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 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.     

Preoperative chemoradiation in resectable pancreatic cancer

Despite advancements in the field of surgical oncology, the diagnosis of pancreatic cancer still carries a grave and dismal prognosis. Surgery alone for adenocarcinoma of the pancreatic head or uncinate process has a median survival time of 12 months. These grim statistics have led many to study the effects of combined multimodality therapy in the fight against pancreatic cancer. The long recovery time associated with pancreaticoduodenectomy has resulted in as many as 25% of patients unable to proceed with planned adjuvant therapy. For these reasons preoperative or neoadjuvant chemoradiation therapy (CRT) has been evaluated. Preoperative CRT ensures that all eligible patients receive the benefits of multimodality therapy, and patients who manifest metastatic disease on restaging evaluations are spared the morbidity of an unnecessary laparotomy. Multimodality therapy appears to lengthen the survival duration in patients with pancreatic cancer. It also affords a selection advantage, in that patients with aggressive disease biology with advanced metastatic disease following CRT are spared the morbidity of surgery. Conversely, a limited subset of patients may even be downstaged, allowing for a potentially curative resection. In this article we review the current status of neoadjuvant chemoradiation in adenocarcinoma of the pancreas. We discuss its rationale in light of the reported strengths and weaknesses of postoperative adjuvant CRT.     

Chemotherapy for pancreatic cancer

To date, no satisfactory treatment has been developed for treatment of patients with advanced pancreatic carcinoma. The median survival of these patients is only three to six months. Of more than 30 agents evaluated over the past three decades, only 5-FU results in a response rate with 95% confidence intervals greater than 20%. Most responses are partial, of short duration, and of questionable clinical benefit. To date, efforts to improve response rates by biochemical modulation of 5-FU have been unsuccessful but additional studies are warranted and are ongoing. Although improved response rates have been reported with some drug combinations, such as streptozotocin, mitomycin and 5-FU (SMF), median survival for combination therapy is no better than that attained with single-agent therapy. Current therapeutic options for patients with advanced disease include 5-FU, supportive care, or investigational treatment in a clinical trial. In three out of four studies, patients with locally advanced pancreatic carcinoma who received combined modality therapy (radiation in combination with 5-FU) survived significantly longer than those treated with either radiation or chemotherapy alone. The brief survival advantage, however, must be considered in the context of the additional toxicity and treatment time required for the combined modality treatment. Radiotherapy in combination with 5-FU should be considered standard adjuvant therapy for patients with completely resected disease. The median survival of treated patients was 20 months and significantly longer than the surgery alone control group (11 months) (Kalser and Ellenberg, 1985; GITSG, 1987). Of greatest significance is the tail-end plateau on the survival curve suggesting that approximately 18% of patients who received combined modality therapy were cured. The results with currently available treatment for all stages of disease are poor; therefore, patients should be informed about ongoing clinical trials which may someday improve the prognosis for pancreatic cancer.     

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.     

Chemotherapy for colorectal carcinoma in the elderly

With nearly 50 % of all colorectal cancers being diagnosed in patients at the age of 70 or above colorectal cancer is a disease of the elderly. In an adjuvant setting, fit elderly patients can receive the same benefit from cytotoxic therapy as younger patients with an only slightly increased toxicity. In a palliative setting, the treatment of elderly patients with respect to clinical endpoints such as response, time to progression or overall survival is as effective as in their younger counterparts. In clinical studies, older patients are generally underrepresented and among the elderly patients involved in clinical studies there is a bias towards particularly fit patients. Therefore it is not possible to extrapolate the results of many randomized trials to all elderly patients. A Comprehensive Geriatric Assessment (CGA) should be applied to detect the diversities in the geriatric population. Based on this assessment elderly patients classified as suitable for chemotherapy should be enrolled into clinical trials for colorectal cancer.     

