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New Chemotherapeutic Advances in Pancreatic, Colorectal, and Gastric Cancers

Department of Medical Oncology, Hospital Clínico San Carlos, Madrid, Spain

Correspondence: Eduardo Diaz-Rubio, M.D., c/o Martin Lagos, M.D. s/n, Department of Medical Oncology, Hospital Clínico San Carlos, 28040-Madrid, Spain. Telephone: 34-91-3303546; Fax: 34-91-3303544; e-mail: ediazrg{at}seom.org

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
After completing this course, the reader will be able to:

1. Explain the need for more effective chemotherapy regimens for the treatment of advanced pancreatic, gastric, and colorectal cancer.
   
2. Select the most appropriate treatment regimen in each of these categories based on the best available evidence.
   
3. Identify the many new agents that target novel molecules in these cancers that are being explored in combination with conventional chemotherapy regimens.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Pancreatic, gastric, and colorectal cancers are major causes of morbidity and mortality worldwide. When curative surgical resection is not an option, these malignancies tend to respond very poorly to chemotherapy and carry a dismal prognosis. There is, therefore, an urgent need for novel treatment strategies for these cancers. Great strides have been made in colon cancer treatment with the recent introduction of several novel agents, including capecitabine, irinotecan, and oxaliplatin either alone or in combination regimens. Treatment of advanced colon cancer, however, remains essentially palliative, and treatment-related toxicity remains a significant problem. The treatment of advanced gastric and pancreatic cancer has also seen the introduction of new agents, such as gemcitabine and irinotecan; however, the impact of these agents on survival has been small, and toxicity continues to be a major obstacle. The search for new chemotherapeutic agents and treatment strategies will need to focus on improving outcomes and safety and tolerability profiles. To date, several new agents have shown promise, including pemetrexed, G17DT, bevacizumab, and other targeted agents. Further research into their optimal use either alone or in combination regimens should be a priority.

Key Words. Chemotherapy • Gastrointestinal malignancy • Pancreatic cancer • Gastric cancer • Colorectal cancer

	INTRODUCTION

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Gastrointestinal cancers are major causes for concern in the biomedical community due to their high mortality rates and the lagging ability for early diagnosis. Pancreatic, gastric, and colorectal cancers have especially high incidence rates and dismal prognoses. Although surgery is a curative option in over half the patients with colorectal cancer, it is rarely curative in pancreatic and gastric cancers. Most patients with pancreatic and gastric cancers still die of their disease despite improvements in surgical techniques and postoperative supportive care and the introduction of adjuvant chemotherapy and radiation. This is often due to the poor responses of these malignancies to current chemotherapeutic regimens. There is, therefore, an urgent need for novel chemotherapy drugs and treatment strategies, with a focus on improving both efficacy and tolerability.

Ries et al. estimated that there would be 30,300 new cases of pancreatic cancer in the U.S. in 2002 and 29,700 deaths from the disease [1]. It is the fifth most common cause of cancer death [2]. Surgically resectable in only 10%–15% of cases [3], long-term survival is rare, with 5-year survival rates of up to 4% reported [1, 4]. Cigarette smoking is the most reliably linked risk factor, although diet, caffeine, alcohol, chronic pancreatitis, and diabetes also have been associated with the development of pancreatic cancer [5].

Gastric cancer is the ninth most common cause of cancer death in the U.S. [2]. In 2002, 21,600 new cases and 12,400 deaths were forecast [1]. While the incidence of gastric cancer has gradually decreased in many parts of the world, it remains one of the most common cancers, with a particularly high prevalence in parts of Latin America and Asia, particularly in Japan [6, 7]. Risk factors for gastric cancer include bacterial infection with Helicobacter pylori, consumption of nitrite-containing cured or smoked meats, and various micronutrient deficiencies [6, 8–10].

Colorectal cancer is the second leading cause of cancer death in the U.S. [2]; 148,300 new cases and 56,600 deaths were expected in 2002 [1]. The majority of colon cancers are preceded by benign adenomas that gradually transform into malignant, invasive tumors [11]. This gradual process allows for effective screening for colorectal cancer and a greater rate of potentially curative resection. Risk factors include dietary factors, inflammatory bowel disease, and a family history of colon cancer [11–13]. Genetically well-defined familial polyposis syndromes lead to the development of invasive colon cancer at an early age in almost all family members with a phenotypic manifestation of the syndrome [14–16].

