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Manisha Palta,
Pretesh Patel,
Gloria Broadwater,
Christopher Willett,
Joseph Pepek,
Douglas Tyler,
S Yousuf Zafar,
Hope Uronis, Herbert Hurwitz,
Rebekah White,
Brian Czito
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ABSTRACT: Ampullary carcinoma is a rare malignancy. Despite radical resection, survival rates remain low with high rates of local failure. We performed a single-institution outcomes analysis to define the role of concurrent chemoradiotherapy (CRT) in addition to surgery.
A retrospective analysis was performed of all patients undergoing potentially curative pancreaticoduodenectomy for adenocarcinoma of the ampulla of Vater at Duke University Hospitals between 1976 and 2009. Time-to-event analysis was performed comparing all patients who underwent surgery alone to the cohort of patients receiving CRT in addition to surgery. Local control (LC), disease-free survival (DFS), overall survival (OS), and metastases-free survival (MFS) were estimated using the Kaplan-Meier method.
A total of 137 patients with ampullary carcinoma underwent Whipple procedure. Of these, 61 patients undergoing resection received adjuvant (n = 43) or neoadjuvant (n = 18) CRT. Patients receiving chemoradiotherapy were more likely to have poorly differentiated tumors (P = .03). Of 18 patients receiving neoadjuvant therapy, 67% were downstaged on final pathology with 28% achieving pathologic complete response (pCR). With a median follow-up of 8.8 years, 3-year local control was improved in patients receiving CRT (88% vs 55%, P = .001) with trend toward 3-year DFS (66% vs 48%, P = .09) and OS (62% vs 46%, P = .074) benefit in patients receiving CRT.
Long-term survival rates are low and local failure rates high following radical resection alone. Given patterns of relapse with surgery alone and local control benefit in patients receiving CRT, the use of chemoradiotherapy in selected patients should be considered.
Annals of Surgical Oncology 11/2011; 19(5):1535-40. · 4.17 Impact Factor
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ABSTRACT: We recently reported that a partner-assisted emotional disclosure intervention for gastrointestinal cancer led to improvements in relationship quality and intimacy for couples in which the patient initially reported higher levels of holding back from discussing cancer-related concerns. The purposes of the present study were to examine outcomes at 8-week follow-up and process variables that may influence treatment effects.
One hundred thirty couples were randomly assigned to either partner-assisted emotional disclosure or an education/support control condition. Participants completed measures of relationship quality, intimacy, and psychological distress before randomization, post-treatment, and 8 weeks later. Patients in the disclosure intervention completed measures of negative affect immediately following each treatment session, and their level of expressiveness during the sessions was rated by trained observers. Data were analyzed using multilevel modeling.
Among couples in which the patient initially reported higher levels of holding back, the disclosure intervention led to improvements in relationship quality and intimacy that were maintained at 8-weeks follow-up. High levels of patient expressiveness during the disclosure sessions were associated with improvements in relationship quality and intimacy, and high levels of patient negative affect immediately following the sessions were associated with reductions in psychological distress at the post-test assessment.
For couples in which the patient tends to hold back from discussing concerns, partner-assisted emotional disclosure is a beneficial intervention leading to improvements in relationship functioning that maintain over time. Future research is needed to examine methods of enhancing intervention effects, including encouraging patient expressiveness and negative affect during the sessions.
Supportive Care in Cancer 09/2011; 20(8):1755-62. · 2.09 Impact Factor
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ABSTRACT: Preclinical studies have suggested accelerated tumor growth, local invasion, and distant metastasis after withdrawal of treatment with some antiangiogenic agents. To investigate whether discontinuation of bevacizumab treatment is associated with accelerated disease progression or increased mortality, we retrospectively analyzed five randomized, placebo-controlled phase III studies in 4,205 patients with breast, colorectal, renal, and pancreatic cancer.
Time from treatment discontinuation to progressive disease or death was analyzed in patients discontinuing bevacizumab/placebo as a result of adverse events (AEs). Mortality rates were assessed at 30, 60, 90, 120, 150, 180, and 210 days after the last bevacizumab/placebo dose in the following two groups: patients discontinuing bevacizumab/placebo as a result of AEs and patients discontinuing bevacizumab/placebo for any reason. In the same groups, time from treatment discontinuation to death was analyzed. Data on disease progression pattern were available and analyzed in four of the five studies.
