David Z. J. Chu

Risk of Venous Thromboembolism With the Angiogenesis Inhibitor Bevacizumab in Cancer Patients: A Meta-analysis

CONTEXT Venous thromboembolism is one of the leading causes of morbidity and mortality in patients with cancer. Concerns have arisen regarding the risk of venous thromboembolism with the novel antiangiogenic agent bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor that is widely used in cancer treatment. Currently, the role of bevacizumab in venous thromboembolism is controversial. OBJECTIVE To assess the overall risk of venous thromboembolism associated with the use of bevacizumab, a systematic review and meta-analysis of published randomized controlled trials was performed. DATA SOURCES The databases of PubMed and Web of Science were searched for articles published in the English language from January 1966 until January 2008 and abstracts presented at American Society of Clinical Oncology conferences held between January 2000 and January 2008 were searched to identify relevant clinical trials. STUDY SELECTION AND DATA EXTRACTION Eligible studies included prospective randomized controlled trials in which standard antineoplastic therapy was used with and without bevacizumab and data on venous thromboembolism were available. Summary incidence rates, relative risks (RRs), and 95% confidence intervals (CIs) were calculated using random-effects or fixed-effects models based on the heterogeneity of included studies. DATA SYNTHESIS A total of 7956 patients with a variety of advanced solid tumors from 15 randomized controlled trials were identified and included for analysis. Among those patients receiving bevacizumab, the summary incidences of all-grade and high-grade venous thromboembolism were 11.9% (95% CI, 6.8%-19.9%) and 6.3% (95% CI, 4.8%-8.3%), respectively. Patients treated with bevacizumab had a significantly increased risk of venous thromboembolism with an RR of 1.33 (95% CI, 1.13-1.56; P < .001) compared with controls. The risk was significantly increased for both all-grade and high-grade venous thromboembolism. In addition, the risk was similarly increased for bevacizumab at 2.5 mg/kg per week (low dose; RR, 1.31 [95% CI, 1.08-1.60]; P = .007) and 5 mg/kg per week (high dose; RR, 1.31 [95% CI, 1.02-1.68]; P = .04). CONCLUSION The use of bevacizumab was significantly associated with an increased risk of developing venous thromboembolism in cancer patients receiving this drug.

Contralateral prophylactic mastectomy improves the outcome of selected patients undergoing mastectomy for breast cancer

BACKGROUND Risk factors for contralateral breast cancer (CBC) may indicate a benefit for contralateral prophylactic mastectomy (CPM) at the time of unilateral mastectomy for breast cancer. The purpose of this study is to evaluate the efficacy of CPM in preventing CBC. METHODS sixty-four patients undergoing CPM and a control group of 182 patients not undergoing CPM and matched for age, stage, surgery, chemotherapy, and hormonal therapy were retrospectively compared for CBC rate, disease-free survival, and overall survival. RESULTS Thirty-six CBCs occurred in the control group. In the CPM group, 3 CBCs were found at the time of prophylactic mastectomy, but none occurred subsequently (P = 0.005). Disease-free survival at 15 years in the CPM group was 55% (95% confidence interval [CI] 38% to 69%) versus 28% (95% CI 19% to 36%) in the control group (P = 0.01). Overall survival at 15 years was 64% (95% CI 45% to 78%) CPM versus 48% (95% CI 39% to 58%) in controls (P = 0.26). CONCLUSION CPM prevented CBC and significantly prolonged disease-free survival. Future studies will need to address risk assessment and contralateral breast cancer prevention in patients treated for early breast cancer.

Increased Risk of High-Grade Hypertension With Bevacizumab in Cancer Patients: A Meta-Analysis

