The epidermal growth factor receptor (EGFR)-mediated pathway is one of the most promising targets for the development of new strategies in anticancer treatments. The so-called "small molecule" tyrosine kinase inhibitor erlotinib has gained marketing authorization in the United States for advanced adenocarcinoma of the lung and for pancreatic cancer, whereas the antibody cetuximab is registered for metastatic colorectal cancer and cancers of the head and neck. Ongoing studies are evaluating the impact of EGFR-targeting therapy in the treatment of locally advanced and metastatic pancreatic cancer.
15.1 Introduction
Epidermal growth factor receptor (EGFR) is known to be of high importance in the development of tumors and their survival in the organism. It belongs to the family of protein tyrosine kinases that have a big influence on the cellular regulation of growth, differentiation, and apoptosis (Ullrich and Schlessinger 1990). Located on the cellular surface, the molecule mediates signal transduction pathways by responding to extracellular signals. Via signal transduction cascades it interacts with different molecules regulating cell proliferation, survival, differentiation and migration (Prenzel et al. 2001; Sonenshein 1997; Alessi and Cohen 1998). Finally, the signal reaches the nucleus, regulating gene expression and transcription (Bromberg and Darnell 2000). Furthermore, EGFR interacts with other members of its receptor family, such as e.g. HER2neu/ErB2 (Gschwind et al. 2001; Earp et al. 1995).
In normal tissue, EGFR is largely controlled by a diversity of regulating mechanisms. In can¬cer tissue, however, these control mechanisms fail, resulting in overexpression and activation (Salomon et al. 1995; Xu et al. 1984). As in other epithelial tumor types, in pancreatic cancer over-expression of EGFR is correlated with bad clini¬cal outcomes due to increased tumoral aggres¬siveness (Yamanaka et al. 1993).
EGFR plays an important role in the develop-ment of pancreatic cancer. In over 90% of cases EGFR is overexpressed (Lemoine et al. 1992), stimulating pancreatic tumor cell growth (Funa-
tomi et al. 1997).
Another important EGFR activity concerns angiogenesis. EGF induces vascular endothelial growth factor and so, in addition to its direct tumor growth induction, it enhances tumor growth by supporting vascularization (Goldman
et al. 1993).
Taking into account all these activities in¬duced by EGFR—regulation of cell growth, tu-morigenesis, and angiogenesis—it is obvious that blocking EGFR activity represents an attractive anticancer treatment approach.
Two ways of EGFR blockade have been devel-oped. One class is represented by small molecule tyrosine kinase (TK) inhibitors, which block adenosine triphosphate binding and so inhibit TK activity. Many of these TK inhibitors have been synthesized, some have been developed clinically, such as gefitinib, lapatinib, and erlo-tinib. For pancreatic cancer, erlotinib is the most developed compound.
The other strategy is inhibiting ligand binding to EGFR by monoclonal antibodies and thereby blocking the following signal transduction cas-cade, including, e.g., cetuximab or matuzumab. As for pancreatic cancer, the most important compound is cetuximab.
15.2 Preclinical Studies
The above-mentioned findings were investigated on a cellular level in several preclinical studies to evaluate EGFR-targeted therapy for human pancreatic cancer. Ng et al. (2002) showed a sig-nificant increase in apoptosis in SCID (severely combined immunodeficient) mice bearing a pan-creatic cancer xenograft. Animals were treated with a combination of gemcitabine, wortmannin (phosphatidylinositol 3'-kinase inhibitor), and erlotinib given intravenously.
In another experiment erlotinib alone showed a significant decrease of proliferation of human pancreatic cancer cells (HPAC) in vitro. Ortho-topically human pancreatic cancer (HPAC)-implanted nude mice showed reduced tumor implantation, size, weight, and jaundice when treated with erlotinib (Durkin et al. 2006).
Additional effects could be shown in experi-ments performed with cetuximab alone or in a combination of cetuximab with gemcitabine. In L3.6pl tumors implanted in the pancreas of nude mice, growth inhibition and tumor regression up to complete tumor disappearance was docu-mented for either cetuximab alone or in com-bination with gemcitabine. No liver metastases were seen in the combination group whereas 50% of the control group (no therapy) showed hepatic spread of the disease. Interestingly, ther¬apy using cetuximab decreased the production of vascular endothelial growth factor and inter-leukin-8 significantly. Consequently, cetuximab reduced microvessel density and increased the percentage of apoptotic endothelial cancer cells. These effects were potentiated when combined with gemcitabine.
