Postoperative adjuvant therapy for pancreatic cancer

The majority of patients diagnosed with pancreatic cancer present at an advanced stage, and only a small percentage are considered technically resectable at diagnosis. The overall prognosis for the majority is dismal, with a median survival in untreated cases of only 24 weeks. Even in resected patients the overall 5-year survival rate is generally only 5% to 10%; however, some reports indicate higher 5-year survival rates in patients treated with surgery who are pathologically staged with no lymph node involvement. Even when macroscopically complete resection is achieved, local recurrence (LR) rates are unacceptably high (30% to 70%), which is usually attributed to the difficulty of obtaining microscopically free surgical margins. Microscopic clearance is difficult to achieve because these tumors frequently extend into the peripancreatic tissues (e.g., retropancreatic fat), abut or invade the adjacent large vessels (the portal vein and superior mesenteric artery), and have a propensity to invade the lymphovascular and perineural space. Other common sites of failure after attempted curative resection include metastasis to the liver and the peritoneal cavity. Patients who present with pancreatic cancer, and for whom curative surgery is deemed possible, are thus potential candidates for adjuvant therapy because of the high local failure rate following resection alone. The radiotherapy dose that can be achieved in the postoperative setting for pancreatic cancer is limited because of the proximity of critical structures (e.g., the kidney, liver, small intestines, stomach, and spinal cord). Newer techniques such as conformal radiotherapy and intensity-modulated radiotherapy have the advantage of being able (theoretically) to precisely localize the dose to the target volume while reducing the dose to critical structures. These techniques may potentially enable the tumorcidal dose to be increased; however, they are only now becoming widespread. Systemic radiation-sensitizing chemotherapy is also a promising approach to take advantage of additive or synergistic effects with radiation locally, and for the sterilization of systemic disease. This concept of concomitant chemotherapy with radiotherapy, or chemoradiotherapy, has proved effective in a number of sites, including the anal canal, rectum, lung, and pancreas. The recent trials reviewed here varied considerably in terms of the total dose and technique used, and the choice of radiation sensitizing treatment.     

Current status of adjuvant therapy for pancreatic cancer

Pancreatic cancer is considered to be one of the malignancies most resistant to therapy. It is characterized by early local invasion and distant spread. Therefore, resection with curative intent is limited to a very small proportion of patients. Even in these selected patients, long-term survival remains very poor because of liver and local recurrence. Therefore, control of occult liver metastasis and local residual tumor with perioperative radiotherapy and chemotherapy may provide some palliative benefits, and should have some impact on overall survival. However, none of the studies to date are considered definitive. Japanese pancreatic surgeons have developed a number of adjuvant therapies which theoretically could be good enough to prolong long term survival, however, they have not been tested in randomized controlled trials. Planning co-operative studies on this important issue in pancreatic cancer therapy is urgently needed.     

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.     

Benefit of postoperative adjuvant therapy for pancreatic cancer

BACKGROUND:

Despite the recent completion of several trials of adjuvant therapy after resection for pancreatic adenocarcinoma, the absolute impact on survival and the identification of appropriate patients for treatment has remained controversial. In the current study, the authors sought to identify the impact of adjuvant therapy and factors associated with any improvement in survival after resection of pancreatic cancer.

METHODS:

Through the California Cancer Registry, all California residents diagnosed with pancreatic cancer between 1994 and 2002 were identified. Factors potentially impacting survival were analyzed, including patient demographics, tumor characteristics, and treatment provided. Univariate and multivariate survival analyses were performed by Kaplan‐Meier and Cox regression methods.

RESULTS:

A total of 26,518 patients were identified; 3196 (12.1%) underwent resection as their primary treatment. The median overall survival was 16 months for patients who underwent resection. Prognostic factors associated with better survival included negative lymph node status, well‐differentiated tumors, younger age, female sex, and the receipt of any adjuvant therapy. On multivariate analysis, adjuvant therapy demonstrated a statistically significant, although modest, impact on survival, with a hazards ratio of 0.79 (95% confidence interval, 0.72‐0.87; P < .001). The benefit of adjuvant therapy was only apparent in those patients with lymph node–positive or poorly differentiated tumors.