	CURRENT CHEMOTHERAPY FOR GASTROINTESTINAL CANCERS

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Until recently, chemotherapy for gastrointestinal cancers was based on 5-fluorouracil (5-FU) and on modulation of 5-FU with leucovorin (LV). Over the last decade, however, other agents, such as gemcitabine, irinotecan, and oxaliplatin, have been found to be useful either alone or in combination with 5-FU. Unfortunately, despite these newer agents and combinations, response rates remain low, and the treatment of metastatic disease remains essentially palliative (Table 1) [17–42].

	PANCREATIC CANCER

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

Gemcitabine has emerged as the cornerstone of current chemotherapy for pancreatic cancer based on the results of a randomized trial comparing it with 5-FU in patients with advanced unresectable disease [17]. In that trial, the primary end point was clinical benefit response, derived from measuring three common debilitating signs or symptoms: pain, functional impairment, and weight loss. Clinical benefit response was experienced by 23.8% of patients in the gemcitabine arm of the trial, compared with 4.8% in the 5-FU arm (p = 0.0022). Survival and objective response were secondary end points. Gemcitabine showed only a slightly longer, but statistically significant, median survival time compared with 5-FU (5.65 months versus 4.41 months; p = 0.0025). Of note, the objective response rates for patients with measurable disease were not significantly different (5.4% and 0% for gemcitabine and 5-FU, respectively). Gemcitabine has also shown activity in pancreatic cancer refractory to 5-FU and seems to produce a similar clinical benefit response when it is used as first-line therapy [46]. Open-label phase II studies of gemcitabine combinations appear promising in terms of radiographic and tumor marker responses, although response rates overall remain low and there is no clearly established survival benefit over gemcitabine alone [47, 48]. A randomized trial comparing gemcitabine alone with gemcitabine in combination with 5-FU showed no significant difference in survival, although there was a trend in favor of the combination (5.4 months versus 6.7 months; p = 0.09) and a significantly longer progression-free survival time in the combination arm (2.2 months versus 3.4 months; p = 0.022) [49].

Recently, preliminary results of three randomized trials of gemcitabine combinations were reported [50–52]. The combination of gemcitabine and cisplatin showed a benefit over gemcitabine alone for both progression-free survival and overall survival (5.4 months versus 2.8 months and 8.3 months versus 6.0 months, respectively) in patients with metastatic or locally advanced disease [50]. Gemcitabine plus irinotecan showed a superior response rate over gemcitabine alone (16.1% versus 4.4%, p < 0.001); however, this did not translate into an improvement in long-term outcome in terms of either time to progression or overall survival [51]. A trial comparing the combination of gemcitabine and oxaliplatin with gemcitabine alone showed that the combination produced a better clinical response rate (25.8% versus 16.1%, p = 0.03) and rate of clinical improvement (39.3% versus 28.4%, p = 0.05) and showed an advantage in time to disease progression (25 weeks versus 16 weeks, p = 0.05), compared with gemcitabine alone in patients with both locally advanced and metastatic pancreatic cancer; patients with locally advanced disease and those with metastatic disease both responded the same to the two treatments [52, 53]. For all patients who achieved a response, median survival was approximately 41 weeks, irrespective of treatment.

Gemcitabine is the new standard of care in pancreatic cancer, offering a slightly better overall survival than 5-FU. Current gemcitabine- or 5-FU-containing combinations may result in longer survival times than those seen with single-agent therapy; however, results to date remain preliminary.