Neoadjuvant chemoradiation in patients with pancreatic adenocarcinoma

In spite of the high mortality in pancreatic cancer, significant progress is being made. This review discusses multimodality therapy for patients with pancreatic cancer. Surgical therapy currently offers the only potential monomodal cure for pancreatic adenocarcinoma. However, only 10-20% of patients present with tumors that are amenable to resection, and even after resection of localized cancers, long-term survival is rare. The addition of chemoradiation therapy significantly increases median survival. To achieve long-term success in treating this disease it is therefore increasingly important to identify effective neoadjuvant/adjuvant multimodality therapies. Preoperative chemoradiation for potentially resectable pancreatic cancer has the following advantages: (1) neoadjuvant treatment would eliminate the delay of adjuvant treatment due to postoperative complications; (2) neoadjuvant treatment could avoid unnecessary surgery for patients with metastatic disease evident on restaging after neoadjuvant therapy; (3) down-staging after neoadjuvant therapy may increase the likelihood of negative surgical margins; and (4) neoadjuvant treatment could prevent peritoneal tumor cell implantation and dissemination caused during surgery. This review systematically summarizes the current status, controversies, and prospects of neoadjuvant treatment of pancreatic cancer.     

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.     

Role of extended surgery for pancreatic cancer: critical review of the four major RCTs comparing standard and extended surgery

Pancreatic ductal carcinoma is one of the most dismal malignancies in the gastrointestinal system. Despite the development of several adjuvant therapeutic options, surgical treatment is still the only procedure that can completely cure this disease. Since pancreatic cancer easily extends to the adjacent tissues or develops distant metastasis, there has been argument as to whether we should perform extended surgery in order to widely eradicate peripancreatic tissue. After the report from Japanese surgeons that showed a survival benefit of the extended surgery for the invasive ductal carcinoma of the pancreas in the late 1980s, many Japanese surgeons applied the extended surgery for pancreatic cancer. However, the major problems of these studies were the retrospective and non-randomized nature of the study design. Thereafter, randomized controlled trials (RCT) comparing a standard and extended resection for the pancreatic cancer have been conducted first in Europe, second and third in the USA, and, subsequently, fourth in Japan. Unexpectedly, the survival benefit of the aggressive surgery has been refuted in all of the four major RCTs. This fact implied to us that surgery alone is not enough and that another adjuvant therapeutic option is necessary in order to improve the patients?? survival of pancreatic cancer.     

Pancreatic neoplasm in 2011: an update

Pancreatic cancer still is a significant, unresolved therapeutic challenge with nearly similar incidence and mortality rates. It is the most lethal type of digestive cancer with a 5-year survival rate of 5%. Adjuvant chemotherapy remains to be gemcitabine alone or combined with infusional 5-fluorouracil with radiation therapy. Nevertheless, only a few patients survive for at least 5 years after R0 resection and adjuvant therapy. Most patients need palliative treatment. Once pancreatic cancer becomes metastatic, it is uniformly fatal with an overall survival of typically 6 months from diagnosis. Chemotherapy is an important component of palliative care but must be administered as a part of a multidisciplinary approach, including palliation of pain, managing weight loss, and deterioration in functional status. Gemcitabine has been the standard in both locally advanced and metastatic disease. The addition of the tyrosine kinase inhibitor erlotinib prolongs median survival for only 2 weeks. While gemcitabine-based regimens are currently accepted as the standard first-line treatment of patients with locally advanced or metastatic pancreatic adenocarcinoma, there is no consensus regarding treatment in the second-line setting. It will not be untrue to say that there are no real medical breakthroughs with regards to improving the prognosis of pancreatic cancer as of 2011. On the other hand, we have made some progress in patients with advanced pancreatic neuroendocrine tumors. These patients have a 5-year survival that can range from 97% in benign insulinomas to as low as 30% in non-functional metastatic pancreatic neuroendocrine tumors. Treatment options may include surgery, transarterial chemoembolization of liver metastases, and cytotoxic therapy such as streptozotocin, 5-fluorouracil or doxorubicin. Somatostatin analogues, like octreotide, have been proven to prolong progression-free survival in patients with metastatic neuroendocrine tumors of midgut origin. In 2011, two targeted agents, a tyrosine kinase inhibitor sunitinib and mTOR inhibitor everolimus have been approved by FDA for pancreatic neuroendocrine tumors. With these approvals, U.S. physicians can now offer their patients with progressive pancreatic neuroendocrine tumors. Patients with any stage of pancreatic cancer should be considered candidates for clinical trials.     

