PubMed Health⌕ Search

Biomedical subjects

Leonard B Saltz

Publications and source records attributed to Leonard B Saltz.

At least 19 recordsLinked to original sources
PubMed2006

Lack of evidence for increased operative morbidity after hepatectomy with perioperative use of bevacizumab: a matched case-control study.

BACKGROUND: Bevacizumab (bev) is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF). Perioperative bev is now commonly used in patients undergoing hepatic resection. Little is known, however, about the safety of perioperative bev use in the setting of hepatic resection. METHODS: Computerized pharmacy records were used to identify all patients who received bev between January 2004 and June 2005. Patients who underwent hepatectomy for colorectal metastases and received bev within 12 weeks of surgery were identified and compared with a group of matched historical controls. RESULTS: Thirty-two patients underwent hepatic resection of colorectal cancer metastases and received bev within the specified perioperative period. Sixteen patients received bev before surgery and 24 received bev after surgery. A subset of eight patients received bev both before and after surgery. The median time between bev administration and surgery was 6.9 weeks before (range, 3-15 weeks) and 7.4 weeks after (range, 5-15 weeks). Perioperative complications occurred in 13 patients (40.6%), two of which were considered major complications. There was no statistically significant difference in perioperative morbidity and severity of complications when compared with a set of matched controls. CONCLUSIONS: Clinical experience thus far does not indicate a statistically significantly increased risk of perioperative complications with the incorporation of bev into pre- and/or postoperative treatment paradigms. Given the long half-life of bev and the potential for anti-VEGF therapy to impede wound healing and/or liver regeneration, we continue to favor a window of 6 to 8 weeks between bev administration and surgery.

Adult↗
PubMed2006

Phase II study of sorafenib in patients with advanced hepatocellular carcinoma.

PURPOSE: This phase II study of sorafenib, an oral multikinase inhibitor that targets Raf kinase and receptor tyrosine kinases, assessed efficacy, toxicity, pharmacokinetics, and biomarkers in advanced hepatocellular carcinoma (HCC) patients. METHODS: Patients with inoperable HCC, no prior systemic treatment, and Child-Pugh (CP) A or B, received continuous, oral sorafenib 400 mg bid in 4-week cycles. Tumor response was assessed every two cycles using modified WHO criteria. Sorafenib pharmacokinetics were measured in plasma samples. Biomarker analysis included phosphorylated extracellular signal regulated kinase (pERK) in pretreatment biopsies (immunohistochemistry) and blood-cell RNA expression patterns in selected patients. RESULTS: Of 137 patients treated (male, 71%; median age, 69 years), 72% had CP A, and 28% had CP B. On the basis of independent assessment, three (2.2%) patients achieved a partial response, eight (5.8%) had a minor response, and 46 (33.6%) had stable disease for at least 16 weeks. Investigator-assessed median time to progression (TTP) was 4.2 months, and median overall survival was 9.2 months. Grade 3/4 drug-related toxicities included fatigue (9.5%), diarrhea (8.0%), and hand-foot skin reaction (5.1%). There were no significant pharmacokinetic differences between CP A and B patients. Pretreatment tumor pERK levels correlated with TTP. A panel of 18 expressed genes was identified that distinguished "nonprogressors" from "progressors" with an estimated 100% accuracy. CONCLUSION: Although single-agent sorafenib has modest efficacy in HCC, the manageable toxicity and mechanisms of action support a role for combination regimens with other anticancer agents.

Adult↗
PubMed2006

Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803.

PURPOSE: Regular physical activity reduces the risk of developing colon cancer, however, its influence on patients with established disease is unknown. PATIENTS AND METHODS: We conducted a prospective observational study of 832 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on various recreational physical activities approximately 6 months after completion of therapy and were observed for recurrence or death. To minimize bias by occult recurrence, we excluded patients who experienced recurrence or died within 90 days of their physical activity assessment. RESULTS: Compared with patients engaged in less than three metabolic equivalent task (MET) -hours per week of physical activity, the adjusted hazard ratio for disease-free survival was 0.51 (95% CI, 0.26 to 0.97) for 18 to 26.9 MET-hours per week and 0.55 (95% CI, 0.33 to 0.91) for 27 or more MET-hours per week. The adjusted P for trend was .01. Postdiagnosis activity was associated with similar improvements in recurrence-free survival (P for trend = .03) and overall survival (P for trend = .01). The benefit associated with physical activity was not significantly modified by sex, body mass index, number of positive lymph nodes, age, baseline performance status, or chemotherapy received. Moreover, the benefit remained unchanged even after excluding participants who developed cancer recurrence or died within 6 months of activity assessment. CONCLUSION: Beyond surgical resection and postoperative adjuvant chemotherapy for stage III colon cancer, for patients who survive and are recurrence free approximately 6 months after adjuvant chemotherapy, physical activity appears to reduce the risk of cancer recurrence and mortality.

