Gastric cancer remains a global public health problem with considerable heterogeneity in pathogenesis and clinical presentation across geographic regions. Improved understanding of the molecular biology of this disease has opened avenues for targeted intervention. An individualized treatment approach is required for optimal management of this cancer. Overcoming resistance to therapy requires combining targeted agents with the traditional options of chemotherapy/radiation therapy, and also targeting more than 1 pathway of carcinogenesis at a time. Encouraging molecular hypothesis and biomarker-driven trials will lead to improved patient outcomes and may eventually enable the therapeutic nihilism associated with gastric cancer to be overcome.
Although its global incidence is decreasing, gastric cancer remains a major cause of morbidity and mortality worldwide. It is the second leading cause of cancer-related death worldwide, with the incidence being highest in eastern Asia, eastern Europe, and Latin America. In 2008, it was estimated that nearly 989,600 new cases were diagnosed, with approximately 738,000 deaths from this disease. Most of these cases occur in developing countries. In the United States, approximately 21,500 new cases of gastric cancer will be diagnosed, with 10,500 deaths predicted, in 2011.
Most patients with gastric cancer present at an advanced stage secondary to delayed symptoms. R0 resection remains the only curative modality of treatment. Despite curative attempts at surgery, the 5-year survival remains poor at approximately 20%, with failure patterns including locoregional recurrence and systemic spread. Hence attempts to improve outcomes in this disease have incorporated the use of adjuvant therapy (chemotherapy, radiation therapy, or a combination thereof) or perioperative therapy. These treatment paradigms, including regimens in use, vary across continents. Results from Intergroup 0116 reported in 2001 using adjuvant fluorouracil-based chemoradiotherapy defined the standard of care in the United States. A 10-year follow-up of this trial confirmed the benefit for adjuvant chemoradiation with a hazard ratio of 1.32 for overall survival favoring the treatment arm. The same treatment dogma does not hold true across the Atlantic or the Pacific where perioperative combination chemotherapy or adjuvant treatment with S-1, an oral fluoropyrimidine, is typically recommended based on results of large randomized clinical trials conducted in those continents. Notwithstanding the approach used, it has become clear that surgery alone can no longer be recommended as the sole modality of therapy; rather a multimodal treatment plan is appropriate for most patients with localized gastric cancer to optimize the chance for cure.
The prognosis in metastatic gastric cancer remains poor and therapy is typically designed for palliation. Systemic chemotherapy improves survival compared with best supportive care and combination chemotherapy yields higher response rates compared with single-agent treatment. This treatment is typically recommended for patients with a good performance status. A variety of drugs and combinations are available to choose from, with cisplatin, 5-fluorouracil (5-FU), epirubicin, taxanes, and irinotecan being the most commonly used. Activity of these agents is modest at best and median survival in the advanced setting rarely exceeds 1 year, suggesting that a plateau has been reached in the therapeutic index of available agents in gastric cancer. Hence there is an urgent need to identify novel drugs. Improved understanding of the biology of neoplasia has allowed definition of cellular pathways that result in the growth, replication, and inhibition of apoptosis in the cancer cell. The focus of research efforts has now moved from examining traditional cytotoxic chemotherapy to evaluating biologic compounds that specifically target the tumor or its microenvironment. There is ample evidence that molecular markers in gastric cancer may provide prognostic data in addition to clinical staging. Some markers studied to date include DNA copy number, microsatellite instability, thymidylate synthase (TS), E-cadherin, β-catenin, p53, cyclooxygenase-2 (COX-2), vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and matrix metalloproteinases (MMPs). Development of drugs that target some of these receptors and proteases may lead to a higher therapeutic gain. Early phase clinical trials examining this is the focus of this review after an initial discussion on the commonly used chemotherapy regimens.
