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Biomedical subjects

Neal J Meropol

Publications and source records attributed to Neal J Meropol.

At least 19 recordsLinked to original sources
PubMed2007

Cost of cancer care: issues and implications.

Medical technology is increasingly costly in most fields of clinical medicine. Oncology has not been spared from issues related to cost, in part resulting from the tremendous scientific progress that has lead to new tools for diagnosis, treatment, and follow-up of our patients. The increasing cost of health care in general (and cancer care in particular) raises complex questions related to its effects on our economy and the citizens of our society. This article reviews the macroeconomic principles and individual behaviors that govern medical spending, and examines how cost disproportionately affects various populations. Our overall goal is to frame debate about health policy concerns that influence the clinical practice of oncology.

Biomedical Technology↗
PubMed2007

The continuum of care: a paradigm for the management of metastatic colorectal cancer.

New agents for the treatment of metastatic colorectal cancer have extended median overall survival to more than 20 months, an increase that has changed the view of advanced colorectal cancer from an acute to a chronic condition. This article proposes a shift in treatment strategy from the concept of successive "lines" of therapy, in which chemotherapy is continued until disease progression, to that of a continuum of care, in which the use of chemotherapy is tailored to the clinical setting and includes switching chemotherapy prior to disease progression, maintenance therapy, drug "holidays," and surgical resection of metastases in selected patients. In this approach, the distinction between lines of therapy is no longer absolute. This represents a paradigm shift in the management of metastatic colorectal cancer to that of a continuum of care approach that includes individualized planning, in which patients are given the opportunity to benefit from exposure to all active agents and modalities while minimizing unnecessary treatment and toxicity, with the ultimate goal of improving survival as well as quality of life.

Antineoplastic Agents↗
PubMed2006

Patients' decision-making process regarding participation in phase I oncology research.

PURPOSE: This study assesses the decision-making process of patients enrolling in phase I oncology studies. PATIENTS AND METHODS: Participants were eligible if they had consented to participate in a phase I cancer study at one of five cancer centers, understood English, and were older than 18 years. Trained interviewers conducted structured in-person interviews. RESULTS: Of the 163 participants, 88% were white, 96% had health insurance, and 51% were college graduates or post graduates. Overall, 81% were aware of hospice, but only 6% had seriously considered hospice for themselves; 84% were aware of palliative care and 10% seriously considered it for themselves; and 7% considered getting no treatment at all. Overall, 75% reported moderate or a lot of pressure to participate in the phase I study because their cancer was growing, whereas 7% reported such pressure from the study investigators and 9% felt such pressure from their families. For 63% of patients, the most important information for decision making was that the phase I drug killed cancer cells; only 12% reported that the adverse effects of the drug(s) was the most useful information. More than 90% of patients said they would still participate in the study even if the experimental drug caused serious adverse effects, including a 10% chance of dying. CONCLUSION: Patients are aware of many alternatives to phase I studies, but do not seriously consider them. Very few experience pressure from family or researchers to participate in research. Their main goal is to fight their cancer, and almost no adverse effect, including death, would dissuade them from enrolling.

Aged↗
PubMed2006

Thymidine phosphorylase expression is associated with response to capecitabine plus irinotecan in patients with metastatic colorectal cancer.

PURPOSE: To evaluate the clinical activity and toxicity of capecitabine plus irinotecan as first-line therapy for patients with metastatic colorectal cancer (mCRC), and to describe the association of expression of thymidine phosphorylase (TP), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) with antitumor activity. PATIENTS AND METHODS: Patients with previously untreated mCRC received irinotecan days 1 and 8 intravenously, and capecitabine days 2 to 15 orally in 21-day cycles. Doses were irinotecan 125 mg/m2 and capecitabine 1,000 mg/m2 bid (n = 15; cohort 1), or irinotecan 100 mg/m2 and capecitabine 900 mg/m2 bid (n = 52; cohort 2). Tissues from primary and metastatic sites were assessed for TP, TS, and DPD gene and protein expression. RESULTS: An unacceptable level of GI toxicity in the first 15 patients led to a protocol modification in starting doses. The response rate was 45% (30 of 67 patients). Overall survival was associated with TP expression assessed by immunohistochemistry in both primary tumors (P = .045) and metastases (P = .001). Objective tumor response was associated with TP expression in primary tumors (odds ratio, 4.77; 95% CI, 1.25 to 18.18), with a similar trend in metastases (odds ratio, 8.67; 95% CI, 0.95 to 79.1). TP gene expression in primary tumors was also associated with response. CONCLUSION: These data indicate that capecitabine plus irinotecan is an active regimen against mCRC. The biomarker analysis (including metastatic tissue) was feasible in a multicenter setting, and provides preliminary evidence that TP expression may be a predictive marker for response.

