Chemotherapy for gallbladder carcinoma--a surgeon's perspective

Surgery is the only curative treatment for gallbladder cancer. However, because of frequent local-regional and distant recurrences, radical surgery during advanced stages of the disease is often unsuccessful. Despite potential improvements in patient survival and quality of life, alternatives such as chemotherapeutic regimens have not been fully developed for treatment of gallbladder cancer. The present paper reviews current publications that deal exclusively with the use of chemotherapy for treatment of gallbladder cancer, with particular attention to adjuvant chemotherapy including postoperative and preoperative systemic or regional hepatic arterial infusion chemotherapy. Treatment outcomes, including response rate, adverse effects, and survival are summarized.     

Chemotherapy of primary and secondary liver tumors

Liver is the most common site of metastatic disease. Although primary liver tumors are relatively rare in the Czech Republic, liver tumors represent a frequently encountered problem because of high incidence of colorectal and pancreatic cancer. Regimens of systemic chemotherapy or biologic therapy are used for secondary liver tumors according the primary site. It was demonstrated in randomized clinical studies that some of these regimens significantly prolong survival. Although only palliative therapy is possible for most of the patients with liver metastases, resection should be considered in patients with isolated liver involvement. Liver resection represents a curative approach and long-term success seems to be enhanced by neoadjuvant (preoperative) chemotherapy or adjuvant (postoperative) hepatic arterial chemotherapy. Hepatic arterial chemotherapy is also effective in the palliative treatment of unresectable liver metastases. Although it is still uncertain whether hepatic arterial chemotherapy increases survival of patients compared to systemic chemotherapy, it may be regarded as the best available treatment in selected patients because of better palliation associated with higher objective response rate and less systemic toxicity. Along with systemic and hepatic arterial chemotherapy, other approaches are being currently investigated in the treatment of primary and secondary liver tumors, including the use of biologic agents, agents with non-cytotoxic mechanism of action, or chronomodulated chemotherapy.     

Systemic chemotherapy for pancreatic cancer

Surgical resection offers the only curative strategy for pancreatic cancer. Yet, because early detection of pancreatic cancer is so difficult and diagnosis is delayed, pancreatic cancer in most patients is surgically unresectable. Even in patients with resectable disease, the long-term outcome remains unsatisfactory due to early recurrence after resection. Early appearance of distant metastasis suggests that systemic treatment, such as chemotherapy, should play a major role in improving patient survival. Although the recently developed gemcitabine has renewed interest in clinical research for pancreatic cancer, other currently available chemotherapeutic agents have little impact on survival. Studies to identify more effective agents or treatment regimens must have the highest priority. The expanding understanding of molecular and genetic biology should facilitate research to develop novel molecule-targeted agents and to establish individualized therapy regimens for this disease.     

Systemic cytotoxic and biological therapies of colorectal liver metastases: expert consensus statement

Systemic therapy for colorectal cancer liver metastases (CRLM) has undergone significant development in the past 15 years. Therapy regimens consisting of combinations of cytotoxic chemotherapeutic agents have demonstrated greater efficacy and contributed to a significant survival improvement. As the majority of patients who undergo resection for liver-only CRLM are at risk of disease recurrence and cancer-related death, combining resection with systemic therapy appears sensible. However, trial-based evidence is sparse to support this concept. Peri-operative FOLFOX has demonstrated a progression-free survival benefit in a single Phase III trial; the safety of chemotherapy and subsequent operations was acceptable and only a few patients showed initial progression. Chemotherapy-associated liver injury (CALI), including sinusoidal obstruction syndrome and steatohepatitis, has been observed after cytotoxic therapy, and should have implications for chemotherapy plans prior to hepatectomy. In general, pre-operative chemotherapy should not extend beyond 3 months. For patients with unresectable liver-only CRLM, a response to chemotherapy could establish resectability and should be considered an initial treatment goal. In patients with unresectable CRLM, oxaliplatin- or irinotecan-containing combinations represent the standard options, although single-agent choices may be appropriate for individual patients. The addition of bevacizumab carries the potential for a greater response and possibly for reduced CALI risks. In tumours without K-ras mutations, anti-epidermal growth factor receptor (EGFR) agents are also reasonable choices for a greater response and improved survival outcomes. It is crucial that all systemic CRLM treatment decisions include proper definitions of treatment goals and endpoints, and are derived based on appropriate multidisciplinary considerations for other potentially applicable local or regional modalities.     

