Review For reprint orders, please contact [email protected]
Pancreatic cancer: advances in medical therapy Expert Rev. Clin. Pharmacol. 2(2), 173–180 (2009)
Andrew Weickhardt and Michael Michael† Author for correspondence Peter MacCallum Cancer Centre, Melbourne, Australia [email protected] †
Progress in the treatment of pancreatic cancer has been notably slow and modest in contrast to other cancers of the GI tract over the last 5 years. Pancreatic cancer still continues to be a devastating illness that is marked by the appearance of early metastatic disease, despite curative surgery and the relative chemoresistance of the disease. However, small incremental benefits have been seen, and point to areas of research and development over the subsequent years. Developments in adjuvant chemotherapy and the use of gemcitabine in combination with other cytotoxic agents or with biological agents have changed clinical practice. Given its poor outlook and the paucity of active therapies, even modest gains can lead to regulatory approval and, therefore, pancreatic cancer represents a common target for pharmaceutical companies. Newer agents are in development with the promise of further refinement in treatment selection based on molecular tumor characteristics. Keywords : EGF receptor • gemcitabine • pancreatic cancer • VEGF receptor
Adjuvant chemotherapy
A significant development in pancreatic cancer is the maturation of data showing support for adjuvant chemotherapy in resected localized disease. Surgical resection offers the only chance of cure in patients with localized disease [1] ; however, only 20% of cases are potentially resectable. Even then, prognosis is poor in patients with resected disease, with 5-year survival rates of between 10 and 25% [2] . The weight of evidence to show the role of postoperative chemotherapy in patients with resected pancreatic cancer emerged from two randomized Phase III trials. The first was the European Study Group for Pancreatic Cancer (ESPAC)-1 trial [3] , which was constructed to answer, with a 2 × 2 factorial design, the relative benefit of chemotherapy and also chemoradiation in patients with resected pancreatic cancer, utilizing a 5-fluorouracil (5FU) backbone. The trial demonstrated a survival advantage of 6 months (19.7 vs 14 months) for the postoperative chemotherapy arm. However, there were major flaws with this trial. These include the fact that physicians and patients chose which treatment they would be allocated, the delivery of ‘background’ chemoradiation or chemotherapy, regardless of the arm patients were randomized to, and the lack of quality control for surgery and radiotherapy [3] . Despite these shortcomings, there were some important useable messages. www.expert-reviews.com
10.1586/17512433.2.2.173
Chemoradiation seemed to have no advantages, with possibly a detrimental effect, with a median survival of 15.5 versus 16.1 months. The 5-year survival rates were also much higher in the group receiving chemotherapy compared with chemoradiotherapy (21 vs 8%). A smaller trial randomizing patients to postoperative adjuvant combination chemotherapy, 5FU, doxorubicin, mitomycin C (AMF; n = 30) once every 3 weeks for six cycles, or into an observation group (n = 31), also showed a significant increase in median survival (23 vs 11 months); however, 5-year survival rates were similar (8 vs 4%) [4] . The role of adjuvant 5FU in pancreatic cancer is further supported by a recently published meta-analysis that looked at the results from ESPAC-1 and similar trials [5] . The pooled hazard ratio (HR) of 0.70 (95% confidence interval [CI]: 0.55–0.88; p = 0.003) and the median survival of 23.2 months (95% CI: 20.1–26.5) with 5FU/folinic acid (FA) vs 16.8 months (95% CI: 14.3–19.2) with resection alone further supports the use of adjuvant 5FU/FA in pancreatic cancer [5] . The second recently published important trial of adjuvant therapy is Charite Onkologie (CONKO)-001 [6] , which aimed to compare postoperative gemcitabine with observation alone in patients with fully resected pancreatic cancer. It involved 368 patients, and randomized patients on the treatment arm to six cycles of
© 2009 Expert Reviews Ltd
ISSN 1751-2433
173
Review
Weickhardt & Michael
gemcitabine 1000 mg/m 2 on days 1, 8 and 15 of a 4-weekly cycle. The updated data show a 5-year survival rate of 21% in the gemcitabine arm versus 9% in the observation arm [7] . The median survival was 22.8 versus 20.2 months, with a disease-free interval of 13.4 versus 6.9 months in the observation arm, both of which were statistically significant results (p
