The case for adjuvant chemotherapy in pancreatic cancer

Pancreatic cancer is a difficult cancer to treat effectively. Only a small proportion of patients are suitable for resection. The long-term survival following resection alone is between 10 and 18%. Adjuvant therapy aims to improve this outcome. There have been five fully reported adjuvant trials in pancreatic cancer. The largest study is the ESPAC-1 trial which demonstrated a significant survival benefit for 5-fluorouracil chemotherapy and no survival benefit for adjuvant chemoradiotherapy. A meta-analysis of these trials has confirmed the survival benefit for chemotherapy and thus adjuvant chemotherapy is recommended as the standard of care following pancreatic resection. There are further large studies which will also help to further define the optimum adjuvant chemotherapy in these patients.     

Adjuvant and neoadjuvant treatment in pancreatic cancer

Pancreatic adenocarcinoma is one of the most aggressive human malignancies, ranking 4th among causes for cancer-related death in the Western world including the United States. Surgical resection offers the only chance of cure, but only 15 to 20 percent of cases are potentially resectable at presentation. Different studies demonstrate and confirm that advanced pancreatic cancer is among the most complex cancers to treat and that these tumors are relatively resistant to chemotherapy and radiotherapy. Currently there is no consensus around the world on what constitutes "standard" adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat with regard to geography and economy, for instance chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America while chemotherapy alone is the current standard in Europe. Regardless of the efforts in adjuvant and neoadjuvant improved therapy, the major goal to combat pancreatic cancer is to find diagnostic markers, identifying the disease in a pre-metastatic stage and making a curative treatment accessible to more patients. In this review, authors examined the different therapy options for advanced pancreatic patients in recent years and the future directions in adjuvant and neoadjuvant treatments for these patients.     

Adjuvant therapy for gastric cancer: Current and future directions

The management of gastric cancer continues to evolve. Whilst surgery alone is effective when tumours present early, a large proportion of patients are diagnosed with loco-regionally advanced disease, resulting in high loco-regional and distant relapse rates, with subsequent poor survival. Early attempts at improving outcomes following resection were disappointing; however, randomized trials have now established either post-operative chemoradiotherapy (INT0116) or peri-operative chemotherapy as standard adjuvant therapies in the Western world. There remain, however, significant differences in the approach to management between the West and East. In Asia, where there is the highest incidence of gastric cancer, extended resection followed by adjuvant chemotherapy represents the standard of care. This review discusses current standard adjuvant therapy in gastric adenocarcinoma, as well as recent and ongoing trials investigating novel (neo)adjuvant approaches, which hope to build on the successes of previous studies.     

Adjuvant and Neoadjuvant Therapies of Pancreatic Cancer: A Review

The survival of patients diagnosed with pancreatic cancer is dismal. Few patients on initial presentation aresuitable for surgical resection. This has prompted clinical studies with chemotherapy and/or radiotherapydesigned either to increase the number of patients eligible for surgery (neoadjuvant therapy) or to prolong thesurvival of patients who had undergone surgery (adjuvant therapy). None of these studies may at this time beconsidered definitive. Wherever possible, patients felt eligible for neoadjuvant or adjuvant therapy should beentered on clinical trials. Where this is not possible, clinicians should exercise their best judgment in offeringthis type of treatment to pancreatic cancer patients under their care.     

Adjuvant and neoadjuvant therapies of pancreatic cancer: a review.

The survival of patients diagnosed with pancreatic cancer is dismal. Few patients on initial presentation are suitable for surgical resection. This has prompted clinical studies with chemotherapy and/or radiotherapy designed either to increase the number of patients eligible for surgery (neoadjuvant therapy) or to prolong the survival of patients who had undergone surgery (adjuvant therapy). None of these studies may at this time be considered definitive. Wherever possible, patients felt eligible for neoadjuvant or adjuvant therapy should be entered on clinical trials. Where this is not possible, clinicians should exercise their best judgment in offering this type of treatment to pancreatic cancer patients under their care.     

The multidisciplinary management of gastrointestinal cancer. Pancreatic cancer: from pathogenesis to cure

Pancreatic cancer is the fourth leading cause of cancer-related death in the USA. The disease has a high mortality rate and the 5-year survival rate is estimated to be 4%. Currently, surgical resection is only possible in 20% of patients; even then, the overall 5-year survival rate is only 25%. As such, surgical therapy alone is not sufficient for pancreatic carcinoma, and prospective investigation of additional modalities is crucial. Numerous negative trials have shown that chemotherapy alone is the standard of care after resection of pancreatic carcinoma. However, results remain poor and progress with new drugs is needed in this setting. For locally advanced disease, the situation is more complicated; the ideal chemoradiation schedule has not been clearly defined, and improvements could come in the near future from the use of new radiotherapy tools and targeted therapies. For advanced disease, chemotherapy alone has given very disappointing results. A multidisciplinary approach combining biological assessment of targets with clinical trials to evaluate new targeted drugs should be considered.     