Chemotherapy of colorectal cancer

Several randomized trials have shown superior response rates for 5-fluorouracil (5-FU) combined with folinic acid as compared to 5-FU alone. Both treatment regimens are well tolerated and generally can be applied in an outpatient setting. To date no other tested drug combination as methyl-CCNU (M), vincristine (O) and 5-FU (MOF), cisplatin and 5-FU (DDP/5-FU) or methotrexate and 5-FU (MTX/5-FU) showed any clear advantage over 5-FU alone. Regional infusion therapy for liver metastasis from colorectal cancer has not been proven superior as yet to systemic therapy with respect to overall survival. Regional chemotherapy is still considered an experimental approach and should only be performed within controlled trials. New results of postoperative adjuvant chemotherapy with the MOF-schedule for colorectal cancer with Dukes stage B and C demonstrated an improvement in disease-free survival and overall survival for patients, who had undergone resection with curative intent. Trials are under way to examine, whether 5-FU combined with folinic acid is superior to the more toxic MOF-regimen in postoperative adjuvant chemotherapy of colorectal cancer. Eligible patients should only be treated within prospective randomized trials.     

Palliative therapy in cholangio- and gallbladder carcinoma

Non-resectable cholangiocarcinoma and gallbladder carcinoma have a poor prognosis. In addition to the general aspects of "best supportive care", biliary drainage is an important part of the palliative treatment of patients with malignant biliary stenosis. Photodynamic therapy has led to an improved median survival in hilar cholangiocarcinoma in two controlled studies. The survival benefit of external radiation or intraluminal brachytherapy has not yet been convincingly demonstrated. Whether or not systemic chemotherapy should be applied is still under debate. A single study including advanced biliary and pancreatic cancer patients has demonstrated a survival benefit for the combined group. In recent years, new chemotherapy protocols have been applied, some with promising results. Intra-arterial chemotherapy and chemotherapeutically coated stents have not been evaluated well enough to be recommended outside clinical studies. Ablative therapies have been used in a limited number of patients only. Further studies are necessary to clarify whether these treatment modalities are effective.     

Non-Hodgkin's lymphomas in children. II. Treatment.

The prognosis of non-Hodgkin's lymphoma (NHL) in childhood has improved steadily in the last 2 decades. This is primarily the result of increasingly effective chemotherapy regimens tailored to defined and relatively homogeneous prognostic categories and tested in prospective clinical trials. Surgical excision remains of prognostic benefit only when near-total resection can be performed without delay of chemotherapy. The role of radiation therapy is now limited to the treatment of overt central nervous system (CNS) lymphoma, disease unresponsive to chemotherapy, and certain emergencies. Effective 'prophylactic' treatment of the CNS has been achieved in most series by intrathecal and systemic chemotherapy alone. The most relevant modality of treatment is chemotherapy and a very large number of protocols have been published. The origins of current multi-agent regimens stem both from early experience with cyclophosphamide in endemic Burkitt's lymphoma and from therapeutic studies of acute lymphoblastic leukaemia. Sub-stratification of non-localized NHL has produced protocols designed for either lymphoblastic (mostly T cell) or non-lymphoblastic (mostly B cell) categories. While the cure rate for lymphoblastic lymphoma now exceed 70%, the non-localized non-lymphoblastic disease remains a major obstacle to cure. These patients frequently present with large abdominal primaries and are prone to regional as well as hematogenous dissemination. In particular, involvement of the CNS is now considered to be the most adverse prognostic variable in this group. Recently, highly intensive regimens are addressing these obstacles. On the other hand, NHL defined as localized has been shown to be curable in up to 95% of children with the use of simple chemotherapy regimens as short as 6 months in duration. Salvage of patients who relapse during or after chemotherapy remains bleak but cures are possible with regimens incorporating bone marrow transplantation from either an autologous or allogeneic source. Experimental methods, including biologic and immune response modifiers may also offer future promise.     

Is there an optimal neoadjuvant therapy for locally advanced pancreatic cancer?

Treatment of locally advanced pancreatic cancer is challenging. Despite continuing research, effective treatments continue to be elusive with median survival of only 8-12 months. Treatment options for locally advanced pancreatic cancer include radiation therapy, concurrent chemoradiation or chemotherapy. It is felt that radiation therapy is a suboptimal treatment as most of patients will die of systemic disease. In the past, radiation with 5-FU was the standard treatment for locally advanced pancreatic cancer. But now radiation has been used with combination other chemo agents such as paclitaxel or gemcitabine in order to increase the efficacy. Chemotherapy such as gemcitabine alone or gemcitabine doublet also has been studied in patients with locally advanced pancreatic cancer as well with overall survival being approximately the same magnitude as chemoradiation. The exact role of chemoradiation or chemotherapy in treatment of locally advanced pancreatic cancer is yet to be defined. Hence, this review summarizes and compares of role of radiation, chemoradiation and chemotherapy in treating this disease.     