Adult↗
PubMed2006

Colon carcinoma cells induce CXCL11-dependent migration of CXCR3-expressing cytotoxic T lymphocytes in organotypic culture.

Adoptive immunotherapy of cancer patients with cytolytic T lymphocytes (CTL) has been hampered by the inability of the CTL to home into tumors in vivo. Chemokines can attract T lymphocytes to the tumor site, as demonstrated in animal models, but the role of chemokines in T-lymphocyte trafficking toward human tumor cells is relatively unexplored. In the present study, the role of chemokines and their receptors in the migration of a colon carcinoma (CC) patient's CTL toward autologous tumor cells has been studied in a novel three-dimensional organotypic CC culture. CTL migration was mediated by chemokine receptor CXCR3 expressed by the CTL and CXCL11 chemokine secreted by the tumor cells. Excess CXCL11 or antibodies to CXCL11 or CXCR3 inhibited migration of CTL to tumor cells. T cell and tumor cell analyses for CXCR3 and CXCL11 expression, respectively, in ten additional CC samples, may suggest their involvement in other CC patients. Our studies, together with previous studies indicating angiostatic activity of CXCL11, suggest that CXCL11 may be useful as an immunotherapeutic agent for cancer patients when transduced into tumor cells or fused to tumor antigen-specific Ab.

Apoptosis↗
PubMed2006

Induction cisplatin and paclitaxel followed by combination chemoradiotherapy with 5-fluorouracil, cisplatin, and paclitaxel before resection in localized esophageal cancer: a phase II report.

BACKGROUND: Multimodality therapy for esophageal cancer holds promise for improving outcome in this lethal disease. On the basis of encouraging data from a phase I trial, we conducted a phase II study of preoperative chemotherapy, followed by concurrent chemoradiotherapy and surgery. METHODS: Patients with clinically staged resectable esophageal cancer were treated with induction cisplatin and paclitaxel, followed by 45 Gy of external beam radiation with concurrent infusional 5-fluorouracil and weekly cisplatin and paclitaxel. Four to eight weeks after multimodality induction, esophagectomy was performed in suitable patients. Study end points were survival, pathologic complete response, and toxicity. RESULTS: Twenty-one patients were enrolled with a median age of 58 years, and all patients were clinically staged II or III. Sixteen (76.2%) patients completed the trial, of whom four (25%) had a pathologic complete response. One patient died from postoperative complications. Grade 3 or 4 toxicity was observed in 76% of patients, and dose-limiting toxicity was seen in 6 of the first 14 patients, thus necessitating a planned dose reduction of paclitaxel. At a median follow-up of 30 months, 13 patients remain alive. The 2-year disease-specific survival for the study population was 78%. CONCLUSIONS: This regimen of multimodality therapy before resection resulted in an encouraging 2-year survival rate but a disappointing rate of pathologic complete response and was toxic, necessitating a predetermined paclitaxel dose reduction. The incorporation of taxanes into induction strategies for esophageal cancer seems promising, but the optimal schedule remains undefined.

Aged↗
PubMed2006

Phase II trial of preoperative chemoradiation with a hyperfractionated radiation boost in locally advanced rectal cancer.

PURPOSE: The purpose of this phase II study was to prospectively determine the efficacy of preoperative chemoradiation with a hyperfractionated (Hfx) RT boost to 61.8 Gy in locally advanced rectal cancer. METHODS: Eligibility stipulated that the primary lesion had to be either T4; or T3 and >4 cm or 40% of the bowel circumference. Radiation (RT) consisted of 45 Gy to the pelvis (1.8 Gy per fraction) followed by 1.2 Gy twice daily (to the gross tumor volume) to a total RT dose of 61.8 Gy. There was 5-FU infused at 1 g/m2/24 hours for 4 days during the 1st and 6th weeks of RT (concurrent with the Hfx boost). Surgical resection was planned 4 to 6 weeks later. Adjuvant chemotherapy (bolus 5-FU/leucovorin) was scheduled for 4 cycles at 28-day intervals. RESULTS: There were 22 patients, ages 22 to 81 years (median, 64) enrolled in the study. Of the 20 patients evaluable for response, 10 (50%) had evidence of clinical downstaging and 5 patients (25%) had > or =90% fibrosis in the resected specimen. With a median f/u of 40 months (7-158), the 4 years actuarial rate for all patients (n = 22) of OS was 64%, of DFS 62%, and of LC 84%. 3/21 patients (14%) had positive margins, all of whom developed a local failure (P < 0.001). CONCLUSION: This regimen of high dose preoperative chemoRT with a Hfx RT boost (to 61.8 Gy) in patients with bulky, locally advanced rectal cancer results in clinical downstaging in half of the patients with significant fibrosis in the operative specimen.

