There is an increasing body of evidence showing that patients with resectable pancreatic cancer might benefit from adjuvant therapy. Based on phase III trials, potential options for adjuvant treatment are chemotherapy alone or a multi-modal approach involving radiotherapy. Avail¬able data are heterogeneous and have been dis¬cussed controversially. Hitherto, a worldwide standard of care has not yet been established. Adequate patient selection might be the key ele-ment for a tailored adjuvant treatment. Clinical research currently focusses on gemcitabine alone or in combination, and some molecular biologic approaches with epidermal growth factor recep-tor monoclonal antibodies (EGFR-MoABs) and anti-angiogenic drugs. Recent advances in ra-diooncology offer better dose conformality and reduced morbidities. Currently, the co-operative Radiotherapy and Gastrointestinal Groups have launched a multicentric European Organization for Research and Treatment of Cancer (EORTC) trial investigating the impact of radiotherapy in combination with gemcitabine in R0-resected pancreatic head cancer.
9.1 Introduction
Only about 10%-20% of pancreatic cancer pa-tients are deemed to be resectable and could be ideal candidates for adjuvant or neoadjuvant treatment strategies (Evans 2005; Kelly and Ben-jamin 1995; Sener et al. 1999). Surgery is the only possibly curative treatment option. Remarkable progress has been made in terms of clear resec¬tion margins, which could be increased from 26% to 43%. From the 1970s through the 1990s, peri-operative mortality improved from 30% to 0.9%, respectively. Five-year survival rates increased from 14% in the 1970s to more than 30% in the 1990s (Yeo et al. 1995; Yeo and Cameron 1999). In the 1990s more than 65% of patients received some form of adjuvant therapy compared to less than 25% in the 1980s. This reflects a major change in the treatment paradigms from thera-peutic nihilism to intensified adjuvant therapy.
Prognostic factors after surgery are perfor-mance status, extent of tumour spread and tu-mour size, nodal status, grading and status of resection margins (Kalser et al. 1985; Kalser and Ellenberg 1985; Neoptolemos et al. 2001, 2004; Sohn et al. 2000). Additional and well-known factors are blood loss during pancreaticoduo-denectomy and time to recovery. Less common ampullary carcinoma and intrapancreatic bile duct carcinoma have a more favourable prog¬nosis than pancreatic ductal adenocarcinoma (Magee et al. 2002). For pancreatic cancer, a pro¬longed median survival of about 15-20 months can be expected after R0 surgery compared to 8 to 12 months after R1 surgery (Evans et al. 1998). Even after R0 surgery, however, relapses occur regularly. Local recurrences account for the ma¬jority (80%), recurrence in the peritoneal cavity for 25%, and liver metastasis for about 50% of all cases (Wayne et al. 2002). Metastases to other re¬gions such as lung are rare and usually occur at a late stage.
Though there is remarkable progress of pan-creatic cancer treatment, survival data are still dismal. Therefore, adjuvant therapy is of major importance.
9.2 Adjuvant Chemoradiation
The Gastrointestinal Tumor Study Group (GITSG) GI-9173 data published in 1985 has proved that post-operative chemora-diation (CRT) is highly effective (Kalser and Ellenberg 1985). This randomized trial investi¬gated surgery followed by a 40-Gy split-course radiotherapy (RT) combined with 5-fluorouracil (5-FU) versus surgery alone. The treatment arm (n = 21) was superior to surgery alone (n = 22), resulting in median survival of 20 months ver¬sus 12 months. These results were confirmed by the GITSG in a non-randomized controlled phase II study in 1987 (Gastrointestinal Tumor Study Group 1987). Both studies had great im¬pact on adjuvant treatment of pancreatic cancer in the USA. This treatment regimen has become the new standard of care, and until recently it was in widespread use in the United States. A number of additional studies confirmed these re¬sults (Foo et al. 1993; Foo and Gunderson 1998; Mehta et al. 2000; Paulino 1999; Yeo et al. 1995, 1997). The combination of 5-FU with leucovorin seemed to be only marginally effective (Abrams et al. 1999). A recent study from Johns Hopkins University compared two schemes of chemora-diation with surveillance. Chemoradiation was either intensified 50-57 Gy to the pancreas and a prophylactic dose of 23-27 Gy to the liver com-bined with 5-FU or a standard dose of 40-45 Gy to the pancreas combined with 5-FU/leucovo-rin. Patients receiving adjuvant therapy had a median survival of 19.5 months compared with only 13.5 months after resection alone. More in¬tense treatment schemes did not appear to fur¬ther improve survival (Sohn et al. 2000; Yeo et al. 1997). A European Organization for Research and Treatment of Cancer (EORTC) multi-centre trial including 207 evaluable patients combined split-course RT with 5-FU and also found a sta-tistically insignificant improved survival trend of 24.5 versus 19 months (Klinkenbijl et al. 1999). Subgroup analysis indicated a benefit for pan-creatic head cancer patients with survival of 17.1 versus 12.6 months.
Some of these studies have methodological limitations. Patient accrual was either slow or the numbers of patients were statistically insufficient.