In the pooled analysis, median time from discontinuation as a result of AEs to progression/death was 3.0 months (95% CI, 2.6 to 3.8 months) for placebo and 4.0 months (95% CI, 3.4 to 4.6 months) for bevacizumab (hazard ratio, 0.93; 95% CI, 0.79 to 1.10). Mortality rates from 30 days to 210 days after treatment discontinuation and time from discontinuation to death were similar in bevacizumab- and placebo-treated patients. In addition, similar patterns of disease progression were seen in bevacizumab- and placebo-treated patients.
This retrospective analysis of five placebo-controlled clinical trials does not support a decreased time to disease progression, increased mortality, or altered disease progression pattern after cessation of bevacizumab therapy.
Journal of Clinical Oncology 01/2011; 29(1):83-8. · 18.37 Impact Factor
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ABSTRACT: Bevacizumab is frequently combined with 5-fluorouracil-based chemotherapy for patients with metastatic colorectal cancer (mCRC). The relative benefit of bevacizumab in older patients has not been widely studied and is of interest.
This retrospective analysis used data from three first-line randomized controlled studies and one second-line randomized controlled study of bevacizumab plus chemotherapy in medically fit (Eastern Cooperative Oncology Group performance status 0 or 1) patients with mCRC. Overall survival (OS) and on-treatment progression-free survival (PFS) were assessed in patients aged <65, > or =65, and > or =70 years. Results were compared using unstratified hazard ratios (HRs). Grade 3-5 adverse events were also assessed.
Bevacizumab statistically significantly improved PFS [HR 0.58; 95% confidence interval (CI) 0.49-0.68] and OS (HR 0.85; 95% CI 0.74-0.97) in patients aged > or =65 years; patients aged > or =70 years had similar improvements. Benefits were consistent across the studies, irrespective of setting, bevacizumab dose, or chemotherapy regimen. Increases in thromboembolic events were observed in patients aged > or =65 and > or =70 years in the bevacizumab group compared with the control group, mainly as a result of increases in arterial thromboembolic events. No other substantial age-related increases in grade 3-5 adverse events were observed.
In medically fit older patients, bevacizumab provides similar PFS and OS benefits as in younger patients.
Journal of Cancer Research and Clinical Oncology 11/2009; 136(5):737-43. · 2.56 Impact Factor
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ABSTRACT: For patients with cancer who are married or in an intimate relationship, their relationships with their partners play a critical role in their adaptation to illness. However, cancer patients and their partners often have difficulty in talking with each other about their cancer-related concerns. Difficulties in communication ultimately may compromise both the patient-partner relationship and the patient's psychological adjustment. The current study tested the efficacy of a novel partner-assisted emotional disclosure intervention in a sample of patients with gastrointestinal (GI) cancer.
One hundred thirty patients with GI cancer and their partners were assigned randomly to receive 4 sessions of either partner-assisted emotional disclosure or a couples cancer education/support intervention. Patients and partners completed measures of relationship quality, intimacy with their partner, and psychological distress before randomization and at the end of the intervention sessions. Data were analyzed using multilevel modeling.
Compared with an education/support condition, the partner-assisted emotional disclosure condition led to improvements in relationship quality and intimacy for couples in which the patient initially reported higher levels of holding back from discussing cancer-related concerns.
Partner-assisted emotional disclosure is a novel intervention that builds on both the private emotional disclosure and the cognitive-behavioral marital literature. The results of this study suggested that this intervention may be beneficial for couples in which the patient tends to hold back from discussing concerns. The authors concluded that future research on methods of enhancing the effects of partner-assisted emotional disclosure is warranted.
