What Are the Treatment Options for Early and Locally Advanced Pancreatic Cancer?
Pancreatic cancer is the 4th leading cause of cancer death in the United States. In 2006, there were approximately 33,730 new cases with 32,300 deaths. Worldwide, incidence is approximately 217,000 new cases per year with 213,000 deaths. The lethality of pancreatic cancer stems largely from the fact that less than 20% of patients present with potentially resectable disease. While management of metastatic disease focuses mainly on palliation of symptoms and prolonging survival, the optimal therapy for early and locally advanced pancreatic cancer remains controversial and is currently the subject of intensive ongoing research.
Surgical management is the only curative option for patients with pancreatic cancer. However, cure rates for patients managed by surgery alone are extremely low, and as mentioned above, less than 20% of patients present with potentially resectable disease. Thus, researchers have focused on adjuvant chemotherapy and chemoradiotherapy in an effort to increase long-term survival. Traditionally, chemotherapeutic options have been largely centered around 5-fluorouracil (5-FU) containing regimens, although more recently, gemcitabine has been increasingly used. The majority of randomized control trials have been underpowered and provide conflicting results. Thus, significant controversy still exists regarding the optimal chemotherapeutic agent, appropriate dosing, the addition of concurrent radiotherapy, and the usefulness of neoadjuvant therapy.
Early pancreatic cancer is defined as stage I and II lesions that are amenable to surgical resection. The anatomic location of the tumor within the pancreas dictates the type of surgery performed. Lesions that are confined to the pancreatic head or uncinate process require pancreaticoduodenectomy (Whipple’s procedure). Pylorus-preserving pancreaticoduodenectomy is also an option and seems to have comparable perioperative morbidity and mortality, without major differences in postoperative delayed gastric emptying or nutritional status. Surgeon preference and experience should dictate which operation to perform. Lesions that are located in the tail are removed with a distal pancreatectomy. Body lesions are approached according to their exact anatomic location. If they are closer to the pancreatic head, an extended pancreaticoduodenectomy may be performed. If closer to the tail, a distal subtotal pancreatectomy is performed.
Since greater than 50% of patients develop locoregional recurrence even after successful surgical resection with negative margins, adjuvant treatment with chemotherapy 6 radiotherapy is currently recommended. The Gastrointestinal Tumor Study Group (GITSG) initially demonstrated a modest improvement in overall survival (20 months vs 11 months) when 5-FU chemotherapy was given with concurrent external beam radiotherapy (EBRT).1 Unfortunately, the results of the European Organization for Research and Treatment of Cancer (EORTC) trial were unable to confirm a significant benefit for adjuvant chemoradiotherapy over resection alone.2 In an attempt to answer the question regarding adjuvant therapy once and for all, the European Study Group for Pancreatic Cancer 1 trial (ESPAC-1) used a 2 X 2 factorial design assessing the benefit of adjuvant 5-FU chemotherapy alone, bolus 5-FU + radiotherapy, or chemoradiotherapy followed by additional chemotherapy, as compared to observation alone.3 There was a significant survival benefit for adjuvant chemotherapy alone, but there was no significant benefit from radiotherapy. In fact, there was a trend toward worse survival for the group that received chemoradiotherapy. Unfortunately, the results of this trial were difficult to interpret due to high rate of protocol non-adherence and the lack of a separate analysis for each of the 4 groups in the 2 X 2 design.
More recently, the United States Intergroup has reported the results from a randomized phase III trial (RTOG-9704) that studied either postoperative infusional 5-FU followed by 5-FU + radiotherapy vs gemcitabine followed by 5-FU + radiotherapy.4 There was significantly better overall survival in the gemcitabine arm for those patients with pancreatic head tumors (20.6 months vs 16.9 months). There was no significant difference for patients with pancreatic body/tail tumors. In addition, the CONKO-001 trial revealed a significant increase in disease-free survival for patients receiving gemcitabine adjuvant therapy vs observation alone (13.4 months vs 6.9 months).5 Although survival was not a primary endpoint, there was a clear trend in favor of gemcitabine (22.1 months vs 20.2 months). However, this difference was not statistically significant (p=0.06).
There are theoretical benefits of preoperative neoadjuvant therapy, such as possible downstaging of the primary tumor and improvement of resection rate, as well as biologically staging patients so as to spare those who go on to develop metastatic disease the morbidity of surgery. Such therapy can be delivered safely without interfering with perioperative morbidity and mortality. However, there are no randomized control trials comparing neoadjuvant with adjuvant therapy.