Patient selection was non-uniform, thereby in-cluding patients with pancreatic cancer and those with periampullary cancer, who have a better prognosis. Mono-institutional studies suffered from selection bias. Up to 25% of the patients did not receive the planned radiochemotherapy because of withdrawal of consent, lack of post-operative recovery or rapid tumour progression. There was no stratification for tumour sites, nor was there a detailed analysis of resection mar-gins. From the current point of view, treatment was often suboptimal, with split-course RT and a heterogeneous dose distribution, and 5-FU given as bolus instead of as continuous infusion.
A rather modern treatment scheme was ap-plied to 52 patients by Mehta et al. (2000). RT
was intensified from 45 Gy (R0) to 54-60 Gy (R1) and in a few cases intraoperative RT was added. This was combined with a continuous infusion of 5-FU. The resulting median survival was a promising 32 months and morbidities were only moderate.
9.3 Adjuvant Chemotherapy
The first randomized trial to demonstrate a posi-tive effect of adjuvant chemotherapy without RT was published in 1993 (Bakkevold et al. 1993). Sixty-one radically resected patients were ran-domized either for post-operative adjuvant com-bination chemotherapy using 5-FU, doxorubicin and mitomycin C (AMF), or as controls (no ad-juvant chemotherapy). The median survival in the treatment group was 23 months compared to 11 months in the control group. The authors con-cluded that adjuvant chemotherapy prolongs the incidence of recurrence during the first 2 years following radical surgery; however, an increased cure rate was not observed.
The benefits of chemoradiation have been questioned since the publication of the European Study Group for Pancreatic Cancer (ESPAC) 1 trial (Neoptolemos et al. 2001, 2004). This was the most ambitious and largest adjuvant trial in pancreatic cancer with 548 patients involved. It had a 2x2 factorial design: of 541 eligible pa-tients, 289 were assigned to chemotherapy versus radiochemotherapy, 68 to chemoradiotherapy only versus no chemoradiotherapy with record of background chemotherapy and 188 to chemo-therapy only versus no chemotherapy with record of background chemotherapy. The 289 patients of the first group were assigned to observation, chemoradiotherapy, chemotherapy, or chemo-radiotherapy and chemotherapy. The treatment concepts were those of other published trials: surgery followed by 5-FU/FA bolus, surgery fol¬lowed by 40 Gy split-course RT+5-FU bolus, or surgery followed by both. In summary the 2x2 factorial design showed no survival benefit with CT or CRT to observation. When all patients were pooled, a survival benefit for adjuvant CT, not for adjuvant CRT, was observed. The Kaplan-Meier analysis showed a reduced survival rate following radiochemotherapy compared to no radiochemotherapy of 29% versus 41%, respec-tively, after 2 years and of 10% versus 20% after 5 years, which was statistically significant.
These data actually suggest that adjuvant ra-diochemotherapy might even harm patients af-ter a potentially curative resection. This trial had substantial impact on therapeutic decisions in Europe, where radiochemotherapy has virtually been abandoned and adjuvant chemotherapy has become the European standard of care.
The results of ESPAC-1, however, need to be discussed, and substantial criticisms have been raised. The trial used various randomization pro-cedures. Because of interaction between the ther-apy arms, the study might be regarded as under-powered. Background chemotherapy was allowed, which was not part of the study medication. Ad¬ditionally, about 40% of the patients did not re¬ceive the originally planned treatment. There was no standardized quality assurance for surgery nor for the radiochemotherapy procedures, and 30% of the RT patients received a non-uniform dose or even no radiation at all. Chemoradiation started on average 2 weeks later than chemotherapy. Nei¬ther RT nor chemotherapy was optimal accord¬ing to modern standards. And last but not least, from a tumour biologic point of view, there is no rationale conceivable for a shorter relapse-free survival with chemoradiation. Insufficient treat-ment quality for the chemoradiation arm might also have contributed to the enhanced treatment-related toxicity (Choti 2004; Koshy et al. 2005). In summary, the published results of the ESPAC-1 trial have to be considered premature and are in no way suited to rule out adjuvant chemoradia-tion for pancreatic cancer.
Recently, a meta-analysis summarized indi-vidual data of 875 patients treated in five ran-domized controlled trials (Stocken et al. 2005). The ESPAC-1 trial contributed 550 patients. The pooled hazard ratio reduction was 25% corre-sponding to a significant reduction of the death risk after chemotherapy. The median survival was 19 months with, and 13.5 months without, chemotherapy, respectively. In this meta-analy-sis an increased risk of death with the addition of RT to chemotherapy could not be observed. The median survival was the same (15.8 months with chemoradiation and 15.2 without). Sub¬group analysis revealed that chemoradiation was more effective compared with chemotherapy in patients with positive resection margins. Still, the authors concluded that the initial use of chemo-radiotherapy might have delayed the effective use of chemotherapy and thereby reduced survival.
The ESPAC-3 trial has meanwhile launched to confirm the beneficial role of adjuvant che-motherapy and to differentiate between the ef-ficacies of 5-FU and gemcitabine (Neoptolemos et al. 2003). A randomization between 5-FU/FA and gemcitabine is used; for ampullary cancer a third arm with observation only is installed. Af¬ter amendment, 680 patients need to be enrolled, so final results will take some time.