BACKGROUND Hypertension is associated with the use of bevacizumab, an angiogenesis inhibitor widely used in cancer therapy. Currently, the risk of severe hypertension associated with bevacizumab is unclear. We performed a systematic review and meta-analysis of published randomized-controlled clinical trials (RCTs) to assess the risk of high-grade hypertension in cancer patients treated with bevacizumab. METHODS Databases from PUBMED, the Web of Science, and abstracts presented at the American Society of Clinical Oncology conferences until May 2009 were searched to identify relevant studies. Eligible studies included prospective RCTs in which bevacizumab was directly compared with controls in cancer patients receiving concurrent antineoplastic therapy. Summary incidence, relative risk (RR), and 95% confidence interval (CI) were calculated employing a fixed- or random-effects model based upon the heterogeneity of the included studies. RESULTS A total of 12,656 patients with a variety of tumors from 20 studies were included for the analysis. The incidence of all-grade hypertension in patients receiving bevacizumab was 23.6% (95% CI: 20.5-27.1) with 7.9% (95% CI: 6.1-10.2) being high-grade (grade 3 or 4). Patients treated with bevacizumab had a significantly increased risk of developing high-grade hypertension with an RR of 5.28 (95% CI: 4.15-6.71, P < 0.001) in comparison with controls. Even though not statistically significant, there was a trend suggesting that bevacizumab may increase the risk of hypertensive crisis (grade 4) with an RR of 3.16 (95% CI: 0.91-10.90). The increased risk of high-grade hypertension was observed in patients receiving bevacizumab at 2.5 mg/kg/week (RR = 4.78, 95% CI: 3.59-6.36) as well as 5 mg/kg/week (RR = 5.39, 95% CI: 3.68-7.90). The risk of high-grade hypertension may vary with tumor types, with RRs ranging from 2.49 (95% CI: 0.94-6.59) in patients with mesothelioma to 14.80 (95% CI: 0.92-238.51) in patients with breast cancer. CONCLUSION Bevacizumab may significantly increase the risk of high-grade hypertension in cancer patients. Close monitoring and adequate management are highly recommended to decrease cardiovascular complications.

Increased Risk of Serious Hemorrhage with Bevacizumab in Cancer Patients: A Meta-Analysis

Background: The role of the widely-used angiogenesis inhibitor bevacizumab in the development of serious hemorrhage is not well defined in cancer patients. This study was conducted to determine the overall risk of hemorrhage with bevacizumab by a systematic review and meta-analysis of randomized controlled trials (RCT). Methods: Databases from PubMed and the Web of Science from January 1966 to May 2009 and abstracts presented at the American Society of Clinical Oncology (ASCO) conferences from January 2000 to May 2009 were searched to identify relevant studies. Eligible studies included prospective RCTs in which bevacizumab was compared to controls concurrently with antineoplastic therapy. Summary incidence rates, relative risks (RR), and 95% confidence intervals (CI) were calculated employing fixed- or random-effects models. Results: A total of 12,617 patients with a variety of solid tumors from 20 RCTs were included for analysis. The incidence of all-grade hemorrhage was 30.4% (95% CI 21.5–40.9), with 3.5% (95% CI 2.2–5.7%) being high grade (grade 3–5). Overall, bevacizumab significantly increased the risk of bleeding with an RR of 2.48 (95% CI 1.93–3.18) when compared to the controls, with RRs of 3.02 (95% CI 2.42–3.78) and 2.01 (95% CI 1.43–2.83) at 5 and 2.5 mg/kg/week, respectively. Significantly increased risks for epistaxis or pulmonary hemorrhage were observed. In addition, bevacizumab significantly increased the risk of high-grade bleeding with an RR of 1.91 (95% CI 1.36–2.68). The risk of fatal bleeding was low (0.8%; 95% CI 0.4–1.7), and significantly elevated only in lung cancer (RR 5.02; 95% CI 1.52–16.66). Conclusion: Bevacizumab may significantly increase the risk of serious hemorrhage in cancer patients.

Outcome of Palliative Operations for Malignant Bowel Obstruction in Patients With Peritoneal Carcinomatosis From Nongynecological Cancer