Adjuvant and neoadjuvant therapies of pancreatic cancer

Summary The survival of patients diagnosed with pancreatic cancer is dismal. Few patients on initial presentation are suitable for surgical resection. This has prompted clinical studies with chemotherapy and/or radiotherapy designed either to increase the number of patients eligible for surgery (neoadjuvant therapy) or to prolong the survival of patients who had undergone surgery (adjuvant therapy). None of these studies may at this time be considered definitive. Wherever possible, patients felt eligible for neoadjuvant or adjuvant therapy should be entered on clinical trials. Where this is not possible, clinicians should exercise their best judgment in offering this type of treatment to pancreatic cancer patients under their care.     

Non-small cell lung cancer: adjuvant and neo-adjuvant chemotherapy

Of all cancers, non-small cell lung cancer is one of the most commonly diagnosed and is the deadliest. With a dismissal survival rate even in the early stages of disease, investigations of adjuvant and neo-adjuvant therapy have not had much impact until the 21st century. Starting in 2004, several randomized trials have shown significant improvements in survival treating patients with stage II and III disease. Adjuvant chemotherapy remains controversial in patients with stage I disease, in which most trials have not demonstrated a survival advantage. Investigators are studying molecular and genetic factors, which may predict who might benefit most from adjuvant therapy. While adjuvant therapy is now standard, neo-adjuvant therapy either with chemotherapy alone or with concurrent chemotherapy and radiation has shown promise, but has yet to become a clear standard of care. Data are presented to support the standard use of adjuvant therapy in patients with stage II and III disease, as well as data supporting the use of neo-adjuvant therapy in selected patients with non-small cell lung cancer.     

Chemotherapy in the treatment of cancer of the pancreas

Opinions about the value of chemotherapy in pancreatic cancer vary from the idea that its use should be abandoned because of lack of proven efficacy and considerable toxicity to the idea that it may produce clinically meaningful responses correlated with improved survival. A systematic review of the available literature-based evidence was undertaken. The results are discussed in relation to supportive evidence from recent studies focusing on patient benefit. Six randomized trials of chemotherapy in advanced disease and two in the adjuvant setting with a no-active treatment group were identified. All eight trials were small, and the methodology was not always what is currently desirable. One of four palliative trials reported during the early 1980s, and both trials completed during the 1990s showed a slight survival benefit with chemotherapy. In one of the trials, quality of life (QoL) was also more often improved after 5-fluorouracil-based chemotherapy than after best supportive care. Supportive evidence for a slight prolongation of survival and a clinical benefit also comes from trials comparing different drugs. No standard regimen is defined, although one drug, gemcitabine, has been approved in some countries for the treatment of advanced pancreatic cancer. The two randomized adjuvant trials included a very small number of patients, and, although a survival benefit was seen, conclusive evidence supporting the use of adjuvant chemo (radio) therapy is still lacking. Chemotherapy has low activity in advanced pancreatic cancer, but it can improve survival and well-being in some patients.     

Adjuvant therapy for margin positive pancreatic cancer: A propensity score matched analysis

BackgroundAdjuvant chemotherapy or chemoradiation is often recommended for resected pancreatic adenocarcinoma. We sought to examine the impact of these therapies on R1 resected pancreatic cancer.MethodsUtilizing the National Cancer Database we identified patients who underwent pancreatic resection for adenocarcinoma. Patients were stratified by resection status and adjuvant therapy.ResultsWe identified 28,440 patients who underwent pancreatic resection. Patients with tumor size >2 cm were more likely to undergo R1 resections, p < 0.001. Adjuvant therapy improved survival in all patients with median and 5-year survival: adjuvant chemotherapy (21.7 months, 17.45%), chemoradiation (23.3 months, 20.9%) vs no adjuvant therapy (19.5 months, 19.1%), p < 0.001. In the R1 resection cohort survival was also improved with adjuvant therapy with chemoradiation demonstrating the most significant improvement: adjuvant chemotherapy (15.9 months, 6.5%), chemoradiation (18.7 months, 11.2%) vs no adjuvant therapy (12.5 months, 8.7%), p < 0.001. Chemoradiation but not adjuvant chemotherapy improved survival in the R1 node negative, p < 0.004, and node positive, p < 0.001. Adjuvant chemotherapy benefited survival in R1 node positive patients, p < 0.001.ConclusionsPatients with pancreatic cancer who undergo R1 resection have significant improvement in survival when treated with adjuvant chemoradiation and adjuvant chemotherapy. However, benefits were greater in those receiving adjuvant chemoradiation.     