CONCLUSIONS:

Adjuvant therapy provided for a modest improvement in overall survival after surgical resection of pancreatic cancer. The absolute effect was most pronounced in those patients with poor prognostic indicators. To identify effective systemic therapy for this deadly cancer, future clinical trials of adjuvant therapy should focus on these groups of patients. Cancer 2009. © 2009 American Cancer Society.     

Chemotherapy for metastatic disease: review from JCOG trials

The Gastrointestinal Oncology Study Group of Japan Clinical Oncology Group (GIOSG/JCOG) has conducted several clinical trials to establish standard chemotherapy for unresectable or recurrent gastric cancer. From the late 1980s to early 1990s, two phase II studies by JCOG evaluated oral fluoropyrimidines, and others introduced Western chemotherapy regimens. Thereafter, the first phase III study (JCOG9205), comparing 5-fluorouracil (5-FU), 5-FU plus ciplatin (CDDP) (FP), and uracil and tegafur (UFT) plus mitomycin (UFTM), could not show a survival benefit of either FP or UFTM over 5-FU alone. In the late 1990s, new active agents such as irinotecan (CPT-11) and S-1 (new oral fluoropyrimidine) showed promising results in their phase II trials. The latest phase III study (JCOG9912), comparing 5-FU, CPT-11 plus CDDP, and S-1, showed significant noninferiority of S-1 to 5-FU in overall survival, associated with a better response rate and progression-free survival and acceptable toxicities, and concluded that S-1 should be considered for the standard chemotherapy of unresectable or recurrent gastric cancer. Simultaneously, another Japanese phase III trial comparing S-1 with S-1 plus CDDP showed a survival benefit of S-1 plus CDDP. At present, S-1 plus CDDP is recognized as standard chemotherapy for unresectable or recurrent gastric cancer, and new treatment with molecular target agents is under development.     

Meta-analysis of randomised adjuvant therapy trials for pancreatic cancer

The aim of this study was to investigate the worldwide evidence of the roles of adjuvant chemoradiation and adjuvant chemotherapy on survival in potentially curative resected pancreatic cancer. Five randomised controlled trials of adjuvant treatment in patients with histologically proven pancreatic ductal adenocarcinoma were identified, of which the four most recent trials provided individual patient data (875 patients). This meta-analysis includes previously unpublished follow-up data on 261 patients. The pooled estimate of the hazard ratio (HR) indicated a 25% significant reduction in the risk of death with chemotherapy (H = 0.75, 95% confidence interval (CI): 0.64, 0.90, P-values(stratified) (Pstrat) = 0.001) with median survival estimated at 19.0 (95% CI: 16.4, 21.1) months with chemotherapy and 13.5 (95% CI: 12.2, 15.8) without. The 2- and 5-year survival rates were estimated at 38 and 19%, respectively, with chemotherapy and 28 and 12% without. The pooled estimate of the HR indicated no significant difference in the risk of death with chemoradiation (HR = 1.09, 95% CI: 0.89, 1.32, Pstrat = 0.43) with median survivals estimated at 15.8 (95% CI: 13.9, 18.1) months with chemoradiation and 15.2 (95% CI: 13.1, 18.2) without. The 2- and 5-year survival rates were estimated at 30 and 12%, respectively, with chemoradiation and 34 and 17% without. Subgroup analyses estimated that chemoradiation was more effective and chemotherapy less effective in patients with positive resection margins. These results show that chemotherapy is effective adjuvant treatment in pancreatic cancer but not chemoradiation. Further studies with chemoradiation are warranted in patients with positive resection margins, as chemotherapy appeared relatively ineffective in this patient subgroup.     