Chemotherapy for bile duct carcinoma in the light of adjuvant chemotherapy to surgery

Chemotherapeutic regimens that markedly improve survival and quality of life in patients with bile duct cancer (cholangiocarcinoma) have not yet been developed. Currently, radical resection is the only potentially curative treatment modality for these patients. However, complete resection is often impossible and, even when achieved, is typically followed by metastasis and/or local recurrence. During the past 25 years, patients with cholangiocarcinoma have received chemotherapy in an attempt to improve their prognosis; effective methods are systemic administration, hepatic arterial infusion, and intraductal infusion. 5-fluorouracil, adriamycin, mitomycin C, and cisplatin remain the agents used most frequently (either singly or in combination) for treating cholangiocarcinoma. In particular, 5-fluorouracil has been a component of most chemotherapy regimens for bile duct cancer. However, regardless of the administration scheme, results from the use of 5-fluorouracil as a single agent have been disappointing. Recent phase II (albeit small-population) trials that addressed the biochemical modulation of 5-fluorouracil in combination with methotrexate, leucovorin, cisplatin, interferon, or mitomycin C yielded better results than did a classic (combination of 5-fluorouracil, adriamycin, and mitomycin C) FAM regimen. Hepatic arterial infusion chemotherapy was associated with the highest response rate and survival in patients with localized cholangiocarcinoma (localized in the liver, with no extra-hepatic metastasis); however, these results need to be confirmed in large, randomized trials. Studies regarding intraductal chemotherapy for patients with obstructive jaundice are still in the preliminary stages; therefore, no associated benefit could be ascertained. The present review discusses current chemotherapy regimens for bile duct cancer and outlines possible future clinical investigations.     

Liver metastases

Opinion Statement Liver metastases, especially from colorectal primary cancers, are treatable and potentially curable. Imaging techniques such as CT, MRI, and sonography have advanced in recent years and led to increased sensitivity and specificity in the diagnosis of liver metastases. Liver surgery also has been revolutionized in the past two decades. Dissections along nonanatomic lines have permitted the resection of multiple lesions that previously might have been considered unresectable. We regard resection of a solitary hepatic metastasis or up to four metastases from colorectal carcinoma as the best treatment for this condition. In patients over 70 years of age and those with medical conditions preventing surgery, we endorse expectant follow-up as long as the tumor remains stable. But if the tumor begins growing rapidly and local techniques cannot be used, we consider systemic chemotherapy. In patients with progressive metastatic liver disease, we initiate systemic therapy or hepatic arterial infusion. In young patients with metastatic disease, even when the disease is indolent or symptomatic, it may be difficult not to treat. We use either local regional therapy (resection or regional infusion) or systemic chemotherapy followed by regional therapy. In patients with neuroendocrine tumors metastatic to the liver, the first approach we use is not to treat because there may be a long period of stable disease. We use Sandostatin (Sandoz Pharmaceuticals, East Hanover, NJ) to treat symptoms. If the tumor progresses and symptoms cannot be controlled, these vascular tumors can be treated by embolization or chemoembolization, with high expectations of response. Newer approaches to liver metastases such as cryosurgery, chemoembolization, and interstitial radiation are also available. Cryosurgery is an ablative procedure that has not been proven yet to be as effective as surgical removal of metastases. However, in a situation where surgery cannot be performed, cryosurgery is an alternative. Chemoembolism has not been proven to be more effective than systemic therapy for liver metastases, but it allows another regional approach. External localized radiation can be used for patients who fail first-line treatment or in new protocols to delineate its value, perhaps in concert with chemotherapy. We also consider offering external localized radiation in patients who fail first-line treatment, perhaps in concert with chemotherapy. The usefulness of these techniques compared with surgery or regional therapy is being investigated.     