Chemotherapy in advanced gastric cancer
A standard regimen in advanced gastric cancer (AGC) remains an enigma because large, randomized clinical trials conducted in the past 3 decades have failed to establish a single regimen as being superior to others. Important considerations for individualized treatment include performance status, nutritional status, and comorbidities. It is common for patients with esophagogastric cancer to present with varying degrees of caloric malnutrition secondary to mechanical obstruction, impaired gastric motility, early satiety, and anorexia. In the meta-analysis by Wagner and colleagues, triplet drug therapy containing 5-FU, cisplatin, and an anthracycline resulted in the best overall survival. The regimen of epirubicin, cisplatin, and infusion 5-FU (ECF) has been commonly used in Europe in the first-line setting. In the Randomized ECF for Advanced and Locally Advanced Esophagogastric Cancer 2 (REAL-2) trial, the combination of epirubicin, oxaliplatin, and capecitabine (EOX) was determined to be as effective as ECF in therapy-naïve patients, and had a more favorable toxicity profile. The response rate to EOX was 47% and the median survival was 11.2 months. This trial clearly showed that oxaliplatin and capecitabine could safely be substituted for cisplatin and 5-FU respectively without compromise of efficacy. This finding also mitigates the need for central venous access. In the V325 study, the triple-drug combination of docetaxel, cisplatin, and 5-FU (DCF) was superior to cisplatin plus 5-FU, although at the risk of considerable toxicity. The high rate of toxicity (complicated neutropenia, 29%; diarrhea, 19%) with this regimen has tempered enthusiasm for its use in the palliative setting and modifications to the doses and schedules of the drugs have been investigated. A modified DCF (mDCF) regimen with dose attenuations in cisplatin and docetaxel along with a shortened infusion 5-FU schedule was tested in a multicenter phase II trial with an impressive response rate of 52% in the 41 evaluable patients assigned to the mDCF arm. The 6-month progression-free survival (PFS) was 57% (95% confidence interval [CI], 37–73) and the median overall survival (OS) was 15.1 months (95% CI, 9–25). Other regimens that are frequently used include irinotecan in combination with cisplatin or leucovorin-modulated 5-FU (FOLFIRI). Combinations of oxaliplatin plus a fluoropyrimidine are well tolerated and consistently elicit response rates of 40% to 50% in metastatic gastric cancer.
In the absence of direct comparison studies, it is not clear whether the triplet combinations mentioned earlier are necessarily superior to doublet therapy when the more modern drugs including oxaliplatin, irinotecan, taxanes, capecitabine, and S-1 are used. The literature is replete with numerous phase II trials exploring different doses, schedules, and combinations of these drugs, but breaking the 1 year median survival in metastatic gastric cancer using chemotherapy has proved an elusive goal. In 2010, the ToGA (Transtuzumab for Gastric Cancer) trial reported positive results for the addition of transtuzumab to a standard platinum-fluoropyrimidine doublet in patients with Her2-positive gastric and gastroesophageal junction cancer, achieving a median survival of 13.8 months (95% CI, 12–17). This is discussed in more detail later. A brief summary of commonly used regimens in the front-line setting is provided in Table 1 . Although this is not an exhaustive list, it summarizes the options that are available, the need for individualizing therapy, and it underscores the need to build on them using chemotherapy as a backbone. Thus far, the heterogeneity of gastric cancers has not allowed for the identification of a dominant driver mutation that is amenable to drug therapy’.
| Regimens | Phase | Number of Patients | Response Rate (%) | OS (mo) |
|---|---|---|---|---|
| ECF/EOX | 3 | 1002 | 41, 48 | 9.9, 11.2 |
| DCF | 3 | 445 | 37 | 9.2 |
| mDCF | 2 | 72 | 52 | 15.1 |
| Cisplatin+capecitabine | 3 | 316 | 46 | 10.5 |
| Cisplatin/irinotecan | 2 | 38 | 58 | 9.0 |
| FOLFIRI | 2 | 136 | 40 | 11.3 |
| FOLFOX | 2 | 61 | 38 | 11.2 |
Inhibitors of angiogenesis
Angiogenesis, the process of formation of new blood vessels from existing vasculature, is fundamental to normal physiologic development and also to the development of tumors and the phenomenon of metastasis. The vascular endothelial growth factor (VEGF) family and its receptors are key mediators in angiogenesis and have been exploited as targets for therapeutic intervention. Numerous factors stimulate and regulate the VEGF/VEGFR axis, important among them being hypoxia. In addition, crosstalk with other molecular pathways adds to the complexity of this mechanism of tumorigenesis, as shown by upregulation of VEGF and neuropilin-1 expression in gastric cancer cell lines by activation of the EGFR pathway. Increased serum or tumor VEGF levels have been found to correlate with nodal metastases, liver metastases, and poor prognosis in gastric cancer. Strategies for interruption of this pathway include ligand and receptor tyrosine kinase blockade.