	GASTRIC CANCER

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
While chemotherapy for gastric cancer is largely palliative, several studies have shown a survival benefit for chemotherapy over best supportive care [22], with 5-FU being the mainstay of chemotherapeutic regimens [20, 21]. Several investigators have attempted to improve on the relatively low response rates and poor survival using 5-FU alone by combining 5-FU with other agents (Table 1). However, these attempts have been largely unsuccessful [21]. Although several combination regimens showed remarkable response rates in phase II trials, as with many other tumor types, the results in well-controlled randomized trials have been far less impressive [22]. For example, in a randomized multicenter trial by Vanhoefer et al., three standard regimens were compared in 399 patients with advanced unresectable gastric cancer. The regimen 5-FU, doxorubicin, and sequential high-dose methotrexate (FAMTX) produced response rates of 30%–60% and median survival times of 7–9 months in prior phase II trials; the regimen etoposide, LV (folinic acid), and 5-FU (ELF) yielded response rates of 27%–53% and median survival times of 7.1–11.5 months in prior phase II trials; and the regimen of infusional 5-FU and cisplatin (FUP) yielded response rates of 41% and 43% and median survival times of 10.6 months and 9 months in two large phase II trials [22]. When these regimens were compared in a large randomized trial, however, response rates for FAMTX, ELF, and FUP were 12%, 9%, and 20%, respectively, and median survival times were 6.7 months, 7.2 months, and 7.2 months, respectively [22]. More promising results have been accomplished using epirubicin, cisplatin, and infusional 5-FU (ECF). In a randomized trial of ECF compared with FAMTX, ECF rendered a significant benefit over FAMTX in both response rate (46% versus 21%, p = 0.00003) and median survival time (8.7 months versus 6.1 months, p = 0.0005) [23].

Regimens not containing 5-FU have also been examined in gastric cancer. In a phase II trial by Wang et al., the combination of etoposide, doxorubicin, and carboplatin produced a response rate of 49%, including a 7% complete response rate [54]. Swiss investigators showed that a regimen combining cisplatin, doxorubicin, and etoposide produced a response rate of 34% with tolerable toxicities [55]. Ridwelski et al. demonstrated a response rate of 37.2% with a combination of docetaxel and cisplatin [56].

Irinotecan, a potent topoisomerase I inhibitor, is the latest therapeutic candidate showing potential in gastric cancer. As a single agent, irinotecan produced response rates of 18.4%–43% [24]. In combination regimens with 5-FU and cisplatin, particularly in chemotherapy-naïve patients, irinotecan produced response rates up to 59% [24]. Despite these impressive results, however, these combination regimens have yet to be rigorously tested in the phase III setting, where previous experience has shown they may produce relatively disappointing results.

Oxaliplatin is a new platinum analogue with great promise in multiple cancers. Phase II studies have shown its potential in gastric cancer therapy when combined with 5-FU and folinic acid [57]. Docetaxel also has been shown to have activity in gastric cancer. As a single agent, docetaxel achieved response rates of 20%–24% [58, 59]. Several recent reports of docetaxel combinations also have demonstrated significant activity in gastric cancer, although toxicity, particularly neutropenia, remains limiting [60, 61].

There is no standard chemotherapeutic regimen for gastric cancer. Current therapies offer some benefit in terms of palliation and survival; however, the benefit is small.

	COLORECTAL CANCER

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
5-FU, often modulated with LV, is the most widely used agent for the treatment of colorectal cancer, both in the adjuvant and in the advanced disease settings [34, 62–64]. Adjuvant chemotherapy with 5-FU regimens clearly improves disease-free survival and overall survival times in patients with surgically resected stage III (and subpopulations of stage II) colon cancer and in patients with advanced disease [34, 62–64]. Despite this, objective response rates with LV-modulated 5-FU in two recently published large randomized trials of first-line metastatic colon cancer were 15.5% and 21%, leaving substantial room for improvement [32, 65].

There are variations in objective response rates among high- and low-dose LV modulation and continuous infusion (CI) 5-FU. Most studies comparing CI with bolus administration are in favor of CI in relation to response rate and, probably, time to progression, although overall survival is not clearly better [66]. One meta-analysis with 1,219 patients from six randomized studies ratified the superiority of CI 5-FU over the 5-FU/LV regimen in terms of response rate (22% versus 14%; p = 0.0002), but not as significantly in terms of time to progression and survival [26]. Another meta-analysis showed that the two regimens had similar toxicity profiles, except for hematologic toxicity (neutropenia) in the bolus regimen and hand-foot syndrome in the CI regimen [67]. There is, however, no consensus on the optimal schedule of CI 5-FU. Until recently, the bolus 5-FU plus LV regimen (the Mayo Clinic regimen) was considered the standard treatment in the U.S., while CI 5-FU has been widely used in Europe. The most popular CI schedules in Europe are the de Gramont regimen (France) [27], AIO (Germany) [28] and TTD (Spain) (the basis for the combination with new drugs, such as irinotecan or oxaliplatin) [29].

