- Email: [email protected]
Emerging Agents for the Treatment of Advanced Bladder Cancer
Seminars in Oncology Nursing, Vol 23, No, 4, Suppl 3 (November), 2007: pp S11-S14
S11
OBJECTIVES: To review the treatment options for advanced or metastatic bladder cancer, including novel agents.
DATA SOURCES: Research literature and clinical trial data.
CONCLUSION: Knowledge of current and novel therapies for the treatment of advanced or metastatic bladder cancer is essential in caring for patients in this stage of disease, for whom options are relatively limited.
EMERGING AGENTS FOR THE TREATMENT OF ADVANCED BLADDER CANCER
IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can play an important role in assessing patients for appropriate treatments, including enrollment in clinical trials of new agents.
Elizabeth Manchen, RN, MS, OCNÒ: Genitourinary Research Nurse Associate, University of Chicago, Chicago, IL. Address correspondence to Elizabeth Manchen, RN, MS, OCNÒ, Genitourinary Research Nurse Associate, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Ave, MC2115, Chicago, IL 60637; e-mail: [email protected]. uchicago.edu
Ó 2007 Elsevier Inc. All rights reserved. 0749-2081/07/2304, Suppl 3-$30.00/0 doi:10.1016/j.soncn.2007.10.008
ELIZABETH MANCHEN
T
HE FACT that patients with muscle-invasive disease have a risk of recurrence of approximately 50% has promoted the use of systemic chemotherapy for locally advanced disease. Neoadjuvant combination therapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) is the gold-standard treatment for transitional cell carcinoma (TCC) as it has been shown to improve disease-free and overall survival. Gemcitabine/ cisplatin (GC) is an acceptable alternative with a good clinical profile and less toxicity.1 Cisplatin and methotrexate, and cisplatin/ methotrexate plus vinblastine have also been used, but most centers still consider MVAC or GC the standard regimen. This approach can provide considerable symptomatic palliation in many patients and cure a very small minority. Unfortunately, the available data supporting an adjuvant approach are less compelling, primarily because of deficiencies in trial design and outcomes. For instance, the Cancer and Leukemia Group B (CALGB) 90104 trial of adjuvant therapy in T3-4 and/or pelvic node-positive TCC was closed prematurely in 2005 because of poor accrual; of the targeted enrollment of 800 patients, only 38 had been accrued after 16 months. The study was designed to evaluate doxorubicin plus gemcitabine for four cycles followed by paclitaxel plus cisplatin for four cycles, as compared with standard therapy with GC. While this rationale justifies investigation, the utility of adjuvant chemotherapy in bladder cancer remains controversial and requires further study.
TRIALS IN THE FIRST-LINE METASTATIC SETTING
T
here is a critical need to improve upon the outcomes of advanced bladder cancer. Novel agents and their combination with standard treatment regimens are being assessed in clinical trials in an attempt to fill this need. In the metastatic setting, first-line regimens under investigation include GC plus bevacizumab, GC
S12
E. MANCHEN
plus paclitaxel, gemcitabine plus vinflunine, halichondrin as monotherapy, and novel orally available targeted agents. The identification of a more effective regimen for unresectable locally advanced or metastatic disease continues to be a research goal. In the first-line metastatic setting, the addition of paclitaxel to a regimen of GC was recently evaluated in a large study by the European Organization for Research and Treatment of Cancer (EORTC). At the 2007 American Society of Clinical Oncology meeting, Bellmunt et al2 reported the results of the EORTC3098/Intergroup Study, which included 627 chemotherapy-naive patients with locally advanced (20%) or metastatic (80%) disease. Patients were randomized to gemcitabine 1,000 mg/m2 on days 1, 8, and 15 plus cisplatin 70 mg/m2 on day 2 every 28 days, or to gemcitabine 1,000 mg/m2 plus paclitaxel 80 mg/m2 on days 1 and 8 plus cisplatin