Chemotherapy for pancreatic cancer

Pancreatic cancer has one of the worst prognosis of any malignant disease. The National Registry of Japan Pancreas Society has reported that only 13% of patients achieve 5 years survival after surgical resection. The vast majority of patients present with metastatic or unresectable disease. Gemcitabine (GEM) has replaced 5-fluorouracil (5-FU)-based chemotherapy as the standard of care. GEM first generated improvements in symptom control and survival in advanced disease, spurring further research. For locally advanced disease, most recent studies have incorporated GEM into combined-modality therapy. However, subsequent trials have not demonstrated that combinations of other agents with GEM extend clinical benefits yet. Similarly, in surgically resectable disease, current trials are incorporating GEM into adjuvant therapy. According to several clinical trials it has been demonstrated that improvements in locoregional control and survival may be achieved when chemotherapy using 5-FU is added to radiation for locally advanced pancreatic cancer. The new regimen for locally advanced disease has demonstrated that the better outcome is expected by chemoradiation therapy with 5-FU followed by GEM treatment. Furthermore, one of the patients showed the significant regression of pancreas tumor, resulting in the successful surgical resection. In order to develop chemotherapy for pancreatic cancer, we are analyzing mRNA expression of pancreas cancer cell lines and examined their resistant against to GEM. One of the genes is demonstrated to be a responsible for drug sensitivity by clustering analysis.     

Chemotherapy for metastatic disease: current status

Chemotherapy now has an established role in the treatment of hormone-refractory metastatic prostate cancer. This review summarises the results of the latest trials and discusses ongoing studies investigating the role of chemotherapy earlier in the disease.     

Chemotherapy for metastatic breast cancer

The treatment of metastatic breast cancer aims to relieve symptoms by controlling disease and prolonging survival with better QOL. The meta-analysis demonstrated the significant advantage for overall survival by chemotherapy with a longer period. It means that chemotherapy can prolong survival. The major chemotherapies contain anthracyclines or taxanes. For HER 2-overexpressing breast cancer, a standard treatment utilizes trastuzumab-containing chemotherapy. The other active agents include vinorelbine, capecitabine, S-1, mitomycin and gemcitabine. Bisphosphonates combined with chemotherapy or hormone therapy are able to alleviate pain or complications of osteolytic bone metastasis. Experimental agents, such as monoclonal antibody or small molecular kinase inhibitor, are investigated for clinical use. The treatments, either chemotherapy or hormone therapy, could be performed in sequence in order to minimize toxicities and maximize efficacy. In selecting the most appropriate treatment for metastatic breast cancer, it is recommended to consider patients' preference by providing the correct information on the status of disease, efficacy and toxicities of chemotherapy.     

Chemotherapy for metastatic breast cancer

Cytotoxic chemotherapy is a mainstay of treatment for advanced breast cancer. Treatment of metastatic (also called stage IV, advanced, or recurrent) breast cancer is not considered curative. Rather, the goals of treatment with chemotherapy are to prolong survival, alleviate or prevent tumor-related symptoms or complications, and improve quality of life. While the purpose of chemotherapy is to prevent or alleviate symptoms, chemotherapy paradoxically carries considerable toxicities that cause substantial symptoms in patients, notoriously including fatigue, nausea, vomiting, diarrhea, hair loss, mucositis, neutropenia, and neuropathy. Balancing the benefits and the side effects of chemotherapy is further complicated by the natural history of advanced breast cancer, which can be quite prolonged and typically involves multiple lines of chemotherapy, especially in patients whose tumors respond to treatment.     

Chemotherapy for metastatic colorectal cancer

The past decade has seen a significant survival improvement for patients with metastatic colorectal cancer, fueled in large part by the arrival of active novel chemotherapeutic drugs and their incorporation into combination regimens. Several randomized trials have successfully integrated oxaliplatin and irinotecan into previously existing 5-fluorouracil (5-FU)-based regimens for advanced colorectal cancer, resulting in median survivals that have risen from 9 months to almost 2 years. Even as the ideal combinations and sequences of these regimens are elucidated, targeted therapies such as recently approved bevacizumab and cetuximab have been added to treatment protocols, with favorable consequences. We review the evolution of primary chemotherapy for advanced colorectal cancer, focusing on the trials that have led to the new standard first-line treatments. We also review the data on newer targeted therapies, especially in combination with cytotoxic therapy.     

Chemotherapy for metastatic bladder cancer

This paper reviews the current status of systemic chemotherapy in the management of advanced and metastatic urothelial cancer. The activity of a number of single agents and combination drug regimens is discussed, and the small number of randomised-controlled studies available is also considered. Prognostic factors for response and survival, particularly long-term survival after systemic chemotherapy, are also reviewed. Special consideration is given to the role of systemic chemotherapy as a precursor to surgery (or radiotherapy) in locally advanced disease that is initially considered incurable. Therapeutic options for patients unable to tolerate cisplatin owing to renal impairment or other comorbidities are explored. Future directions are explored, including the role of molecular phenotyping in providing prognostic information, indicators of the likely success of conventional therapeutic measures and the development of specific targeted therapies.     