Cancer 09/2009; 115(18 Suppl):4326-38. · 4.77 Impact Factor
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ABSTRACT: BACKGROUND:For patients with cancer who are married or in an intimate relationship, their relationships with their partners play a critical role in their adaptation to illness. However, cancer patients and their partners often have difficulty in talking with each other about their cancer-related concerns. Difficulties in communication ultimately may compromise both the patient-partner relationship and the patient's psychological adjustment. The current study tested the efficacy of a novel partner-assisted emotional disclosure intervention in a sample of patients with gastrointestinal (GI) cancer.METHODS:One hundred thirty patients with GI cancer and their partners were assigned randomly to receive 4 sessions of either partner-assisted emotional disclosure or a couples cancer education/support intervention. Patients and partners completed measures of relationship quality, intimacy with their partner, and psychological distress before randomization and at the end of the intervention sessions. Data were analyzed using multilevel modeling.RESULTS:Compared with an education/support condition, the partner-assisted emotional disclosure condition led to improvements in relationship quality and intimacy for couples in which the patient initially reported higher levels of holding back from discussing cancer-related concerns.CONCLUSIONS:Partner-assisted emotional disclosure is a novel intervention that builds on both the private emotional disclosure and the cognitive-behavioral marital literature. The results of this study suggested that this intervention may be beneficial for couples in which the patient tends to hold back from discussing concerns. The authors concluded that future research on methods of enhancing the effects of partner-assisted emotional disclosure is warranted. Cancer 2009;115(18 suppl):4326–38. © 2009 American Cancer Society.
Cancer 09/2009; 115(S18):4326 - 4338. · 4.77 Impact Factor
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Andrew J Armstrong,
Patricia Creel,
James Turnbull,
Cassandra Moore,
Tracy A Jaffe,
Sherri Haley,
William Petros,
Sarah Yenser,
Jon P Gockerman,
Darryl Sleep, Herbert Hurwitz,
Daniel J George
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ABSTRACT: The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer.
Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m(2) every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity.
Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m(2), 19 at 70 mg/m(2), and 4 at 75 mg/m(2)) including dose expansion at 70 mg/m(2). The maximum tolerated dose of docetaxel was 70 to 75 mg/m(2). Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy.
The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m(2). Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.
Clinical Cancer Research 11/2008; 14(19):6270-6. · 7.74 Impact Factor
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ABSTRACT: Kohne et al. [Ann Oncol 2002;13:308-317] showed that four prognostic variables can be used to classify patients with metastatic colorectal cancer (CRC) treated with 5-fluorouracil (5-FU)/leucovorin (LV) into three risk groups with different overall survival (OS). This model was applied to data from phase II/III trials of first-line bevacizumab plus 5-FU/LV with/without irinotecan (IFL).
Data on tumor sites, Eastern Cooperative Oncology Group performance status, alkaline phosphatase levels and white blood cell counts were used to classify patients into Kohne prognostic high-, intermediate- and low-risk groups. Median OS and progression-free survival (PFS) were calculated for patients receiving 5-FU/LV plus bevacizumab or placebo (n = 489) and IFL plus bevacizumab or placebo (n = 812).
Median OS was longer in 5-FU/LV/bevacizumab (11.2-22.6 months) than in the 5-FU/LV/placebo (5.7-17.5 months), and in the IFL/bevacizumab arm (14.3-22.5 months) than in the IFL/placebo arm (8.4-17.9 months) across the Kohne high-, intermediate- and low-risk groups. The addition of bevacizumab also extended median PFS across the Kohne risk groups compared with placebo.
Bevacizumab improves OS and PFS across the Kohne risk classification in patients with metastatic CRC. The Kohne model can be extended to patients treated with 5-FU/LV/bevacizumab, IFL and IFL/bevacizumab and to PFS data.
Oncology 11/2008; 75(3-4):215-23. · 2.27 Impact Factor
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ABSTRACT: Few studies identifying variables associated with prognosis after resection of colorectal liver metastases (CLM) account for treatment with multiagent chemotherapy (fluoropyrmidines with irinotecan, oxaliplatin, bevacizumab, and/or cetuximab). The objective of this retrospective study was to determine the effect of multiagent chemotherapy on long-term survival after resection of CLM.
Demographics, clinicopathologic tumor characteristics, treatments, and long-term outcomes were reviewed.
From 1996 to 2006, 230 patients underwent resection of CLM. Treatment strategies before and after resection included fluoropyrimidine monotherapy (n = 34 and n = 39), multiagent chemotherapy (n = 81 and n = 73), and observation (n = 115 and n = 118). Prehepatectomy treatment strategy was not associated with overall survival. Actuarial 4-year survival was 63%, 39%, and 40% for patients treated with multiagent chemotherapy, fluoropyrimidine monotherapy, and observation after hepatectomy, p = 0.06. Posthepatectomy multiagent chemotherapy (p = 0.04, HR 0.52 [0.27-1.03]), duration of posthepatectomy chemotherapy treatment of 2 months or longer (p = 0.05, HR 0.49 [0.25-0.99]), carcino-embryonic antigen level >10 ng/mL (p = 0.03, HR 2.09, 95% CI [1.32-3.32]), and node positive primary tumor (p = 0.002, HR 1.79 [1.06-3.02]) were associated with overall survival in multivariate analysis.