Preclinical investigations demonstrated a strong rationale for EGFR-targeting strategies against cancer of the pancreas and were therefore translated into a variety of clinical protocols in combination with chemotherapy or radiotherapy (or both).
15.3 Clinical Trials in Pancreatic Cancer
Standard of care in pancreatic cancer is chemo-therapeutic treatment with gemcitabine. How¬ever, response rates and survival data are poor (Burris et al. 1997) and there is a strong clinical need for improved systemic therapy. Few data are available on compounds interfering with EGFR in pancreatic cancer. These clinical studies will be discussed here.
15.3.1 Clinical Trials with TKIs
15.3.1.1 Erlotinib (Tarceva) in First-Line Treatment of Pancreatic Cancer
Moore et al. (2007) compared gemcitabine plus erlotinib (Tarceva, Roche Pharmaceuticals, Ba¬sel) versus gemcitabine plus placebo in a phase III trial. From 176 sites in 17 countries, 569 patients were randomized to receive either gemcitabine 1,000 mg/m2 weekly on days 1 to 43 (i.e., for 6 weeks), followed by 1 week's rest and then, on days 1, 8, and 15 of a 4-week cycle with erlotinib, given at a dose of 100 or 150 mg/day orally or plus placebo. The primary endpoint of the trial was overall survival; secondary endpoints in-cluded progression-free survival (PFS), response rate, response duration, toxicity, and quality of life. Response was evaluated every 8 weeks using Response Evaluation Criteria In Solid Tumors
(RECIST) criteria.
An interim safety analysis was performed once 50 patients had shown no major increase in toxicity after receiving gemcitabine plus erlotinib at 100 mg/day. Thus, accrual at 150 mg/day was opened. However, recruitment in the 100-mg/ day group was so fast that by the time of the in¬terim analysis for the 150-mg/day group the trial was almost completed with patients on 100 mg/ day. It was therefore decided to include the ap-propriate number of patients for 80% statistical power for the 100-mg/day group.
Survival analysis included 486 and showed a significantly longer overall survival for the gemcitabine plus erlotinib group than for gem-citabine alone with an estimated hazard ratio of 0.82 (95% CI 0.69-0.99, p = 0.038). Median sur¬vival times were 6.24 vs 5.91 months, 1-year sur¬vival rates were 23% (95% CI 18%-28%) and 17%
(95% CI 12%-21%), respectively. Progression-free survival was also longer in the gemcitabine-erlotinib arm (median 3.75 vs 3.55 months, HR 0.77, p = 0.004). Response rates slightly favored gemcitabine-erlotinib (ORR 8.6% vs 8%) with a duration of response of 163 days in both arms.
The treatment was generally well tolerated and comparable in both treatment arms. Known EGFR-induced side effects (Shepherd et al. 2005) included rash, diarrhea, and ILD-like symptoms were more common in the gemcitabine-erlotinib arm, but usually mild to moderate. Hematotoxic-ity did not differ between treatment arms (Grade 3/4 neutropenia 24% vs 27%, thrombocytopenia 10% vs 11%). The toxicity profile of both com-pounds did not differ to that known as single agents.
Quality of life was comparable between both treatment arms.
As seen before with EGFR inhibitors (Xiong and Abbruzzese 2002), the presence of rash in the gemcitabine-erlotinib arm was correlated with a greater likelihood of treatment response.
This significant improvement in overall sur-vival of 22% compared to gemcitabine plus pla-cebo led to marketing authorization in the USA for erlotinib in combination with gemcitabine in
2006.
At the ASCO 2007 Gastrointestinal Cancer Symposium, a phase I of a triple therapy com-bining erlotinib, the monoclonal VEGF receptor antibody bevacizumab, and gemcitabine was re-ported. In 12 patients the combination seemed to be well tolerated, and the maximum tolerated dose (MTD) has not yet been reached. Two pa-tients showed partial response, 4 had stable dis-ease (Gomez-Martin et al. 2007).
15.3.1.2 Erlotinib (Tarceva) in the Treatment of Relapsed Pancreatic Cancer
As patients who fail standard first-line treatment with gemcitabine have no standard treatment options, the impact of new compounds is being examined in this population.