Monoclonal Antibodies
Bevacizumab, an anti-VEGF-A humanized monoclonal antibody, is currently approved in the United States for the treatment of colorectal cancer, lung cancer, kidney cancer, and recurrent glioblastoma. Following encouraging results from the addition of bevacizumab to chemotherapy in colorectal cancer, its evaluation in other tumors of the gastrointestinal tract was a natural and rationale succession plan. Shah and colleagues from the Memorial Sloan Kettering Cancer Institute reported an impressive 65% response rate in a phase II trial of 42 patients with advanced gastric or gastroesophageal junction (GEJ) carcinoma from the addition of bevacizumab administered on day 1 to combination cisplatin and irinotecan given on days 1 and 8 in a 21-day cycle of therapy. The median time to progression was 8.3 months (95% CI, 5.5–9.9 months) and median OS was 12.3 months (95% CI, 11.3–17.2 months). One-fourth of the patients experienced a grade 3 or 4 thromboembolic event and 28% developed grade 3 hypertension, both now well-known adverse effects of this drug. Three additional phase II trials have examined the addition of bevacizumab to different chemotherapeutic regimens reporting response rates of 42% to 67%. In the study of bevacizumab plus mDCF, the 6-month PFS was 79%, median PFS was 12 months (95% CI, 8.8–18.2 months), and median OS was 16.8 months (95% CI, 12.1–26.1 months). Patients with the diffuse variant of gastric cancer had poorer outcomes compared with proximal and GEJ tumors. Thirty-nine percent of patients developed a grade 3 or 4 thromboembolic event, although more than half of these patients were asymptomatic. This high rate of thrombotic events and the need for therapeutic anticoagulation warrant caution in the ongoing study of bevacizumab in this setting.
The AVAGAST (Avastin in Gastric Cancer) trial was an international effort that followed the phase II trials mentioned earlier to better define the role of bevacizumab in the treatment of gastric cancer. Of 917 eligible patients with locally advanced unresectable or metastatic gastric or GEJ cancer, 774 were randomized to receive a cisplatin-fluoropyrimidine (capecitabine or infusion 5-FU) doublet with or without bevacizumab administered every 21 days. The statistical plan hypothesized that the addition of the biologic agent would improve the median OS from 10 months to 12.8 months. Bevacizumab improved response rates (46% vs 37.4%, P = .0315) and median PFS (6.7 months vs 5.3 months; hazard ratio, 0.80; P = .037) but failed to significantly affect OS (12.1 months with bevacizumab plus chemotherapy vs 10.1 months for placebo plus chemotherapy, P = .1002; hazard ratio, 0.87; 95% CI, 0.73–1.03). The addition of bevacizumab did not seem to cause an increase in clinically significant toxicity apart from diarrhea and the hand-foot syndrome. The rate of thromboembolic events was more common in the placebo arm (9%) compared with the bevacizumab group (6%). The remainder toxicity profile was commensurate with what is known for this agent. Although these negative results will likely inhibit further development of bevacizumab in the treatment of gastric cancer, some interesting observations from these trials may suggest that certain populations of patients may benefit and need further study. Second-line chemotherapy was more frequently administered in the Pan-Asian population (66%) within this study cohort compared with the Pan-European (31%) and Pan-American (21%) counterparts. Patients treated in the Pan-American cohort seemed to derive benefit from the addition of bevacizumab to chemotherapy (median OS, 11.5 months vs 6.8 months for placebo; hazard ratio, 0.63; 95% CI, 0.43–0.93) compared with the Pan-Asian subgroup. This adds further credibility to the notion that there may be inherent biologic differences in gastric cancer behavior based on geographic regions of the world. The dose of bevacizumab used in AVAGAST was lower (7.5 mg/kg every 21 days) compared with the trials mentioned earlier that used 10 or 15 mg/kg every 21 days. Pooling data (n = 156) from 5 US investigator-initiated clinical trials using bevacizumab plus chemotherapy in AGC, Smyth and colleagues attempted to contrast the Western experience with the population treated on the AVAGAST trial. Significant differences were noted in the location of the primary tumor (GEJ more frequent in the United States), histology (diffuse histology less common in the United States), and presence of liver metastases (more common in the US cohort). The median OS for the diffuse gastric cancer, nondiffuse gastric cancer, and GEJ cancer was 12 months, 15 months, and 20 months respectively ( P = .02), with pooled OS of 14 months (95% CI, 12–16 months) Hence further investigation of this antibody in combination with chemotherapy in AGC learning from lessons derived from these early, hypothesis-generating trials is warranted.