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.     

Surgery for pancreatic cancer: recent controversies and current practice

Pancreatic duct carcinoma remains a common disease with a poor prognosis. More than 30,000 Americans will die of the disease in 2004, making it the fourth leading cause of cancer death. Despite significant advances in the treatment of many other human tumors, the 5-year survival rate for persons diagnosed with pancreatic cancer has not changed in decades and remains <5%. This is due both to the inherently aggressive biology of the disease and to its late diagnosis in most cases. Surgical resection of localized disease remains the only hope for cure of pancreatic cancer. Over the past 2 decades, significant advances in diagnostic imaging, staging, surgical technique, and perioperative care have led to marked improvement in the surgical management of pancreatic cancer patients. Operative mortality rates for pancreaticoduodenectomy are now <5% at major centers, and the average length of hospital stay has been reduced to <2 weeks. Improvements in patient outcome after pancreatic cancer surgery have made possible, for the first time, the design and conduct of large adjuvant therapy studies in pancreatic cancer. Such clinical trials are critical for improving outcomes for pancreatic cancer patients.     

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.     

Prognostic factors in Stage T2NO rectal cancer

PURPOSE: To further define the indications for postoperative pelvic irradiation and chemotherapy, an analysis of the influence of extent of tumor invasion into perirectal fat, lymphatic or venous vessel invasion, and tumor grade on the clinical course of patients with Stage T2NO rectal cancer undergoing surgery was undertaken. METHODS: From 1968 to 1985, 117 patients with Stage T3NO rectal cancer underwent resection with curative intent. No patient received neoadjuvant or adjuvant irradiation or chemotherapy. Surgical specimens were assessed for maximum depth of tumor invasion into perirectal fat, lymphatic or venous involvement, and tumor grade. After surgery the clinical course of these patients was assessed for local control, distant metastases, and survival rate. RESULTS: For 25 patients with tumors exhibiting favorable histologic features (well-differentiated or moderately well-differentiated carcinomas invading less than 2 mm into perirectal fat, without lymphatic or venous vessel involvement), the ten-year actuarial rates of local control and recurrence-free survival were 95 and 87 percent, respectively. In contrast, the ten-year actuarial rates of local control and recurrence-free survival were inferior (71 and 55 percent, respectively) for 88 patients with tumors exhibiting moderate to deep perirectal fat invasion, vessel involvement, or poor differentiation. CONCLUSIONS: In the design of future trials of rectal cancer, selection of patients with rectal cancer for postoperative adjuvant therapy should be based not only on stage, but also on depth of invasion into the perirectal fat, vessel involvement, tumor grade, and integrity of the radial resection margin. For subsets of patients with Stage T3NO rectal cancer, there may be little benefit to adjuvant therapy after surgery.     

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.     

A phase II study of adjuvant gemcitabine plus docetaxel followed by concurrent chemoradation in resected pancreaticobiliary carcinoma