Guidelines for chemotherapy of biliary tract and ampullary carcinomas

Few randomized controlled trials (RCTs) with large numbers of patients have been conducted to date in patients with biliary tract cancer, and standard chemotherapy has not been established yet. In this article we review previous studies and clinical trials regarding chemotherapy for unresectable biliary tract cancer, and we present guidelines for the appropriate use of chemotherapy in patients with biliary tract cancer. According to an RCT comparing chemotherapy and best supportive care for these patients, survival was significantly longer and quality of life was significantly better in the chemotherapy group than in the control group. Thus, chemotherapy for patients with biliary tract cancer seems to be a significant treatment of choice. However, chemotherapy for patients with biliary tract cancer should be indicated for those with unresectable, locally advanced disease or distant metastasis, or for those with recurrence after resection. That is why making the diagnosis of unresectable disease should be done with greatest care. As a rule, pathological diagnosis, including cytology or histopathological diagnosis, is preferable. Chemotherapy is recommended in patients with a good general condition, because in patients with general deterioration, such as those with a performance status of 2 or 3 or those with insufficient biliary decompression, the benefit of chemotherapy is limited. As chemotherapy for unresectable biliary tract cancer, the use of gemcitabine or tegafur/gimeracil/oteracil potassium is recommended. As postoperative adjuvant chemotherapy, no effective adjuvant therapy has been established at the present time. It is recommended that further clinical trials, especially large multi-institutional RCTs (phase III studies) using novel agents such as gemcitabine should be performed as soon as possible in order to establish a standard treatment.     

Adjuvant therapy of pancreatic cancer: beyond gemcitabine. Highlights from the "2011 ASCO Gastrointestinal Cancers Symposium". San Francisco, CA, USA. January 20-22, 2011

There is no consensus on what constitutes "standard" adjuvant therapy for pancreatic cancer. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary somewhat on the geography as chemo-radiotherapy followed by chemotherapy or vice versa is considered the optimal therapy in North America (GITSG, RTOG) while chemotherapy alone is the current standard in Europe (ESPAC-1, CONKO, ESPAC-3). The high rate of locoregional failure following surgical resection for adenocarcinoma of the pancreas has made it clear that some form of adjuvant therapy should be considered in these patients. A phase II study was presented at the 2011 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium to assess the effect of the addition of algenpantucel-L immunotherapy to standard adjuvant therapy on survival in patients with resected pancreas cancer (Abstract #236). The author reviews the abstract in the context of our previous knowledge.     

Adjuvant Therapy of Pancreatic Cancer. Highlights from the "2011 ASCO Annual Meeting". Chicago, IL, USA; June 3-7, 2011

Strong evidence exists for the use of adjuvant chemotherapy following surgical resection in pancreatic cancer, whereas the role of adjuvant chemoradiotherapy remains controversial. The optimal time to initiate adjuvant therapy has yet to be elucidated, but is usually started 2-10 weeks following resection. First line adjuvant chemotherapy is gemcitabine, as this drug has demonstrated the better efficacy in studies. Other chemotherapeutic agents and gemcitabine in combination with biologic agents are under investigation. Furthermore, predicting response to gemcitabine based chemotherapy and other adjuvant therapies will be invaluable in guiding the practitioner to choose the most appropriate adjuvant treatment. Once adjuvant therapy has been started, accurately quantifying response to therapy is also important. The adjuvant regimen may be appropriately modified if response is inadequate. This review is an update from the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting regarding recent developments in the adjuvant treatment of pancreatic cancer with regards to choice of adjuvant regimen, timing of adjuvant therapy, predicting response to therapy and measuring response to adjuvant therapy. We will present the findings from Abstracts #4039, #4042, #e14519, #4118, and #4024. In conclusion, multiple adjuvant therapeutic regimens are associated with incremental improvements in the management of pancreatic cancer. The timing of initiation of adjuvant therapy appears to be important in outcomes. Research is ongoing into markers that can predict response to adjuvant therapy.     