Background:Malignant bowel obstruction (MBO) secondary to peritoneal carcinomatosis carries a grave prognosis. We evaluated clinicopathologic factors that predict outcomes after palliative operations for MBO.Methods:Data on patients undergoing laparotomy for palliation of gastrointestinal MBO at City of Hope between 1995 and 2000 were retrospectively collected. Successful palliation was defined as the ability to tolerate solid food (TSF).Results:Sixty-three patients underwent operative treatment. In 20 patients, MBO was the first presentation of disease; for others, the median disease-free interval was 15 months. The complication rate was 44%, and postoperative mortality was 15%. The median length of stay was 12 days. Twenty-nine patients (45%) were discharged from the hospital on a regular diet; 22 (76%) continued to eat until their last follow-up. Median survival was 90 days. Univariate factors for longer survival were TSF on discharge, colorectal primary, and nonmetastatic status at first diagnosis. Patients with ascites and whose cancer first presented with MBO had an inferior survival. Noncolorectal primary remained a multivariate predictor for decreased survival. TSF was predicted by the absence of ascites, an obstruction not involving the small bowel, and a preoperative albumin of >3.0 mg/dl. Multiple logistic regression analysis yielded presence of ascites and small-bowel obstruction as predictors of inability to TSF.Conclusions:Only one third of patients with MBO from peritoneal carcinomatosis will have prolonged postoperative palliation with significant, but acceptable, treatment-related morbidity. TSF at discharge is a useful predictor of continued palliation for most patients. Patients with colorectal cancer may have superior survival outcome and better palliation; others are at risk for poor outcomes, especially in the presence of ascites and MBO of small bowel. In these patients, highly selective use of laparotomy is recommended.

Revision and psychometric testing of the City of Hope Quality of Life-Ostomy Questionnaire

Purpose: Ostomies may be performed for bowel or urinary diversion, and occur in both cancer and non-cancer patients. Impact on physical, psychological, social and spiritual well-being is not unexpected, but has been minimally described in the literature. The City of Hope Quality of Life (COH-QOL)-Ostomy Questionnaire is an adult patient self-report instrument designed to assess quality of life. This report focuses on the revision and psychometric testing of this questionnaire. Patients and methods: The revised COH-QOL-Ostomy Questionnaire involved in-depth patient interviews and expert panel review. The format consisted of a 13-item disease and demographic section, a 34-item forced-choice section, and a 41-item linear analogue scaled section. A mailed survey to California members of the United Ostomy Association resulted in a 62% response rate (n = 1513). Factor analysis was conducted to refine the instrument. Construct validity involved testing a number of hypotheses identifying contrasting groups. Results: Factor analysis confirmed the conceptual framework. Reliability of subscales ranged from 0.77 to 0.90. The questionnaire discriminated between subpopulations with specific concerns. Conclusions: Overall, the analyses provide evidence for the validity and reliability of the COH-QOL-Ostomy Questionnaire as a comprehensive, multidimensional self-report questionnaire for measuring quality of life in patients with intestinal ostomies.

Indications and use of palliative surgery-results of society of surgical oncology survey

Background: Despite increasing attention to end-of-life care in oncology, palliative surgery (PS) remains poorly defined. A survey to test the definition, assess the extent of use, and evaluate attitudes and goals of surgeons regarding PS was devised.Methods: A survey of Society of Surgical Oncology (SSO) members.Results: 419 SSO members completed a 110-item survey. Surgeons estimated 21% of their cancer surgeries as palliative in nature. Forty-three percent of respondents felt PS was best defined based on pre-operative intent, 27% based on post-operative factors, and 30% on patient prognosis. Only 43% considered estimated patient survival time an important factor in defining PS, and 22% considered 5-year survival rate important. The vast majority (95%) considered tumor still evident following surgery in a patient with poor prognosis constituted PS. Most surgeons felt PS could be procedures due to generalized illness related to cancer (80%) or related to cancer treatment complications (76%). Patient symptom relief and pain relief were identified as the two most important goals in PS, with increased survival the least important.Conclusion: PS is a major portion of surgical oncology practice. Quality-of-life parameters, not patient survival, were identified as the most important goals of PS.

Pilot Trial Evaluating an 123I-Labeled 80-Kilodalton Engineered Anticarcinoembryonic Antigen Antibody Fragment (cT84.66 Minibody) in Patients with Colorectal Cancer

