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Biomedical subjects

B Fisher

Publications and source records attributed to B Fisher.

At least 55 records · Page 3Linked to original sources
PubMed2000

Use of hypertonic saline in the treatment of severe refractory posttraumatic intracranial hypertension in pediatric traumatic brain injury.

OBJECTIVES: To evaluate the effect of prolonged infusion of 3% hypertonic saline (514 mEq/L) and sustained hypernatremia on refractory intracranial hypertension in pediatric traumatic brain injury patients. DESIGN: A prospective study. SETTING: A 24-bed Pediatric Intensive Care Unit (Level III) at Children's Hospital. PATIENTS: We present ten children with increased intracranial pressure (ICP) resistant to conventional therapy (head elevation at 30 degrees, normothermia, sedation, paralysis and analgesia, osmolar therapy with mannitol, loop diuretic, external ventricular drainage in five patients), controlled hyperventilation (Pco2, 28-35 mm Hg), and barbiturate coma. We continuously monitored ICP, cerebral perfusion pressure (CPP), mean arterial pressure, central venous pressure, serum sodium concentrations, serum osmolarity, and serum creatinine. INTERVENTIONS: A continuous infusion of 3% saline on a sliding scale was used to achieve a target serum sodium level that would maintain ICP <20 mm Hg once the conventional therapy and barbiturate coma as outlined above failed to control intracranial hypertension. MEASUREMENTS AND MAIN RESULTS: The mean duration of treatment with 3% saline was 7.6 days (range, 4-18 days). The mean highest serum sodium was 170.7 mEq/L (range, 157-187 mEq/L). The mean highest serum osmolarity was 364.8 mosm/L (range, 330-431 mosm/L). The mean highest serum creatinine was 1.31 mg/dL (range, 0.4-5.0 mg/dL). There was a steady increase in serum sodium versus time zero that reached statistical significance at 24, 48, and 72 hrs (p < .01). There was a statistically significant decrease in ICP spike frequency at 6, 12, 24, 48, and 72 hrs (p < .01). There was a statistically significant increase in CPP versus time zero at 6, 12, 24, 48, and 72 hrs (p < .01). There was a statistically significant increase in serum osmolarity versus time zero at 12 hrs (p < .05) and at 24, 48, and 72 hrs (p < .01). Two patients developed acute renal failure and required continuous veno-venous hemodialysis; these were concurrent with an episode of sepsis and multisystem organ dysfunction. Both recovered full renal function with no electrolyte abnormalities at the time of discharge. CONCLUSION: An increase in serum sodium concentration significantly decreases ICP and increases CPP. Hypertonic saline is an effective agent to increase serum sodium concentrations. Sustained hypernatremia and hyperosmolarity are safely tolerated in pediatric patients with traumatic brain injury. Controlled trials are needed before recommendation of widespread use.

Acute Disease↗
PubMed2000

Containment of simian immunodeficiency virus infection: cellular immune responses and protection from rechallenge following transient postinoculation antiretroviral treatment.

To better understand the viral and host factors involved in the establishment of persistent productive infection by primate lentiviruses, we varied the time of initiation and duration of postinoculation antiretroviral treatment with tenofovir (9-[2-(R)-(phosphonomethoxy)propyl]adenine) while performing intensive virologic and immunologic monitoring in rhesus macaques, inoculated intravenously with simian immunodeficiency virus SIVsmE660. Postinoculation treatment did not block the initial infection, but we identified treatment regimens that prevented the establishment of persistent productive infection, as judged by the absence of measurable plasma viremia following drug discontinuation. While immune responses were heterogeneous, animals in which treatment resulted in prevention of persistent productive infection showed a higher frequency and higher levels of SIV-specific lymphocyte proliferative responses during the treatment period compared to control animals, despite the absence of either detectable plasma viremia or seroconversion. Animals protected from the initial establishment of persistent productive infection were also relatively or completely protected from subsequent homologous rechallenge. Even postinoculation treatment regimens that did not prevent establishment of persistent infection resulted in downmodulation of the level of plasma viremia following treatment cessation, compared to the viremia seen in untreated control animals, animals treated with regimens known to be ineffective, or the cumulative experience with the natural history of plasma viremia following infection with SIVsmE660. The results suggest that the host may be able to effectively control SIV infection if the initial exposure occurs under favorable conditions of low viral burden and in the absence of ongoing high level cytopathic infection of responding cells. These findings may be particularly important in relation to prospects for control of primate lentiviruses in the settings of both prophylactic and therapeutic vaccination for prevention of AIDS.

