Controversies in the adjuvant treatment of pancreatic adenocarcinoma

There is no universally accepted standard approach to treat patients with pancreatic cancer in the adjuvant setting. This controversy derives from several studies, each fraught with its own limitations. Standards of care also vary depending on which side of the Atlantic you are on: chemo-radiotherapy followed by chemotherapy is considered the optimal therapy in North America (GITSG, RTOG) while chemotherapy alone is the current standard in Europe (ESPAC-1, CONKO). Whether gemcitabine is superior to 5-FU remains to be learnt from the ESPAC-3 study currently on-going in Europe. A number of important questions have yet to be fully addressed: What is the absolute value of radiotherapy in this setting? How should radiotherapy be delivered, if at all? What should be the time to deliver of either or both therapeutic modalities in the adjuvant setting? Are there any patients who can benefit from the combined modality? What is the most appropriate chemotherapeutic agent(s) to administer in the adjuvant setting? Is there any role of integrating the novel/targeted agents, albeit the negative studies in the metastatic setting? What are the new developments (such as vaccines, pancreas cancer stem cells, etc.) in this area? The author summarizes the evolution of adjuvant therapy for resected pancreatic cancer and highlights the controversies that originate from several studies, each fraught with its own limitations.     

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.     

The role of chemotherapy in locally advanced, metastatic and recurrent cervical cancer

Cervical cancer is among the major health problems world-wide although advances in screening programs. Surgery and radiotherapy are the treatment modalities of choice for early and locally advanced cervical cancer. However, the role of chemotherapy in this setting has been better investigated in the latest years. To improve loco-regional control in locally advanced disease, authors have tested both neo-adjuvant chemotherapy and concurrent chemoradiotherapy. From 1999 NCI clinical announcement, concurrent cisplatin-based chemoradiation is considered the treatment of choice for cervical cancer patients requiring radiation therapy. Neo-adjuvant chemotherapy is reaching encouraging results in IB bulky-IIA cervical cancer, but further investigation are ongoing in locally advanced cervical setting. The optimal treatment for patients with metastatic or recurrent cervical cancer is still undefined and chemotherapy is used with palliation intent. Cisplatin remains the most active cytotoxic agents, although combinations of cisplatin with paclitaxel, topotecan, vinorelbine, have shown encouraging results in phase II and in early phase III studies. This paper reviews the role of chemotherapy in the management of patients with locally advanced, metastatic and recurrent cervical cancer. Studies discussed in this paper were selected trough a search in the med-line database performed in October 2003.     

Adjuvant treatments for resectable pancreatic cancer

Pancreatic cancer remains one of the most challenging malignancies to treat successfully. The majority of patients present with unresectable advanced-stage cancer, and only 20% of patients can undergo resection. Even if surgical resection is performed, the recurrence rate is high and the survival rate after surgery is poor. Therefore, effective adjuvant therapy is needed to improve the prognosis of patients with pancreatic cancer. Until now, no universally accepted standard adjuvant therapy for this disease has been available: chemoradiotherapy followed by chemotherapy is considered the optimal therapy in the United States, while chemotherapy alone is the current standard in Europe. However, recent randomized controlled trials (RTOG [Radiation Therapy Oncology Group] 9704; CONKO [Charité Onkologie]-001; and a Japanese study) have suggested a benefit of adjuvant chemotherapy with gemcitabine for patients with resectable pancreatic cancer. This article will review the clinical trials of adjuvant therapy for this disease, including the results of recent trials.     

Adjuvant therapy in pancreatic cancer

The outlook for patients with pancreatic cancer has been grim. There have been major advances in the surgical treatment of pancreatic cancer, leading to a dramatic reduction in post-operative mortality from the development of high volume specialized centres. This stimulated the study of adjuvant and neoadjuvant treatments in pancreatic cancer including chemoradiotherapy and chemotherapy. Initial protocols have been based on the original but rather small GITSG study first reported in 1985. There have been two large European trials totalling over 600 patients (EORTC and ESPAC-1) that do not support the use of chemoradiation as adjuvant therapy. A second major finding from the ESPAC-1 trial (541 patients randomized) was some but not conclusive evidence for a survival benefit associated with chemotherapy. A third major finding from the ESPAC-1 trial was that the quality of life was not affected by the use of adjuvant treatments compared to surgery alone. The ESPAC-3 trial aims to assess the definitive use of adjuvant chemotherapy in a randomized controlled trial of 990 patients.     

