapies have led to an evolution in strategies to treat metastatic CRC to the liver. Under most conditions the management of these patients remains complex; and as chemotherapy options and new targeted therapies continue to improve outcomes, it is clear that a multidisciplinary approach must be the foundation on which advanced surgical and medical techniques are employed. Here, in this review, we highlight the role of targeted therapies in the surgical management of patients with metastatic CRC to the liver.Key Words: Colorectal cancer (CRC), metastatic colorectal cancer (mCRC), liver, targeted therapies, chemotherapy, surgical management     

Metastatic colorectal cancer: recent advances in its clinical management

Colorectal cancer (CRC) is frequently complicated by metastatic disease, with the liver being the most common site of metastasis. Surgical resection is the only realistic cure for colorectal liver metastases; however only 10–25% of cases are initially resectable. The introduction of combination chemotherapy has improved survival rates by enabling 10–20% cases with previously unresectable hepatic metastases to become amenable to surgery. Recent results with the biologic agent bevacizumab, a chimeric human–mouse monoclonal antibody against VEGF, and cetuximab, a chimeric human–mouse monoclonal antibody against EGF receptor, have shown that they improve clinical surgical outcomes when added to current first-line regimens in patients with metastatic colorectal cancer. Dual biologic therapy in combination with chemotherapy has, however, yielded disappointing results. Identification of biological markers is expected to help determine which patients are most likely to respond to these newer agents and thus improve targeted therapy.     

Surgical management of rectal cancer

Rectal cancer affects more than 40,000 people in the United States annually. Despite recent advances in radiation and chemotherapy, surgical resection remains an integral part of curative therapy for this disease. Although rectal cancer is thought to be biologically similar to colon cancer, the anatomic complexity of the pelvis makes therapy for this disease considerably more complicated. Local recurrence is also a greater concern in rectal cancer than in colon cancer. The choice of surgical therapy depends on the location of the tumor, depth of rectal wall invasion, and clinical stage. Surgical options include local excision (transanal excision and transanal endoscopic microsurgery) and radical resection (low anterior resection, extended low anterior resection with coloanal anastomosis, abdominoperineal resection [APR], and pelvic exenteration). Technical advances such as transanal endoscopic microsurgery and laparoscopy also are changing the surgical approach to rectal tumors. Finally, chemotherapy and radiation are now frequently recommended in conjunction with surgical therapy. This article reviews the current surgical approach to treating patients with rectal cancer.     

Treatment of muscle-invasive bladder cancer: progress and new challenges

The management of muscle-invasive bladder cancer has evolved over the last 20 years. Radical surgery, while curative for a significant number of patients, is inadequate for a subgroup with aggressive features including, but not limited to, advanced local stage, lymphovascular invasion on transurethral resection specimen, or variant histology such as small cell carcinoma. It is now clear that chemotherapy can improve the outcome for such patients. Combination platinum-based neoadjuvant chemotherapy is associated with a survival advantage of 5–8% at 5 years over local therapy alone. Improvements in surgical technique are also important and need to be further refined. Biologic-based staging and targeted therapies hold promise for the future. The critical issue in multimodal therapy for this very heterogeneous disease is individualized patient selection. In this review, data are presented with emphasis on the practical application of current knowledge to the management of patients with muscle-invasive bladder cancer.     

Treatment of muscle-invasive bladder cancer: progress and new challenges

The management of muscle-invasive bladder cancer has evolved over the last 20 years. Radical surgery, while curative for a significant number of patients, is inadequate for a subgroup with aggressive features including, but not limited to, advanced local stage, lymphovascular invasion on transurethral resection specimen, or variant histology such as small cell carcinoma. It is now clear that chemotherapy can improve the outcome for such patients. Combination platinum-based neoadjuvant chemotherapy is associated with a survival advantage of 5-8% at 5 years over local therapy alone. Improvements in surgical technique are also important and need to be further refined. Biologic-based staging and targeted therapies hold promise for the future. The critical issue in multimodal therapy for this very heterogeneous disease is individualized patient selection. In this review, data are presented with emphasis on the practical application of current knowledge to the management of patients with muscle-invasive bladder cancer.     