Aged↗
PubMed2006

Comparison of two antibodies for immunohistochemical evaluation of epidermal growth factor receptor expression in colorectal carcinomas, adenomas, and normal mucosa.

BACKGROUND: Immunohistochemical staining for epidermal growth factor receptor (EGFR) has been used as a criterion for the selection of patients with colon cancer for anti-EGFR therapy. Two antibodies, the PharmDx kit and the 31G7 clone, are used commonly for immunohistochemistry by various laboratories. No comparative studies on the performance of these 2 antibodies are available. METHODS: EGFR status was evaluated in 744 tissue microarray core samples from primary and metastatic colorectal carcinomas, colorectal adenomas, and normal colorectal mucosa with both the PharmDx kit and the clone 31G7 monoclonal antibodies. The stains were compared for staining intensity by using an automated image-analysis system. The intensity of positive staining (brown color) was measured on a scale from 0 to 255. The staining intensity also was scored manually as 0, 1 +, 2 +, and 3 +. RESULTS: Statistically, the median staining intensities scored by the automated system between the 2 antibodies did not differ significantly, although, within each category of samples (normal, adenoma, carcinoma, and metastases), the PharmDx antibody staining was slightly more intense than the clone 31G7 antibody staining. There was a linear correlation between automated image-analysis and manual scoring categories. The median automated image-analysis intensity scores for the 4 manual scoring categories with the PharmDx kit were as follows: 0 staining, 67.5; 1 + staining, 75.5; 2 + staining, 89.6; and 3 + staining, 106.0. The median automated image-analysis intensity scores for the 4 manual scoring categories with the clone 31G7 antibody were as follows: 0 staining, 71.3; 1 + staining, 73.6; 2 + staining, 84.6; and 3 + staining, 99.1. The classification of tumors as EGFR-negative (0 staining) or positive (1 +, 2 +, or 3 + staining) was concordant in 151 of 160 carcinomas (94.4%) with 2 antibodies using manual scoring. Five samples (3%) that scored 1 + with the PharmDx kit antibody scored 0 with the clone 31G7 antibody; whereas 4 samples (2.5%) that scored 1 + with the clone 31G7 antibody scored 0 with the PharmDx kit antibody. CONCLUSIONS: The EGFR expression results obtained by immunohistochemistry using both the EGFR PharmaDx kit and the 31G7 clone were comparable. Either antibody may be used for immunohistochemical detection of EGFR in colorectal carcinomas. In addition, manual scoring had an excellent correlation with automated scoring.

Adenocarcinoma↗
PubMed2005

Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer.

PURPOSE: To assess whether 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, might enhance the efficacy of neoadjuvant chemoradiation in rectal cancer. METHODS AND MATERIALS: Between 1996 and 2001, 358 patients with clinically resectable, nonmetastatic rectal cancer underwent surgery at Memorial Sloan-Kettering Cancer Center after neoadjuvant chemoradiation for either locally advanced tumors or low-lying tumors that would require abdominoperineal resection. We excluded 9 patients for radiation therapy dose <45 Gy or if statin use was unknown, leaving 349 evaluable patients. Median radiation therapy dose was 50.4 Gy (range, 45-55.8 Gy), and 308 patients (88%) received 5-fluorouracil-based chemotherapy. Medication use, comorbid illnesses, clinical stage as assessed by digital rectal examination and ultrasound, and type of chemotherapy were analyzed for associations with pathologic complete response (pCR), defined as no microscopic evidence of tumor. Fisher's exact test was used for categoric variables, Mantel-Haenszel test for ordered categoric variables, and logistic regression for multivariate analysis. RESULTS: Thirty-three patients (9%) used a statin, with no differences in clinical stage according to digital rectal examination or ultrasound compared with the other 324 patients. At the time of surgery, 23 nonstatin patients (7%) were found to have metastatic disease, compared with 0% for statin patients. The unadjusted pCR rates with and without statin use were 30% and 17%, respectively (p = 0.10). Variables significant univariately at the p = 0.15 level were entered into a multivariate model, as were nonsteroidal anti-inflammatory drugs (NSAIDs), which were strongly associated with statin use. The odds ratio for statin use on pCR was 4.2 (95% confidence interval, 1.7-12.1; p = 0.003) after adjusting for NSAID use, clinical stage, and type of chemotherapy. CONCLUSION: In multivariate analysis, statin use is associated with an improved pCR rate after neoadjuvant chemoradiation for rectal cancer. The low prevalence of statin use limits the power to detect a significant difference at a type I error threshold of p = 0.05 in this analysis. Although no definitive conclusions can be drawn on the basis of this retrospective study, the unusually high incidence of pCR after chemoradiation suggests that the use of statins in the treatment of rectal cancer warrants further evaluation.