on day 1, every 21 days. The study was designed to show a 4-month difference in median survival with the addition of the taxane. While response rates were higher in the paclitaxel-containing arm, progression-free and overall survival times were not improved. Response rates were 57% for the triple therapy compared with 46% for the doublet (P ¼ .02), with complete responses observed in 15% and 10%, respectively. Median survival was numerically but not statistically higher with the triple therapy (15 months vs 12.8 months), and progression-free survival was 8.8 months versus 7.7 months, respectively. In subgroup analyses, however, a significant survival benefit was seen in patients considered at low risk for progression—those with the bladder as their primary tumor site, and those with # 1 risk factor (visceral metastases and WHO performance status of 1). Overall tolerability of the two regimens was similar, although triple therapy was associated with higher rates of grade 3 or 4 neutropenic fever when compared with the doublet (12.5% vs 3.8%) and a greater need for growth factor support (17% vs 11%). However, more thrombocytopenia and bleeding were seen with the doublet (11% vs 7%). This study confirms that GC is an acceptable substitute for MVAC in the metastatic setting and provides the support for its role as the backbone chemotherapy for trials using the combination with novel agents. The Hoosier Oncology Group (Indianapolis, IN) is currently conducting a phase II trial of cisplatin, gemcitabine, and bevacizumab. Cisplatin 70 mg/m2,
gemcitabine 1,000 mg/m2, and bevacizumab 15 mg/kg are given on day 1; gemcitabine is given again on day 8, every 21 days for eight cycles until progression or unacceptable toxicity. Patients achieving stable disease have the option to continue to receive maintenance bevacizumab for a total of 12 months. (The study was suspended but was reopened June 2007.) Novel Agents A phase I/II study of halichondrin (E7389) in locally advanced or metastatic TCC is being coordinated by the California Cancer Consortium (City of Hope, Duarte, CA). Halichondrin is an antimitotic agent that inhibits tubulin polymerization and microtubule assembly, thus preventing cell reproduction. The drug is given as an intravenous bolus on days 1 and 8 of a 21-day cycle. The toxicity profile includes myelosuppression, fatigue, anorexia, and nausea. The phase I study is evaluating the safety of halichondrin in patients with moderate renal insufficiency and severe renal insufficiency. The phase II study will assess the overall response rate in all patients. Further along in development is the novel vinca alkaloid vinflunine. Vinflunine blocks cells at the G2/M phase of the cell cycle, thus interrupting cell reproduction. The drug binds weakly to the tubulin during cell reproduction, which may result in less neurotoxicity than other drugs of its class, such as vinorelbine and vincristine. The most frequent toxicities seen with vinflunine are myelosuppression, fatigue, nausea, and constipation. Vinflunine could answer an unmet need by being appropriate for the 30% of advanced bladder patients who are ineligible for cisplatin because of renal insufficiency or congestive heart failure. This, in fact, is the issue being explored in a randomized, placebo-controlled clinical trial comparing gemcitabine with or without vinflunine in patients clinically ineligible for cisplatin. The primary endpoint is progression-free survival, with secondary objectives being the evaluation of response rate, overall survival, disease control, duration of response, time to response, and safety. The study will randomize 450 treatment-naive patients with metastatic disease, stratified by performance status, age, presence of visceral metastases, and perioperative chemotherapy (Fig 1). In 2006, European investigators reported success with vinflunine as salvage therapy in a phase II study of patients with TCC.3 The study included
EMERGING AGENTS FOR ADVANCED BLADDER CANCER
Treatment D8
Treatment D1
Arm 1 (vg) R A N D O M I Z E