Therapeutic options for peritoneal metastasis arising from colorectal cancer

Peritoneal metastasis is a common sign of advanced tumor stage, tumor progression or tumor recurrence in patients with colorectal cancer. Due to the improvement of systemic chemotherapy, the development of targeted therapy and the introduction of additive treatment options such as cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC), the therapeutic approach to peritoneal metastatic colorectal cancer(pm CRC) has changed over recent decades, and patient survival has improved. Moreover, in contrast to palliative systemic chemotherapy or best supportive care, the inclusion of CRS and HIPEC as inherent components of a multidisciplinary treatment regimen provides a therapeutic approach with curative intent. Although CRS and HIPEC are increasingly accepted as the standard of care for selected patients and have become part of numerous national and international guidelines, the individual role, optimal timing and ideal sequence of the different systemic, local and surgical treatment options remains a matter of debate. Ongoing and future randomized controlled clinical trials may help clarify the impact of the different components, allow for further improvement of patient selection and support the standar-dization of oncologic treatment regimens for pm CRC. The addition of further therapeutic options such as neo-adjuvant intraperitoneal chemotherapy or pressurized intraperitoneal aerosol chemotherapy, should be investig-ated to optimize therapeutic regimens and further improve the oncological outcome.     

Advanced gastric cancer:Is there enough evidence to call second-line therapy standard?

Gastric cancer and cancer of the gastro-oesophageal junction (GOJ) are the 4th most common cancer diagnoses worldwide with regional differences in incidence rates. The treatment of gastric and GOJ cancers is complex and requires multimodality treatment including chemotherapy treatment, surgery, and radiotherapy. During the past decade considerable improvements were achieved by advanced surgical techniques, tailored chemotherapies/radiotherapy and technical innovations in clinical diagnostics. In patients with advanced or metastatic gastric/GOJ cancer systemic chemotherapy with fluoropyrimidine/platinum-based regimens (+/-human epidermal growth factor receptor-2 antibody) is the mainstay of treatment. Despite these improvements, the clinical outcome for patients with advanced or metastatic disease is generally poor with 5-year survival rates ranging between 5%-15%. These poor survival rates may to some extent be related that standard therapies beyond first-line therapies have never been defined. Considering that this patient population is often not fit enough to receive further treatments there is an increasing body of evidence from phase-2 studies that in fact second-line therapies may have a positive impact in terms of overall survival. Moreover two recently published phase-3 studies support the use of second-line chemotherapy. A South Korean study compared either, irinotecan or docetaxel with best supportive care and a German study compared irinotecan with best supportive care-both studies met their primary endpoint overall survival. In this “Field of Vision” article, we review these recently published phase-3 studies and put them into the context of clinical prognostic factors helping to guide treatment decisions in patients who most likely benefit.     

Role of hematopoietic stem cell transplantation for advanced-stage diffuse large cell B-cell lymphoma-B

The prognosis of patients with relapsed or refractory diffuse large cell B-cell lymphoma-B (DLCL-B) is poor with conventional salvage chemotherapy; therefore, high-dose therapy (HDT) combined with autologous stem cell transplant (ASCT) has become the treatment of choice for these patients. The outcomes of transplant are better in patients with chemosensitive relapse: those with a longer duration of first remission (>12 month) and those with an age-adjusted low-risk International Prognostic Index (IPI) at relapse. Several high-dose regimens with or without total body irradiation (TBI) have been used with similar outcomes. Relapse remains the most common cause of treatment failure, and thus the use of radioimmunotherapy (RIT) in the high-dose regimens and incorporation of rituximab in the transplant setting have been explored. Several studies have shown that RIT both at conventional dose and at high dose can be given in combination with high-dose chemotherapy regimens without additional toxicity or delay in hematopoietic recovery after ASCT. Additional studies using RIT in combination with high-dose chemotherapy and ASCT are ongoing, and preliminary results suggest that these approaches may be superior to conventional high-dose regimens. Since rituximab is an effective therapy for B-cell non-Hodgkin's lymphoma and given its limited toxicity, rituximab has been incorporated into HDT and ASCT for DLCL-B as in vivo purging, as part of high-dose regimens, and as maintenance therapy to prevent relapse. Preliminary results suggested that rituximab during ASCT and as maintenance therapy post-transplant reduces the risk of relapse and improves survival; however, these results need to be confirmed in phase III randomized trials. The role of ASCT during first remission as consolidative therapy in patients with DLCL-B remains controversial and should not be performed outside of the clinical trial setting. Allogeneic stem cell transplant (allo-SCT) for patients with relapsed DLCL-B is associated with significant toxicity and should be reserved for patients who relapse after ASCT or those with persistent marrow involvement. Innovative approaches are needed for primary refractory and chemoresistant relapsed DLCL-B since these patients have very poor outcomes after ASCT.     

Effect of primary treatment modality on the metastatic pattern of mammary carcinoma.