Adenine↗
PubMed2000

Single-arm, open-label phase II study of intravenously administered tirapazamine and radiation therapy for glioblastoma multiforme.

PURPOSE: This phase II study tested the efficacy and safety of tirapazamine (Sanofi Synthelabo Research, Malvern, PA), a bioreductive agent, in glioblastoma multiforme (GBM) patients. The patients were staged according to a model constructed by a recursive partitioning analysis (RPA) of glioma patients in prior Radiation Therapy Oncology Group (RTOG) trials and compared with a matched standard population, as predicted by the model. PATIENTS AND METHODS: A total of 124 patients diagnosed with a GBM were treated with radiation therapy and intravenous tirapazamine between January 27,1995, and April 25,1997. All patients received 60 Gy in 2-Gy fractions. Tirapazamine was delivered three times a week for 12 treatments during radiotherapy. Fifty-five patients received tirapazamine at 159 mg/m(2). A second dose level, 260 mg/m(2), was opened, and 69 patients were entered. RESULTS: There was no significant survival advantage to the drug in any RPA class at either dose level. The median survival time was 10.8 months for the patient population treated with the 159-mg/m(2) dose of tirapazamine and 9.5 months for the group treated with the 260-mg/m (2) dose of tirapazamine. Survival times by RPA class for patients receiving tirapazamine at 159 mg/m(2) were 27.4 months (class III), 10.8 months (class IV), 7.9 months (class V), and 3.8 months (class VI). Survival times by RPA class for patients receiving tirapazamine at 260 mg/m(2) were 16.2 months (class III), 10.3 months (class IV), 5. 1 months (class V), and 1.3 months (class VI). Patients in RPA class III treated in the 159 mg/m(2) dose arm had a notably longer survival than patients in the RTOG database RPA class III, but the difference did not reach statistical significance. There were no fatal toxicities. Grade 3/4 toxicities were more frequent at the higher dose level. CONCLUSION: Survival in the population treated with radiation and tirapazamine was equivalent to the control population. Patients in RPA class III treated with radiation and tirapazamine at the 159-mg/m(2) dose had a longer survival when compared with the historical controls. The improvement in survival did not reach statistical significance. Toxicity was acceptable in both treatment arms, but grade 3/4 toxicities were more frequent in the higher dose regimen.

Adult↗
PubMed1999

Pretreatment factors predict overall survival for patients with low-grade glioma: a recursive partitioning analysis.

PURPOSE: Three databases were pooled and analyzed to determine which groupings of prognostic factors best predicted overall survival for patients with low-grade gliomas treated with surgery and immediate or delayed radiotherapy. METHODS AND MATERIALS: Databases of patients with low-grade gliomas compiled at the London Regional Cancer Centre (LRCC), the Norwegian Radium Hospital (NRH), and the University of California, San Francisco (UCSF) were merged. Inclusion criteria for the pooled analysis included: age > or =18 years and histologically confirmed low-grade (World Health Organization Grade II) supratentorial fibrillary astrocytoma, oligodendroglioma or mixed oligoastrocytoma. Factors analyzed for prognostic significance included: age at diagnosis, gender, seizures at presentation, presence of enhancement on computed tomography (CT) or magnetic resonance imaging (MRI), Karnofsky Performance Status (KPS) at diagnosis, histology, extent of surgical resection, timing of radiotherapy, and treating institution. Univariate and multivariate analysis of overall survival for these factors was performed. Recursive partitioning was performed to generate prognostic groups using these factors. RESULTS: From the combined databases, 401 patients were eligible for analysis. Median survival for the entire group was 95 months/7.9 years. On univariate analysis age 18-40, presence of seizures at presentation, KPS > or =70, treating institution, and absence of contrast enhancement were associated with improved overall survival. On multivariate analysis, these factors remained independent predictors of improved overall survival. Recursive partitioning analysis yielded four prognostic groups with statistically different median survivals (MS): Group I (n = 41: KPS <70, age >40) MS 12 months; Group II (n = 34: KPS > or =70, age >40, enhancement present) MS 46 months; Group III (n = 138: KPS <70, age 18-40 or KPS > or =70 age >40, no enhancement) MS 87 months; Group IV (n = 188: KPS > or =70, age 18-40) MS 128 months. CONCLUSION: Clusters of pretreatment prognostic factors described subgroups of low-grade glioma patients with divergent overall survivals. Consideration of these prognostic subgroups may be important when considering timing of interventions for these patients and in the stratification of patients for clinical trials.