An additional step toward improving upon 5-FU-based therapy is the oral fluoropyrimidine prodrug capecitabine. When compared with standard 5-FU/LV in a phase III randomized trial, capecitabine showed a significantly greater response rate as assessed by the individual investigators (24.8% versus 15.5%; p = 0.005), but no significant differences in progression-free or overall survival times, or in response rates as assessed by an independent review committee [32]. There were, however, lower incidences of diarrhea, stomatitis, alopecia, nausea, and neutropenia and higher incidences of hand-foot syndrome and hyperbilirubinemia in capecitabine-treated patients. This superior safety profile and equivalent response rate were also confirmed by another study [33]. With the convenience of oral dosing and the overall superior toxicity profile, capecitabine represents an attractive option for the palliative treatment of metastatic colorectal cancer and is in trials in combination with irinotecan and oxaliplatin.

Two phase III studies have investigated other fluoropyrimidines, including uracil/tegafur and LV versus 5-FU/LV, showing significantly better safety profiles and equivalent survival times [68, 69].

Until the introduction of irinotecan, there was no standard therapy for patients with metastatic colon cancer who had progressive disease despite 5-FU-based chemotherapy. Various infusional 5-FU regimens had response rates of 5%–30%; however, none showed a clear survival or quality of life benefit over best supportive care [34]. Two large randomized trials in the second-line setting, one comparing irinotecan with best supportive care and the other comparing irinotecan with infusional 5-FU, showed that irinotecan produced a better quality of life than best supportive care and a longer survival time than either best supportive care or infusional 5-FU when used after 5-FU failure [34, 35]. Subsequently, irinotecan was moved into the first-line setting in combination with 5-FU. Saltz et al. conducted a randomized phase III trial comparing standard weekly bolus LV-modulated 5-FU with irinotecan alone and with a combination of LV-modulated 5-FU and irinotecan [65]. The irinotecan/5-FU/LV arm showed a significantly longer median progression-free survival time (7 versus 4.3 months; p = 0.004), a significantly longer median overall survival time (14.8 versus 12.6 months; p = 0.04), and a significantly higher objective response rate (39% versus 21%; p < 0.001) than LV-modulated 5-FU alone. Results for the irinotecan alone arm were similar to the 5-FU/LV arm. Quality of life was not compromised by the addition of irinotecan to 5-FU/LV, with the exception of grade 3 diarrhea. Similarly, in a European study of 387 patients comparing CI 5-FU/LV with CI 5-FU/LV/irinotecan, the response rate (22% versus 35%; p < 0.001), time to progression (4.4 versus 6.7 months; p < 0.001), and overall survival time (14.1 versus 17.4 months; p = 0.03) were all better in the irinotecan combination arm [36]. In spite of the higher toxicity of the irinotecan combination regimen, a quality-of-life analysis showed that adding irinotecan was not deleterious in terms of patient performance during the treatment. These studies led to the adoption of this combination regimen as the standard treatment for first-line metastatic disease.

Oxaliplatin is a third-generation platinum agent having synergistic activity with 5-FU. It is active against first- and second-line colorectal cancer [37, 38] and, in combination with 5-FU/LV, it was shown to be superior to 5-FU/LV alone in terms of response rate and time to progression in two randomized studies [40, 41]. The infusional 5-FU/LV/oxaliplatin combination was approved by the U.S. Food and Drug Administration in August 2002 for the treatment of patients with metastatic colorectal cancer whose disease had recurred or progressed during or within 6 months of completing first-line therapy with combination 5-FU/LV/irinotecan. The approval was based on a pivotal trial with an interim analysis of 59 patients, showing response rates of 0%, 1%, and 9% for infusional 5-FU/LV, oxaliplatin alone, and 5-FU/LV/oxaliplatin, respectively. The median time to progression in the combination arm was 2 months longer than that in the infusional 5-FU/LV arm and 3 months longer than that seen with oxaliplatin alone [39]. A comparison between the 5-FU/LV/oxaliplatin and 5-FU/LV/irinotecan regimens was presented to the American Society of Clinical Oncology (ASCO) as part of the N9741 study, indicating that the first regimen had a more favorable toxicity profile and led to a higher response rate (40% versus 30%), longer time to progression (8.8 versus 6.9 months), and longer survival time (19.1 versus 14.8 months) than the second regimen [70].