The association of posthepatectomy multiagent chemotherapy with overall survival in this retrospective study indicates the need for prospective randomized trials comparing multiagent chemotherapy and fluoropyrimidine monotherapy for CLM.
Journal of Gastrointestinal Surgery 08/2008; 13(1):74-84. · 2.83 Impact Factor
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Frank A Scappaticci,
Jamey R Skillings,
Scott N Holden,
Hans-Peter Gerber,
Kathy Miller,
Fairooz Kabbinavar,
Emily Bergsland,
James Ngai,
Eric Holmgren,
Jiuzhou Wang, Herbert Hurwitz
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ABSTRACT: Although combination treatment with bevacizumab (humanized monoclonal antibody against vascular endothelial growth factor) and chemotherapy improves survival of patients with various metastatic carcinomas, an increased risk of arterial thromboembolic events has been observed in some trials. We characterized this risk by performing post hoc analyses of randomized controlled trials that evaluated combination treatment with bevacizumab and chemotherapy versus chemotherapy alone. Low-dose aspirin was permitted in these trials, and its safety was also analyzed.
Data were pooled from five randomized controlled trials that included a total of 1745 patients with metastatic colorectal, breast, or non-small-cell lung carcinoma. The risk of an arterial or venous thromboembolic event was assessed by simple incidence rates, rates per 100 person-years, and/or hazard ratios (HRs). The association between patient characteristics and risk of an arterial thromboembolic event was investigated primarily by Cox proportional hazards regression. The relationship between low-dose aspirin and bleeding was explored by incidence rates and rates per 100 person-years.
Combined treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with increased risk for an arterial thromboembolic event (HR = 2.0, 95% confidence interval [CI] = 1.05 to 3.75; P = .031) but not for a venous thromboembolic event (HR = 0.89, 95% CI = 0.66 to 1.20; P = .44). The absolute rate of developing an arterial thromboembolism was 5.5 events per 100 person-years for those receiving combination therapy and 3.1 events per 100 person-years for those receiving chemotherapy alone (ratio = 1.8, 95% CI = 0.94 to 3.33; P = .076). Development of an arterial thromboembolic event was associated with a prior arterial thromboembolic event (P<.001) or age of 65 years or older (P = .01). Baseline or on-study aspirin use was associated with modest increases in grade 3 and 4 bleeding events in both treatment groups, from 3.6% to 4.7% for bevacizumab-treated patients and from 1.7% to 2.2% for control subjects.
Combination treatment with bevacizumab and chemotherapy, compared with chemotherapy alone, was associated with an increased risk of arterial thromboembolism but not venous thromboembolism.
CancerSpectrum Knowledge Environment 08/2007; 99(16):1232-9. · 14.07 Impact Factor
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ABSTRACT: Bevacizumab is well suited for use in combination with first- or second-line chemotherapy in the treatment of metastatic colorectal cancer because its side effects are predictable and appear not to add to the incidence or severity of the side effects of chemotherapy. Clinical trials of bevacizumab in combination with oxaliplatin-containing and 5-fluorouracil-based regimens have shown that combination therapy is well tolerated and its toxicity is not substantially greater than that of the chemotherapy alone. Preliminary data from community-based and observational studies show that the incidence and severity of adverse events with combinations of bevacizumab and newer chemotherapy regimens are similar to those in the pivotal phase III trial with irinotecan, 5-fluorouracil, and leucovorin plus bevacizumab. Across trials, these side effects include a greater risk of grade 3 hypertension and grade 1 or 2 proteinuria, a slight increase (<2 percentage points) in grade 3 or 4 bleeding, and impaired surgical wound healing in patients who undergo surgery during treatment with bevacizumab. Potentially life-threatening events (arterial thrombotic events and gastrointestinal perforation) have occurred in a small number of patients. Close patient monitoring, especially in patients who are at greater risk of adverse events, is important.