Progress in multidisciplinary treatment for esophageal cancer in Japan as reflected in JCOG studies

Changes in the standard treatment for esophageal cancer in Japan are reflected in the history of consecutive studies conducted by the Japan Esophageal Oncology Group (JEOG), a subgroup of the Japan Clinical Oncology Group (JCOG). Following the era of preoperative radiotherapy in the 1970s, the emphasis in surgical adjuvant therapy shifted from postoperative radiotherapy in the 1980s to postoperative chemotherapy including cisplatin as a key drug in the 1990s. Later, the optimal timing for perioperative adjuvant therapy returned to before surgery based on the results of a JCOG study (JCOG9907) that compared preoperative chemotherapy with postoperative chemotherapy in the late 2000s. Next, the clinical question of which is better, preoperative aggressive chemotherapy or preoperative chemoradiotherapy, still needs to be resolved. Concurrent chemoradiotherapy using cisplatin and 5-fluorouracil became a standard non-surgical treatment for esophageal cancer from the early 1990s onwards. Based on the preferable results of definitive chemoradiotherapy for unresectable advanced disease, definitive chemoradiotherapy was considered to be a possible alternative treatment modality in stage I esophageal cancer patients. Therefore, JEOG conducted a phase III study (JCOG0502) to demonstrate the non-inferiority of chemoradiotherapy compared with surgery in patients with stage I esophageal squamous cell carcinoma. If definitive chemoradiotherapy fails in patients with stage II/III esophageal cancer, salvage surgery is now recommended. Therefore, JEOG has initiated a phase II study (JCOG0909) to evaluate the efficacy and safety of this combined treatment modality.     

Non-surgical treatments of esophageal cancers

INTRODUCTION: Despite improvements in surgical techniques and perioperative mortality, only slight improvements in the 5-year survival of patients with esophageal cancer have been observed in the last 20 years. Many patients with apparently localized cancer will have recurrences or metastatic disease despite surgery with curative resection. Consequently, multimodal therapies, including chemotherapy and radiotherapy, were introduced. This review outlines and critically analyzes current non-surgical treatments, including palliative care. CURRENT KNOWLEDGE AND KEY POINTS: Esophageal cancers appear to be chemosensitive but the median duration of response is short and toxicity consistent, especially in metastatic disease. Consequently, palliative chemotherapy should be offered preferably within a clinical trial. Chemotherapy as the only adjuvant treatment cannot be recommended outside clinical trials. Radiotherapy alone as a curative treatment has been proven to be inferior to chemoradiotherapy in inoperable tumors. Some data support the use of preoperative chemoradiotherapy, but randomized trials are conflicting. A pathological complete response has been identified as a favorable prognostic factor for survival. Self-expanding esophageal metal stents are a simple and effective palliative treatment of malignant dysphagia and can be considered as the reference treatment in patients with obstruction of the lower esophagus or with fistula. FUTURE PROSPECTS AND PROJECTS: Taxanes should be evaluated in randomized studies using chemotherapy or chemo-radiotherapy. Progress in radiotherapy, such as accelerated fractionation, greater radiation dose, and the addition of brachytherapy, will increase locoregional control and probably survival. The role of secondary surgery in patients responding to chemoradiotherapy still needs to be answered.     

Should concomitant and adjuvant treatment with temozolomide be used as standard therapy in patients with anaplastic glioma?

Malignant gliomas are devastating tumors associated with poor prognosis. Standard treatment has been surgery followed by radiotherapy while the role of chemotherapy has remained controversial. Concomitant and adjuvant treatment with temozolomide has recently been shown to improve survival in patients with glioblastoma. While it seems intuitive to apply this regimen to patients with anaplastic gliomas which have traditionally been considered more chemosensitive, chemotherapy has not been shown to prolong life in patients with anaplastic gliomas. Despite promising preclinical and early clinical results, there is currently not enough level 1 evidence to justify concomitant and adjuvant temozolomide as standard therapy for patients with newly diagnosed anaplastic gliomas. Further investigation is needed to better define the role of chemotherapy in patients with anaplastic gliomas. Trials evaluating chemoradiotherapy as well as targeted therapeutic agents are the subject of further research.     

Postoperative adjuvant chemoradiotherapy in D2-dissected gastric cancer: Is radiotherapy necessary after D2-dissection?

Studies from the Far East have demonstrated that D2-dissection is superior to D0/1-dissection. The ef-fect of postoperative chemoradiotherapy(CRT) after D2-dissection has not been accepted due to the lack of D2-dissection in Western countries, as well as the potential harmful effect of radiotherapy. In the current NCCN guideline, adjuvant chemotherapy alone is rec-ommended in D2-dissected patients. However, three recent prospective randomized controlled trials in South Korea and China(ARTIST, NCC and Multicenter IMRT Trials) demonstrated that adjuvant CRT can be safely administered to D2-dissected patients with notable benefits. To identify the role of radiotherapy(RT) in the D2-dissected postoperative setting, clinical research attempts should include(1) identification of high-risk patients for loco-regional recurrence who might benefit from CRT;(2) modification of RT target volume based on the findings that failure patterns should be differ-ent after D1- and D2-dissection; and(3) integrationof new RT techniques to decrease treatment-related toxicity. The present paper is a review of recent studies addressing these fields. Well-designed prospective ran-domized studies are needed to clearly define the role of adjuvant CRT in D2-dissected gastric cancer, however, future clinical studies should also focus on answering these questions.     