Adult↗
PubMed2005

Metabolic signatures associated with a NAD synthesis inhibitor-induced tumor apoptosis identified by 1H-decoupled-31P magnetic resonance spectroscopy.

PURPOSE: Attempts to selectively initiate tumor cell death through inducible apoptotic pathways are increasingly being exploited as a potential anticancer strategy. Inhibition of NAD+ synthesis by a novel agent FK866 has been recently reported to induce apoptosis in human leukemia, hepatocarcinoma cells in vitro, and various types of tumor xenografts in vivo. In the present study, we used 1H-decoupled phosphorus (31P) magnetic resonance spectroscopy (MRS) to examine the metabolic changes associated with FK866 induced tumor cell death in a mouse mammary carcinoma. EXPERIMENTAL DESIGN: Induction of apoptosis in FK866-treated tumors was confirmed by histology and cytofluorometric analysis. FK866-induced changes in mammary carcinoma tumor metabolism in vivo were investigated using 1H-decoupled 31P MRS. To discern further the changes in metabolic profiles of tumors observed in vivo, high-resolution in vitro 1H-decoupled 31P MRS studies were carried out with perchloric acid extracts of mammary carcinoma tumors excised after similar treatments. In addition, the effects of FK866 on mammary carcinoma tumor growth and radiation sensitivity were studied. RESULTS: Treatment with FK866 induced a tumor growth delay and enhanced radiation sensitivity in mammary carcinoma tumors that was associated with significant increases in the 31P MR signal in the phosphomonoester region and a decrease in NAD+ levels, pH, and bioenergetic status. The 31P MRS of perchloric acid extracts of treated tumors identified the large unresolved signal in the phosphomonoester region as the resultant of resonances originating from intermediates of tumor glycolysis and guanylate synthesis in addition to alterations in pyridine nucleotide pools and phospholipid metabolism. CONCLUSION: The present results suggest that FK866 interferes with multiple biochemical pathways that contribute to the increased cell death (apoptosis) and subsequent radiation sensitivity observed in the mammary carcinoma that could be serially monitored by 31P MRS.

Acrylamides↗
PubMed2005

Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with Fluorouracil in patients with advanced solid tumors.

PURPOSE: Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with UCN-01. PATIENTS AND METHODS: FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FU, at a dose of 135 mg/m(2) over 72 hours in cycle 1 and 67.5 mg/m(2) over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymidylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction. RESULTS: We escalated the weekly FU dose to 2,600 mg/m(2) in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 micromol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines. CONCLUSION: The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m(2).

Adult↗
PubMed2005

Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry.

PURPOSE: To establish evidence of activity, or lack thereof, of cetuximab-based therapy in patients with refractory colorectal cancer with tumors that do not demonstrate epidermal growth factor receptor (EGFR) expression by immunohistochemistry (IHC). PATIENTS AND METHODS: Pharmacy computer records were reviewed to identify all patients who received cetuximab at Memorial Sloan-Kettering Cancer Center in a nonstudy setting during the first 3 months of cetuximab's commercial availability. Medical records of these patients were then reviewed to identify colorectal cancer patients who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by IHC. Pathology slides from these patients were reviewed by a reference pathologist to confirm EGFR negativity, and computed tomography scans during cetuximab-based therapy were reviewed by a reference radiologist. Response rates were reported using WHO criteria. RESULTS: Sixteen chemotherapy-refractory, EGFR-negative colorectal cancer patients who received cetuximab in a nonstudy setting were identified. Fourteen of these patients received cetuximab plus irinotecan, and two received cetuximab monotherapy. In the 16 patients, four major objective responses were seen (response rate, 25%; 95% CI, 4% to 46%). CONCLUSION: Colorectal cancer patients with EGFR-negative tumors have the potential to respond to cetuximab-based therapies. EGFR analysis by current IHC techniques does not seem to have predictive value, and selection or exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted.