ObjectivesAdjuvant gemcitabine with or without chemoradiation is a standard therapeutic option for patients with resected pancreatic cancer. The feasibility and toxicity of gemcitabine with docetaxel before and after 5‐fluorouracil (5FU)‐based chemoradiation in the adjuvant pancreatic and biliary cancer setting were investigated.MethodsAfter a curative‐intent resection, eligible patients with pancreaticobiliary cancers were treated with two cycles of gemcitabine and docetaxel followed by 5FU‐based chemoradiation. Four weeks after completing chemoradiation, two cycles of gemcitabine and docetaxel were administered. The primary endpoint was the incidence of severe toxicities. Secondary endpoints included disease‐free survival (DFS) and overall survival (OS).ResultsFifty patients with pancreaticobiliary cancers were enrolled. Twenty‐nine patients had pancreatic cancer whereas 21 patients had biliary tract or ampullary cancers. There was one death as a result of pneumonia, and 15% of patients experienced grade 3 or greater non‐haematological toxicities. The median DFS and OS for patients with pancreatic cancer were 9.6 and 17 months, respectively, and for those with resected biliary tract cancer were 12 and 23 months, respectively.ConclusionsThis combination of gemcitabine and docetaxel with chemoradiation is feasible and tolerable in the adjuvant setting. Future studies utilizing a different gemcitabine/taxane combination and schedule may be appropriate in the adjuvant treatment of both pancreatic cancer and biliary tumours.     

Role of adjuvant surgery for patients with initially unresectable pancreatic cancer with a long-term favorable response to non-surgical anti-cancer treatments: results of a project study for pancreatic surgery by the Japanese Society of Hepato-Biliary-Pancreatic Surgery

Purpose

A multicenter survey was conducted to explore the role of adjuvant surgery for initially unresectable pancreatic cancer with a long-term favorable response to non-surgical cancer treatments.

Methods

Clinical data including overall survival were retrospectively compared between 58 initially unresectable pancreatic cancer patients who underwent adjuvant surgery with a favorable response to non-surgical cancer treatments over 6 months after the initial treatment and 101 patients who did not undergo adjuvant surgery because of either unchanged unresectability, a poor performance status, and/or the patients’ or surgeons’ wishes.

Results

Overall mortality and morbidity were 1.7 and 47 % in the adjuvant surgery group. The survival curve in the adjuvant surgery group was significantly better than in the control group (p < 0.0001). The propensity score analysis revealed that adjuvant surgery was a significant independent prognostic variable with an adjusted hazard ratio (95 % confidence interval) of 0.569 (0.36–0.89). Subgroup analysis according to the time from initial treatment to surgical resection showed a significant favorable difference in the overall survival in patients who underwent adjuvant surgery over 240 days after the initial treatment.

Conclusion

Adjuvant surgery for initially unresectable pancreatic cancer patients can be a safe and effective treatment. The overall survival rate from the initial treatment is extremely high, especially in patients who received non-surgical anti-cancer treatment for more than 240 days.     

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.     

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 for stage II colorectal cancer: Who and with what?

Opinion statement The role of adjuvant chemotherapy for patients with stage II colon adenocarcinoma remains controversial. The high surgical cure rate for patients with "low-riskrd stage II colon cancer, ranging from 75% to 80%, and the available clinical trials and metaanalyses provide conflicting recommendations for or against adjuvant chemotherapy for this group of patients. For fit "high-riskrd stage II patients with clinical obstruction or perforation at presentation, in which the 5-year survival rate is 60% to 70%, there is little controversy, as these patients are routinely treated with adjuvant chemotherapy. Other potential high-risk factors, including high histologic grade, microsatellite instability, and loss of 18q, have yet to be validated in prospective trials. Patients with fewer than 12 regional lymph nodes identified in the surgical specimen have a statistically unclear risk of lymph node involvement. These patients may have stage III disease and should receive adjuvant therapy. The decision to use adjuvant chemotherapy to treat low-risk stage II colon cancer patients (no obstruction or perforation) should be an informed decision weighing the magnitude of a net 2% to 5% survival benefit, a 0.5% to 1.0% risk of mortality with chemotherapy in addition to 6 months of chemotherapy-related toxicities, other coexisting patient morbidities, and the anticipated life expectancy of each patient. As adjuvant chemotherapy is therapy addressing local or metastatic microscopic disease, and the effectiveness of systemic and biologically targeted therapy for advanced macroscopic colon cancer continues to improve rapidly, it remains to be determined by clinical trials whether therapies including newer agents such as cetuximab and bevacizumab administered in the adjuvant setting may affect survival for stage II cancer patients.