Gemcitabine has come into focus recently. It is a potent radiation sensitizer of pancreatic tu¬mour cells in vitro (Lawrence et al. 1996). It is active in pancreatic cancer and improves clini¬cal benefit (23.8 versus 4.8%) and survival rate (5.7 versus 4.4 months) over 5-FU, which led to the Gemzar (Eli Lilly, Indianapolis) registration (Burris and Storniolo 1997; Burris et al. 1997; Rothenberg et al. 1996). Toxicity is minimal and it can be administered on an outpatient setting.
Preliminary data of the CONKO-001 study, presented at the American Society of Clinical Oncology annual meeting (ASCO) 2005, con-firmed the efficacy of gemcitabine. In a random-ized manner, median survival with gemcitabine was 14 months, without it, 7 months (Neuhaus
et al. 2005).
9.4 Pre-operative Chemoradiotherapy
The concept of pre-operative radiochemotherapy is alluring, but its value for resectable cancer is not yet clear. Using radiochemotherapy first, a possibly systemic disease could receive a sys-temic treatment without the delay of post-opera-tive recovery. Multi-modal treatment ought to start with the least toxic treatment, thus sparing surgery in patients, who currently suffer from rapid progression or metastasis. Further possible advantages have been suggested, including the prevention of intraoperative tumour spread and improved radiosensitivity, as tumour oxygen-ation has not been hampered by surgery and the higher probability of R0 resection (Bergenfeldt and Albertsson 2006; Crane et al. 2006b; Evans
2005).
There have been very promising data from a sequence of trials performed by the MD An¬derson Cancer Centre. Only patients with a pos¬sibly resectable disease were included, surgical techniques and pathological evaluation were standardized. First, 5-FU and concomitant RT with 50.4 Gy did result in a median survival of
18 months. Toxicity, though, was severe enough to necessitate hospital admission in one-third of the patients (Evans et al. 1992). The subsequent trials did use an accelerated, so-called "rapid frac¬tionation" programme delivered over 2 weeks, with a 30-Gy total dose and a 3-Gy single frac¬tion dose. During surgery an additional intraop-erative RT of 10-15 Gy was administered. Com¬bining this scheme with 5-FU led to a median survival of 25 months (Pisters et al. 1998). Pacli-taxel was less effective, with a median survival of
19 months (Pisters et al. 2002). Best results were achieved when combining RT with gemcitabine. Median survival was 36 months, toxicities were manageable, with a hospitalization rate of 43% (Wolff et al. 2001). These trials all suffered from a positive selection bias. Recently, results of a French phase II study have been published com-bining 5-FU with cisplatin and concurrent RT to 50 Gy in a pre-operative setting for potentially resectable pancreatic cancer. Among 40 evalu-able patients, 15 did not undergo resection of the pancreatic tumour because of local or metastatic progression. Median survival for those patients, who completed treatment, was 11.7 months. The scheme was concluded to be feasible, but the use of more efficient drugs such as gemcitabine and optimized RT seemed justified (Mornex et al.
2006).
Numerous trials investigated pre-operative chemoradiotherapy (Bergenfeldt and Albertsson 2006) based on heterogeneous patient populations including patients with locally advanced disease. Pre-operative chemoradiation seems to offer a downstaging effect, shifting patients from locally advanced to potentially resectable stages (White et al. 1999, 2001). Median survival in those pa¬tients who were resected exceeded 16 months. When comparing 5-FU-based chemoradiation in a pre-operative and post-operative setting, actuarial survival rates at 2, 3 and 5 years were
39% versus 52%, 35% versus 40% and 28% ver-sus 40%, respectively, in favour of adjuvant treat¬ment. This difference did not reach statistical significance and was attributed to larger, more locally advanced tumours in the preoperative therapy group (Spitz et al. 1997). Pathological findings after pre-operative chemoradiotherapy showed fewer involved lymph nodes, more nega-tive resection margins, similar toxicity and a non-significant median survival difference of 20 versus 25 months (Pendurthi et al. 1998).
So far, randomized controlled trials proving an overall survival benefit for neoadjuvant treat¬ment approaches are missing.
9.1 Introduction
Only about 10%-20% of pancreatic cancer pa-tients are deemed to be resectable and could be ideal candidates for adjuvant or neoadjuvant treatment strategies (Evans 2005; Kelly and Ben-jamin 1995; Sener et al. 1999). Surgery is the only possibly curative treatment option. Remarkable progress has been made in terms of clear resec¬tion margins, which could be increased from 26% to 43%. From the 1970s through the 1990s, peri-operative mortality improved from 30% to 0.9%, respectively. Five-year survival rates increased from 14% in the 1970s to more than 30% in the 1990s (Yeo et al. 1995; Yeo and Cameron 1999). In the 1990s more than 65% of patients received some form of adjuvant therapy compared to less than 25% in the 1980s. This reflects a major change in the treatment paradigms from thera-peutic nihilism to intensified adjuvant therapy.