Adenocarcinoma↗
PubMed2006

Isolation and characterization of circulating tumor cells in patients with metastatic colorectal cancer.

PURPOSE: Development of targeted therapeutic agents in colorectal cancer (CRC) is impeded by the lack of a noninvasive surrogate of drug effect. This pilot study evaluated the ability of immunomagnetic separation to isolate circulating tumor cells (CTCs) and of the fluorescent microscope system and flow cytometry to enumerate and characterize CTCs from patients with metastatic CRC. PATIENTS AND METHODS: Fifty patients with metastatic CRC contributed 50 mL of blood at treatment initiation and disease evaluation timepoints. Fresh tumor specimens were obtained from 17 patients for comparison of circulating and in situ tumor cell characteristics. Epithelial cells were magnetically isolated from whole blood targeting the antiepithelial cell adhesion molecule (EpCAM). Circulating tumor cells were defined as EpCAM isolated, cytokeratin positive, nuclear stain positive, and CD45 negative. Total RNA was isolated from EpCAM-enriched CTCs and multigene reverse-transcriptase polymerase chain reaction analyses were performed. RESULTS: The median number of CTCs detected by flow cytometry was 2/7.5 mL blood. Mean change in cell count was significantly different for patients with tumor progression versus nonprogression (+6.7 vs. +0.2/7.5 mL; P = 0.001). A correlation was noted between mean fluorescence intensity (flow cytometry) of cytokeratin in CTC and matched tumor specimens (r = 0.79, P = 0.06). Nearly 80% (15 of 19) of samples with >or= 2 CTCs expressed >or= 1 epithelial marker gene (CK19, CK20, carcinoembryonic antigen, or epidermal growth factor receptor). CONCLUSION: Isolating and characterizing CTCs from patients with metastatic CRC is feasible. Change in the CTC number might reflect clinical status, and flow cytometric and gene expression data suggest similarity of circulating and in situ tumor cells. Further evaluation of CTCs for pharmacodynamic and clinical monitoring in patients with CRC is warranted.

Adult↗
PubMed2005

A phase I study of docetaxel, Cisplatin, 5-Fluorouracil and leucovorin.

OBJECTIVES: Cisplatin, 5-fluorouracil (5-FU) and docetaxel are active agents in the treatment of upper gastrointestinal malignancies. This phase I study was undertaken to determine the maximally tolerated dose and dose-limiting toxicities of a combination of these drugs given in an ambulatory setting using a bolus schedule of 5-FU. METHODS: Twenty patients with gastrointestinal malignancies were treated with docetaxel on day 1, cisplatin on day 2 and bolus 5-FU with leucovorin each day for 5 days, without prophylactic antibiotics or colony-stimulating factors. The cycle was repeated at 21-day intervals. A dose-escalating phase I design was used. RESULTS: There were two treatment-related deaths as a result of neutropenia and sepsis. The maximally tolerated dose was docetaxel at 60 mg/m2 on day 1, cisplatin at 75 mg/m2 on day 2 and 5-FU at 200 mg/m2 with leucovorin at 20 mg/m2 daily from day 1 to day 5. At this dose, neutropenia was occurring in 4 of 6 patients treated. There were three partial responses, 1 patient with esophagogastric cancer and 2 with gastric cancer. CONCLUSIONS: This regimen demonstrates efficacy in upper gastrointestinal malignancies. Strategies to improve the tolerance of these agents in combination should be pursued.

Adult↗
PubMed2005

Targeting signal transduction pathways in colorectal cancer--more than skin deep.

Colorectal cancer is the second leading cause of cancer death in the United States. The nihilism that previously often characterized the treatment of patients with this disease has been replaced by a measure of excitement, given recent therapeutic advances. These advances have been stimulated in part through identification of cellular processes characteristic of colorectal cancers that permit therapeutic targeting with favorable therapeutic index. Inhibition of the epidermal growth factor receptor in the clinic has provided proof of principle that interruption of signal transduction cascades in patients with colorectal cancer has therapeutic potential. This experience has also taught us that resistance to such rationally developed targeted therapeutic strategies is common. In this article, we review the role of signal transduction in colorectal cancer, introduce promising molecular targets, and outline therapeutic approaches under development. We will describe the barriers to success, and highlight paradigms to facilitate rapid and successful evaluation of new agents, in a clinical context that has (by virtue of recent clinical successes) become a somewhat crowded playing field.