S13
Arm 1 (vg)
• Vinflunine 280 mg/m2 IV over 20 minutes • Gemcitabine 1000 mg/m2 IV over 30 min
Gemcitabine 1000 mg/m2 IV over 30 min
Arm 2 (pg)
Arm 2 (pg)
• Placebo (NS or D5W) IV over 20 minutes • Gemcitabine 1000 mg/m2 IV over 30 min
Gemcitabine 1000 mg/m2 IV over 30 min
Evaluate for response every 6 wks
FIGURE 1. Phase II/III vinflunine/gemcitabine versus placebo/gemcitabine in patients ineligible for CDDP (cisplatin). (Reprinted from www.cancer.gov.) 51 patients who had received systemic platinum chemotherapy either in the metastatic, adjuvant, or neoadjuvant setting. After single-agent treatment with 320 mg/m2 of vinflunine every 3 weeks, nine out of 51 patients responded, including patients with poor prognostic factors, for an overall response rate of 18%, and 67% achieved disease control (partial response plus stable disease). Median duration of response was 9.1 months, median progression-free survival was 3.0 months, and median overall survival was 6.6 months. The toxicity profile was manageable (Fig 2). While there was a high incidence of neutropenia, this was ameliorated somewhat with growth factor support. Constipation was frequently reported but was managed with over- the-counter products, was noncumulative, and reached grade 3-4 in only 8% of patients. Grade 3 nausea and vomiting was rare (4% and 6%, respectively), and serious sensory neuropathy and renal function impairment were not observed. nia pe yto nia c bo ope ia tr rom Th Neu open a i c u Le Anem n o i t pa sti igue n Co Fat n tio dra hy iting e D om a V se u Na titis a m o St pain l ia a n mi ec do Alop Ab 0
Maintenance Therapy Maintenance therapy may offer a bridge to prolonged progression-free survival, which is a meaningful end point in this tumor stage. The oral multitargeted receptor tyrosine kinase inhibitor sunitinib is being evaluated for its benefit in this setting. Sunitinib is approved by the US Food and Drug Administration for advanced renal cell cancer and gastrointestinal stromal tumor. Typical side effects include fatigue, diarrhea, mucositis, hypertension, and hand/foot skin reactions. The hypothesis in the bladder cancer setting is that sunitinib will delay if not eliminate the time to recurrence in patients who have achieved disease control (complete or partial response plus stable disease) after standard platinum-based chemotherapy in the metastatic setting. This possibility is being tested in a randomized phase II study of sunitinib given at 50 mg/day for 4 weeks followed by a 2-week break. Patients who have achieved disease control after four to six cycles of platinum-based chemotherapy will be randomized to sunitinib or placebo, and on progression will be allowed to cross over to sunitinib.
TRIALS IN THE SECOND-LINE METASTATIC SETTING
Grade 3-4 Overall incidence
P 20
40
60
80
100
Patients Experiencing Adverse Events (%)
FIGURE 2. Vinflunine salvage therapy (320 mg/m2 every 3 weeks) for patients with bladder cancer: common adverse events. (Data from Culine et al.3)
atients who relapse after responding to initial systemic therapy for metastatic disease represent an unmet need, based on their poor prognosis and the lack of proven therapeutic options in the second-line treatment setting. Novel agents are being investigated specifically for this purpose. One compound under active development is vascular endothelial growth factor (VEGF) trap
S14
E. MANCHEN
(AVE 0005). VEGF trap is a unique fusion protein combining the Fe portion of IgG1 with ligand-binding domains of VEGF receptor 1 and VEGF receptor 2, resulting in potent inhibition of angiogenesis. Potential adverse events include hypertension, proteinuria, delayed wound healing, and hypersensitivity reaction. VEGF trap is also under development for macular degeneration and diabetic macular edema via intravitreal delivery. The California Cancer Consortium is spearheading a phase II study of VEGF trap given intravenously every 2 weeks to patients with recurrent or metastatic TCC who have been treated with one prior platinum-based regimen.