Given the results of the above trials, current recommendations for the treatment of early pancreatic cancer differ between North America and Europe. The European approach emphasizes the results of EORTC and ESPAC-1 and does not include chemoradiation. The North American approach emphasizes the high risk of local failure and potential benefit of chemoradiotherapy. Thus, standard guidelines include radical pancreatic resection + postoperative 5-FU chemotherapy 6 radiotherapy (Table 33-1). There is an emerging consensus that adjuvant chemotherapy with gemcitabine improves survival and represents an appropriate choice for current management and may be considered as a building block for future clinical trials.
Locally advanced pancreatic cancer refers to stage III disease with tumor extension to adjacent organs (lymph nodes, liver, duodenum, superior mesenteric artery, celiac trunk) such that complete surgical excision with negative pathologic margins is not possible. Depending on symptomatology and tumor location, these patients may benefit from palliation via endoscopic, surgical, or radiologic procedures. Biliary obstruction can be treated with stent placement by ERCP or percutaneous approaches. Gastric outlet obstruction can be managed by gastrojejunostomy or endoscopic placement of expandable metal stents. Chronic pain refractory to medication can be managed with celiac plexus neurolysis via percutaneous, radiologically guided or EUS-guided injection of steroids, analgesic agents, or ethanol.
Therapeutic options for locally advanced pancreatic cancer in the United States are mainly centered around chemoradiotherapy, although chemotherapy alone is becoming an increasingly utilized approach. Chemoradiotherapy has been mostly defined by 2 GITSG trials and an ECOG trial. The GITSG-9173 trial studied EBRT alone vs EBRT + bolus 5-FU.6 The chemoradiation therapy arm was found to have significantly better 1-year survival (38% vs 11%). However, the E-8282 trial found no survival benefit when comparing EBRT to EBRT + infusional 5-FU + mitomycin.7 Due to experience in other gastrointestinal malignancies, most notably rectal cancer, infusional 5-FU has largely supplanted bolus 5-FU as the most common approach. In this light, there is mounting evidence that oral capecitabine can safely replace infusional 5-FU as a radiation sensitizer. However, randomized control trials comparing these approaches are not available.
There have been few trials comparing chemoradiotherapy vs chemotherapy alone, and these have provided conflicting results. One notable study, a recent phase III study comparing 5-FU + cisplatin + EBRT initially followed by gemcitabine vs gemcitabine alone, found that gemcitabine monotherapy was less toxic and more effective (overall survival 13 months vs 8.6 months) than combination therapy.8
Studies looking at a stepwise approach of chemotherapy followed by chemoradiotherapy have supported this approach, but are comprised of only retrospective analysis. This offers the advantage of sparing those patients with rapidly progressive disease and subsequent metastasis from undergoing unnecessary radiotherapy.
Given the results of the above studies, optimal treatment for locally advanced pancreatic cancer remains controversial. Most would suggest external beam radiotherapy with concurrent low dose infusional 5-FU (see Table 33-1). Alternatively, gemcitabine monotherapy may be used, but it should be recognized that there are no randomized control trials evaluating conventional EBRT + 5-FU vs gemcitabine monotherapy. Future clinical trials will need to be performed to further elucidate the optimal choice of chemoradiotherapy vs chemotherapy alone, as well as to explore novel therapeutic agents, such as paclitaxel, erlotinib, cetuximab, bevacizumab, and others.
1. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and chemotherapy following curative resection of pancreatic cancer. Cancer. 1987;59:2006-2010.
2. Klinkenbijl JH, Jeekel J, Sahmoid T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230:776-782.
3. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350:1200-1210.
4. Regine WF, Winter KA, Abrams RA, et al. Fluorouracil vs. gemcitabine chemotherapy before and after fluorouracil-based chemoradiation following resection of pancreatic adenocarcinoma: a randomized control trial. JAMA. 2008;299:1019-1026.
5. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs. observation in patients undergoing curative-intent resection of pancreatic cancer: a randomized control trial. JAMA. 2007;297:267-277.
6. Gastrointestinal Tumor Study Group. A multi-institutional comparative trial of radiation therapy alone and in combination with 5-fluorouracil for locally unresectable pancreatic carcinoma. Ann Surg. 1979;189:205-208.
7. Cohen SJ, Dobelbower R, Lipsitz S, et al. A randomized phase III study of radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with locally advanced adenocarcinoma of the pancreas: Eastern Cooperative Oncology Group study E8282. Int J Radiat Oncol Biol Phys. 2005;62:1345-1350.
8. Chauffert B, Mornex F, Bonnetain F, et al. Phase III trial comparing intenstive induction chemoradiotherapy (60 Gy, infusional 5-FU, and intermittent cisplatin) followed by maintenance gemcitabine with gemcitabine alone for locally advanced unresectable pancreatic cancer. Definitive results of the 2000-01 FFCD/SFRO study. Ann Oncol. 2008;19:1592-1599.