At the ASCO 2007 Gastrointestinal Cancer Symposium, a trial of single-agent erlotinib for patients with relapsed pancreatic cancer has been reported. In 13 patients having received two prior lines of chemotherapy (1-5), erlotinib showed clinical activity in 5 patients, resulting in stabili-zation or improvement for up to 12 months. No grade IV toxicity was described; 4 patients had grade 2 rash, 2 had grade 3 diarrhea (Epelbaum
et al. 2007).
Another trial examined the impact of capecitabine plus erlotinib after failure of a gemcitabine-based chemotherapy in pancreatic cancer. Receiving capecitabine, 2,000 mg/m2, plus erlotinib, 150 mg per day, were 28 patients. The toxicity profile met the expectations with grade 3/4 rash and diarrhea (14% each), hand-foot syndrome (11%), and stomatitis (7%). Par¬tial response was reported in 11% and stable dis¬ease in 57% of patients. The median survival was 6.7 months (Blaszkowsky et al. 2005).
15.3.1.3 TK-Inhibitors in Combination with Radiation Therapy in Pancreatic Cancer
The combination of the TK inhibitor gefitinib, capecitabine, and radiotherapy led to an in-creased toxicity in 10 patients with pancreatic cancer without responses in a phase I dose-finding study (Czito et al. 2006). When given simultaneously to radiation therapy, 825 mg/m2 capecitabine plus 250 mg/day gefitinib induced dose-limiting toxicity in all 3 patients on this dose level (grade 3 nausea, diarrhea), resulting finally in patient withdrawal. On dose level 1 (capecitabine 650 mg/nr* + gefitinib 250 mg/day) DLTs appeared in 3/7 patients. As for efficacy, no responses have been reported; stable disease was reported for 6 out of 7 patients on dose level 1, and 1 out of 3 patients on dose level 2. No patient was converted to resectable status.
15.3.2 Clinical Trials with Anti-EGFR Antibodies
15.3.2.1 Cetuximab (Erbitux) in the First-Line Treatment of Pancreatic Cancer
Cetuximab (Erbitux, Merck, Darmstadt, Ger-many) has also been combined with standard gemcitabine chemotherapy as a first-line treat-ment of pancreatic cancer. A phase II trial has been performed in 41 patients, receiving cetux-imab (initial dose 400 mg/m2, then 250 mg/m2 weekly) followed by gemcitabine 1,000 mg/m2 weekly for 7 weeks plus 1 week's rest. Subsequent cycles were 4 weeks long with gemcitabine given on days 1, 8 and 15 and a rest on day 22. Patients were treated until progression or intolerable tox-icity.
Patients had a median Karnofski score of 80%; 85.4% had metastatic disease.
Out of 41 patients, 5 (12.2%) showed partial response, and a further 26 (63.4%) had stable dis-ease, resulting in a disease control rate of 75.6%.
As discussed above, the effect of EGFR block-ade combines the reduction of tumor growth with antiangiogenesis, both of which in the short run do not result in tumor shrinkage but appear clinically as disease stabilization. Furthermore, the accurate assessment of pancreatic tumor imaging is difficult due to its anatomic location. Therefore, time to progression, which includes objective response plus stable disease, and overall survival may be more appropriate parameters for tumor response assessment in pancreatic cancer.
Median time to best response was 1.7 months, median duration of response was 3.8 months, duration of disease control was 5.4 months, and median time to progression 3.8 months. Median survival duration was 7.1 months; the 1-year overall survival rate was 31.7% and the 1-year PFS rate 12% (Xiong et al. 2004).
These data clearly exceed the results of gem-citabine monotherapy, which showed a 1-year survival rate of 18% and a 1-year PFS of 9%. Also, median TTP and overall survival (3.8 and 7.1 months, respectively) favor the combina-tion of cetuximab and gemcitabine (Burris et al.
1997).
Response data, PFS, and overall survival of the combination cetuximab plus gemcitabine are also comparable to those of other EGF-targeted therapies combined with gemcitabine, as men-tioned above.
Acne-like rash (85.4%), asthenia (85.4%),
nausea (61%), weight loss (58.5%), diarrhea (53.7%), abdominal pain (53.7%), and vomiting (51.2%) were the most common adverse events. As for grades 3 and 4, neutropenia (39%), asthe-nia (22%), abdominal pain (22%), and throm-bocytopenia (17.1%) were the most commonly reported severe toxicities.