Combinations of capecitabine and oxaliplatin (XELOX) and oxaliplatin and irinotecan have also been studied in colorectal cancer, with encouraging results [71, 72]. In a phase II study of 96 patients with advanced colorectal cancer, XELOX demonstrated a 55% partial response rate, a 32% stable disease rate, an 8.9 months median duration of response, a 67% 1-year survival rate, and a 19.5 months mean survival time [42]. These positive results merit further research on this regimen.

Although surgical resection of liver metastases is beneficial for patient survival, it is only feasible in a small proportion of patients. The combination of neoadjuvant chemotherapy with subsequent tumor resection is an important step toward improving survival for more patients. This idea is based on the premise that treatment with neoadjuvant chemotherapy leads to the development of resectable liver metastases that can then be removed by surgery. Two studies have demonstrated the success of this technique in patients with unresectable liver metastases: one using 5-FU/folinic acid/oxaliplatin [73] and the other using 5-FU/LV/oxaliplatin [74]. In the first study, 70% of patients underwent major hepatectomy, and 30% had minor resection after chemotherapy, achieving a 5-year survival of 40% [73]. In the second, 51% of patients had surgery (38% complete resection), achieving a median survival time of 48 months and a 5-year survival rate of 50% [74].

	NEW APPROACHES IN DEVELOPMENT

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Many new agents for the treatment of advanced gastrointestinal cancers are in development. While greater efficacy remains paramount, a superior toxicity profile and ease of administration are also key considerations.

	CYTOTOXIC AGENTS

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Pemetrexed
Pemetrexed (Alimta^®; Eli Lilly & Co.; Indianapolis, IN) is a multitargeted antifolate that inhibits multiple enzymes important in folate metabolism, including thymidylate synthase, dihydrofolate reductase, glycinamide ribonucleotide formyl-transferase, and aminoimidazole carboxamide ribonucleotide formyl-transferase [75, 76].

As a single agent given at a dose of 500 mg/m² every 21 days, pemetrexed has demonstrated promising activity in several malignancies, including malignant pleural mesothelioma, non-small cell lung cancer, breast cancer, colorectal cancer, pancreatic cancer, gastric cancer, bladder cancer, cervical cancer, and cancer of the head and neck [76–80]. Initial clinical experience with pemetrexed was complicated by severe adverse events, including neutropenia, thrombocytopenia, mucositis, diarrhea, and drug-related death [81], due to vitamin B₁₂ and folate pool depletion. These toxicities are significantly reduced by vitamin B₁₂ and folate supplementation [81, 82].

In a phase II trial of 35 patients with pancreatic cancer, pemetrexed showed an objective response rate of 5.7%, disease stabilization in 40% of patients, and a median survival time of 6.5 months, with 28% of patients alive at 1 year [83]. These results are similar to those achieved with single-agent gemcitabine in this patient population. Pemetrexed also seems to be effective in gastric cancer. Preliminary results of a phase II trial of single-agent pemetrexed in patients with locally advanced or metastatic gastric cancer showed a response rate of 28% and tolerable adverse events in patients treated with folic acid and B₁₂ supplementation [84]. Two phase II studies of single-agent pemetrexed in patients with locally advanced or metastatic colorectal cancer have been reported [79, 85]. Those trials resulted in response rates of 15.4% and 17.2% and median survival times of 16.2 and 15.1 months, with few adverse events.

Combinations of pemetrexed with agents such as gemcitabine and oxaliplatin are under investigation and have shown promising results in several traditionally resistant tumors, such as cholangiocarcinoma, colon cancer, and mesothelioma [80]. In a phase II trial, pemetrexed/gemcitabine showed promising survival results (6.6 months, with a 1-year survival rate of 32%) and acceptable toxicities (mainly hematologic, including grade 3/4 neutropenia and grade 3 leukopenia, thrombocytopenia, and anemia) in chemotherapy-naïve patients with pancreatic cancer [86]. This led to an ongoing phase III randomized trial comparing pemetrexed with and without gemcitabine in patients with stage II, III, and IV pancreatic cancer (study ID No. NCI-G02-2125) [87]. In a phase II trial conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) cooperative group, the pemetrexed/oxaliplatin combination showed activity in advanced colorectal cancer (23% response rate) and was generally well tolerated, with grade 3/4 neutropenia (23%) being the major toxicity [88]. As a 10-minute infusion every 21 days, pemetrexed is easy to administer, and with appropriate folate and vitamin B₁₂ supplementation, it is associated with a very favorable toxicity profile. Overall, pemetrexed shows promising activity in several gastrointestinal malignancies.