Adjuvant therapy in pancreatic cancer

Pancreatic cancer is one of the major causes of cancer death in Europe with a 5-year survival rate of less than 5%. Although surgery cannot guarantee a cure, the 5-year survival does improve to around 10% following resection and increases to 20-30% with adjuvant chemotherapy. The European Study Group for Pancreatic Cancer (ESPAC) 1 trial was the first adequately powered, randomized study to assess chemoradiotherapy (CRT), concurrent with 5-fluorouracil (5-FU) and chemotherapy [5-FU/folinic acid (FA)] in resected pancreatic cancer. There was a survival benefit for adjuvant chemotherapy, but not for adjuvant CRT. Adjuvant CRT also did not improve survival in the EORTC multicenter prospective randomized trial by Klinkenbijl et al. (1999). The phase 3 RTOG 9704 trial compared pre- and postchemoradiation gemcitabine to pre- and postchemoradiation 5-FU. Overall there was no difference in overall survival between the 2 arms. Adjuvant gemcitabine significantly improved disease-free survival and later overall survival compared to surgery alone in the CONKO-001 randomized trial. The ESPAC-3(v2) trial compared adjuvant gemcitabine versus 5-FU/FA. The final 2-year analysis demonstrated median survival from resection of patients treated with 5-FU/FA was 23.0 months (95% CI: 21.1, 25.0) and 23.6 months (95% CI: 21.4, 26.4) for patients treated with gemcitabine. Further randomized studies will assess the role of adjuvant combination chemotherapy (ESPAC-4). The key to the future of adjuvant therapy in pancreatic cancer will be the identification of novel and effective agents, and better biomarker technology underpinned by translational research which will inform the design of future trials.     

The role of neoadjuvant chemoradiation in pancreatic cancer

Although complete surgical resection, when possible, leads to prolonged survival in pancreatic cancer, if used alone, its results remain sub-optimal. Neoadjuvant strategies are recent in pancreatic cancer: in primary resectable tumors, they ensure that all patients obtain additional treatment to complete surgery; in locally advanced tumors, they allow a better selection of candidates for curative resection. By delaying surgery, neoadjuvant strategies modify the initial diagnostic process and the symptomatic treatment of pancreatic cancer. Several recent phase I-II studies have confirmed the feasibility and efficacy of the association of chemotherapy and radiotherapy, which is well-tolerated and is associated with better local control and survival. Due to the aggressiveness of pancreatic cancers, most recent cytotoxic agents should be associated with modern radiation techniques. Neoadjuvant chemoradiation is under evaluation in pancreatic cancers, and no randomized phase III trials comparing neoadjuvant and adjuvant therapeutic sequences has been reported. Moreover, radiological and pathological evaluations, not only at diagnosis, but also after preoperative chemoradiation, must be standardized to improve the selection of patients who will benefit from this multi-modal treatment.     

Adjuvant Chemotherapy for Early-Stage Non-small Cell Lung Cancer

Lung cancer is the leading cause of cancer-related mortality in the developed world. Non-small cell lung cancer (NSCLC) represents 85% of cases of lung cancer, and patients have a poor 5-year survival rate. Approximately one third of NSCLC patients present with early-stage disease that is amenable to potentially curative resection and multimodality therapy. Several randomized trials now have confirmed the survival benefit with adjuvant platinum-based chemotherapy, as seen in the 1995 meta-analysis from the NSCLC Collaborative Group. The International Adjuvant Lung Cancer Collaborative Group Trial demonstrated a 4.5% improvement in survival for patients with stage I to III NSCLC. Studies from Japan have reported an improvement of 15.4% in the 5-year survival rate among patients with T1N0 disease after they had received adjuvant therapy with a combination of platinum and uracil-tegafur, and an improvement in the 5-year survival of 11% rate favoring chemotherapy with uracil-tegafur in a subgroup analysis of patients with T2N0 disease. Two recently published meta-analyses have estimated a relative risk reduction in mortality of 11 to 13% at 5 years. Significant improvement in the long-term survival rate has been demonstrated for patients with stage IB and II disease by the Cancer and Leukemia Group B 9633 trial (4-year survival rate, 12%) and the The National Cancer Institute of Canada Clinical Trials Group BR.10 trial (5-year survival rate, 15%; risk reduction for recurrence, 40%). Thus, there is compelling evidence to now recommend adjuvant platinum-based combination chemotherapy for patients after resection of early-stage NSCLC.     