Seminars in Oncology 11/2006; 33(5 Suppl 10):S26-34. · 3.50 Impact Factor
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ABSTRACT: ZD6474 is an inhibitor of the VEGFR-2 receptor tyrosine kinase with additional activity against EGFR-1 receptor tyrosine kinases that has been shown to inhibit tumor growth and wound-induced neovascularization in pre-clinical studies and phase I clinical trials. The purpose of this study was to determine the effects of ZD6474 on breaking strength in a murine model of cutaneous wound healing.
Balb/C mice were given ZD6474 (50 or 100 mg/kg p.o.) or vehicle starting 7 days before wounding. Two full-thickness incisions were made in each mouse and closed using suture. On post-wounding day 7 or 28, laser Doppler blood flow measurements were made, and the breaking strength of the wounded skin was determined. Microvessel density measurements were performed using computer image analysis of CD31-stained sections.
Compared with controls, mice treated with ZD6474 showed a significantly reduced dose-dependent decline in breaking strength, both at POD 7 (P < 0.001) and at POD 28 (P < 0.005). Histologically, the ZD6474-treated mice showed a qualitative reduction in the degree of fibrosis and epithelial proliferation at the wound site, but no significant difference was noted between the 50 mg/kg and 100 mg/kg ZD6474-treated groups. Also, microvessel density measurements demonstrated no significant difference between groups.
In a murine model of wound healing, ZD6474 treatment did not prevent wound healing, but was associated with a reduced skin breaking strength compared with vehicle-treated controls at both 7 and 28 days post-wounding. These observations may have clinical relevance for the perioperative management of patients treated with inhibitors of angiogenesis.
Journal of Surgical Research 01/2006; 129(2):251-9. · 2.25 Impact Factor
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ABSTRACT: This study examined patterns of disclosure about cancer-related concerns between patients with GI cancer and their spouses, and associations between patient and spouse disclosure and patient adjustment, spouse adjustment, and aspects of relationship functioning. A sample of 47 patients and 45 of their spouses completed a measure of disclosure which included ratings of their level of disclosure and level of holding back from disclosure of cancer-related concerns. Patients completed a measure of quality of life, spouses completed a measure of caregiver strain, and all participants completed measures of psychological distress and relationship functioning (intimacy, empathy, and partner avoidance and criticism). Data analyses revealed that patients and spouses reported moderately high levels of disclosure and low levels of holding back, with patients reporting higher levels of disclosure than spouses. Among patients and spouses, low levels of disclosure and high levels of holding back were associated with poorer relationship functioning. There were also some indications that high levels of holding back, and to a lesser extent low levels of disclosure, were associated with increased psychological distress for both patients and spouses. However, there were no indications that patient or spouse disclosure was harmful for the other person. Considered overall, the results of this study suggest that levels of disclosure between cancer patients and their spouses may be important in understanding how they adjust as a couple to the demands of the patient's illness.
Psycho-Oncology 01/2006; 14(12):1030-42. · 3.34 Impact Factor
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ABSTRACT: This study examined the role of patient and caregiver ambivalence over emotional expression (AEE) in pain and quality of life (QOL) in a sample of 78 patients with gastrointestinal (GI) cancer. Measures of ambivalence over emotional expression as well as ratings of patient pain and pain behavior were collected from patients and caregivers. Measures of pain catastrophizing, perceptions of social support, and QOL were obtained from patients. Data analyses revealed that patients high in AEE engaged in more catastrophizing and reported higher levels of pain behaviors and poorer QOL. In addition, patients whose caregivers were high in AEE engaged in more catastrophizing, had higher levels of pain and pain behavior, and reported lower emotional well-being. Patient catastrophizing mediated the effects of both patient and caregiver AEE on some patient outcomes. Taken together, these findings suggest that emotional regulation in both patients and their caregivers may be an important factor in understanding cancer patients' experience of and coping with symptoms such as pain.
Pain 11/2005; 117(3):340-8. · 5.78 Impact Factor
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ABSTRACT: Bevacizumab (Avastin; rhuMab VEGF), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), significantly prolongs survival when added to intravenous 5-fluorouracil-based chemotherapy in first-line metastatic colorectal cancer (CRC) treatment. Because antiangiogenic agents might inhibit wound healing, we assessed postoperative wound healing complications in two randomized trials of 5 mg/kg bevacizumab in CRC treatment.
