Adjuvant therapy in pancreatic cancer

 Paula Ghaneh, John Slavin, Robert Sutton, Mark Hartley, John P Neoptolemos

Department of Surgery, University of Liverpool, 5th Floor UCD Building, Daulby Street, Liverpool, L69 3GA, UKª¤
Correspondence to  Professor JP Neoptolemos, Department of Surgery, University of Liverpool,  5th Floor UCD Building,
Daulby Street, Liverpool,  L69 3GA, UK. j.p.neoptolemos@liverpool.ac.uk
Tel: 0044-151-706-4175, Fax: 0044-151-706-5798ª¤
Received 2001-05-15 Accepted 2001-06-15


Abstract 

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 postª²operative 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.

Subject headings  pancreatic neoplasms/drug therapy; pancreatic neoplasms/radiotherapy; human; review

Ghaneh P, Slavin J, Sutton R, Hartley M, Neoptolemos JP. Adjuvant therapy in pancreatic cancer.
World J Gastroenterol, 2001;7(4):482-489



INTRODUCTIONª¤

Pancreatic cancer is the 5th most common site of deaths due to cancer among all cancer sites in the Western world. Low cure rates ensure that the mortality is nearly as high as the incidence. It is responsible for 7000 deaths per year in the UK^£Û1£Ý, ª©40000 per year in Europe and 28000 in the USA^£Û2£Ý. The peak mortality ages are estimated to be between 65 and 72 years in Europe and 55 and 75 years in the USA^£Û2£Ý. The incidence of this deadly disease has been rising during the last century. In the past 20 years however, there have been vast improvements in the surgical management of patients with pancreatic cancer. The surgical procedures have been improved and become more standardized between centres and countries. The level of pre- and post-operative support for these patients has been optimized, particularly in established centres with a high throughput^£Û3£Ý. These measures have ensured that the outlook for patients with resectable disease has certainly improved, particularly in the short term. Extending patient survival still remains a problem. The overall five-year survival for all patents with pancreatic cancer is only 0.4%^£Û4£Ý. Patients who are suitable for resection have five-year survival rates of between 10% and 24%^£Û5-8£Ý and are virtually never cured. Therefore, even for the 10% to 15% of patients who undergo surgery, there appears to be no guarantee of cure or indeed long- term survival. These outcomes would suggest a role for the use of additional or adjuvant therapy to attempt to improve patient survival and quality of life.ª¤ª¤