胰腺癌:靶向治疗的前景

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.     

Neoadjuvant therapy for gastric cancer: current evidence and future directions

Although surgical resection remains the only potentially curative treatment for gastric cancer (GC), poor long-term outcomes with resection alone compel a multimodality approach to this disease. Multimodality strategies vary widely; while adjuvant approaches are typically favored in Asia and the United States (USA), a growing body of evidence supports neoadjuvant and/or perioperative strategies in locally advanced tumors. Neoadjuvant approaches are particularly attractive given the morbidity associated with surgical management of GC and the substantial risk of omission of adjuvant therapy. The specific advantages of chemoradiotherapy (CRT) compared to chemotherapy have not been well defined, particularly in the preoperative setting and trials aimed at determining the optimal elements and sequencing of therapy are underway. Future studies will also define the role of targeted and biologic therapies.     

Seeking improved outcome in the curative treatment of non-small-cell lung cancer

Progress is being made in the treatment of patients with early (stage I-III) and unresectable locally advanced (stage III) non-small-cell lung cancer (NSCLC). The primary modality of treatment is complete surgical resection of the malignant growths. However, not all patients are appropriate candidates for surgery, and the majority who undergo surgical resection have a poor survival. Recurrence and death are most commonly due to systemic failure, indicating micrometastatic disease. Treatments targeted at eradicating micrometastatic disease, such as adjuvant therapy, induction chemotherapy, concurrent chemoradiotherapy, and intensified radiotherapy, are currently being explored as a means to improve outcome in the curative treatment of NSCLC.     

Current developments,problems and solutions in the non-surgical treatment of pancreatic cancer

Pancreatic cancer is a common malignant neoplasm of the pancreas with an increasing incidence, a low early diagnostic rate and a fairly poor prognosis. To date, the only curative therapy for pancreatic cancer is surgical resection, but only about 20% patients have this option at the time of diagnosis and the mean 5-year survival rate after resection is only 10%-25%. Therefore, developing new treatments to improve the survival rate has practical significance for patients with this disease. This review deals with a current unmet need in medical oncology: the improvement of the treatment outcome of patients with pancreatic cancer. We summarize and discuss the latest systemic chemotherapy treatments (including adjuvant, neoadjuvant and targeted agents), radiotherapy, interventional therapy and immunotherapy. Besides discussing the current developments, we outline some of the main problems, solutions and prospects in this field.     

Adjuvant therapy for resectable liver metastases: Can metastatic colorectal cancer be cured?

Surgery remains the only curative therapy for patients with liver metastases from colorectal cancer. Unfortunately, only a minority of patients are candidates. The use of clinical prognostic indicators and computer programs, such as OncoSurge, may help to identify optimal candidates. Neoadjuvant chemotherapy may render previously ineligible patient candidates for curative surgery after downsizing. Neoadjuvant chemotherapy is associated with histopathologic changes of the liver, and the effect of such changes on survival is unclear. Promising results have been seen with chemotherapy infused through the hepatic artery in conjunction with systemic chemotherapy in the neoadjuvant and adjuvant settings. Adjuvant therapy with oxaliplatin-or irinotecan-based regimens after resection of liver metastases is generally recommended. Individuals should be encouraged to participate in clinical trials to help clarify the role and optimal sequencing of systemic chemotherapy, targeted agents, local therapies, and surgery for patients with hepatic metastases from colorectal cancer.     

Surgical treatment of pancreatic cancer: the role of adjuvant and multimodal therapies.