Chemotherapy for metastatic lung cancer

The effects of chemotherapy for lung metastasis in 284 cancer patients using various anti-tumor drugs, including classic ones and modern active agents for the past 18 years, were presented. Lung metastasis for lung cancer was excluded. The response was achieved in cervical carcinoma of the uterus (17/62, 27%), endometrial carcinoma of the uterus (1/7, 14%), colorectal cancer (6/39, 15%), breast cancer (5/28, 18%) and stomach cancer (4/28, 14%). A high response was achieved in myosarcoma (5/12, 42%), testicular cancer (5/11, 45%) and also in ovarian cancer (3/10, 30%). Though there were few cases, a high response was achieved in malignant melanoma (2/3), choriocarcinoma (2/4) and esophageal cancer (1/3). In total patients the response rate was 20%. In these cases a complete response was achieved in 4 cervical cancers; one testicular cancer, ovarian cancer, esophageal cancer and renal cancer, respectively. However, the effect was temporary and no longterm survivor was observed except for one case of renal cancer treated continuously with interferon (3 X 10(6) units daily) and showing complete remission after 7 months of therapy. The effect of chemotherapy for lung metastasis was compared between nodular metastasis (NM) and lymphagiosis carcinomatosa (LC). In cervical carcinoma of the uterus, the response rate in NM (39%) was higher than in LC (11%). However, no difference was observed in breast cancer (NM 15%, LC 13%) nor in stomach cancer (NM 13%, LC 18%).     

Chemotherapy for metastatic colorectal cancer

The treatment of metastatic colorectal cancer(mCRC)has developed significantly over the past 10 years. For nearly 40 years, the fluoropyrimidine 5-fluorouracil(5-FU)was the only active agent used for advanced metastatic disease. However, since the 1990s, the chemotherapy treatment options for patients with mCRC have been greatly facilitated with the introduction of several new cytotoxic agents. In particular, combination regimens that incorporate infusional schedules of 5-FU in combination with oxaliplatin(FOLFOX)and/or irinotecan(FOLFIRI)have significantly improved clinical efficacy as related to overall response rates, time to tumor progression, and median overall survival. More recently, monoclonal antibodies such as bevacizumab, cetuximab, and panitumumab have become available for use in mCRC treatment in combination with cytotoxic agents and as monotherapies in Western countries. The addition of these target agents to the mCRC treatment armamentarium has resulted in more therapeutic options and improved treatment outcomes for patients. Currently, bevacizumab is the only target drug that is available for mCRC in Japan. In this article we review various treatment options, including cytotoxic and targeted agents, currently available for patients with mCRC in Japan and Western countries.     

Chemotherapy for colorectal cancer in the metastatic and adjuvant setting: past, present and future

There have been significant advances in the use of chemotherapy in the treatment of colorectal cancer patients over the last 20 years. Initial improvements in treatment were made with increased understanding of the pharmacology of 5-fluorouracil and the discovery of modulators of its activity (e.g., leucovorin). However, in the last few years the discovery of new cytotoxic drugs with efficacy in large bowel cancer (e.g., oxaliplatin and irinotecan) and monoclonal antibodies (e.g., bevacizumab and cetuximab) have significantly improved patient outcome and prognosis. Systemic chemotherapy in the metastatic setting has been shown to prolong survival and improve quality of life. Chemotherapy now also has a clear role as an adjunct to surgery to improve survival in stage III and certain 'high-risk' stage II colorectal cancer patients. The evolution of chemotherapy use, current practice in the metastatic and adjuvant setting and possible future directions are discussed.     

胰腺癌辅助治疗研究进展

近几年一些抗肿瘤新药如吉西他滨、紫杉醇等在胰腺癌辅助治疗中的应用以及放疗技术的改进,使胰腺癌辅助治疗有了一定进展.现综述胰腺癌辅助放化疗、新辅助放化疗的研究进展.