We assessed the wound healing complications in patients who: (1) underwent cancer surgery 28-60 days before study treatment and (2) underwent major surgery during study treatment. Cases were reviewed for wound healing complications occurring < or = 60 days after surgery.
With cancer surgery 28-60 days before study treatment, wound healing complications occurred in 3/230 (1.3%) bevacizumab-treated patients and 1/194 (0.5%) control patients. With major surgery during study treatment, 10/75 bevacizumab-treated patients (13%) and 1/29 control patients (3.4%) had wound healing complications. Bevacizumab-treated patients experienced complications with surgery < or = 30 and 31-60 days after the last dose.
Bevacizumab administered in combination with 5-fluorouracil/leucovorin-based chemotherapy 28-60 days after primary cancer surgery caused no increased risk of wound healing complications compared with chemotherapy alone. While wound healing complications were increased in patients who had major surgery during bevacizumab therapy, the majority of bevacizumab-treated patients experienced no complications.
Journal of Surgical Oncology 10/2005; 91(3):173-80. · 2.10 Impact Factor
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Herbert Hurwitz
The Oncologist 06/2005; 10(5):320-2. · 3.91 Impact Factor
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ABSTRACT: For several decades, 5-fluorouracil (5-FU) with or without leucovorin defined the standard of care for the treatment of metastatic colorectal cancer (CRC). The addition of other chemotherapy regimens to 5-FU has improved survival, but often at the expense of increased toxicity. Recent advances in our understanding of the molecular basis of CRC have led to the production of novel targeted agents, such as bevacizumab (Avastin). Bevacizumab is currently approved for the first-line treatment of metastatic CRC and is currently being tested in combination with standard therapies for a range of indications. Phase II/III trials have demonstrated that the addition of bevacizumab to 5-FU-based first-line chemotherapy improves survival, progression-free survival and response rate compared with chemotherapy alone. Combination therapy does not appear to exacerbate side effects known to be associated with the chemotherapy regimen. The most common side effects attributable to bevacizumab therapy include hypertension, proteinuria and bleeding. Although uncommon, gastrointestinal perforation and arterial thromobembolic events are the most serious side effects reported to date. Bevacizumab is currently being evaluated in combination with oxaliplatin (Eloxatin)-based therapies and preliminary data are encouraging. Ongoing trials of bevacizumab in combination with standard first-line chemotherapy regimens will evaluate bevacizumab's potential in a range of cancer types. .
Oncology 02/2005; 69 Suppl 3:17-24. · 2.27 Impact Factor
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Herbert Hurwitz
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ABSTRACT: Recent advances in the treatment of colorectal cancer (CRC) include the incorporation of new drugs to treat a disease where only one drug was known to be active. Oxaliplatin and irinotecan have been incorporated into 5-fluorouracil (5-FU)-based regimens where they have increased response rates and survival. Targeted therapies against the epidermal growth factor pathway and the vascular endothelial growth factor (VEGF) pathway are also on the forefront of oncology research, and are beginning to play a role in the treatment of CRC. Current research efforts are trying to optimize the integration of targeted therapies into chemotherapy regimens such as IFL (irinotecan/bolus 5-FU/leucovorin [LV]), FOLFIRI (irinotecan/infusional 5-FU/LV), and FOLFOX (oxaliplatin/infusional 5-FU/LV). In this article, the incorporation of the monoclonal antibody bevacizumab into the IFL regimen will be reviewed in detail. Bevacizumab targets VEGF-A, an important angiogenesis signaling factor commonly expressed in metastatic CRC. The addition of bevacizumab to the IFL regimen significantly increased response rates, median time to progression, and overall survival in patients receiving first-line treatment for CRC, thus leading the Food and Drug Administration to approve bevacizumab for the treatment of CRC in combination with 5-FU-based regimens. Bevacizumab treatment is associated with an increased rate of hypertension. In addition, there may be slight (1%-2%) but relevant increased risks related to gastrointestinal perforations and cardiovascular events. A modest increased risk of wound healing complications was observed in patients who underwent surgery while still receiving, or shortly after receiving, bevacizumab. Bevacizumab plus 5-FU is also a highly active first-line regimen. The role of bevacizumab with other first-line combination regimens, as well as its activity in the second-line setting, is now being determined by ongoing clinical trials.