One trial explored the efficacy and safety of cetuximab (250 mg/m2 per week) combined with gemcitabine (1,000 mg/m2 q2w) and oxalipla-tin (100 mg/nr* q2w) in 43 patients as first-line treatment of metastatic pancreatic cancer (GE-MOXCET). Toxicity was mainly hematological with grades 3/4 of leucopenia 10%, anemia 15%, and thrombocytopenia 12%. Nonhematological toxicity involved nausea 17%, infection 16%, di¬arrhea 7%, and allergy 6%. Of the patients, 71% had skin rash, 5% grade 3. The overall response rate (34 evaluable patients) was 38% with 1 com¬plete and 12 partial responses. In all, 9 patients
(26%) had stable disease. GEMOXCET has been
shown to be a feasible regimen with moderate toxicity and promising efficacy data (Kullmann
et al. 2007).
15.3.2.2 Cetuximab (Erbitux) in Combination with Radiation Therapy in Pancreatic Cancer
For locally advanced pancreatic cancer, chemo-radiation using gemcitabine or 5-fluouracil plus radiotherapy, is standard care, but results are poor with overall survival of between 7 and 12 months and 1-year survival rates of 30%-45% (Tsai et al. 2003). Given the promising results of EGFR targeting therapy in pancreatic cancer, the introduction of cetuximab in this setting as a novel treatment strategy was a stringent thera¬peutic demand.
Two phase II trials examined the combination of gemcitabine, cetuximab, and radiotherapy as a preoperative induction treatment (Pipas
et al. 2006; Krempien et al. 2006) (PARC trial
ISRCTN56652283). Though still small in num¬ber and preliminary (10 and 20 patients, respec-tively), the first data report shows promising re-sults, with tumor control rates of 80% and 85%, rendering 60% of patients operable by tumor downstaging. The toxicity profile did not differ from that known for gemcitabine and cetuximab, with rash, diarrhea, and hematotoxicity as the main adverse events. Therefore, even as a neoad-juvant approach, the combination of gemcitabine plus cetuximab is feasible and warrants efficacy. The PARC trial will include 66 patients with lo¬cally advanced nonresectable pancreatic cancer, evaluating feasibility via the toxicity profile as its primary study aim, and response rates, time to progression, downstaging of tumor size, post-therapy resectability, and quality of life will be its secondary study aims.
15.4 Conclusion
EGFR-targeting therapies with TK inhibitors and monoclonal antibodies such as cetuximab repre-sent a substantial improvement in the treatment options for patients with pancreatic cancer and probably will enhance the chances and the prog-nosis of those patients.
15.1 Introduction
Epidermal growth factor receptor (EGFR) is known to be of high importance in the development of tumors and their survival in the organism. It belongs to the family of protein tyrosine kinases that have a big influence on the cellular regulation of growth, differentiation, and apoptosis (Ullrich and Schlessinger 1990). Located on the cellular surface, the molecule mediates signal transduction pathways by responding to extracellular signals. Via signal transduction cascades it interacts with different molecules regulating cell proliferation, survival, differentiation and migration (Prenzel et al. 2001; Sonenshein 1997; Alessi and Cohen 1998). Finally, the signal reaches the nucleus, regulating gene expression and transcription (Bromberg and Darnell 2000). Furthermore, EGFR interacts with other members of its receptor family, such as e.g. HER2neu/ErB2 (Gschwind et al. 2001; Earp et al. 1995).
In normal tissue, EGFR is largely controlled by a diversity of regulating mechanisms. In can¬cer tissue, however, these control mechanisms fail, resulting in overexpression and activation (Salomon et al. 1995; Xu et al. 1984). As in other epithelial tumor types, in pancreatic cancer over-expression of EGFR is correlated with bad clini¬cal outcomes due to increased tumoral aggres¬siveness (Yamanaka et al. 1993).
EGFR plays an important role in the develop-ment of pancreatic cancer. In over 90% of cases EGFR is overexpressed (Lemoine et al. 1992), stimulating pancreatic tumor cell growth (Funa-
tomi et al. 1997).
Another important EGFR activity concerns angiogenesis. EGF induces vascular endothelial growth factor and so, in addition to its direct tumor growth induction, it enhances tumor growth by supporting vascularization (Goldman
et al. 1993).
Taking into account all these activities in¬duced by EGFR—regulation of cell growth, tu-morigenesis, and angiogenesis—it is obvious that blocking EGFR activity represents an attractive anticancer treatment approach.