Aged↗
PubMed2005

Antibody-based therapies for colorectal cancer.

The recent successful development of novel monoclonal antibodies that target key components of biologic pathways has expanded the armamentarium of treatment options for patients with colorectal cancer. Two targets in particular--the process of new blood vessel development, or angiogenesis, and the epidermal growth factor receptor and its signaling pathway--are exploited by the newest monoclonal antibodies that are available for use in colorectal cancer patients. This clinical review focuses on the defining role of the two most clinically advanced novel agents, bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, http://www.gene.com) and cetuximab (Erbitux; ImClone Systems, Inc., New York, http://www.imclone.com), in colorectal cancer.

Antibodies, Monoclonal↗
PubMed2005

Metastatic colorectal cancer: is there one standard approach?

Despite enormous advances in the treatment of colorectal cancer, there is no single standard treatment approach for all patients. However, there are general principles of management that can be used to guide therapy. The clinician who fails to individualize therapy for colorectal cancer is likely not taking full advantage of all therapeutic options available. Reviewing key clinical evidence that can help inform decision-making, this article addresses important questions in colorectal cancer management, including: Should bevacizumab (Avastin) be a component of most patients' first-line treatment? Is there a role for continuing bevacizumab in subsequent regimens? Is there a role for cetuximab (Erbitux) in standard first-line chemotherapy? Are there practices in colorectal cancer that have become widely accepted without direct supportive data?

Antibodies, Monoclonal↗
PubMed2004

Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor.

PURPOSE: To evaluate the antitumor activity and toxicity of single-agent cetuximab in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. PATIENTS AND METHODS: Phase II, open-label clinical trial. Patients were required to have EGFr expression demonstrated on formalin-fixed paraffin-embedded tumor tissue by immunohistochemical staining before study participation. Patients were required to have received irinotecan, either alone or in a combination regimen, and to have demonstrated clinical failure on this regimen before study entry. Cetuximab was administered weekly by intravenous infusion. The first dose of 400 mg/m(2) was given during the course of 2 hours. Subsequent weekly treatments were given at a dose of 250 mg/m(2) during the course of 1 hour. RESULTS: Fifty-seven eligible patients were treated. All were assessable for toxicity and response. The most commonly encountered grade 3 to 4 adverse events, regardless of relationship to study drug, were an acne-like skin rash, predominantly on the face and upper torso (86% with any grade; 18% with grade 3), and a composite of asthenia, fatigue, malaise, or lethargy (56% with any grade, 9% with grade 3). Two patients (3.5%) experienced grade 3 allergic reactions requiring discontinuation of study treatment. A third patient experienced a grade 3 allergic reaction that resolved, and the patient continued on the study. Neither diarrhea nor neutropenia were dose limiting in any of the 57 patients treated. Five patients (9%; 95% CI, 3% to 19%) achieved a partial response. Twenty-one additional patients had stable disease or minor responses. The median survival in these previously treated patients with chemotherapy-refractory colorectal cancer is 6.4 months. CONCLUSION: Cetuximab on this once-weekly schedule has modest activity and is well-tolerated as a single agent in patients with chemotherapy-refractory colorectal cancer whose tumors express the epidermal growth factor receptor. Further studies of cetuximab will evaluate the use of cetuximab in conjunction with first-line and adjuvant treatments for this disease.

Adult↗
PubMed2004

A phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for five days every three weeks to patients with metastatic adenocarcinoma of the colon or rectum.