RADICAL SURGERYª¤

Japanese groups amongst others have been enthusiastic in pursuing radical resection as means of increasing disease free margins and thus hopefully improving patient survival. Radical surgery includes extensive lymph node dissection and retroperitoneal connective tissue clearance as well as pancreatic resection. The Japanese groups have suggested that these approaches are superior to conventional Kausch-Whipple resection but several studies have not shown significant survival advantages when compared with conventional
resection^£Û9-13£Ý. Kayahara et alª« found that radical resection in patients with Stage ¢ñ and ¢ò disease (Japanese classification) and clear margins (R0) resulted in a reduction of local recurrence but did not translate into improved survival because of hepatic
metastases^£Û14£Ý. Interestingly highly detailed serial section analysis of presumed R0 specimens has revealed microscopic margin disease (R1) in up to 38% of specimens^£Û14£Ý.ª¥ 
           Difficulties are encountered when comparing survival figures of Western and Japanese studies because of the different staging systems used (UICC vs JPS respectively). This is because of the phenomenon of ¡®staging system migration¡¯ that may give apparently better survival for each stage in one system compared to the other even though there is no overall difference in survival. Satake et al^{ª«£Û15£Ý} compared the Japanese and UICC staging systems in a large cohort of patients. Stage for stage the Japanese system revealed a better survival from Stage ¢ñ to ¢ô compared with UICC system. The overall five-year survival however, was the same (11%) because the systems had been analysed in identical patients.ª¥
           The majority of radical resection studies have been non-randomized and performed in single institutions. The radical lymph node dissection allows more accurate staging of disease and these tumours will tend to be upstaged because of this. Thus it is necessary to examine overall group survival within the context of randomized studies by an intention to treat analysis. There has been one multicentre prospective randomized trial comparing traditional partial pancreatoduodenectomy with and without a more extensive lymph node dissection^£Û16£Ý. Eighty-one patients were randomized to receive a standard (n=40) or extended (n=41) lymphadenectomy and retroperitoneal soft tissue clearance.
          The standard lymphadenectomy included removal of lymph nodes situated at the anterior and posterior pancreatoduodenal, pyloric, main bile duct, superior and inferior pancreatic head and pancreatic body stations. The extended lymphadenectomy also included the removal of lymph nodes from the hepatic hilum, along the aorta from the diaphragmatic hiatus to the inferior mesenteric artery, laterally to both renal hila and clearance of the coeliac trunk and superior mesenteric artery. There was no significant difference of overall survival between the two groups. Patients who had lymph node positive disease demonstrated better survival following an extended resection compared to those who did not have an extended lymphadenectomy but must be regarded as a statistically invalid manoeuvre as this was a postª²hoc subgroup analysis. In light of these findings the ultimate benefit of extended lymphadenectomy surgery still needs to be proven with further critical evaluation.ª¥
          There appears to be no additional survival benefit associated with total pancreatectomy compared to Kausch-Whipple pancreatoduodenectomy and at the present time the pylorus preserving pancreatoduodenectomy has been shown to produce similar results to the more traditional Kausch Whipple procedure^{£Û17,18£Ý}. The latter approach is now the procedure of choice in most centres.ª¥
          The lack of survival benefit associated with radical resection may be due in part to the pattern of disease recurrence in resected pancreatic cancer. Most tumour recurrences are local, peritoneal and hepatic^{£Û19-24£Ý}. The early appearance of hepatic metastases following resection almost certainly indicates the presence of hepatic micrometastases at the time of surgery. Microscopic peritoneal disease also tends to occur early in contrast to the relatively later presentation of local recurrence. Pancreatic cancer cells tend to spread within a range of peripancreatic tissues. Lymphatic infiltration and perineural invasion may be found in 90%-100% of resected
specimens^£Û25£Ý. Reasons for recurrence following an apparently curative resection include residual retroperitoneal disease, perineural invasion, hepatic micrometastases and lymph node involvement. The pattern of relapse after surgery reflects the natural course of the disease without resection. The most commonly affected organs include abdominal lymph nodes (72%-83%), liver (64%-80%), peritoneum (40%-53%) and lung (27%-50%)^£Û14£Ý. An R0 resection in patients with no lymph node metastases cannot be achieved in more than about half of the patients undergoing resection. Kayahara et al^£Û14£Ý at post mortem examined 15 patients who had undergone radical resection. The local recurrence rate in this group of patients was 80%. The local recurrences were associated with perineural invasion, lymphatic invasion and soft tissue infiltration. High rates of local recurrence have been confirmed in numerous studies of patients who have undergone pancreatoduodenectomy and the majority occur within 1 to 2 years of surgery^{£Û23,24£Ý}.
       Identification of extrapancreatic disease at the preª²operative stage has improved due to accurate imaging techniques^£Û26£Ýand laparoscopy^£Û27£Ý. Peritoneal cytology has been shown to be positive in 58% of patients who may have unresectable tumours or have a limited postoperative survival^£Û27£Ý. The best predictors of outcome following surgery also reflect the causes of disease relapse. These include tumour stage (which also includes the lymph node status), grade of primary tumour and resection margin status^{£Û28-32£Ý}. Not surprisingly patients with stage ¢ñ or ¢ò disease and negative resection margins tend to demonstrate the best survival.ª¥
          The poor overall survival of patients with pancreatic cancer, even following optimal surgical intervention, and the pattern of disease progression and recurrence are clear indications for the use of additional treatment modalities.ª¤ª¤