ROLE OF SURGERY IN METASTATIC DISEASE
T
he benefits provided by surgery in the setting of advanced TCC continue to evolve coincident with the development of increasingly effective systemic regimens. In the advanced setting, surgery can be considered in patients with good responses to chemotherapy. However, despite a significant response rate to MVAC or other combination regimens, the median survival for patients with advanced urothelial cancers has remained at a modest 13 months. The attainment of a complete response, either with chemotherapy alone or with surgery in combination, is necessary to achieve long-term survival.4,5 Surgical intervention after chemotherapy for advanced disease is usually aimed at targeting initially unresectable local disease, involved
regional or distant lymph nodes, and visceral or soft tissue metastases. However, recurrence in sites that respond to chemotherapy is still common.6
CONCLUSION
P
atients with muscle-invasive bladder cancer have a risk of recurrence of approximately 50%, prompting studies of various chemotherapy agents and regimens for locally advanced and metastatic disease. A reasonable first-line regimen is combination therapy with MVAC or GC, which is better tolerated. The addition of bevacizumab to standard GC is also being investigated for this patient population. A recent study evaluated the addition of paclitaxel to GC, but failed to show a survival benefit except in low-risk patients. Several novel agents are under active investigation for the first-line treatment of metastatic bladder cancer, including halichondrin and vinflunine. As salvage therapy for advanced disease, single-agent vinflunine produced a high disease control rate. It is currently being investigated in combination with gemcitabine in patients clinically ineligible for cisplatin. VEGF trap is under study in the second-line treatment of advanced and metastatic disease, and sunitinib is being investigated to delay progression in patients who have achieved disease control after treatment with platinum-based agents.
REFERENCES 1. Meliani E, Lapini A, Serni S, et al. Gemcitabine plus cisplatin in adjuvant regimen for bladder cancer. Toxicity evaluation. Urol Int 2003;71:37-40. 2. Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC3098/Intergroup Study [abstract LBA5030]. J Clin Oncol 2007;25:LBA5030. 3. Culine S, Theodore C, De Santis M, et al. A phase II study of vinflunine in bladder cancer patients progressing after firstline platinum-containing regimen. Br J Cancer 2006;94: 1395-1401.
4. Dodd PM, McCaffrey JA, Herr H, et al. Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. J Clin Oncol 1999;17:2546-2552. 5. Siefker-Radtke AO, Millikan RE, Tu SM, et al. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol 2002;20:1361-1367. 6. Barjorin DF, Bochner BH, Sandler HM, et al. Changing Paradigms in Advanced Bladder Cancer. American Society of Clinical Oncology 2005 Educational Book Alexandria, VA: American Society of Clinical Oncology; 2005. pp 330-350.
S11
OBJECTIVES: To review the treatment options for advanced or metastatic bladder cancer, including novel agents.
DATA SOURCES: Research literature and clinical trial data.
CONCLUSION: Knowledge of current and novel therapies for the treatment of advanced or metastatic bladder cancer is essential in caring for patients in this stage of disease, for whom options are relatively limited.
EMERGING AGENTS FOR THE TREATMENT OF ADVANCED BLADDER CANCER
IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses can play an important role in assessing patients for appropriate treatments, including enrollment in clinical trials of new agents.
Elizabeth Manchen, RN, MS, OCNÒ: Genitourinary Research Nurse Associate, University of Chicago, Chicago, IL. Address correspondence to Elizabeth Manchen, RN, MS, OCNÒ, Genitourinary Research Nurse Associate, Section of Hematology/Oncology, University of Chicago, 5841 S. Maryland Ave, MC2115, Chicago, IL 60637; e-mail: [email protected]. uchicago.edu
Ó 2007 Elsevier Inc. All rights reserved. 0749-2081/07/2304, Suppl 3-$30.00/0 doi:10.1016/j.soncn.2007.10.008
ELIZABETH MANCHEN
T
HE FACT that patients with muscle-invasive disease have a risk of recurrence of approximately 50% has promoted the use of systemic chemotherapy for locally advanced disease. Neoadjuvant combination therapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) is the gold-standard treatment for transitional cell carcinoma (TCC) as it has been shown to improve disease-free and overall survival. Gemcitabine/ cisplatin (GC) is an acceptable alternative with a good clinical profile and less toxicity.1 Cisplatin and methotrexate, and cisplatin/ methotrexate plus vinblastine have also been used, but most centers still consider MVAC or GC the standard regimen. This approach can provide considerable symptomatic palliation in many patients and cure a very small minority. Unfortunately, the available data supporting an adjuvant approach are less compelling, primarily because of deficiencies in trial design and outcomes. For instance, the Cancer and Leukemia Group B (CALGB) 90104 trial of adjuvant therapy in T3-4 and/or pelvic node-positive TCC was closed prematurely in 2005 because of poor accrual; of the targeted enrollment of 800 patients, only 38 had been accrued after 16 months. The study was designed to evaluate doxorubicin plus gemcitabine for four cycles followed by paclitaxel plus cisplatin for four cycles, as compared with standard therapy with GC. While this rationale justifies investigation, the utility of adjuvant chemotherapy in bladder cancer remains controversial and requires further study.