Two ways of EGFR blockade have been devel-oped. One class is represented by small molecule tyrosine kinase (TK) inhibitors, which block adenosine triphosphate binding and so inhibit TK activity. Many of these TK inhibitors have been synthesized, some have been developed clinically, such as gefitinib, lapatinib, and erlo-tinib. For pancreatic cancer, erlotinib is the most developed compound.
The other strategy is inhibiting ligand binding to EGFR by monoclonal antibodies and thereby blocking the following signal transduction cas-cade, including, e.g., cetuximab or matuzumab. As for pancreatic cancer, the most important compound is cetuximab.
15.2 Preclinical Studies
The above-mentioned findings were investigated on a cellular level in several preclinical studies to evaluate EGFR-targeted therapy for human pancreatic cancer. Ng et al. (2002) showed a sig-nificant increase in apoptosis in SCID (severely combined immunodeficient) mice bearing a pan-creatic cancer xenograft. Animals were treated with a combination of gemcitabine, wortmannin (phosphatidylinositol 3'-kinase inhibitor), and erlotinib given intravenously.
In another experiment erlotinib alone showed a significant decrease of proliferation of human pancreatic cancer cells (HPAC) in vitro. Ortho-topically human pancreatic cancer (HPAC)-implanted nude mice showed reduced tumor implantation, size, weight, and jaundice when treated with erlotinib (Durkin et al. 2006).
Additional effects could be shown in experi-ments performed with cetuximab alone or in a combination of cetuximab with gemcitabine. In L3.6pl tumors implanted in the pancreas of nude mice, growth inhibition and tumor regression up to complete tumor disappearance was docu-mented for either cetuximab alone or in com-bination with gemcitabine. No liver metastases were seen in the combination group whereas 50% of the control group (no therapy) showed hepatic spread of the disease. Interestingly, ther¬apy using cetuximab decreased the production of vascular endothelial growth factor and inter-leukin-8 significantly. Consequently, cetuximab reduced microvessel density and increased the percentage of apoptotic endothelial cancer cells. These effects were potentiated when combined with gemcitabine.
Preclinical investigations demonstrated a strong rationale for EGFR-targeting strategies against cancer of the pancreas and were therefore translated into a variety of clinical protocols in combination with chemotherapy or radiotherapy (or both).
15.3 Clinical Trials in Pancreatic Cancer
Standard of care in pancreatic cancer is chemo-therapeutic treatment with gemcitabine. How¬ever, response rates and survival data are poor (Burris et al. 1997) and there is a strong clinical need for improved systemic therapy. Few data are available on compounds interfering with EGFR in pancreatic cancer. These clinical studies will be discussed here.
15.3.1 Clinical Trials with TKIs
15.3.1.1 Erlotinib (Tarceva) in First-Line Treatment of Pancreatic Cancer
Moore et al. (2007) compared gemcitabine plus erlotinib (Tarceva, Roche Pharmaceuticals, Ba¬sel) versus gemcitabine plus placebo in a phase III trial. From 176 sites in 17 countries, 569 patients were randomized to receive either gemcitabine 1,000 mg/m2 weekly on days 1 to 43 (i.e., for 6 weeks), followed by 1 week's rest and then, on days 1, 8, and 15 of a 4-week cycle with erlotinib, given at a dose of 100 or 150 mg/day orally or plus placebo. The primary endpoint of the trial was overall survival; secondary endpoints in-cluded progression-free survival (PFS), response rate, response duration, toxicity, and quality of life. Response was evaluated every 8 weeks using Response Evaluation Criteria In Solid Tumors
(RECIST) criteria.
An interim safety analysis was performed once 50 patients had shown no major increase in toxicity after receiving gemcitabine plus erlotinib at 100 mg/day. Thus, accrual at 150 mg/day was opened. However, recruitment in the 100-mg/ day group was so fast that by the time of the in¬terim analysis for the 150-mg/day group the trial was almost completed with patients on 100 mg/ day. It was therefore decided to include the ap-propriate number of patients for 80% statistical power for the 100-mg/day group.
Survival analysis included 486 and showed a significantly longer overall survival for the gemcitabine plus erlotinib group than for gem-citabine alone with an estimated hazard ratio of 0.82 (95% CI 0.69-0.99, p = 0.038). Median sur¬vival times were 6.24 vs 5.91 months, 1-year sur¬vival rates were 23% (95% CI 18%-28%) and 17%
(95% CI 12%-21%), respectively. Progression-free survival was also longer in the gemcitabine-erlotinib arm (median 3.75 vs 3.55 months, HR 0.77, p = 0.004). Response rates slightly favored gemcitabine-erlotinib (ORR 8.6% vs 8%) with a duration of response of 163 days in both arms.