Prognostic factors after surgery are perfor-mance status, extent of tumour spread and tu-mour size, nodal status, grading and status of resection margins (Kalser et al. 1985; Kalser and Ellenberg 1985; Neoptolemos et al. 2001, 2004; Sohn et al. 2000). Additional and well-known factors are blood loss during pancreaticoduo-denectomy and time to recovery. Less common ampullary carcinoma and intrapancreatic bile duct carcinoma have a more favourable prog¬nosis than pancreatic ductal adenocarcinoma (Magee et al. 2002). For pancreatic cancer, a pro¬longed median survival of about 15-20 months can be expected after R0 surgery compared to 8 to 12 months after R1 surgery (Evans et al. 1998). Even after R0 surgery, however, relapses occur regularly. Local recurrences account for the ma¬jority (80%), recurrence in the peritoneal cavity for 25%, and liver metastasis for about 50% of all cases (Wayne et al. 2002). Metastases to other re¬gions such as lung are rare and usually occur at a late stage.
Though there is remarkable progress of pan-creatic cancer treatment, survival data are still dismal. Therefore, adjuvant therapy is of major importance.
9.2 Adjuvant Chemoradiation
The Gastrointestinal Tumor Study Group (GITSG) GI-9173 data published in 1985 has proved that post-operative chemora-diation (CRT) is highly effective (Kalser and Ellenberg 1985). This randomized trial investi¬gated surgery followed by a 40-Gy split-course radiotherapy (RT) combined with 5-fluorouracil (5-FU) versus surgery alone. The treatment arm (n = 21) was superior to surgery alone (n = 22), resulting in median survival of 20 months ver¬sus 12 months. These results were confirmed by the GITSG in a non-randomized controlled phase II study in 1987 (Gastrointestinal Tumor Study Group 1987). Both studies had great im¬pact on adjuvant treatment of pancreatic cancer in the USA. This treatment regimen has become the new standard of care, and until recently it was in widespread use in the United States. A number of additional studies confirmed these re¬sults (Foo et al. 1993; Foo and Gunderson 1998; Mehta et al. 2000; Paulino 1999; Yeo et al. 1995, 1997). The combination of 5-FU with leucovorin seemed to be only marginally effective (Abrams et al. 1999). A recent study from Johns Hopkins University compared two schemes of chemora-diation with surveillance. Chemoradiation was either intensified 50-57 Gy to the pancreas and a prophylactic dose of 23-27 Gy to the liver com-bined with 5-FU or a standard dose of 40-45 Gy to the pancreas combined with 5-FU/leucovo-rin. Patients receiving adjuvant therapy had a median survival of 19.5 months compared with only 13.5 months after resection alone. More in¬tense treatment schemes did not appear to fur¬ther improve survival (Sohn et al. 2000; Yeo et al. 1997). A European Organization for Research and Treatment of Cancer (EORTC) multi-centre trial including 207 evaluable patients combined split-course RT with 5-FU and also found a sta-tistically insignificant improved survival trend of 24.5 versus 19 months (Klinkenbijl et al. 1999). Subgroup analysis indicated a benefit for pan-creatic head cancer patients with survival of 17.1 versus 12.6 months.
Some of these studies have methodological limitations. Patient accrual was either slow or the numbers of patients were statistically insufficient.
Patient selection was non-uniform, thereby in-cluding patients with pancreatic cancer and those with periampullary cancer, who have a better prognosis. Mono-institutional studies suffered from selection bias. Up to 25% of the patients did not receive the planned radiochemotherapy because of withdrawal of consent, lack of post-operative recovery or rapid tumour progression. There was no stratification for tumour sites, nor was there a detailed analysis of resection mar-gins. From the current point of view, treatment was often suboptimal, with split-course RT and a heterogeneous dose distribution, and 5-FU given as bolus instead of as continuous infusion.
A rather modern treatment scheme was ap-plied to 52 patients by Mehta et al. (2000). RT
was intensified from 45 Gy (R0) to 54-60 Gy (R1) and in a few cases intraoperative RT was added. This was combined with a continuous infusion of 5-FU. The resulting median survival was a promising 32 months and morbidities were only moderate.
9.3 Adjuvant Chemotherapy
The first randomized trial to demonstrate a posi-tive effect of adjuvant chemotherapy without RT was published in 1993 (Bakkevold et al. 1993). Sixty-one radically resected patients were ran-domized either for post-operative adjuvant com-bination chemotherapy using 5-FU, doxorubicin and mitomycin C (AMF), or as controls (no ad-juvant chemotherapy). The median survival in the treatment group was 23 months compared to 11 months in the control group. The authors con-cluded that adjuvant chemotherapy prolongs the incidence of recurrence during the first 2 years following radical surgery; however, an increased cure rate was not observed.
The benefits of chemoradiation have been questioned since the publication of the European Study Group for Pancreatic Cancer (ESPAC) 1 trial (Neoptolemos et al. 2001, 2004). This was the most ambitious and largest adjuvant trial in pancreatic cancer with 548 patients involved. It had a 2x2 factorial design: of 541 eligible pa-tients, 289 were assigned to chemotherapy versus radiochemotherapy, 68 to chemoradiotherapy only versus no chemoradiotherapy with record of background chemotherapy and 188 to chemo-therapy only versus no chemotherapy with record of background chemotherapy. The 289 patients of the first group were assigned to observation, chemoradiotherapy, chemotherapy, or chemo-radiotherapy and chemotherapy. The treatment concepts were those of other published trials: surgery followed by 5-FU/FA bolus, surgery fol¬lowed by 40 Gy split-course RT+5-FU bolus, or surgery followed by both. In summary the 2x2 factorial design showed no survival benefit with CT or CRT to observation. When all patients were pooled, a survival benefit for adjuvant CT, not for adjuvant CRT, was observed. The Kaplan-Meier analysis showed a reduced survival rate following radiochemotherapy compared to no radiochemotherapy of 29% versus 41%, respec-tively, after 2 years and of 10% versus 20% after 5 years, which was statistically significant.