TRIALS IN THE FIRST-LINE METASTATIC SETTING
T
here is a critical need to improve upon the outcomes of advanced bladder cancer. Novel agents and their combination with standard treatment regimens are being assessed in clinical trials in an attempt to fill this need. In the metastatic setting, first-line regimens under investigation include GC plus bevacizumab, GC
S12
E. MANCHEN
plus paclitaxel, gemcitabine plus vinflunine, halichondrin as monotherapy, and novel orally available targeted agents. The identification of a more effective regimen for unresectable locally advanced or metastatic disease continues to be a research goal. In the first-line metastatic setting, the addition of paclitaxel to a regimen of GC was recently evaluated in a large study by the European Organization for Research and Treatment of Cancer (EORTC). At the 2007 American Society of Clinical Oncology meeting, Bellmunt et al2 reported the results of the EORTC3098/Intergroup Study, which included 627 chemotherapy-naive patients with locally advanced (20%) or metastatic (80%) disease. Patients were randomized to gemcitabine 1,000 mg/m2 on days 1, 8, and 15 plus cisplatin 70 mg/m2 on day 2 every 28 days, or to gemcitabine 1,000 mg/m2 plus paclitaxel 80 mg/m2 on days 1 and 8 plus cisplatin on day 1, every 21 days. The study was designed to show a 4-month difference in median survival with the addition of the taxane. While response rates were higher in the paclitaxel-containing arm, progression-free and overall survival times were not improved. Response rates were 57% for the triple therapy compared with 46% for the doublet (P ¼ .02), with complete responses observed in 15% and 10%, respectively. Median survival was numerically but not statistically higher with the triple therapy (15 months vs 12.8 months), and progression-free survival was 8.8 months versus 7.7 months, respectively. In subgroup analyses, however, a significant survival benefit was seen in patients considered at low risk for progression—those with the bladder as their primary tumor site, and those with # 1 risk factor (visceral metastases and WHO performance status of 1). Overall tolerability of the two regimens was similar, although triple therapy was associated with higher rates of grade 3 or 4 neutropenic fever when compared with the doublet (12.5% vs 3.8%) and a greater need for growth factor support (17% vs 11%). However, more thrombocytopenia and bleeding were seen with the doublet (11% vs 7%). This study confirms that GC is an acceptable substitute for MVAC in the metastatic setting and provides the support for its role as the backbone chemotherapy for trials using the combination with novel agents. The Hoosier Oncology Group (Indianapolis, IN) is currently conducting a phase II trial of cisplatin, gemcitabine, and bevacizumab. Cisplatin 70 mg/m2,
gemcitabine 1,000 mg/m2, and bevacizumab 15 mg/kg are given on day 1; gemcitabine is given again on day 8, every 21 days for eight cycles until progression or unacceptable toxicity. Patients achieving stable disease have the option to continue to receive maintenance bevacizumab for a total of 12 months. (The study was suspended but was reopened June 2007.) Novel Agents A phase I/II study of halichondrin (E7389) in locally advanced or metastatic TCC is being coordinated by the California Cancer Consortium (City of Hope, Duarte, CA). Halichondrin is an antimitotic agent that inhibits tubulin polymerization and microtubule assembly, thus preventing cell reproduction. The drug is given as an intravenous bolus on days 1 and 8 of a 21-day cycle. The toxicity profile includes myelosuppression, fatigue, anorexia, and nausea. The phase I study is evaluating the safety of halichondrin in patients with moderate renal insufficiency and severe renal insufficiency. The phase II study will assess the overall response rate in all patients. Further along in development is the novel vinca alkaloid vinflunine. Vinflunine blocks cells at the G2/M phase of the cell cycle, thus interrupting cell reproduction. The