CHEMOTHERAPYª¤

Advanced pancreatic cancerª¤
There have been many studies of chemotherapy in patients with advanced pancreatic cancer. Single agents and combination regimens have been used. At the present time there is no accepted standard chemotherapeutic agent for the treatment of pancreatic cancer. 5-fluorouracil (5-FU) remains the most effective and most frequently used single chemotherapy agent. 5-FU works partly by interference with enzymes such as thymidylate synthase and partly by incorporation of 5-FU metabolites into DNA and RNA. The response rates of ¡«15% with a median survival of 3-5 months^£Û33£Ý. The addition of the modulator folinic acid has produced marginal survival benefit over
5-FU alone but this has not been a significant increase^£Û33£Ý. The addition of other modulators such as phosphonacetyl-L-aspartate (PALA), and interferon has also not produced significant improvements in survival^{£Û34,35£Ý}. Comparisons of 5-FU alone and 5-FU with a combination of other agents have not shown any advantage for the combination groups in randomized trials^£Û33£Ý.ª¥
          A new agent, gemcitabine has been compared to 5-FU in a randomized multi-centre phase ¢ó clinical trial^£Û36£Ý. Gemcitabine is a deoxycytidine analogue that is phosphorylated to an active form and competes with dCTP for incorporation into DNA. The study, in which over 70% of patients had stage ¢ô disease, randomized 63 patients to receive gemcitabine and 63 patients to receive 5-FU. Median survival in the gemcitabine group was 5.7 months compared to 4.4 months in the 5-FU group but no patient survived beyond 19 months. The clinical benefit response was also significantly higher in the gemcitabine group^£Û36£Ý. Despite the fact that this is the only trial with a straight comparison between the two agents gemcitabine has been recommended as the drug of choice in the USA. Gemcitabine has also been combined with 5-FU in several phase ¢ò studies. It is generally well tolerated but can have unpredictable side effects such as neutropaenia, abnormal liver function tests and nausea and vomiting. In patients who have had previous radiotherapy to the mediastinum there have been unpredictable reactions^£Û37£Ý.ª¥
          There is good evidence from several randomized controlled trials comparing chemotherapy with a no treatment group that chemotherapy is of benefit in patients with advanced pancreatic cancer. Mallinson et al^£Û38£Ý demonstrated a median survival of 11 months for patients treated with 5-FU, cyclophosphamide, methotrexate, vincristine and mitomycin C compared to 2.2 months for the untreated control group. This regimen did not produce a significantly greater survival when compared to 5-FU alone in a much larger randomized control trial^£Û39£Ý. Another rather poorly controlled study compared 5-FU and carmustine to untreated controls^£Û40£Ý. There was no significant survival benefit associated with this regimen but the majority of patients in this study received only a single treatment and did not finish the course. A further trial of the combination of 5-FU, doxorubicin and mitomycin C (FAM) resulted in median survival of 33 weeks compared with median survival of 15 weeks in untreated control patients^£Û41£Ý. A recent study compared the use of 5-FU + folinic acid (+/- etoposide) with best supportive care and showed that the median survival in the treated group was 6 months compared to 2.5 months in the control group^£Û42£Ý. Moreover there was better overall quality of life score for the treated patients.ª¤ª¤