These data actually suggest that adjuvant ra-diochemotherapy might even harm patients af-ter a potentially curative resection. This trial had substantial impact on therapeutic decisions in Europe, where radiochemotherapy has virtually been abandoned and adjuvant chemotherapy has become the European standard of care.
The results of ESPAC-1, however, need to be discussed, and substantial criticisms have been raised. The trial used various randomization pro-cedures. Because of interaction between the ther-apy arms, the study might be regarded as under-powered. Background chemotherapy was allowed, which was not part of the study medication. Ad¬ditionally, about 40% of the patients did not re¬ceive the originally planned treatment. There was no standardized quality assurance for surgery nor for the radiochemotherapy procedures, and 30% of the RT patients received a non-uniform dose or even no radiation at all. Chemoradiation started on average 2 weeks later than chemotherapy. Nei¬ther RT nor chemotherapy was optimal accord¬ing to modern standards. And last but not least, from a tumour biologic point of view, there is no rationale conceivable for a shorter relapse-free survival with chemoradiation. Insufficient treat-ment quality for the chemoradiation arm might also have contributed to the enhanced treatment-related toxicity (Choti 2004; Koshy et al. 2005). In summary, the published results of the ESPAC-1 trial have to be considered premature and are in no way suited to rule out adjuvant chemoradia-tion for pancreatic cancer.
Recently, a meta-analysis summarized indi-vidual data of 875 patients treated in five ran-domized controlled trials (Stocken et al. 2005). The ESPAC-1 trial contributed 550 patients. The pooled hazard ratio reduction was 25% corre-sponding to a significant reduction of the death risk after chemotherapy. The median survival was 19 months with, and 13.5 months without, chemotherapy, respectively. In this meta-analy-sis an increased risk of death with the addition of RT to chemotherapy could not be observed. The median survival was the same (15.8 months with chemoradiation and 15.2 without). Sub¬group analysis revealed that chemoradiation was more effective compared with chemotherapy in patients with positive resection margins. Still, the authors concluded that the initial use of chemo-radiotherapy might have delayed the effective use of chemotherapy and thereby reduced survival.
The ESPAC-3 trial has meanwhile launched to confirm the beneficial role of adjuvant che-motherapy and to differentiate between the ef-ficacies of 5-FU and gemcitabine (Neoptolemos et al. 2003). A randomization between 5-FU/FA and gemcitabine is used; for ampullary cancer a third arm with observation only is installed. Af¬ter amendment, 680 patients need to be enrolled, so final results will take some time.
Gemcitabine has come into focus recently. It is a potent radiation sensitizer of pancreatic tu¬mour cells in vitro (Lawrence et al. 1996). It is active in pancreatic cancer and improves clini¬cal benefit (23.8 versus 4.8%) and survival rate (5.7 versus 4.4 months) over 5-FU, which led to the Gemzar (Eli Lilly, Indianapolis) registration (Burris and Storniolo 1997; Burris et al. 1997; Rothenberg et al. 1996). Toxicity is minimal and it can be administered on an outpatient setting.
Preliminary data of the CONKO-001 study, presented at the American Society of Clinical Oncology annual meeting (ASCO) 2005, con-firmed the efficacy of gemcitabine. In a random-ized manner, median survival with gemcitabine was 14 months, without it, 7 months (Neuhaus
et al. 2005).
9.4 Pre-operative Chemoradiotherapy
The concept of pre-operative radiochemotherapy is alluring, but its value for resectable cancer is not yet clear. Using radiochemotherapy first, a possibly systemic disease could receive a sys-temic treatment without the delay of post-opera-tive recovery. Multi-modal treatment ought to start with the least toxic treatment, thus sparing surgery in patients, who currently suffer from rapid progression or metastasis. Further possible advantages have been suggested, including the prevention of intraoperative tumour spread and improved radiosensitivity, as tumour oxygen-ation has not been hampered by surgery and the higher probability of R0 resection (Bergenfeldt and Albertsson 2006; Crane et al. 2006b; Evans
2005).
There have been very promising data from a sequence of trials performed by the MD An¬derson Cancer Centre. Only patients with a pos¬sibly resectable disease were included, surgical techniques and pathological evaluation were standardized. First, 5-FU and concomitant RT with 50.4 Gy did result in a median survival of
18 months. Toxicity, though, was severe enough to necessitate hospital admission in one-third of the patients (Evans et al. 1992). The subsequent trials did use an accelerated, so-called "rapid frac¬tionation" programme delivered over 2 weeks, with a 30-Gy total dose and a 3-Gy single frac¬tion dose. During surgery an additional intraop-erative RT of 10-15 Gy was administered. Com¬bining this scheme with 5-FU led to a median survival of 25 months (Pisters et al. 1998). Pacli-taxel was less effective, with a median survival of
19 months (Pisters et al. 2002). Best results were achieved when combining RT with gemcitabine. Median survival was 36 months, toxicities were manageable, with a hospitalization rate of 43% (Wolff et al. 2001). These trials all suffered from a positive selection bias. Recently, results of a French phase II study have been published com-bining 5-FU with cisplatin and concurrent RT to 50 Gy in a pre-operative setting for potentially resectable pancreatic cancer. Among 40 evalu-able patients, 15 did not undergo resection of the pancreatic tumour because of local or metastatic progression. Median survival for those patients, who completed treatment, was 11.7 months. The scheme was concluded to be feasible, but the use of more efficient drugs such as gemcitabine and optimized RT seemed justified (Mornex et al.