drug binds weakly to the tubulin during cell reproduction, which may result in less neurotoxicity than other drugs of its class, such as vinorelbine and vincristine. The most frequent toxicities seen with vinflunine are myelosuppression, fatigue, nausea, and constipation. Vinflunine could answer an unmet need by being appropriate for the 30% of advanced bladder patients who are ineligible for cisplatin because of renal insufficiency or congestive heart failure. This, in fact, is the issue being explored in a randomized, placebo-controlled clinical trial comparing gemcitabine with or without vinflunine in patients clinically ineligible for cisplatin. The primary endpoint is progression-free survival, with secondary objectives being the evaluation of response rate, overall survival, disease control, duration of response, time to response, and safety. The study will randomize 450 treatment-naive patients with metastatic disease, stratified by performance status, age, presence of visceral metastases, and perioperative chemotherapy (Fig 1). In 2006, European investigators reported success with vinflunine as salvage therapy in a phase II study of patients with TCC.3 The study included
EMERGING AGENTS FOR ADVANCED BLADDER CANCER
Treatment D8
Treatment D1
Arm 1 (vg) R A N D O M I Z E
S13
Arm 1 (vg)
• Vinflunine 280 mg/m2 IV over 20 minutes • Gemcitabine 1000 mg/m2 IV over 30 min
Gemcitabine 1000 mg/m2 IV over 30 min
Arm 2 (pg)
Arm 2 (pg)
• Placebo (NS or D5W) IV over 20 minutes • Gemcitabine 1000 mg/m2 IV over 30 min
Gemcitabine 1000 mg/m2 IV over 30 min
Evaluate for response every 6 wks
FIGURE 1. Phase II/III vinflunine/gemcitabine versus placebo/gemcitabine in patients ineligible for CDDP (cisplatin). (Reprinted from www.cancer.gov.) 51 patients who had received systemic platinum chemotherapy either in the metastatic, adjuvant, or neoadjuvant setting. After single-agent treatment with 320 mg/m2 of vinflunine every 3 weeks, nine out of 51 patients responded, including patients with poor prognostic factors, for an overall response rate of 18%, and 67% achieved disease control (partial response plus stable disease). Median duration of response was 9.1 months, median progression-free survival was 3.0 months, and median overall survival was 6.6 months. The toxicity profile was manageable (Fig 2). While there was a high incidence of neutropenia, this was ameliorated somewhat with growth factor support. Constipation was frequently reported but was managed with over- the-counter products, was noncumulative, and reached grade 3-4 in only 8% of patients. Grade 3 nausea and vomiting was rare (4% and 6%, respectively), and serious sensory neuropathy and renal function impairment were not observed. nia pe yto nia c bo ope ia tr rom Th Neu open a i c u Le Anem n o i t pa sti igue n Co Fat n tio dra hy iting e D om a V se u Na titis a m o St pain l ia a n mi ec do Alop Ab 0
Maintenance Therapy Maintenance therapy may offer a bridge to prolonged progression-free survival, which is a meaningful end point in this tumor stage. The oral multitargeted receptor tyrosine kinase inhibitor sunitinib is being evaluated for its benefit in this setting. Sunitinib is approved by the US Food and Drug Administration for advanced renal cell cancer and gastrointestinal stromal tumor. Typical side effects include fatigue, diarrhea, mucositis, hypertension, and hand/foot skin reactions. The hypothesis in the bladder cancer setting is that sunitinib will delay if not eliminate the time to recurrence in patients who have achieved disease control (complete or partial response plus stable disease) after standard platinum-based chemotherapy in the metastatic setting. This possibility is being tested in a randomized phase II study of sunitinib given at 50 mg/day for 4 weeks followed by a 2-week break. Patients who have achieved disease control after four to six cycles of platinum-based chemotherapy will be randomized to sunitinib or placebo, and on progression will be allowed to cross over to sunitinib.