Clinical Colorectal Cancer 11/2004; 4 Suppl 2:S62-8. · 1.68 Impact Factor
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ABSTRACT: Fibrin formation is required for tumor angiogenesis, metastasis, and invasion. D-dimer, a fibrin degradation product, is produced when crosslinked fibrin is degraded by plasmin. The current study prospectively examined D-dimer levels in patients with metastatic colorectal carcinoma treated in a Phase II randomized trial comparing bevacizumab (Avastin, Genentech, South San Francisco, CA) plus 5-fluorouracil/leucovorin (5-FU/LV) with 5-FU/LV alone.
At least one circulating D-dimer level was evaluable in 98 of the 104 previously untreated patients with metastatic colorectal carcinoma in the current trial. Plasma D-dimer levels were determined using a quantitative immunoassay kit at enrollment, before each treatment, and at the time of trial completion or disease progression.
At trial enrollment, 86 of 104 patients (88%) had elevated D-dimer levels (> 20 ng/mL), and 86 of 102 patients (84%) had elevated carcinoembryonic antigen (CEA) levels (> 3 ng/mL). Baseline D-dimer levels were correlated with the following baseline characteristics: CEA (Pearson coefficient, 0.31; P = 0.002), albumin levels (Pearson coefficient, -0.32; P = 0.002), tumor burden (Pearson coefficient, 0.30; P = 0.003), and number of metastatic sites (Pearson coefficient, 0.21; P = 0.04). At the time of progression, plasma D-dimer levels reached a maximum postbaseline value in 51 of 61 patients (84%), whereas the CEA level was at its maximum postbaseline value in 39 of 55 patients (71%). Baseline D-dimer levels were a strong predictor of overall survival on univariate analysis (P = 0.008) and multivariate analysis (P = 0.03). Overall, treatment with bevacizumab (5 mg/kg) and baseline D-dimer levels were the only predictors of overall survival (P < 0.05).
The current study indicates that fibrin remodeling is an important prognostic feature in metastatic colorectal carcinoma. D-dimer levels should be incorporated into prognostic models, and D-dimer may represent a useful biomarker for patients treated with antiangiogenic agents.
Cancer 08/2004; 101(1):77-82. · 4.77 Impact Factor
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Herbert Hurwitz,
Louis Fehrenbacher,
William Novotny,
Thomas Cartwright,
John Hainsworth,
William Heim,
Jordan Berlin,
Ari Baron,
Susan Griffing,
Eric Holmgren,
Napoleone Ferrara,
Gwen Fyfe,
Beth Rogers,
Robert Ross,
Fairooz Kabbinavar
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ABSTRACT: Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promising preclinical and clinical activity against metastatic colorectal cancer, particularly in combination with chemotherapy.
Of 813 patients with previously untreated metastatic colorectal cancer, we randomly assigned 402 to receive irinotecan, bolus fluorouracil, and leucovorin (IFL) plus bevacizumab (5 mg per kilogram of body weight every two weeks) and 411 to receive IFL plus placebo. The primary end point was overall survival. Secondary end points were progression-free survival, the response rate, the duration of the response, safety, and the quality of life.
The median duration of survival was 20.3 months in the group given IFL plus bevacizumab, as compared with 15.6 months in the group given IFL plus placebo, corresponding to a hazard ratio for death of 0.66 (P<0.001). The median duration of progression-free survival was 10.6 months in the group given IFL plus bevacizumab, as compared with 6.2 months in the group given IFL plus placebo (hazard ratio for disease progression, 0.54; P<0.001); the corresponding rates of response were 44.8 percent and 34.8 percent (P=0.004). The median duration of the response was 10.4 months in the group given IFL plus bevacizumab, as compared with 7.1 months in the group given IFL plus placebo (hazard ratio for progression, 0.62; P=0.001). Grade 3 hypertension was more common during treatment with IFL plus bevacizumab than with IFL plus placebo (11.0 percent vs. 2.3 percent) but was easily managed.
The addition of bevacizumab to fluorouracil-based combination chemotherapy results in statistically significant and clinically meaningful improvement in survival among patients with metastatic colorectal cancer.
New England Journal of Medicine 06/2004; 350(23):2335-42. · 53.30 Impact Factor