2006).
Numerous trials investigated pre-operative chemoradiotherapy (Bergenfeldt and Albertsson 2006) based on heterogeneous patient populations including patients with locally advanced disease. Pre-operative chemoradiation seems to offer a downstaging effect, shifting patients from locally advanced to potentially resectable stages (White et al. 1999, 2001). Median survival in those pa¬tients who were resected exceeded 16 months. When comparing 5-FU-based chemoradiation in a pre-operative and post-operative setting, actuarial survival rates at 2, 3 and 5 years were
39% versus 52%, 35% versus 40% and 28% ver-sus 40%, respectively, in favour of adjuvant treat¬ment. This difference did not reach statistical significance and was attributed to larger, more locally advanced tumours in the preoperative therapy group (Spitz et al. 1997). Pathological findings after pre-operative chemoradiotherapy showed fewer involved lymph nodes, more nega-tive resection margins, similar toxicity and a non-significant median survival difference of 20 versus 25 months (Pendurthi et al. 1998).
So far, randomized controlled trials proving an overall survival benefit for neoadjuvant treat¬ment approaches are missing.
9.5 Intraoperative Radiotherapy
A possible advantage of intraoperative radiother-apy (IORT) is the ability to deliver high doses of radiation to sites at high risk of local recurrence while organs at risk can be shielded. IORT has been used in the adjuvant and neoadjuvant situa-tion, alone or in combination with chemotherapy (for an overview see Bergenfeldt and Alberts-son 2006). IORT has been proved effective over surgery alone in pancreatic cancer with respect to local recurrence, which was reduced by half (Reni et al. 2001). This trial also found a survival benefit for selected stage I-II patients. Operative morbidity and mortality were not increased. In a subgroup analysis, a combination of IORT with
RT and chemotherapy improved survival signifi-cantly (Di Carlo et al. 1997).
IORT can act as a valuable partner in a combined modality treatment setting that in-cludes chemoradiation. However, accelerated re-population during the interval between IORT and external RT has to be taken into account
(Wilkowski et al. 2005).
9.6 Radiotherapy Treatment Planning
Many of the patients treated in the aforemen-tioned trials had their RT based on 2D-treat-ment planning, which led to large dose burden on the surrounding healthy normal tissue and consequential acute and late radiation damage. The introduction of a split-course technique and a total dose not exceeding 40 Gy was mainly driven by the acute toxicities observed. 2D dose distributions in the target volume often were less than optimal, leading to cold and hot spots. In the meantime, technical progress enables 3D-treatment planning with optimized protec¬tion of normal tissue, thus offering the opportu¬nity to treat without a split to higher total doses of 54 to 60 Gy. Still, the critical dose-limiting struc¬tures neighbouring the target volume is the small bowel, which has a tolerance dose of 45-50 Gy, depending on the single fraction dose, and the kidney, which has a tolerance dose of about 23 Gy to the whole organ. With regard to a potentially enhanced toxicity by combining with chemo¬therapy, no more than 30% of the kidneys should reach a dose level of 20 Gy. In contrast to these structures, the liver, as an organ with great regen¬eration capacities, tolerates much higher doses, up to 50 Gy in up to 1/3 of the liver volume. A rather conservative approach with regard to pos¬sible toxic damage of the liver is 12.5 Gy to 75%, 25 Gy to 50% and 37.5 Gy to 25% of liver volume (Emami et al. 1991; Wilkowski et al. 2005).
Pancreatic cancer carries a high risk, exceeding 80%, for dissemination to loco-regional lymph nodes. The lymphatic drainage from the pancreas consists of peripancreatic nodes and along the upper mesenteric artery, the a. gastroduodena-lis, a. hepatica communis, a. lienalis and coeliac trunk. Involvement of nodes near the portal vein and para-aortal and para-caval nodes happens frequently (Kayahara et al. 1995, 1996, 1999).
Treatment planning should be based on a pre-operative 3D data set with intravenous con-trast medium and contrast enhancement of the small bowel. The patients should be immobi¬lized with raised arms. A clinical target volume (CTV) should be defined, which includes the primary tumour region, involved lymph nodes and any subclinical region at risk, with an addi¬tional margin of 0.5 cm. To reduce toxicity, part of the pancreatic tail, which is not involved, may be excluded. Loco-regional lymph nodes should be included, at least between the upper mes-enteric artery and coeliac trunk. The planning target volume is equal to the CTV plus a safety margin to account for patient and organ move¬ment of 1-3 cm. An extension of the target vol¬ume to include the liver for prophylactic reasons did not result in an increased survival (Yeo et al. 1997). Shrinking of the planning target volume (PTV) after 45 Gy is recommended. Dose should be prescribed according to the guidelines of the International Commission on Radiation Units, report 50 (ICRU-50), dose heterogeneity should not exceed ±5% (see EORTC 40013 (Wilkowski et al. 2005)). When sophisticated techniques such as intensity modulated RT (IMRT) or stereotac-
tically guided RT (SRT) are involved, ICRU-50
criteria might not be fulfilled; still, dose homoge-neity should be aimed for.