TRIALS IN THE SECOND-LINE METASTATIC SETTING
Grade 3-4 Overall incidence
P 20
40
60
80
100
Patients Experiencing Adverse Events (%)
FIGURE 2. Vinflunine salvage therapy (320 mg/m2 every 3 weeks) for patients with bladder cancer: common adverse events. (Data from Culine et al.3)
atients who relapse after responding to initial systemic therapy for metastatic disease represent an unmet need, based on their poor prognosis and the lack of proven therapeutic options in the second-line treatment setting. Novel agents are being investigated specifically for this purpose. One compound under active development is vascular endothelial growth factor (VEGF) trap
S14
E. MANCHEN
(AVE 0005). VEGF trap is a unique fusion protein combining the Fe portion of IgG1 with ligand-binding domains of VEGF receptor 1 and VEGF receptor 2, resulting in potent inhibition of angiogenesis. Potential adverse events include hypertension, proteinuria, delayed wound healing, and hypersensitivity reaction. VEGF trap is also under development for macular degeneration and diabetic macular edema via intravitreal delivery. The California Cancer Consortium is spearheading a phase II study of VEGF trap given intravenously every 2 weeks to patients with recurrent or metastatic TCC who have been treated with one prior platinum-based regimen.
ROLE OF SURGERY IN METASTATIC DISEASE
T
he benefits provided by surgery in the setting of advanced TCC continue to evolve coincident with the development of increasingly effective systemic regimens. In the advanced setting, surgery can be considered in patients with good responses to chemotherapy. However, despite a significant response rate to MVAC or other combination regimens, the median survival for patients with advanced urothelial cancers has remained at a modest 13 months. The attainment of a complete response, either with chemotherapy alone or with surgery in combination, is necessary to achieve long-term survival.4,5 Surgical intervention after chemotherapy for advanced disease is usually aimed at targeting initially unresectable local disease, involved
regional or distant lymph nodes, and visceral or soft tissue metastases. However, recurrence in sites that respond to chemotherapy is still common.6
CONCLUSION
P
atients with muscle-invasive bladder cancer have a risk of recurrence of approximately 50%, prompting studies of various chemotherapy agents and regimens for locally advanced and metastatic disease. A reasonable first-line regimen is combination therapy with MVAC or GC, which is better tolerated. The addition of bevacizumab to standard GC is also being investigated for this patient population. A recent study evaluated the addition of paclitaxel to GC, but failed to show a survival benefit except in low-risk patients. Several novel agents are under active investigation for the first-line treatment of metastatic bladder cancer, including halichondrin and vinflunine. As salvage therapy for advanced disease, single-agent vinflunine produced a high disease control rate. It is currently being investigated in combination with gemcitabine in patients clinically ineligible for cisplatin. VEGF trap is under study in the second-line treatment of advanced and metastatic disease, and sunitinib is being investigated to delay progression in patients who have achieved disease control after treatment with platinum-based agents.
REFERENCES 1. Meliani E, Lapini A, Serni S, et al. Gemcitabine plus cisplatin in adjuvant regimen for bladder cancer. Toxicity evaluation. Urol Int 2003;71:37-40. 2. Bellmunt J, von der Maase H, Mead GM, et al. Randomized phase III study comparing paclitaxel/cisplatin/gemcitabine and gemcitabine/cisplatin in patients with locally advanced or metastatic urothelial cancer without prior systemic therapy: EORTC3098/Intergroup Study [abstract LBA5030]. J Clin Oncol 2007;25:LBA5030. 3. Culine S, Theodore C, De Santis M, et al. A phase II study of vinflunine in bladder cancer patients progressing after firstline platinum-containing regimen. Br J Cancer 2006;94: 1395-1401.
4. Dodd PM, McCaffrey JA, Herr H, et al. Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. J Clin Oncol 1999;17:2546-2552. 5. Siefker-Radtke AO, Millikan RE, Tu SM, et al. Phase III trial of fluorouracil, interferon alpha-2b, and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in metastatic or unresectable urothelial cancer. J Clin Oncol 2002;20:1361-1367. 6. Barjorin DF, Bochner BH, Sandler HM, et al. Changing Paradigms in Advanced Bladder Cancer. American Society of Clinical Oncology 2005 Educational Book Alexandria, VA: American Society of Clinical Oncology; 2005. pp 330-350.