All the trials listed earlier discontinued bevacizumab on progression of disease. Little is known about continuation of this agent with second-line chemotherapy or its use as part of a second-line regimen after failure of chemotherapy alone. Early stage clinical trials to this effect are ongoing. Similarly, bevacizumab is also being investigated in the context of multimodal therapy for localized gastric cancer but efficacy data are not yet available. Early reports have outlined its safety in this setting without any significant increase in the risk of perioperative complications.
Another antiangiogenic antibody that has shown promise in early study is ramucirumab. It is a fully human immunoglobulin G1 monoclonal antibody that targets the extracellular domain of VEGFR-2 with high affinity. Preclinical studies showed efficacy in several tumor types. In a phase I dose-finding study, 37 patients with solid tumors refractory to standard therapy were treated with weekly ramucirumab in doses ranging from 2 mg/kg to 16 mg/kg. Dose-limiting toxicities included hypertension, venous thrombosis, proteinuria, and vomiting. In patients with measurable disease, the response rate was 15%. One patient with gastric cancer (dose 4 mg/kg) experienced a partial response that lasted for 103 weeks. Secondary end points in this trial included pharmacodynamic marker sampling (VEGF-A, sVEGFR-1, sVEGFR-2) and measurement of perfusion and vascularity in liver metastases by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Clinical trials of ramucirumab as a single agent or in combination with paclitaxel in advanced gastric, esophageal, and GEJ cancers are currently underway.
Receptor Tyrosine Kinase Inhibitors
Unlike the monoclonal antibodies, the numerous antiangiogenic receptor tyrosine kinase inhibitors (TKI) in clinical development have multiple targets. Some of these agents include sunitinib, axitinib, pazopanib, sorafenib, and vandetanib. However, they have limited activity as single agents in gastric cancer. In 2 phase II trials, sunitinib as monotherapy after failure of first-line therapy in AGC elicited response rates of less than 5%. In both trials, the US Food and Drug Administration (FDA)–approved dosing schedule of 50 mg daily for 4 weeks followed by a break for 2 weeks was adopted. The toxicities conformed to its known profile and included myelosuppression, nausea, fatigue, anorexia, diarrhea, and stomatitis. With its limited single-agent activity, further investigation of this agent would have to involve a backbone of chemotherapy. At our institution, we are conducting a phase I trial of sunitinib added to irinotecan and leucovorin-modulated infusion 5-FU (FOLFIRI) in therapy-naïve patients with advanced gastric or GEJ carcinoma. Our initial experience led to alterations in sunitinib dosing to an intermittent schedule of 14 days in a 28-day cycle along with dose attenuation of biweekly FOLFIRI. A standard 3-plus-3 phase I design is being used with the sunitinib dose starting at 25 mg/d with escalations in increments of 12.5 mg. Pharmacokinetic parameters for sunitinib, irinotecan, and SN-38 are being measured. Accrual to this trial is currently ongoing.