9.7 Advances in Radiotherapy
Stereotactically guided RT is a means to further reduce the irradiated volume by shrinking the PTV (Fig. 9.1). The technique is still emerging since set-up uncertainties caused by breathing and organ motion are of concern. A stereotacti-cally guided boost of 25 Gy following an IMRT treatment of 45 Gy combined with 5-FU enabled dose escalation up to 70 Gy with a tolerable acute toxicity. Of 19 patients, 16 completed treatment, local control was excellent and overall survival was not influenced in these patients suffering from advanced disease (Koong et al. 2005). On the other hand, a trial from Denmark reports unacceptable toxicity, poor outcome and a questionable palliative effect of a fractionated stereo-tactically guided treatment of 15 x 3 Gy, again in locally advanced cancer (Hoyer et al. 2005).
Inverse treatment planning and IMRT allows specific dose distributions in order to either es-calate the total dose given to the tumour with¬out a further protection of surrounding organs at risk, such as the small bowel, or to better pro¬tect the organs at risk at the same total dose level (Landry et al. 2002). In general, the high dose volume is reduced, whereas the low dose volume is increased. A dosimetric analysis using differ¬ent planning techniques revealed an advantage for using an integrated boost with doses of up to 64.8 Gy, which could have been given safely (Brown et al. 2006). A first phase I study combin¬ing gemcitabine 350 mg/m2 with IMRT 33 Gy in 11 fractions had to be closed due to exces-sive toxicity. Even after reducing gemcitabine to 250 mg/m2, patients suffered from dose-limit¬ing gastrointestinal toxicity and myelosuppres-sion (Crane et al. 2001a). A trial using IMRT as a boost following conventionally fractionated RT of 30 Gy with another 21-30 Gy, and a 3-Gy single fraction dose combined with 5-FU had a tolerable acute toxicity and some palliative ef¬fect in locally advanced cancer (Bai et al. 2003). Without dose escalation, IMRT has been found to be effective and tolerable in combination with capecitabine (Ben-Josef et al. 2004). Currently, the PARC study is investigating IMRT in combi¬nation with cetuximab and gemcitabine (Krem-
pien et al. 2005).
9.8 Advances in Chemotherapy
in the Combined Therapy Setting
Gemcitabine has been widely investigated in the adjuvant and neoadjuvant setting to replace 5-FU-based regimens. In the United States, the randomized Radiation Therapy Oncology Group
(RTOG) 9704 trial tested the sequence 5-FU/
FA-5-FU/RT-5-FU/FA versus gemcitabine (Gem)->5-FU/RT->Gem. The data were pre¬sented at the ASCO 2006 meeting (Regine and Abrams 1998; Saif 2006). From 1998 to 2002, 538 patients entered the trial (stage T1-T4, N0-N1); 381 had pancreatic head carcinoma, and 442 pa-tients were eligible and analysable. Haematologi-cal toxicity was elevated in the gemcitabine arm, but manageable. For patients with pancreatic head carcinoma, median survival improved to 36.9 months compared to 20.6 months without gemcitabine. There was no improvement in sur¬vival for patients with tumours of the pancreatic body or tail. It was concluded that gemcitabine might be considered as a new standard adjuvant therapy, at least for pancreatic head carcinoma.
Data on gemcitabine combined with RT is emerging, but dose finding is still an issue. About 170 patients were treated in approx. 15 phase II trials. The gemcitabine dose was limited to 300 mg/m2 weekly. The RT dose was 50.4 Gy for a limited target volume of less than 1,500 cm3 (Van Laethem et al. 2003). There was a promising activity combined with moderate and manage-able haematological and gastrointestinal toxic-ity. Median survival was 15 months, disease-free survival was 6 months; grade 3-4 haematologi-cal and non-haematological toxicity was 25%-36%. The Eastern Cooperative Oncology Group (ECOG) 4201 study evaluating gemcitabine plus RT versus gemcitabine alone was closed recently.
There were dose-finding phase I/II-studies of gemcitabine with concurrent radiation for advanced pancreatic cancer with a significant grade 3-4 toxicity of anorexia and dehydration when doses exceeded 350 mg/m2 (McGinn and Zalupski 2003; Wolff et al. 2001). Toxicity was related to radiation dose. The infusion rate is re-lated to the systemic efficacy (Crane et al. 2001b). Since gemcitabine as a prodrug must be phos-phorylated to its active metabolites there is tissue saturation. Administration with a fixed dose rate is feasible (Tempero et al. 2003); data on combi¬nation with RT is not available.