Adjuvant chemotherapyª¤
There have been only a few studies of adjuvant chemotherapy in pancreatic cancer and (up until the ESPAC-1 trial) there was only one randomized controlled trial comparing surgery and chemotherapy with surgery alone (Table 1)^{£Û43-46£Ý}. Splinter et al^{ª«£Û43£Ý}reported no evidence of improvement or survival using a FAM regimen in 16 patients who had undergone pancreatoduodenectomy with a three year survival of 24% compared to a three year survival of 28% in 36 patients who had undergone surgery only. Patients from different time periods were included in the two groups and there were only nine patients with pancreatic ductal adenocarcinoma in the adjuvant group and 18 in the surgery only group.
           Baumel et al^£Û46£Ý reported adjuvant chemotherapy in 43 selected patients with a median survival of 12 months but there was no difference in median survival from those patients who underwent surgery only (12 months). Bakkevold et al^£Û45£Ý randomized 61 patients who had undergone pancreatoduodenectomy for pancreatic cancer or ampullary cancer to receive either six courses of FAM or no chemotherapy. There was a significant difference in the median survival rates between the two groups: 23 months. Unfortunately this did not translate into a significantly improved long-term survival however: the 5-year survival rates were 4% for the treatment arm versus 8% for the surgery only arm. There was also considerable toxicity encountered with the FAM regimen. Only 24 out of 30 patients randomized to treatment actually started therapy. Sixteen patients needed hospitalization after the first chemotherapy course and a total of 13 patients managed to complete all six cycles of FAM.ª¥
           The European Study Group for Pancreatic Cancer (ESPAC) has commenced the ESPAC-3 trial with the objective of definitively defining the role of adjuvant chemotherapy following curative resection for pancreatic ductal adenocarcinoma. Two adjuvant regimens are being studied against a no chemotherapy control: ¢Ù 5-FU + folinic acid for 24 weeks versus ¢Ú gemcitabine for 24 weeks versus ¢Û observation. All patients will have undergone potentially curative resection for pancreatic ductal adenocarcinoma. A total of 990 patients (330 in each arm) will be recruited over the next few years and survival analysis will be completed after two years of follow-up. At the present time recruitment is underway from centres across Europe with further centres in Canada, Australia and New Zealand due to join.

RADIOTHERAPY (CHEMORADIOTHERAPY)ª¤

Advanced pancreatic cancerª¤
External beam radiotherapy (EBRT) although used in the treatment of advanced pancreatic cancer, has never been compared with an untreated control arm in any randomized controlled trial. The most commonly used and probably the best radiosensitizer used with EBRT for advanced pancreatic cancer is 5-FU. Many retrospective studies of EBRT, usually in relatively small groups of selected patients report median survival times of 10-15 months with good palliation of symptoms^{£Û47,48£Ý}.ª¥
          The improved local control of disease achieved with EBRT has not translated into significantly longer survival times, so there have been various refinements in an attempt to enhance the effectiveness of radiotherapy. Wide field irradiation has been used to address the problem of hepatic micrometastases. A Radiation Therapy Oncology Group (RTOG) study of 79 patients who received pancreatic and hepatic irradiation resulted in a median survival of 8.4 months but at the expense of considerable toxicity^£Û49£Ý. Intraoperative radiation therapy (IORT) aims to deliver higher doses of radiation with greater precision and thus reducing the exposure of neighbouring organs. Experimentally, its effectiveness may be as high as five times the equivalent dose given by EBRT. In advanced pancreatic cancer the survival times achieved using IORT have not been encouraging (median survival ¡«6 months) and it has been mainly used to boost
EBRT^{£Û50,51£Ý}. A study comparing EBRT + IORT + 5-FU with EBRT +5-FU demonstrated no significant survival difference (12 and 13 months respectively)^{£Û50,51£Ý}.
          Complications encountered during IORT include, duodenal and gastric ulceration, vascular sclerosis and pancreatic abscess^£Û52£Ý. IORT offers good local control and pain relief but cannot be recommended as a standard treatment as it has not been possible to demonstrate any advantages over conventional therapy.