	VACCINES

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
G17DT
Gastrin acts as a growth factor for several gastrointestinal tumor types, including pancreatic, gastric, and colon cancers. G17DT (Gastrimmune^TM; Aphton Corp.; Miami, FL) is an immunoconjugate of the amino-terminal sequence of gastrin-17 (G-17) linked by means of a spacer peptide to diphtheria toxoid. Given as an intramuscular vaccination, it has been shown to induce the formation of antibodies that can neutralize endogenous G-17 and precursor glycine-extended G-17 [89]. These antigastrin antibodies can inhibit the proliferation of pancreatic cancer cells. In a phase II study of 30 patients with pancreatic cancer, 67% of patients were shown to mount an immune response to the vaccine [89]. Eighty-two percent of patients given the highest dose of the vaccine (250 µg) achieved a response. There was a significant difference between the median survival times noted for patients who produced an immune response and for those who did not (217 versus 121 days). While analyses such as these are not conclusive (responders may have had a better prognosis independent of the intervention), the results are promising, and G17DT is being evaluated in several phase III trials both alone and in combination with chemotherapy [89].

CEA-TRICOM
A recombinant pox-virus-based vaccine that incorporates costimulatory molecules and carcinoembryonic antigen (CEA), CEA-TRICOM, has been shown, in preclinical murine models, to boost the immune response to eradicate cancer cells. It is being studied in a National Cancer Institute-sponsored phase I trial of patients with advanced or metastatic CEA-expressing adenocarcinomas (study ID No. NCI-1133) [87, 90].

	KINASE INHIBITORS

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Bryostatin
Protein kinase C (PKC) is a family of lipid-dependent membrane-associated enzymes with important roles in cell signaling pathways. Bryostatin 1, a compound derived from the marine invertebrate Bugula neritina, has a modulatory effect on PKC-mediated cell biology. It has direct cytotoxic effects on some human cancer cell lines and mediates the in vitro cytotoxic effects of several chemotherapeutic agents [91]. In a phase II study of patients with advanced colon cancer, bryostatin 1 showed no responses as a single agent [91]. However, bryostatin 1 continues to be developed as a response modifier to traditional cytotoxic agents, with active protocols in several tumor types, including gastric cancer in combination with cisplatin (study ID No. NCI-T99-0040) and pancreatic cancer in combination with paclitaxel [87].

UCN-01
UCN-01 is a PKC inhibitor that, in isolated enzyme assays, can also inhibit cyclin-dependent kinases (CDKs), which are important regulators of cell cycle progression. UCN-01 blocks cell cycle progression and induces apoptosis [92]. Initial trials showed some clinical activity in patients with melanoma and lymphoma [92]. There are several ongoing trials of UCN-01 in various solid tumors, including two trials in pancreatic cancer, one in combination with 5-FU (study ID No. NCI-5509) and one in combination with gemcitabine (study ID No. NCI-5510) [87].

Flavopiridol
Flavopiridol was the first CDK inhibitor tested in clinical trials. Preclinical features of this drug include the ability to block cell cycle progression, induce apoptosis, promote differentiation, and inhibit angiogenic processes [92]. Initial clinical trials with infusional flavopiridol demonstrated activity in some patients with lymphomas and renal, colon, and gastric carcinomas [92]. Toxicity was manageable and included mainly diarrhea, which was controlled with appropriate diarrheal prophylaxis, and hypotension. Flavopiridol is being tested in combination chemotherapy trials with several agents including irinotecan, platinum, and docetaxel [87].