Purpose: The chimeric T84.66 (cT84.66) minibody is a novel engineered antibody construct (VL-linker-VH-CH3; 80 kDa) that demonstrates bivalent and high affinity (4 × 1010 m−1) binding to carcinoembryonic antigen (CEA). The variable regions (VL and VH) assemble to form the antigen-combining sites, and the protein forms dimers through self-association of the CH3 domains. In animal models, the minibody demonstrated high tumor uptake, approaching that of some intact antibodies, substantially faster clearance than intact chimeric T84.66, and superior tumor-to-blood ratios compared with the cT84.66 F(ab′)2 fragment, making it attractive for further evaluation as an imaging and therapy agent. The purpose of this pilot clinical study was to determine whether 123I-cT84.66 minibody demonstrated tumor targeting and was well tolerated as well as to begin to evaluate its biodistribution, pharmacokinetics, and immunogenicity in patients with colorectal cancer. Experimental Design: Ten patients with biopsy-proven colorectal cancer (6 newly diagnosed, 1 pelvic recurrence, 3 limited metastatic disease) were entered on this study. Each received 5–10 mCi (1 mg) of 123I-labeled minibody i.v. followed by serial nuclear scans and blood and urine sampling over the next 48–72 h. Surgery was performed immediately after the last nuclear scan. Results: Tumor imaging was observed with 123I-labeled minibody in seven of the eight patients who did not receive neoadjuvant therapy before surgery. Two patients received neoadjuvant radiation and chemotherapy, which significantly reduced tumor size before surgery and minibody infusion. At surgery, no tumor was detected in one patient and only a 2-mm focus was seen in the second patient. 123I-labeled minibody tumor targeting was not seen in either of these pretreated patients. Mean serum residence time of the minibody was 29.8 h (range, 10.9–65.4 h). No drug-related adverse reactions were observed. All 10 patients were evaluated for immune responses to the minibody, with no significant responses observed. Conclusion: This pilot study represents one of the first clinical efforts to evaluate an engineered intermediate-molecular-mass radiolabeled antibody construct directed against CEA. cT84.66 minibody demonstrates tumor targeting to colorectal cancer and a faster clearance in comparison with intact antibodies, making it appropriate for further evaluation as an imaging and therapy agent. The mean residence time of the minibody in patients is longer than predicted from murine models. We therefore plan to further evaluate its biodistribution and pharmacokinetic properties with minibody labeled with a longer-lived radionuclide, such as 111In.

A prospective evaluation of palliative outcomes for surgery of advanced malignancies.

Background: We prospectively evaluated the effectiveness of major surgery in treating symptoms of advanced malignancies.Methods: Fifty-nine patients were evaluated for major symptoms of intent to treat and were followed up until death or last clinical evaluation. Surgeons identified planned operations before surgery as either curative or palliative and estimated patient survival time. An independent observer assessed symptom relief. A palliative surgery outcome score was determined for each symptomatic patient.Results: Surgeons identified 22 operations (37%) as palliative intent and 37 (63%) as curative intent. The median overall survival time was 14.9 months and did not differ between curative and palliative operations. Surgical morbidity was high but did not differ between palliative (41%) and curative (44%) operations. Thirty-three patients (56%) were symptomatic before surgery, and major symptom resolution was achieved after surgery in 26 (79%) of 33. Good to excellent palliation, defined as a palliative surgery outcome score >70, was achieved in 64% of symptomatic patients.Conclusions: Most symptomatic patients with advanced malignancies undergoing major operations attained good to excellent symptom relief. Outcome measurements other than survival are feasible and can better define the role of surgery in multimodality palliative care. A new outcome measure to evaluate major palliative operations is proposed.

Factors predictive of the status of sentinel lymph nodes in melanoma patients from a large multicenter database.

BackgroundNumerous predictive factors for cutaneous melanoma metastases to sentinel lymph nodes have been identified; however, few have been found to be reproducibly significant. This study investigated the significance of factors for predicting regional nodal disease in cutaneous melanoma using a large multicenter database.MethodsSeventeen institutions submitted retrospective and prospective data on 3463 patients undergoing sentinel lymph node (SLN) biopsy for primary melanoma. Multiple demographic and tumor factors were analyzed for correlation with a positive SLN. Univariate and multivariate statistical analyses were performed.ResultsOf 3445 analyzable patients, 561 (16.3%) had a positive SLN biopsy. In multivariate analysis of 1526 patients with complete records for 10 variables, increasing Breslow thickness, lymphovascular invasion, ulceration, younger age, the absence of regression, and tumor location on the trunk were statistically significant predictors of a positive SLN.ConclusionsThese results confirm the predictive significance of the well-established variables of Breslow thickness, ulceration, age, and location, as well as consistently reported but less well-established variables such as lymphovascular invasion. In addition, the presence of regression was associated with a lower likelihood of a positive SLN. Consideration of multiple tumor parameters should influence the decision for SLN biopsy and the estimation of nodal metastatic disease risk.