Adjuvant radiotherapy (chemoradiotherapy)ª¤
Adjuvant EBRT and IORT have been used alone and in combination in the adjuvant setting (Table 2)^{£Û21,32,53-60£Ý}. The majority of studies indicate that EBRT alone or in combination with IORT has a significant survival advantage over the use of IORT alone. In a randomized trial IORT was observed to reduce the local recurrence rate by 50% following surgery, but this did not translate into a significant survival advantage (3-year survival with IORT=7% vs no IORT 3%)^£Û21£Ý. In selected patients IORT and resection produced 3 and 5-year survival rates of 53% and 29%^{£Û61,62£Ý}. The use of IORT however requires specialised facilities and can be associated with severe complications.ª¥
          EBRT (with concomitant chemotherapy) following resection is generally well tolerated but the degree of survival advantage, if any, is uncertain. To address this issue a multicentre Phase ¢ó trial organized by the European Organisation for Research and Treatment of Cancer (EORTC) compared chemoradiotherapy in patients following potentially curative surgery for pancreatic cancer with surgery alone^£Û58£Ý. Between 1987 and 1995, 218 patients were randomized to receive either chemoradiotherapy or no chemoradiotherapy following curative surgery for pancreatic or ampullary cancer. Ninety-three out of 110 patients randomized to treatment received a total of 40 Gy with concomitant continuous infusion of 5-FU. There were a total of 54 patients in the observation group and 60 patients in the treatment group with pancreatic ductal adenocarcinoma. There was no significant difference in median survival (with treatment 17ª±1 months vs 12.6 months with observation) and in five year survival £Ûwith treatment 20 (95% CI, 5-35)% ª«vsª« 10 (0-20)% with observation£Ý. Similarly there was no significant difference in survival between the treatment and observation groups in patients with ampullary cancer. This study showed that there was no survival advantage for adjuvant chemoradiotherapy for pancreatic and ampullary cancer but has been criticized because it was almost certainly underpowered.ª¤

REGIONAL THERAPYª¤

Advanced pancreatic cancerª¤
Regional therapy has been developed with the objective of delivering high doses of cytotoxic drug to the tumour. The systemic side effects should be reduced with this approach. The coeliac and hepatic arteries and portal vein have all been used to deliver chemotherapeutic drugs to the tumour bed. Good control of hepatic metastases has been reported, with disease progression mainly due to local progression or peritoneal deposits. The combination of 5-FU, folinic acid and cisplatin produced median survival times of 9-14 months in selected patients^{£Û63,64£Ý}.  It has also been reported that some apparently irresectable tumours have become resectable following regional therapy^£Û64£Ý.ª¤ª¤

Adjuvant regional therapy
There have been several studies which have demonstrated improved survival in patients receiving regional chemotherapy following pancreatic resection largely in comparison with historical controls (Table 3)^{£Û65-68£Ý}. Link ª«et al^£Û69£Ý found a median survival of 21 months in 18 patients who had undergone pancreatoduodenectomy for pancreatic ductal adenocarcinoma and then coeliac artery infusion of 5-FU, folinic acid, mitoxantrone and cisplatin compared to 9.3 months for historical controls. Disease progression occurred principally locally or in the peritoneum and was rarely detected in the liver. The rate of hepatic recurrence was greatly reduced using a combination of hepatic artery and portal vein infusion in patients with resected pancreatic, which in one study cancer produced a 54% three-year survival compared to 34% in historical controls^£Û65£Ý. Ozaki et al^£Û66£Ý found a 5-year survival rate of 32% patients treated with extended resection, IORT and hepatic artery and portal vein. The encouraging results of these small studies have prompted the ESPAC-2 trial, which is a multicentre, prospective randomized controlled Phase ¢ó trial. This study will compare adjuvant intra-arterial chemotherapy (cisplatin, 5-FU, folinic acid and mitoxantrone) and radiotherapy (Arm A) with surgery alone (Arm B) in patients who have undergone potentially curative resection for pancreatic ductal adenocarcinoma or ampullary carcinoma. The trial will recruit 110 patients into each arm and will be completed by 2007 aiming to provide a definitive answer to the role of adjuvant regional therapy for
pancreatic cancer.

Table 1 Survival following surgery and adjuvant chemotherapy for pancreatic cancerª¤  

5-FU = 5-fluorouracil; DOX = doxorubicin; MMC = mitomycin C; * randomised cont rolled trial, PDAC = pancreatic ductal adenocarcinoma.

Table 2 Survival following surgery and radiotherapy for pancreatic cancerª¤