The treatment was generally well tolerated and comparable in both treatment arms. Known EGFR-induced side effects (Shepherd et al. 2005) included rash, diarrhea, and ILD-like symptoms were more common in the gemcitabine-erlotinib arm, but usually mild to moderate. Hematotoxic-ity did not differ between treatment arms (Grade 3/4 neutropenia 24% vs 27%, thrombocytopenia 10% vs 11%). The toxicity profile of both com-pounds did not differ to that known as single agents.
Quality of life was comparable between both treatment arms.
As seen before with EGFR inhibitors (Xiong and Abbruzzese 2002), the presence of rash in the gemcitabine-erlotinib arm was correlated with a greater likelihood of treatment response.
This significant improvement in overall sur-vival of 22% compared to gemcitabine plus pla-cebo led to marketing authorization in the USA for erlotinib in combination with gemcitabine in
2006.
At the ASCO 2007 Gastrointestinal Cancer Symposium, a phase I of a triple therapy com-bining erlotinib, the monoclonal VEGF receptor antibody bevacizumab, and gemcitabine was re-ported. In 12 patients the combination seemed to be well tolerated, and the maximum tolerated dose (MTD) has not yet been reached. Two pa-tients showed partial response, 4 had stable dis-ease (Gomez-Martin et al. 2007).
15.3.1.2 Erlotinib (Tarceva) in the Treatment of Relapsed Pancreatic Cancer
As patients who fail standard first-line treatment with gemcitabine have no standard treatment options, the impact of new compounds is being examined in this population.
At the ASCO 2007 Gastrointestinal Cancer Symposium, a trial of single-agent erlotinib for patients with relapsed pancreatic cancer has been reported. In 13 patients having received two prior lines of chemotherapy (1-5), erlotinib showed clinical activity in 5 patients, resulting in stabili-zation or improvement for up to 12 months. No grade IV toxicity was described; 4 patients had grade 2 rash, 2 had grade 3 diarrhea (Epelbaum
et al. 2007).
Another trial examined the impact of capecitabine plus erlotinib after failure of a gemcitabine-based chemotherapy in pancreatic cancer. Receiving capecitabine, 2,000 mg/m2, plus erlotinib, 150 mg per day, were 28 patients. The toxicity profile met the expectations with grade 3/4 rash and diarrhea (14% each), hand-foot syndrome (11%), and stomatitis (7%). Par¬tial response was reported in 11% and stable dis¬ease in 57% of patients. The median survival was 6.7 months (Blaszkowsky et al. 2005).
15.3.1.3 TK-Inhibitors in Combination with Radiation Therapy in Pancreatic Cancer
The combination of the TK inhibitor gefitinib, capecitabine, and radiotherapy led to an in-creased toxicity in 10 patients with pancreatic cancer without responses in a phase I dose-finding study (Czito et al. 2006). When given simultaneously to radiation therapy, 825 mg/m2 capecitabine plus 250 mg/day gefitinib induced dose-limiting toxicity in all 3 patients on this dose level (grade 3 nausea, diarrhea), resulting finally in patient withdrawal. On dose level 1 (capecitabine 650 mg/nr* + gefitinib 250 mg/day) DLTs appeared in 3/7 patients. As for efficacy, no responses have been reported; stable disease was reported for 6 out of 7 patients on dose level 1, and 1 out of 3 patients on dose level 2. No patient was converted to resectable status.
15.3.2 Clinical Trials with Anti-EGFR Antibodies
15.3.2.1 Cetuximab (Erbitux) in the First-Line Treatment of Pancreatic Cancer
Cetuximab (Erbitux, Merck, Darmstadt, Ger-many) has also been combined with standard gemcitabine chemotherapy as a first-line treat-ment of pancreatic cancer. A phase II trial has been performed in 41 patients, receiving cetux-imab (initial dose 400 mg/m2, then 250 mg/m2 weekly) followed by gemcitabine 1,000 mg/m2 weekly for 7 weeks plus 1 week's rest. Subsequent cycles were 4 weeks long with gemcitabine given on days 1, 8 and 15 and a rest on day 22. Patients were treated until progression or intolerable tox-icity.