Pancreatic cancer: advances in medical therapy Expert Rev. Clin. Pharmacol. 2(2), 173–180 (2009)
Andrew Weickhardt and Michael Michael† Author for correspondence Peter MacCallum Cancer Centre, Melbourne, Australia [email protected] †
Progress in the treatment of pancreatic cancer has been notably slow and modest in contrast to other cancers of the GI tract over the last 5 years. Pancreatic cancer still continues to be a devastating illness that is marked by the appearance of early metastatic disease, despite curative surgery and the relative chemoresistance of the disease. However, small incremental benefits have been seen, and point to areas of research and development over the subsequent years. Developments in adjuvant chemotherapy and the use of gemcitabine in combination with other cytotoxic agents or with biological agents have changed clinical practice. Given its poor outlook and the paucity of active therapies, even modest gains can lead to regulatory approval and, therefore, pancreatic cancer represents a common target for pharmaceutical companies. Newer agents are in development with the promise of further refinement in treatment selection based on molecular tumor characteristics. Keywords : EGF receptor • gemcitabine • pancreatic cancer • VEGF receptor
Adjuvant chemotherapy
A significant development in pancreatic cancer is the maturation of data showing support for adjuvant chemotherapy in resected localized disease. Surgical resection offers the only chance of cure in patients with localized disease [1] ; however, only 20% of cases are potentially resectable. Even then, prognosis is poor in patients with resected disease, with 5-year survival rates of between 10 and 25% [2] . The weight of evidence to show the role of postoperative chemotherapy in patients with resected pancreatic cancer emerged from two randomized Phase III trials. The first was the European Study Group for Pancreatic Cancer (ESPAC)-1 trial [3] , which was constructed to answer, with a 2 × 2 factorial design, the relative benefit of chemotherapy and also chemoradiation in patients with resected pancreatic cancer, utilizing a 5-fluorouracil (5FU) backbone. The trial demonstrated a survival advantage of 6 months (19.7 vs 14 months) for the postoperative chemotherapy arm. However, there were major flaws with this trial. These include the fact that physicians and patients chose which treatment they would be allocated, the delivery of ‘background’ chemoradiation or chemotherapy, regardless of the arm patients were randomized to, and the lack of quality control for surgery and radiotherapy [3] . Despite these shortcomings, there were some important useable messages. www.expert-reviews.com
10.1586/17512433.2.2.173
Chemoradiation seemed to have no advantages, with possibly a detrimental effect, with a median survival of 15.5 versus 16.1 months. The 5-year survival rates were also much higher in the group receiving chemotherapy compared with chemoradiotherapy (21 vs 8%). A smaller trial randomizing patients to postoperative adjuvant combination chemotherapy, 5FU, doxorubicin, mitomycin C (AMF; n = 30) once every 3 weeks for six cycles, or into an observation group (n = 31), also showed a significant increase in median survival (23 vs 11 months); however, 5-year survival rates were similar (8 vs 4%) [4] . The role of adjuvant 5FU in pancreatic cancer is further supported by a recently published meta-analysis that looked at the results from ESPAC-1 and similar trials [5] . The pooled hazard ratio (HR) of 0.70 (95% confidence interval [CI]: 0.55–0.88; p = 0.003) and the median survival of 23.2 months (95% CI: 20.1–26.5) with 5FU/folinic acid (FA) vs 16.8 months (95% CI: 14.3–19.2) with resection alone further supports the use of adjuvant 5FU/FA in pancreatic cancer [5] . The second recently published important trial of adjuvant therapy is Charite Onkologie (CONKO)-001 [6] , which aimed to compare postoperative gemcitabine with observation alone in patients with fully resected pancreatic cancer. It involved 368 patients, and randomized patients on the treatment arm to six cycles of
© 2009 Expert Reviews Ltd
ISSN 1751-2433
173
Review
Weickhardt & Michael
gemcitabine 1000 mg/m 2 on days 1, 8 and 15 of a 4-weekly cycle. The updated data show a 5-year survival rate of 21% in the gemcitabine arm versus 9% in the observation arm [7] . The median survival was 22.8 versus 20.2 months, with a disease-free interval of 13.4 versus 6.9 months in the observation arm, both of which were statistically significant results (p