In animal tumor systems, all three major treatment modalities, surgery, radiotherapy, and chemotherapy, may increase the incidence of metastases in the presence of circulating viable tumor cells. In breast cancer patients, selected studies can be found which report an increased incidence of metastases after surgery, radiotherapy, or chemotherapy, but these effects appear to exert little influence on overall survival. Caution is advised in using systemic therapy prior to effective primary tumor cytoreductive treatment. Clinical trials in advanced local disease should be done to test this concern. Minimal surgery, loco-regional radiotherapy, and effective adjuvant systemic therapy may result in the improved survival of patients with breast cancer with minimal functional or cosmetic impairment.     

Metastatic pancreatic cancer: Is there a light at the end of the tunnel?

Due to extremely poor prognosis,pancreatic cancer(PDAC)represents the fourth leading cause of cancerrelated death in Western countries.For more than a decade,gemcitabine(Gem)has been the mainstay of first-line PDAC treatment.Many efforts aimed at improving single-agent Gem efficacy by either combining it with a second cytotoxic/molecularly targeted agent or pharmacokinetic modulation provided disappointing results.Recently,the field of systemic therapy of advanced PDAC is finally moving forward.Polychemotherapy has shown promise over single-agent Gem:regimens like PEFG-PEXG-PDXG and GTX provide significant potential advantages in terms of survival and/or disease control,although sometimes at the cost of poor tolerability.The PRODIGE 4/ACCORD 11 was the first phaseⅢtrial to provide unequivocal benefit using the polychemotherapy regimen FOLFIRINOX;however the less favorable safety profile and the characteristics of the enrolled population,restrict the use of FOLFIRINOX to young and fit PDAC patients.The nanoparticle albumin-bound paclitaxel(nab-Paclitaxel)formulation was developed to overcome resistance due to the desmoplastic stroma surrounding pancreatic cancer cells.Regardless of whether or not this is its main mechanisms of action,the combination of nabPaclitaxel plus Gem showed a statistically and clinically significant survival advantage over single agent Gem and significantly improved all the secondary endpoints.Furthermore,recent findings on maintenance therapy are opening up potential new avenues in the treatment of advanced PDAC,particularly in a new era in which highly effective first-line regimens allow patients to experience prolonged disease control.Here,we provide an overview of recent advances in the systemic treatment of advanced PDAC,mostly focusing on recent findings that have set new standards in metastatic disease.Potential avenues for further development in the metastatic setting and current efforts to integratenew effective chemotherapy regimens in earlier stages of disease(neoadjuvant,adjuvant,and multimodal approaches in both resectable and unresectable patients)are also briefly discussed.     

Curative treatment of gastric cancer: towards a multidisciplinary approach?

Despite marked decreases in incidence over the last century, particularly in developed countries, gastric cancer is still the second-most common tumor worldwide. Surgery remains the gold standard for the cure of locoregional disease. However, in most countries, the diagnosis is made at an advanced stage, and the 5-year survival for surgically resectable disease stays far below 50%. The efficacy of chemotherapy and/or radiation therapy in addition to surgery has been actively studied over the last 30 years. Unfortunately, with few exceptions, most studies of adjuvant therapy in gastric cancer have given deceiving results. The purpose of this review is to address the reasons for our failure to objectivate an improvement in the cure of gastric cancer with adjuvant treatment in most trials, and to consider potential solutions. The low efficacy of chemotherapy regimens available up to now may have hampered our progress. In addition, many previous studies suffered limitations of design or methodology (e.g. low accrual, inadequate disease stage selection, inadequate surgical treatment) that may have obscured a treatment effect. Furthermore, the reduced treatment tolerance of post-gastrectomy patients, perhaps due to their poor nutritional status, results in decreased or delayed adjuvant systemic therapy, with potential adverse consequences in its efficacy. Among potential solutions, the arrival of new drugs, taxanes and topoisomerase I inhibitors in particular, which have shown encouraging results in metastatic disease, may increase the impact of chemotherapy in a multidisciplinary treatment approach. Pre-treatment with chemotherapy and/or radiation therapy prior to surgery may also be advantageous, averting the problems associated with post-surgical treatment. Such an approach has been shown to be feasible in phase II studies, and is relatively well tolerated by patients. Several carefully designed randomized phase III trials are underway to answer this question.     