BACKGROUND: To evaluate the antitumor activity, toxicities, and pharmacokinetics (PK) of DX-8951f administered as a 30-min infusion daily for 5 days every 3 weeks in patients with fluorouracil-resistant metastatic colorectal carcinoma. PATIENTS AND METHODS: Sixteen patients were enrolled. All had metastatic colorectal carcinoma resistant to or progressing after chemotherapy containing 5-fluorouracil and no prior chemotherapy with camptothecin derivatives. DX-8951f was administered until disease progression or unacceptable toxicity. Responses were assessed after every two courses. RESULTS: Fifteen patients were evaluable. Fifty-one courses of therapy were delivered (median 2). Responses were one minor response, six stable disease, and eight progressive disease. The principal adverse event was neutropenia, with grade 3 and 4 toxicities in three and eight patients, respectively. Non-hematologic toxicities were mild to moderate; the most common were fatigue, nausea, and diarrhea. Plasma concentrations of DX-8951 were well described using a linear two-compartment PK model. There was no evidence of nonlinearity in the elimination of PK or auto-inhibition or induction of DX-8951 clearance over the 5 days of administration. CONCLUSIONS: DX-8951f at this dose and schedule had no significant activity in this patient population. The toxicity profile, mainly hematologic, was consistent with previous reports. The clearance and volume of distribution were not different from those previously reported.

Adenocarcinoma↗
PubMed2003

The camptothecins.

Supported by detailed understanding of their mechanism of action, and facilitated by chemical manipulations that have amplified their solubility, the camptothecins have advanced to the forefront of several areas of therapeutic and developmental chemotherapy. Additive and synergistic laboratory interactions with other cytotoxic drugs have been exploited to allow development of camptothecin-based multidrug regimens, which are showing important activity in several malignancies. Topotecan and irinotecan are already in widespread use in clinical practice, and newer agents with promising preclinical activity are in various stages of clinical assessment. As knowledge of molecular and biochemical mechanisms of action and resistance continues to expand, newer and better camptothecin-based strategies for treatment of malignant disease are likely to evolve.

Animals↗
PubMed2003

Irinotecan (Campto) in the treatment of pancreatic cancer.

Irinotecan (Campto) is a topoisomerase I inhibitor currently approved for the treatment of metastatic colon cancer. Single-agent irinotecan has also demonstrated modest activity in a number of other advanced solid tumors, including lung, gastric and pancreatic cancer. Preclinical data suggest a potentially additive and/or synergistic interaction between irinotecan and gemcitabine (Gemzar). This combination has demonstrated improved response rates in patients with pancreatic cancer. Unfortunately, a recently reported Phase III trial of gemcitabine with or without irinotecan revealed no survival benefit for the combination. Future combinations of irinotecan continue to be explored in an effort to further improve the treatment of this relatively chemorefractory disease. Thus far, no single agent or combination has been shown to be superior to gemcitabine alone as palliative therapy for advanced/metastatic pancreatic cancer. A promising combination of irinotecan with oxaliplatin (Eloxatin) and fluorouracil will be assessed in a Phase III study.

Animals↗
PubMed2002

Clinical characteristics and outcomes from an institutional series of acinar cell carcinoma of the pancreas and related tumors.

PURPOSE: Acinar cell carcinoma is a rare tumor of the exocrine pancreas. Clinical features such as prognostic information, survival, and treatment outcomes are unknown. We present the largest retrospective review to date. PATIENTS AND METHODS: Thirty-nine patients with pathologically confirmed acinar neoplasms of the pancreas were identified between August 1981 and January 2001. Demographic data, tumor characteristics, and treatment information were obtained by chart review. Survival probabilities were estimated by using the Kaplan-Meier method and compared using the log-rank test. RESULTS: The median survival for all patients was 19 months. On the basis of a univariate analysis, the patients' stage of disease correlated significantly with survival. The median survival of patients with localized disease was 38 months, versus 14 months for those presenting with metastases (P = 0.03). Patients who could be treated with surgery as first-line therapy had a longer survival time (36 months) compared with those who did not have surgery (14 months). Two of 18 patients who received chemotherapy and three of eight patients who received radiation had a major response. CONCLUSION: The survival curves suggest a more aggressive cancer than pancreatic endocrine neoplasms but one that is less aggressive than ductal adenocarcinoma of the pancreas. Those patients who present with localized disease have a much better prognosis than those who present with metastases. There is a high recurrence rate after complete surgical resection, suggesting that micrometastases are present even in localized disease and that adjuvant therapies may be indicated. Chemotherapy and radiation afford disappointing results, however, and novel therapies are needed.

Adolescent↗