The RAS-mitogen–activated protein kinase (MAPK) pathway plays a central role in regulating cellular signaling, growth, and survival. Raf is an essential serine-threonine kinase that functions as an effector downstream of Ras . The MAPK pathway has been shown to upregulate VEGF expression through hypoxia-inducible factor-1α. Sorafenib is a multitargeted TKI that inhibits activation of the MAPK pathway (by abrogating the activity of c-raf and b-raf ) and extracellular signal-regulated kinase (ERK) phosphorylation. In addition, it is a potent inhibitor of VEGFR-2 and VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and fibroblast growth factor receptor-1. Sorafenib has regulatory approval in the United States for the treatment of hepatocellular carcinoma and renal cell carcinoma. In gastric cancer xenografts, sorafenib inhibited cellular proliferation and angiogenesis. In a phase I clinical trial in gastric cancer, sorafenib was combined with capecitabine and cisplatin, achieving a response rate of 63% and an OS of 14.7 months (95% CI, 12–20 months). The dose-limiting toxicities of this combination were diarrhea and neutropenia; sorafenib at 400 mg twice daily, with capecitabine 800 mg/m 2 twice daily on days 1 to 14, and cisplatin 60 mg/m 2 on day 1 of a 21-day cycle, was the recommended dose for further study. In the Eastern Cooperative Oncology Group (ECOG) Trial 5203, sorafenib was added to docetaxel and cisplatin in therapy-naïve patients with gastric or GEJ cancer (n = 44). Eighteen of 44 patients attained a partial response (41%) with a median PFS of 5.8 months and median OS of 13.6 months. The principle toxicity was neutropenia (grades 3 and 4), seen in two-thirds of the patients treated. There were 2 treatment-related deaths in this cohort.
Other TKIs are undergoing study in AGC, including phase I evaluation of cediranib with cisplatin plus a fluoropyrimidine and phase II study of pazopanib in combination with capecitaine and oxaliplatin. Results from these trials are forthcoming.
Based on reported data, it is unlikely that the addition of antiangiogenic receptor TKIs will dramatically alter the therapeutic landscape in gastric cancer. Biomarker and pharmacodynamic end points must be mandated in future studies to establish whether there is a cohort of patients with this disease that would benefit from their addition.
Inhibitors of angiogenesis
Angiogenesis, the process of formation of new blood vessels from existing vasculature, is fundamental to normal physiologic development and also to the development of tumors and the phenomenon of metastasis. The vascular endothelial growth factor (VEGF) family and its receptors are key mediators in angiogenesis and have been exploited as targets for therapeutic intervention. Numerous factors stimulate and regulate the VEGF/VEGFR axis, important among them being hypoxia. In addition, crosstalk with other molecular pathways adds to the complexity of this mechanism of tumorigenesis, as shown by upregulation of VEGF and neuropilin-1 expression in gastric cancer cell lines by activation of the EGFR pathway. Increased serum or tumor VEGF levels have been found to correlate with nodal metastases, liver metastases, and poor prognosis in gastric cancer. Strategies for interruption of this pathway include ligand and receptor tyrosine kinase blockade.
Monoclonal Antibodies
Bevacizumab, an anti-VEGF-A humanized monoclonal antibody, is currently approved in the United States for the treatment of colorectal cancer, lung cancer, kidney cancer, and recurrent glioblastoma. Following encouraging results from the addition of bevacizumab to chemotherapy in colorectal cancer, its evaluation in other tumors of the gastrointestinal tract was a natural and rationale succession plan. Shah and colleagues from the Memorial Sloan Kettering Cancer Institute reported an impressive 65% response rate in a phase II trial of 42 patients with advanced gastric or gastroesophageal junction (GEJ) carcinoma from the addition of bevacizumab administered on day 1 to combination cisplatin and irinotecan given on days 1 and 8 in a 21-day cycle of therapy. The median time to progression was 8.3 months (95% CI, 5.5–9.9 months) and median OS was 12.3 months (95% CI, 11.3–17.2 months). One-fourth of the patients experienced a grade 3 or 4 thromboembolic event and 28% developed grade 3 hypertension, both now well-known adverse effects of this drug. Three additional phase II trials have examined the addition of bevacizumab to different chemotherapeutic regimens reporting response rates of 42% to 67%. In the study of bevacizumab plus mDCF, the 6-month PFS was 79%, median PFS was 12 months (95% CI, 8.8–18.2 months), and median OS was 16.8 months (95% CI, 12.1–26.1 months). Patients with the diffuse variant of gastric cancer had poorer outcomes compared with proximal and GEJ tumors. Thirty-nine percent of patients developed a grade 3 or 4 thromboembolic event, although more than half of these patients were asymptomatic. This high rate of thrombotic events and the need for therapeutic anticoagulation warrant caution in the ongoing study of bevacizumab in this setting.