CI-1040
An oral, highly selective inhibitor of the dual specificity mitogen-activated protein kinase (MAPK)/extracellular-signal-related kinase (ERK) kinases MEK-1 and MEK-2, CI-1040 prevents the phosphorylation and subsequent activation of MAPK, an important mediator of several signal transduction pathways. In a phase I study, one patient with pancreatic cancer obtained a partial response that lasted longer than 6 months, and stable disease was observed in approximately 30% of patients [93]. An open-label phase II study for patients with breast, pancreatic, colon, or non-small cell lung cancer is ongoing [87].

	EPIDERMAL GROWTH FACTOR RECEPTOR INHIBITORS

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Because of the ubiquitous nature of the epidermal growth factor receptor (EGFR) in epithelial tumors and its neoplastic activity, various EGFR inhibitors are currently being examined in gastrointestinal cancers.

Cetuximab
Cetuximab (Erbitux^®; ImClone Systems, Inc.; New York, NY) is a chimeric monoclonal antibody against the EGFR. Cetuximab/5-FU/LV/irinotecan chemotherapy was examined in patients with untreated metastatic colorectal EGFR-positive cancer, and a response rate of 44% was achieved, with grade 3/4 diarrhea and neutropenia as major adverse events [94]. In combination with irinotecan in irinotecan-refractory colorectal cancer patients, cetuximab has a 17% response rate [95]. Recently reported preliminary data show that the combination of cetuximab with irinotecan produced a higher response rate (17.9% versus 9.9%) and longer time to progression (126 days versus 45 days) than cetuximab alone in metastatic colon cancer, and that the combination of cetuximab with irinotecan and infusional 5-FU was feasible and has promising activity in this disease [96, 97].

Gefitinib
Gefitinib (Iressa^®; AstraZeneca Pharmaceuticals; Wilmington, DE), an orally available pharmaceutical, was recently approved in several countries, including Japan and the U.S., for the treatment of lung cancer [98, 99]. Gefitinib is being studied in several tumor types, including colon cancer (study ID Nos. NCI-3792, NCI-3857, and NCI-4370) [87]. Although preliminary data in lung cancer patients showed no benefit to adding gefitinib to commonly used chemotherapy, there is still more to understand about how these novel agents work and how best to combine them with other agents. Recently, a small phase II trial of gefitinib in combination with infusional 5-FU/LV/oxaliplatin (FOLFOX) in metastatic colorectal cancer showed promising activity in early results, with a response rate of 75% for previously untreated patients and a response rate of 23% for patients previously treated for metastatic disease [100].

GW572016 and CI-1033
The pan erbB receptor inhibitor GW572016 has been shown, in vivo, to have activity against both EGFR- and erbB-2 (Her-2/Neu)-overexpressing tumors in mice [101]. A phase II trial of this agent in refractory colon cancer is ongoing [102]. CI-1033 is an irreversible pan erbB inhibitor. Initial studies of this agent were limited by hypersensitivity reactions; however, with the addition of diphenhydramine, no further reactions were observed [103]. Phase I studies of this agent to determine an optimal dosing regimen remain ongoing [104].

Erlotinib
Erlotinib (Tarceva^TM; Genentech, Inc.; South San Francisco, CA), is orally available and under investigation in several tumor types, including pancreatic cancer and colon cancer in combination with chemotherapy (study ID Nos. NCI-V02-1694, NCI-5371, and OSI-774-PA3) [87].

	VASCULAR ENDOTHELIAL GROWTH FACTOR INHIBITORS

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Bevacizumab
Bevacizumab (Avastin^TM; Genentech, Inc.; South San Francisco, CA), is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), a growth factor important in tumor angiogenesis. Phase II trials have shown the effectiveness of bevacizumab in combination with 5-FU/LV in patients with metastatic colorectal cancer [105]. Results presented at the latest meeting of ASCO have confirmed this observation. Bevacizumab, in combination with irinotecan/5-FU/LV, achieved a longer survival time (20.3 versus 15.6 months), higher response rate (45% versus 35%), and longer progression-free survival time (10.6 versus 6.24 months) than irinotecan/5-FU/LV in colorectal cancer [106]. Bevacizumab plus irinotecan/5-FU/LV was generally well tolerated; the most frequent toxicity was grade 3 hypertension that was manageable with oral medications. Based on the above results, bevacizumab is now an exciting new candidate for the treatment of colorectal cancer. Trials of several tumor types, including pancreatic and colon cancer, are under way (study ID Nos. NCI-2675, ID02-146, and OSI2520G) [87].