Hodgkin's lymphoma: current treatment strategies and novel approaches

Approximately 80% of Hodgkin's lymphoma (HL) patients achieve long-term remission after primary chemotherapy or chemo/radiotherapy. Despite these excellent results, further treatment improvement is necessary. HL therapy is associated with severe acute and long-term toxicities. Thus, a major aim of clinical HL research is to evaluate novel schemes that are less toxic than current standard regimens without being less effective. Another focus is the treatment of patients with multiple relapses. Standard treatment for these patients has not yet been defined, and their prognosis is still poor. Reduced-intensity conditioning allogeneic stem cell transplantation was recently shown to be effective in carefully selected young chemosensitive patients. Furthermore, new strategies such as antibody- and small-molecule-based therapy have demonstrated encouraging results in preclinical studies and the first clinical trials.     

The Present Status of Immuno-Oncolytic Viruses in the Treatment of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is the fifth leading cause of cancer-related death in Western countries. The incidence of PDAC has increased over the last 40 years and is projected to be the second leading cause of cancer death by 2030. Despite aggressive treatment regimens, prognosis for patients diagnosed with PDAC is very poor; PDAC has the lowest 5-year survival rate for any form of cancer in the United States (US). PDAC is very rarely detected in early stages when surgical resection can be performed. Only 20% of cases are suitable for surgical resection; this remains the only curative treatment when combined with adjuvant chemotherapy. Treatment regimens excluding surgical intervention such as chemotherapeutic treatments are associated with adverse effects and genetherapy strategies also struggle with lack of specificity and/or efficacy. The lack of effective treatments for this disease highlights the necessity for innovation in treatment options for patients diagnosed with early- to late-phase PDAC and immuno-oncolytic viruses (OVs) have been of particular interest since 2006 when the first oncolytic virus was approved as a therapy for nasopharyngeal cancers in China. Interest resurged in 2015 when T-Vec, an oncolytic herpes simplex virus, was approved in the United States for treatment of advanced melanoma. While many vectors have been explored, few show promise as treatment for pancreatic cancer, and fewer still have progressed to clinical trial evaluation. This review outlines recent strategies in the development of OVs targeting treatment of PDAC, current state of preclinical and clinical investigation and application.     

Gastro-oesophageal complications in patients receiving cancer therapy: the role of proton pump inhibitors

Chemotherapy and radiotherapy, both alone and in combination, remain important tools in the successful treatment of cancer. Because the oral and gastrointestinal (GI) mucosa is often significantly damaged by cancer therapy, management of these problems is an important challenge for oncologists. Such treatment complications are generally not severe or life threatening, but they can result in both treatment delays and dose reductions in potentially curative regimens. Numerous therapeutic approaches have been evaluated as prophylaxis or treatment for mucosal damage in patients undergoing cancer therapy. The results of large-scale, placebo-controlled, comparative trials demonstrate that administration of a proton pump inhibitor (PPI) can provide both significant symptom relief and prophylaxis against upper GI ulceration in patients receiving cancer chemotherapy. Although no corresponding clinical trial has been conducted in patients undergoing irradiation, PPIs are also likely to be effective in preventing gastro-oesophageal mucosal injury in such individuals. Thus, PPIs may play a crucial role in supportive care for patients undergoing cancer therapy.     

Treatment options in patients with metastatic gastric cancer:Current status and future perspectives

Despite advances in the treatment of gastric cancer,it remains the world’s second highest cause of cancer death.As gastric cancer is often diagnosed at an advanced stage,systemic chemotherapy is the mainstay of treatment for these patients.However,no standard palliative chemotherapy regimen has been accepted for patients with metastatic gastric cancer.Palliative chemotherapy including fluoropyrimidine,platin compounds,docetaxel and epirubicin prolongs survival,and improves a high quality of life to a greater extent than best supportive care.The number of clinical investigations associated with targeted agents has recently increased.Agents targeting the epidermal growth factor receptor 1 and human epidermal growth factor receptor 2(HER2)have been widely tested.Trastuzumab was the first target drug developed,and pivotal phaseⅢtrials showed improved survival when trastuzumab was integrated into cisplatin/fluoropyrimidine-based chemotherapy in patients with metastatic gastric cancer.Trastuzumab in combination with chemotherapy was thus approved to be a new standard of care for patients with HER2-positive advanced esophagogastric adenocarcinoma.Thus,the evaluation of HER2 status in all patients with metastatic gastroesophageal adenocarcinoma should be considered.Other agents targeting vascular endothelial growth factor,mammalian target of rapamycin,and other biological pathways have also been investigated in clinical trials,but showed little impact on the survival of patients.In this review,systemic chemotherapy and targeted therapies for metastatic gastric cancer in the first-and second-line setting are summarized in the light of recent advances.