The role of chemotherapy in biliary tract carcinoma

Cholangiocarcinoma is a rare malignancy associated with poor prognosis and high mortality. Surgical resection is the only chance for cure depending on careful patient selection. There are no well-conducted studies regarding the role of adjuvant chemotherapy. Preliminary data suggest that liver transplantation could offer long-term survival in selected patients when combined with neoadjuvant chemoradiotherapy. The literature regarding treatment results with specific regimens in the adjuvant setting is limited and no general recommendation can be given. In patients with locally advanced or metastatic disease, most studies are small, non-randomized phase II trials, and many studies comprise a mix of bile duct cancers, gallbladder cancer, and either pancreatic or hepatocellular cancers. In metastatic cancer, phase II studies with several cytotoxics, including gemcitabine, the platinums, and the fluoropyrimidines, have shown a modest and often short-lasting activity. No single chemotherapy agent or combination regimen can therefore be recommended as a standard of care at present. In this review, we give an overview of chemotherapy in the adjuvant, neoadjuvant, and advanced settings.     

Neoadjuvant therapy for pancreas cancer: Past lessons and future therapies

Pancreatic adenocarcinoma remains a most deadly malignancy, with an overall 5-year survival of 5%. A subset of patients will be diagnosed with potentially resectable disease, and while complete surgical resection provides the only chance at cure, data from trials of postoperative chemoradiation and/or chemotherapy demonstrate a modest survival advantage over those patients who undergo resection alone. As such, most practitioners believe that completion of multimodality therapy is the optimal treatment. However, the sequence of surgery, chemotherapy and radiation therapy is frequently debated, as patients may benefit from a neoadjuvant approach by initiating chemotherapy and/or chemoradiation prior to resection. Here we review the rationale for neoadjuvant therapy, which includes a higher rate of completion of multimodality therapy, minimizing the risk of unnecessary surgical resection for patients who develop early metastatic disease, improved surgical outcomes and the potential for longer overall survival. However, there are no prospective, randomized studies of the neoadjuvant approach compared to a surgery-first strategy; the established and ongoing investigations of neoadjuvant therapy for pancreatic cancer are discussed in detail. Lastly, as the future of therapeutic regimens is likely to entail patient-specific genetic and molecular analyses, and the treatment that is best applied based on those data, a review of clinically relevant biomarkers in pancreatic cancer is also presented.     

Adjuvant chemotherapy for resectable biliary tract cancer: current status and future direction

The prognosis of patients with biliary tract cancer remains unsatisfactory even with surgery owing to the high recurrence rate. Therefore, an effective adjuvant chemotherapy is required to prolong survival. A few randomized controlled trials in patients with limited biliary tract cancer have been reported, but the efficacy of adjuvant chemotherapy could not be clarified. To date, effective adjuvant chemotherapy with evidence has not been established, and the standard therapy for patients with resectable biliary tract cancer has only been surgical treatment. Recently, a number of newer toxic agents have been shown to induce response in patients with advanced biliary tract cancer. Moreover, the morbi-mortality rate of operation for this cancer has been decreasing owing to advances in operative techniques and perioperative management. Given this background, a number of adjuvant chemotherapy trials have been started using gemcitabine, capecitabine, S-1, and combination chemotherapy with platinum. The results of these trials will be reported in the near future. Overall, the important aspects of adjuvant chemotherapy for biliary tract cancer are to establish well-organized and active clinical trial study groups, to conduct well-designed multicenter randomized controlled trials, and to continue such trials without interruption in the future.     

Medical management of gastric cancer: A 2014 update

Gastric cancer represents a serious health problem on a global scale. It is the second leading cause of cancer-related death worldwide. Novel therapeutic targets are desperately needed because the meager improvement in the cure rate of about 10% realized by adjunctive treatments to surgery is unacceptable as > 50% patients with localized gastric cancer succumb to their disease. Either postoperative chemoradiotherapy (United States), pre-and post-operative chemotherapy (Europe), and adjuvant chemotherapy after a D2 resection (Asia) can all be regarded as standards of care in the localized gastric cancer management. In metastatic disease the addition of trastuzumab to chemotherapy is standard of care in Her2 positive disease. In the HER2 negative population, the treatments remain limited. In the first line setting, the standard of care is a combination of fluoropyrimidine and platinum containing chemotherapy, with or without epirubicin or docetaxel. The results of targeted therapy trials have by and large been disappointing, but none of these trials looked at an appropriately enriched population. Finally there is a meager overall survival benefit in treating patients with metastatic disease in the second line setting, with either irinotecan, docetaxel or ramucirumab however none of these drugs have been compared head to head in a well-powered randomized controlled trial.