PTK787/ZK 222584
PTK787/ZK 222584 (PTK/ZK) is an oral selective inhibitor of the VEGF receptor VEGFR-1, VEGFR-2, and VEGFR-3 tyrosine kinases. In nude mice models, PTK/ZK was shown to reduce growth and microvasculature of human tumor xenografts. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), a sensitive noninvasive method for evaluating tumor perfusion, has been studied as providing a surrogate marker of efficacy of PTK/ZK. To date, particularly in patients with liver metastases from colorectal cancer treated with PTK/ZK, tumor perfusion as assessed by DCE-MRI has been a useful predictor of the biological response of VEGFR inhibition [107]. Recently reported preliminary data from a phase I study of PTK/ZK in combination with oxaliplatin and 5-FU as first-line treatment of metastatic colon cancer show promising results [108].

Angiozyme
Angiozyme is a stabilized ribozyme that targets the pre-mRNA of VEGFR-1 and may reduce both the cell surface receptor and its truncated, soluble form sVEGFR-1. It is currently under investigation in combination with chemotherapy for the treatment of metastatic colorectal cancer [109].

ZD6474
ZD6474 is a small-molecule VEGFR tyrosine kinase inhibitor with some EGFR inhibitory activity. Recent animal data suggest that combined inhibition of the EGFR and VEGF pathways may produce synergistic results, and that resistance to EGFR inhibition may be overcome by inhibition of VEGFR tyrosine kinase [110].

	MISCELLANEOUS AGENTS

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
Numerous experimental, epidemiological, and clinical studies suggest that cyclooxygenase-2 (COX-2) may be an important therapeutic target. Selective COX-2 inhibitors, such as celecoxib, have been successful in preventing adenomatous polyps and causing their regression in patients with familial adenomatous polyposis [111]. There is interest in using COX-2 inhibitors with standard chemotherapeutic agents to treat advanced disease [111]. Substantial data have implicated coagulation cascades in the pathogenesis of malignancy. Various animal tumor models have confirmed that the anticoagulant heparin limits tumor growth and metastasis and prolongs survival [112]. A clinical trial of gemcitabine plus dalteparin, a low-molecular-weight heparin, is under way in patients with pancreatic cancer (study ID No. NCI-5012) [87]. Heat shock protein 90 (Hsp90) is a molecular chaperone of multiple mutated and overexpressed signaling proteins that promote cancer growth [113]. Geldanamycin (17-Allylamino-geldanamycin or 17AAG) inhibits Hsp90 activity by destabilizing Hsp90 protein complexes and has shown promising antitumor activity in preclinical models [113]. Geldanamycin is currently being studied in a phase I trial in patients with refractory tumors, including pancreatic, gastric, and colorectal cancers (NCI-T99-0035) [87].

	CONCLUSIONS

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 
While traditional chemotherapeutic agents remain the standard of care, it is clear that current combinations that are successfully used in other malignancies may not be sufficiently effective for the treatment of gastrointestinal cancers. In colorectal cancer, for instance, new combinations have dramatically improved therapy, although treatments continue to be palliative, with few exceptions where surgery for liver metastases can be integrated. In this context, it is absolutely necessary to explore new compounds in order to find much better treatments. Novel drugs that show broad activities, high efficacies, good tolerabilities, and ease of use will rapidly find their place in the armamentarium of useful agents. Bevacizumab is one of the drugs with great promise in colorectal cancer. Pemetrexed and G17DT also have shown great potential and offer hope for the development of more effective therapeutic strategies, as single agents or in combination. Palliation is another important area where chemotherapeutics may be necessary, as disease progression is often associated with poor quality of life. Continued research in gastrointestinal oncology is still a high priority, since the burden of disease is high and the outlook for the majority of patients with advanced disease remains grim.

	REFERENCES

Top Learning Objectives Abstract Introduction Current Chemotherapy for... Pancreatic Cancer Gastric Cancer Colorectal Cancer New Approaches in Development Cytotoxic Agents Vaccines Kinase Inhibitors Epidermal Growth Factor Receptor... Vascular Endothelial Growth... Miscellaneous Agents Conclusions References

 

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