In general, the therapeutic index seemed to be rather narrow (Crane et al. 2002). A dose of 40 mg/m2 twice weekly concurrent to RT fol¬lowing an induction therapy of irinotecan/gem-citabine was feasible too (Blackstock et al. 1999, 2002) but of only moderate activity (Mishra et al. 2005). Combination of gemcitabine with cisplatin and concomitant with RT was feasible (Wilkowski et al. 2003). Other partners are un¬der evaluation. Of special interest are non-cyto-toxic partners such as trastuzumab or epidermal growth factor receptor (EGFR) antibodies. Inhib-itors of the ras protein, metalloproteinases, COX inhibitors, and vascular-endothelial-growth-re-ceptor (VEGF) inhibitors are being investigated pre-clinically or in early clinical studies (Wayne
et al. 2002).
Three major randomized studies are evaluat-ing the role of bevacizumab and cetuximab with gemcitabine and irinotecan with docetaxel (Saif 2006). The ECOG 2204 trial, activated in Febru-ary 2006 is a phase II randomized study of ad-juvant therapy comprising bevacizumab versus cetuximab in combination with gemcitabine, capecitabine, and RT in patients with completely resected carcinoma of the pancreas (see the ECOG homepage). Activity is of interest for a possible combined regimen with RT as the toxic-ity profiles are favourable. A phase I trial com¬bining capecitabine and bevacizumab with RT in locally advanced pancreatic cancer had shown promising results, although there was ulceration and bleeding in the RT field (Crane et al. 2006).
In Europe, the EORTC is recruiting patients in the protocol 22012/40013 (Fig. 9.2; see the EORTC homepage). This is a multi-institutional trial of the gastrointestinal tract cancer group and the RT group, with the Federation Francophone de la Cancerologie Digestive (FFCD) cooperating. There is a phase II feasibility part with a planned 80 patients, followed by a phase III part with a planned 540 patients. Endpoint will be an improvement in disease-free survival by 10%. A strict patient selection will take place, as only patients with pancreatic head carcinoma after R0 pancreaticoduodenectomy will be included. Tak-ing into account the ESPAC-1 data, an initially planned surveillance arm was dropped. After a first amendment, the standard arm now offers gemcitabine 1,000 mg/m2 for four cycles. The ex-perimental arm offers gemcitabine 1,000 mg/m2 for two cycles followed by chemoradiotherapy with gemcitabine 300 mg/m2 once weekly with concurrent 50.4 Gy RT. Eligibility criteria include R0 pancreaticoduodenectomy for pancreatic head cancer with a complete recovery within 8 weeks. So far the accrual has reached 80 patients.
In 2006, during the German Cancer Congress, the first data from the Heidelberg Phase III Trial CapRI (post-operative cisplatin, interferon alpha-2b, and 5-FU combined with external radiation treatment versus 5-FU alone for patients with re¬sected pancreatic adenocarcinoma) was reported. In all, 52 patients were enrolled. The treatment scheme was less toxic than expected; patients could be treated on an outpatient basis. The main common toxicity criteria (CTC) grade III toxici-ties are leukopenia, hand-foot-syndrome, stoma¬titis, fatigue syndrome and hypo-calcemia. The treatment scheme was deemed to be feasible, but an experienced interdisciplinary group is needed (Knaebel et al. 2005).
A phase II study of the CAO/ARO/AIO evaluating a pre-operative radiochemotherapy for potentially resectable patients with cancer of the pancreatic head has started. Gemcitabine 300 mg/m2 weekly is combined with cisplatin 30 mg/m2 weekly and concurrent RT to 50.4¬55.8 Gy followed by surgery versus surgery alone (see the AIO homepage, www.aio-portal.de).
9.9 Summary and Conclusion
As surgery has improved, the outcome has re-mained predictable by factors such as tumour size, resection margin status, N-stage, grading and blood loss at surgery.
In the United States, the adjuvant standard of care is a combined chemoradiation with 5-FU based on the GITSG study results from 1985 with a very limited number of patients. Results have been confirmed by several authors and the randomized EORTC 40891 study, which was, however, underpowered.
In Europe, most patients receive adjuvant che-motherapy only, with 5-FU or with gemcitabine based on the ESPAC-1 data, which have been criticized for considerable inherent limitations concerning statistical power and quality assur-ance. Gemcitabine is currently evaluated in com-bined modality treatment with other partners, varying doses and administration forms, and es-pecially with concurrent RT. Still, in the United States and Europe there is a strong belief in adju-vant therapy based on a survival advantage in the major randomized studies.
Many trials investigating adjuvant therapy in pancreatic cancer are outdated or statistically questionable. This is why the recent phase III studies, ESPAC-3 and EORTC 22012/40013, de-serve support.
When planning adjuvant therapy, some pre-cautions have to be taken into consideration.
- Patients should be selected carefully.
- Chemoradiotherapy may be more effective for patients with cancer of the pancreatic head than pancreatic body and tail and for patients with positive resection margins.
- Treatment planning should be state-of-the-art to minimize treatment-related toxicity.
- RT planning should be three-dimensional, and should aim for 50-Gy doses without split.
- IMRT or IORT should be evaluated.
The concurrent chemotherapy can be 5-FU, given as continuous infusion with 200-250 mg/m2 per day, 7 days per week during the entire treatment cycle. Possible partners are interferon-a and cis-platin, but toxicity has to be monitored carefully. Finally, gemcitabine to a dose of 300 mg/m2 once weekly concurrent to RT is a safe and possibly more effective treatment, which is being evalu¬ated in a randomized multi-centre trial of the
EORTC.
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