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 chemotherapy in pancreatic cancer

Summary There is increasing interest in the use of adjuvant treatment for pancreatic cancer since although postoperative mortality is much improved, median long-term survival is only on the order of 11–15 mo. Despite a proliferation of studies in advanced pancreatic cancer indicating a benefit for chemotherapy, there has only been one small randomized adjuvant trial. A combination of 5-fluorouracil, doxorubicin, and mitomycin-C demonstrated a significantly improved median survival (23 vs 11 mo in controls) but no significant improvement in 5-yr survival (4 vs 8%, respectively). At present there is insufficient evidence to support the routine use of adjuvant chemotherapy (even with radiotherapy) outside of controlled trials. What is required is large randomized trials of adjuvant chemotherapy. A further important question that needs addressing is the role of adjuvant radiotherapy (with concomitant chemotherapy) with or without sequential chemotherapy.     

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.     

Systemic treatment of pancreatic cancer

Patients with pancreatic cancer have a poor prognosis although systemic treatment has slightly improved the outcome for those with advanced pancreatic cancer, The approach to a patient with pancreatic cancer remains a great challenge. Patients often present with advanced disease and many are already in poor general condition at the time of diagnosis. Today, surgery remains the only curative therapeutic option. A small number of pancreatic adenocarcinomas, however, are resectable and relapses after surgery are very frequent. The reference treatment in patients with metastatic pancreatic cancer is gemcitabine. The median survival of patients with advanced pancreatic cancer who are treated with gemcitabine is approximately 6 months and only approximately 20% of patients will be alive at 1 year. Combinations of gemcitabine with new cytotoxic agents and with novel targeted agents hold the promise for improving the outcome. Randomized phase III studies are, however, still ongoing. Since most patients will relapse after complete surgical resection of pancreatic cancer, a search for a better adjuvant or neoadjuvant treatment is important. Although several randomized studies have suggested an improved outcome for a postoperative chemoradiotherapy or chemotherapy, the role of an adjuvant treatment remains today controversial. Randomized phase III studies are ongoing. A neoadjuvant strategy might therefore also play a role, but phase III studies are lacking. The systematic evaluation of new drugs in well designed clinical trials and the search for new molecular targets for treatment are crucial in our aim to improve the outcome for patients with pancreatic cancer.     

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.     

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 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.     

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.     

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.     

Morbidities of adjuvant chemotherapy and radiotherapy for resectable rectal cancer

PURPOSE: Although adjuvant chemoradiotherapy may improve outcomes after surgery for high-risk rectal cancer, its toxicities are not well documented. This is a review of complications associated with adjuvant therapy in randomized, controlled trials. METHODS: A MEDLINE and literature search was performed for randomized, controlled trials of adjuvant therapy for rectal cancer. Modalities of adjuvant therapy evaluated included preoperative radiotherapy, preoperative chemoradiotherapy, postoperative radiotherapy, and postoperative chemoradiotherapy. All documented complications were analyzed, including any effect on pelvic floor function and quality of life. RESULTS: Short-term (acute) complications of preoperative radiotherapy include lethargy, nausea, diarrhea, and skin erythema or desquamation. These acute effects develop to some degree in most patients during treatment but are usually self-limiting. With preoperative radiotherapy the incidence of perineal wound infection increases from 10 to 20 percent. The acute toxicities after postoperative radiotherapy for rectal cancer occur in 4 to 48 percent of cases, and serious toxicities, requiring hospitalization or surgical intervention, occur in 3 to 10 percent of cases. Postoperative radiotherapy is associated with more complications than preoperative radiotherapy. The main problems with postoperative radiotherapy are small-bowel obstruction (5–10 percent), delay in starting radiotherapy caused by delayed wound healing (6 percent) and postoperative fatigue (14 percent), and toxicities precluding completion of adjuvant therapy (49–97 percent). The morbidity and mortality of both preoperative and postoperative radiotherapy are higher in elderly patients and when two-portal rather than three-portal or four-portal radiation technique is used. Meticulous radiation technique is important, and multiple fields of irradiation are mandatory. After combined adjuvant chemotherapy and radiotherapy acute hematologic and gastrointestinal toxic effects are frequent (5–50 percent). Delayed radiation toxicities include radiation enteritis (4 percent), small-bowel obstruction (5 percent), and rectal stricture (5 percent). Pelvic floor function and quality of life have not been well evaluated in randomized, controlled trials. CONCLUSION: Adjuvant therapy for rectal cancer has considerable adverse effects. Adverse effects on bowel and sphincter function and quality of life have not been defined.Dr. Ooi is supported in part by the Irene and Margaret Stewardson Charitable Trusts.     

Adjuvant treatment

Exocrine pancreatic cancer (pancreatic ductal adenocarcinoma) is one of the leading causes of cancer deaths in the western world, accounting for 5% of all cancer-related deaths. Only a small percentage of patients with pancreatic cancer are able to undergo potentially curative resection, even in specialized centres, and prognosis remains poor after successful surgery. Over the last few years efforts have been directed towards the development of adjuvant therapies in attempts to improve outcome. The main trials of adjuvant chemotherapy, chemoradiotherapy and chemoradiotherapy with follow-on chemotherapy are described in this paper, followed by the results of the ESPAC-1 trial and the status of ESPAC-2 and -3 trials.