Patients had a median Karnofski score of 80%; 85.4% had metastatic disease.
Out of 41 patients, 5 (12.2%) showed partial response, and a further 26 (63.4%) had stable dis-ease, resulting in a disease control rate of 75.6%.
As discussed above, the effect of EGFR block-ade combines the reduction of tumor growth with antiangiogenesis, both of which in the short run do not result in tumor shrinkage but appear clinically as disease stabilization. Furthermore, the accurate assessment of pancreatic tumor imaging is difficult due to its anatomic location. Therefore, time to progression, which includes objective response plus stable disease, and overall survival may be more appropriate parameters for tumor response assessment in pancreatic cancer.
Median time to best response was 1.7 months, median duration of response was 3.8 months, duration of disease control was 5.4 months, and median time to progression 3.8 months. Median survival duration was 7.1 months; the 1-year overall survival rate was 31.7% and the 1-year PFS rate 12% (Xiong et al. 2004).
These data clearly exceed the results of gem-citabine monotherapy, which showed a 1-year survival rate of 18% and a 1-year PFS of 9%. Also, median TTP and overall survival (3.8 and 7.1 months, respectively) favor the combina-tion of cetuximab and gemcitabine (Burris et al.
1997).
Response data, PFS, and overall survival of the combination cetuximab plus gemcitabine are also comparable to those of other EGF-targeted therapies combined with gemcitabine, as men-tioned above.
Acne-like rash (85.4%), asthenia (85.4%),
nausea (61%), weight loss (58.5%), diarrhea (53.7%), abdominal pain (53.7%), and vomiting (51.2%) were the most common adverse events. As for grades 3 and 4, neutropenia (39%), asthe-nia (22%), abdominal pain (22%), and throm-bocytopenia (17.1%) were the most commonly reported severe toxicities.
One trial explored the efficacy and safety of cetuximab (250 mg/m2 per week) combined with gemcitabine (1,000 mg/m2 q2w) and oxalipla-tin (100 mg/nr* q2w) in 43 patients as first-line treatment of metastatic pancreatic cancer (GE-MOXCET). Toxicity was mainly hematological with grades 3/4 of leucopenia 10%, anemia 15%, and thrombocytopenia 12%. Nonhematological toxicity involved nausea 17%, infection 16%, di¬arrhea 7%, and allergy 6%. Of the patients, 71% had skin rash, 5% grade 3. The overall response rate (34 evaluable patients) was 38% with 1 com¬plete and 12 partial responses. In all, 9 patients
(26%) had stable disease. GEMOXCET has been
shown to be a feasible regimen with moderate toxicity and promising efficacy data (Kullmann
et al. 2007).
15.3.2.2 Cetuximab (Erbitux) in Combination with Radiation Therapy in Pancreatic Cancer
For locally advanced pancreatic cancer, chemo-radiation using gemcitabine or 5-fluouracil plus radiotherapy, is standard care, but results are poor with overall survival of between 7 and 12 months and 1-year survival rates of 30%-45% (Tsai et al. 2003). Given the promising results of EGFR targeting therapy in pancreatic cancer, the introduction of cetuximab in this setting as a novel treatment strategy was a stringent thera¬peutic demand.
Two phase II trials examined the combination of gemcitabine, cetuximab, and radiotherapy as a preoperative induction treatment (Pipas
et al. 2006; Krempien et al. 2006) (PARC trial
ISRCTN56652283). Though still small in num¬ber and preliminary (10 and 20 patients, respec-tively), the first data report shows promising re-sults, with tumor control rates of 80% and 85%, rendering 60% of patients operable by tumor downstaging. The toxicity profile did not differ from that known for gemcitabine and cetuximab, with rash, diarrhea, and hematotoxicity as the main adverse events. Therefore, even as a neoad-juvant approach, the combination of gemcitabine plus cetuximab is feasible and warrants efficacy. The PARC trial will include 66 patients with lo¬cally advanced nonresectable pancreatic cancer, evaluating feasibility via the toxicity profile as its primary study aim, and response rates, time to progression, downstaging of tumor size, post-therapy resectability, and quality of life will be its secondary study aims.
15.4 Conclusion
EGFR-targeting therapies with TK inhibitors and monoclonal antibodies such as cetuximab repre-sent a substantial improvement in the treatment options for patients with pancreatic cancer and probably will enhance the chances and the prog-nosis of those patients.
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