Antineoplastic Agents↗
PubMed2005

Global gene expression profiling of circulating tumor cells.

Metastases from primary tumors are responsible for most cancer deaths. It has been shown that circulating tumor cells (CTCs) can be detected in the peripheral blood of patients with a variety of metastatic cancers and that the presence of these cells is associated with poor clinical outcomes. Characterization of CTCs in metastatic cancer patients could provide additional information to augment management of the disease. Here, we describe a novel approach for the identification of molecular markers to detect and characterize CTCs in peripheral blood. Using an integrated platform to immunomagnetically isolate and immunofluorescently detect CTCs, we obtained blood containing > or = 100 CTCs from one metastatic colorectal, one metastatic prostate, and one metastatic breast cancer patient. Using the RNA extracted from the CTC-enriched portion of the sample and comparing it with the RNA extracted from the corresponding CTC-depleted portion, for the first time, global gene expression profiles from CTCs were generated and a list of cancer-specific, CTC-specific genes was obtained. Subsequently, samples immunomagnetically enriched for CTCs from 74 metastatic cancer patients and 50 normal donors were used to confirm by quantitative real-time reverse transcription-PCR CTC-specific expression of selected genes and to show that gene expression profiles for CTCs may be used to distinguish normal donors from advanced cancer patients as well as to differentiate among the three different metastatic cancers. Genes such as AGR2, S100A14, S100A16, FABP1, and others were found useful for detection of CTCs in peripheral blood of advanced cancer patients.

Breast Neoplasms↗
PubMed2005

UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan.

PURPOSE: Capecitabine and irinotecan are commonly used in the treatment of metastatic colorectal cancer (CRC). We hypothesized that germline polymorphisms within genes related to drug target (thymidylate synthase) or metabolizing enzymes (UDP-glucuronosyltransferase, UGT) would impact response and toxicity to the combination of capecitabine plus irinotecan (CPT-11). EXPERIMENTAL DESIGN: Sixty-seven patients with measurable CRC were treated with irinotecan i.v. (100 or 125 mg/m(2)) on days 1 and 8 and capecitabine orally (900 or 1,000 mg/m(2), twice daily) on days 2 through 15 of each 3-week cycle. Genomic DNA was extracted from peripheral blood and genotyped using Pyrosequencing, GeneScan, and direct sequencing (Big Dye terminator) technologies. RESULTS: The overall objective response rate was 45% with 21 patients (31%) exhibiting grade 3 or 4 diarrhea and 3 patients (4.5%) demonstrating grade 3 or 4 neutropenia in the first two cycles. Low enzyme activity UGT1A7 genotypes, UGT1A7*2/*2 (six patients) and UGT1A7*3/*3 (seven patients), were significantly associated with antitumor response (p = 0.013) and lack of severe gastrointestinal toxicity (p = 0.003). In addition, the UGT1A9 -118 (dT)(9/9) genotype was significantly associated with reduced toxicity (p = 0.002) and increased response (p = 0.047). There were no statistically significant associations between UGT1A1, UGT1A6, or thymidylate synthase genotypes and toxicity or tumor response. CONCLUSIONS: These data strongly suggest that UGT1A7 and/or UGT1A9 genotypes may be predictors of response and toxicity in CRC patients treated with capecitabine plus irinotecan. Specifically, patients with genotypes conferring low UGT1A7 activity and/or the UGT1A9 (dT)(9/9) genotype may be particularly likely to exhibit greater antitumor response with little toxicity.

Adult↗
PubMed2005

Understanding of an aggregate probability statement by patients who are offered participation in Phase I clinical trials.

BACKGROUND: There is concern that patients with poor numeracy may have difficulty understanding the information necessary to make informed treatment decisions. The authors sought to characterize a special form of numeracy among patients with advanced cancer who were offered participation in Phase I oncology clinical trials. METHODS: Surveys were administered to 328 cancer patients who were considering Phase I trials. Their frequency-type numeracy was assessed using a multiple-choice question involving a hypothetical scenario in which a physician stated that an experimental treatment would control cancer in "40% of cases like yours." In univariate and multivariable analyses, patient characteristics that were associated with better numeracy were identified. RESULTS: The correct frequency-type interpretation was selected by 72% of respondents. Fourteen percent of respondents incorrectly selected a belief-type answer, "The doctor is 40% confident that the treatment will control my cancer." In a multivariable model, patients who answered incorrectly tended to have less formal education and less experience with experimental therapies. CONCLUSIONS: Because the misunderstandings some patients demonstrated may influence their treatment decision making adversely, it is critical to identify such patients and to give them special consideration when communicating information about potential risks and benefits of treatment.

Adult↗