Surgical treatment in specialized referral centers has improved the prognosis of resectable pancreatic cancer considerably despite the generally aggressive behavior of this malignancy. At the same time, adjuvant therapy for pancreatic cancer has been shown to be effective in providing a survival benefit. However, some controversy remains over whether to use chemotherapy alone or combined chemoradiation. Few prospective randomized controlled clinical trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation have demonstrated a distinct survival advantage of systemic chemotherapy (5-FU/FA or gemcitabine) following surgical resection. The most notable published trial is the European Study Group for Pancreatic Cancer (ESPAC)-1 trial. In addition, there are several retrospective analyses and two randomized studies on adjuvant radiation and chemoradiation. Some of these suggested increased survival rates using chemoradiation, which was subsequently widely introduced in clinical routine, especially in the United States. RCTs and a recent meta-analysis of these RCTs confirm, however, the superiority of chemotherapy over chemoradiation, except for a subgroup of patients with positive resection margins. Thus, curative surgery followed by adjuvant systemic chemotherapy should be the standard treatment for patients with resectable, locally confined pancreatic cancer. Further RCTs may clarify potential benefits of chemoradiation in the adjuvant treatment setting. Moreover, the best chemotherapy, or a combination thereof, remains to be determined in large-scale randomized trials.     

Role of Chemoradiotherapy in the Adjuvant and Neoadjuvant Settings for Resectable Pancreatic Cancer

Pancreatic cancer is the 10th most commonly diagnosed malignancy in the USA and the fourth most common cause of cancer-related death. Worldwide, the mortality incidence ratio approaches 98%. Although only 15–20% of patients present with resectable disease, there is international consensus that complete surgical resection (R0, i.e. grossly and microscopically negative margins) is a vital part of any curative treatment paradigm. Despite advances in surgical technique, peri-operative care, chemotherapy and radiation delivery techniques over the past two decades, 5 year overall survival rates for resected pancreatic cancer with modern therapies remain around 20–25%. There is level I evidence for adjuvant chemotherapy in fully resected pancreatic cancer, but randomised trials examining the role of adjuvant chemoradiotherapy to date do not provide clear support for radiation therapy in this setting. In addition, efforts to increase the proportion of long-term survivors have recently centred on increasing the resectability of locoregional disease by incorporating neoadjuvant treatment before definitive surgery. Post-hoc analysis of randomised data as well as retrospective reviews have shown that there are several independent prognostic factors that may have considerable impact on survival outcomes, complicating interpretation and comparison of historical data. There is considerable interest in adjuvant and neoadjuvant therapy, but there is significant controversy as to whether radiation is of value, especially in the adjuvant context. Herein, we explore the sources of those controversies.     

Liver resection for advanced or aggressive colorectal cancer metastases in the era of effective chemotherapy: a review

Liver surgery has been known to cure metastatic colorectal cancer in a small proportion of patients. However, advances in procedural technique and chemotherapy now allow more patients to have safe, potentially curative surgery. Here we review surgery for unresectable colorectal liver metastases using an expert multidisciplinary approach. With multidisciplinary management of patients with effective chemotherapy that can downstage metastases, more patients with previously inoperable disease can benefit from surgery. Portal vein embolization results in hypertrophy of the future liver remnant; on occasions, combining embolization with staged liver resection permits potentially curative surgery for patients previously unable to survive resection. However, increasing use of chemotherapy has raised awareness of potential hepatotoxicity and other deleterious effects of cytotoxic agents. Prolonged prehepatectomy chemotherapy therefore can reduce resectability even using a 2-stage procedure. Suitable timing of surgery for unresectable liver metastases during chemotherapy is critical. Because of advances in chemotherapy, colorectal cancer, like ovarian cancer, can now show survival benefit from maximum surgical debulking. Benefit from such maximum hepatic debulking surgery for metastatic colorectal disease is uncertain, but likely. Surgery in isolation may be approaching technical limits, but is now likely to help more patients because of the success of complementary strategies, particularly newer chemotherapy and targeted therapy. Expert individualized multidisciplinary treatment planning and problem-solving is essential.