The AVAGAST (Avastin in Gastric Cancer) trial was an international effort that followed the phase II trials mentioned earlier to better define the role of bevacizumab in the treatment of gastric cancer. Of 917 eligible patients with locally advanced unresectable or metastatic gastric or GEJ cancer, 774 were randomized to receive a cisplatin-fluoropyrimidine (capecitabine or infusion 5-FU) doublet with or without bevacizumab administered every 21 days. The statistical plan hypothesized that the addition of the biologic agent would improve the median OS from 10 months to 12.8 months. Bevacizumab improved response rates (46% vs 37.4%, P = .0315) and median PFS (6.7 months vs 5.3 months; hazard ratio, 0.80; P = .037) but failed to significantly affect OS (12.1 months with bevacizumab plus chemotherapy vs 10.1 months for placebo plus chemotherapy, P = .1002; hazard ratio, 0.87; 95% CI, 0.73–1.03). The addition of bevacizumab did not seem to cause an increase in clinically significant toxicity apart from diarrhea and the hand-foot syndrome. The rate of thromboembolic events was more common in the placebo arm (9%) compared with the bevacizumab group (6%). The remainder toxicity profile was commensurate with what is known for this agent. Although these negative results will likely inhibit further development of bevacizumab in the treatment of gastric cancer, some interesting observations from these trials may suggest that certain populations of patients may benefit and need further study. Second-line chemotherapy was more frequently administered in the Pan-Asian population (66%) within this study cohort compared with the Pan-European (31%) and Pan-American (21%) counterparts. Patients treated in the Pan-American cohort seemed to derive benefit from the addition of bevacizumab to chemotherapy (median OS, 11.5 months vs 6.8 months for placebo; hazard ratio, 0.63; 95% CI, 0.43–0.93) compared with the Pan-Asian subgroup. This adds further credibility to the notion that there may be inherent biologic differences in gastric cancer behavior based on geographic regions of the world. The dose of bevacizumab used in AVAGAST was lower (7.5 mg/kg every 21 days) compared with the trials mentioned earlier that used 10 or 15 mg/kg every 21 days. Pooling data (n = 156) from 5 US investigator-initiated clinical trials using bevacizumab plus chemotherapy in AGC, Smyth and colleagues attempted to contrast the Western experience with the population treated on the AVAGAST trial. Significant differences were noted in the location of the primary tumor (GEJ more frequent in the United States), histology (diffuse histology less common in the United States), and presence of liver metastases (more common in the US cohort). The median OS for the diffuse gastric cancer, nondiffuse gastric cancer, and GEJ cancer was 12 months, 15 months, and 20 months respectively ( P = .02), with pooled OS of 14 months (95% CI, 12–16 months) Hence further investigation of this antibody in combination with chemotherapy in AGC learning from lessons derived from these early, hypothesis-generating trials is warranted.
All the trials listed earlier discontinued bevacizumab on progression of disease. Little is known about continuation of this agent with second-line chemotherapy or its use as part of a second-line regimen after failure of chemotherapy alone. Early stage clinical trials to this effect are ongoing. Similarly, bevacizumab is also being investigated in the context of multimodal therapy for localized gastric cancer but efficacy data are not yet available. Early reports have outlined its safety in this setting without any significant increase in the risk of perioperative complications.
Another antiangiogenic antibody that has shown promise in early study is ramucirumab. It is a fully human immunoglobulin G1 monoclonal antibody that targets the extracellular domain of VEGFR-2 with high affinity. Preclinical studies showed efficacy in several tumor types. In a phase I dose-finding study, 37 patients with solid tumors refractory to standard therapy were treated with weekly ramucirumab in doses ranging from 2 mg/kg to 16 mg/kg. Dose-limiting toxicities included hypertension, venous thrombosis, proteinuria, and vomiting. In patients with measurable disease, the response rate was 15%. One patient with gastric cancer (dose 4 mg/kg) experienced a partial response that lasted for 103 weeks. Secondary end points in this trial included pharmacodynamic marker sampling (VEGF-A, sVEGFR-1, sVEGFR-2) and measurement of perfusion and vascularity in liver metastases by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Clinical trials of ramucirumab as a single agent or in combination with paclitaxel in advanced gastric, esophageal, and GEJ cancers are currently underway.
Receptor Tyrosine Kinase Inhibitors
Unlike the monoclonal antibodies, the numerous antiangiogenic receptor tyrosine kinase inhibitors (TKI) in clinical development have multiple targets. Some of these agents include sunitinib, axitinib, pazopanib, sorafenib, and vandetanib. However, they have limited activity as single agents in gastric cancer. In 2 phase II trials, sunitinib as monotherapy after failure of first-line therapy in AGC elicited response rates of less than 5%. In both trials, the US Food and Drug Administration (FDA)–approved dosing schedule of 50 mg daily for 4 weeks followed by a break for 2 weeks was adopted. The toxicities conformed to its known profile and included myelosuppression, nausea, fatigue, anorexia, diarrhea, and stomatitis. With its limited single-agent activity, further investigation of this agent would have to involve a backbone of chemotherapy. At our institution, we are conducting a phase I trial of sunitinib added to irinotecan and leucovorin-modulated infusion 5-FU (FOLFIRI) in therapy-naïve patients with advanced gastric or GEJ carcinoma. Our initial experience led to alterations in sunitinib dosing to an intermittent schedule of 14 days in a 28-day cycle along with dose attenuation of biweekly FOLFIRI. A standard 3-plus-3 phase I design is being used with the sunitinib dose starting at 25 mg/d with escalations in increments of 12.5 mg. Pharmacokinetic parameters for sunitinib, irinotecan, and SN-38 are being measured. Accrual to this trial is currently ongoing.
The RAS-mitogen–activated protein kinase (MAPK) pathway plays a central role in regulating cellular signaling, growth, and survival. Raf is an essential serine-threonine kinase that functions as an effector downstream of Ras . The MAPK pathway has been shown to upregulate VEGF expression through hypoxia-inducible factor-1α. Sorafenib is a multitargeted TKI that inhibits activation of the MAPK pathway (by abrogating the activity of c-raf and b-raf ) and extracellular signal-regulated kinase (ERK) phosphorylation. In addition, it is a potent inhibitor of VEGFR-2 and VEGFR-3, platelet-derived growth factor receptor, Flt-3, c-kit, and fibroblast growth factor receptor-1. Sorafenib has regulatory approval in the United States for the treatment of hepatocellular carcinoma and renal cell carcinoma. In gastric cancer xenografts, sorafenib inhibited cellular proliferation and angiogenesis. In a phase I clinical trial in gastric cancer, sorafenib was combined with capecitabine and cisplatin, achieving a response rate of 63% and an OS of 14.7 months (95% CI, 12–20 months). The dose-limiting toxicities of this combination were diarrhea and neutropenia; sorafenib at 400 mg twice daily, with capecitabine 800 mg/m 2 twice daily on days 1 to 14, and cisplatin 60 mg/m 2 on day 1 of a 21-day cycle, was the recommended dose for further study. In the Eastern Cooperative Oncology Group (ECOG) Trial 5203, sorafenib was added to docetaxel and cisplatin in therapy-naïve patients with gastric or GEJ cancer (n = 44). Eighteen of 44 patients attained a partial response (41%) with a median PFS of 5.8 months and median OS of 13.6 months. The principle toxicity was neutropenia (grades 3 and 4), seen in two-thirds of the patients treated. There were 2 treatment-related deaths in this cohort.
Other TKIs are undergoing study in AGC, including phase I evaluation of cediranib with cisplatin plus a fluoropyrimidine and phase II study of pazopanib in combination with capecitaine and oxaliplatin. Results from these trials are forthcoming.
Based on reported data, it is unlikely that the addition of antiangiogenic receptor TKIs will dramatically alter the therapeutic landscape in gastric cancer. Biomarker and pharmacodynamic end points must be mandated in future studies to establish whether there is a cohort of patients with this disease that would benefit from their addition.
Related posts:
Standard D2 and Modified Nodal Dissection for Gastric Adenocarcinoma
Gastrointestinal Stromal Tumors of the Stomach
Gastric Cancer Eastern Experience
Surgery for Gastric Cancer: What the Trials Indicate
Preoperative and Postoperative Chemotherapy for Gastric Cancer
Endoscopic Mucosal Resection, Endoscopic Submucosal Dissection, and Beyond: Full-Layer Resection for Gastric Cancer with Nonexposure Technique (CLEAN-NET)
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