Adult↗
PubMed1999

Pathologic findings from the National Surgical Adjuvant Breast Project (NSABP) eight-year update of Protocol B-17: intraductal carcinoma.

BACKGROUND: This report is an 8-year update of the authors' previous findings from National Surgical Adjuvant Breast Project (NSABP) Protocol B-17, which relates to the influence of pathologic characteristics on the natural history and treatment of intraductal carcinoma (DCIS). METHODS: Nine pathologic features observed in a pathologic subset of 623 of 814 evaluable women enrolled in this randomized clinical trial were assessed for their role in the prediction of second ipsilateral breast tumors (IBT), other events, and selection of breast irradiation (XRT) following lumpectomy. RESULTS: The frequency of subsequent IBT was reduced from 31% to 13% (P = 0.0001) by XRT. The average annual hazard rates for IBT were reduced by XRT for all pathologic features examined. Four characteristics were individually noted to be significantly related to IBT, but only moderate-to-marked and absent-to-slight comedo necrosis were found to be independent high and low risk predictors, respectively, for such an event in patients of both treatment groups. XRT effected a 7% absolute reduction at 8 years in the low risk group. Despite a relatively high incidence (approximately 40%) of IBT consisting of invasive cancer, mortality due to breast carcinoma after DCIS for the entire cohort was found to be only 1.6% at 8 years. CONCLUSIONS: The degree of comedo necrosis in patients with DCIS appears to be sufficient for discriminating between high and low risks for IBT following lumpectomy for DCIS. Although margin status, unlike in our previous report, was found to have only a slight or borderline influence on the frequency of IBT at 8 years, excision of DCIS with free margins is advised. The low risk group exhibits a statistically significant reduction of IBT from XRT. The decision to forgo XRT in the treatment of this singular subset of patients would appear to depend on clinical considerations and the input of informed patients rather than being standard practice. [See editorial on pages 375-7, this issue.]

Breast Neoplasms↗
PubMed1999

Tamoxifen in treatment of intraductal breast cancer: National Surgical Adjuvant Breast and Bowel Project B-24 randomised controlled trial.

BACKGROUND: We have shown previously that lumpectomy with radiation therapy was more effective than lumpectomy alone for the treatment of ductal carcinoma in situ (DCIS). We did a double-blind randomised controlled trial to find out whether lumpectomy, radiation therapy, and tamoxifen was of more benefit than lumpectomy and radiation therapy alone for DCIS. METHODS: 1804 women with DCIS, including those whose resected sample margins were involved with tumour, were randomly assigned lumpectomy, radiation therapy (50 Gy), and placebo (n=902), or lumpectomy, radiation therapy, and tamoxifen (20 mg daily for 5 years, n=902). Median follow-up was 74 months (range 57-93). We compared annual event rates and cumulative probability of invasive or non-invasive ipsilateral and contralateral tumours over 5 years. FINDINGS: Women in the tamoxifen group had fewer breast-cancer events at 5 years than did those on placebo (8.2 vs 13.4%, p=0.0009). The cumulative incidence of all invasive breast-cancer events in the tamoxifen group was 4.1% at 5 years: 2.1% in the ipsilateral breast, 1.8% in the contralateral breast, and 0.2% at regional or distant sites. The risk of ipsilateral-breast cancer was lower in the tamoxifen group even when sample margins contained tumour and when DCIS was associated with comedonecrosis. INTERPRETATION: The combination of lumpectomy, radiation therapy, and tamoxifen was effective in the prevention of invasive cancer.

Antineoplastic Agents, Hormonal↗
PubMed1999

From Halsted to prevention and beyond: advances in the management of breast cancer during the twentieth century.

This commentary evaluates progress made in the treatment of breast cancer during the twentieth century. Most of the period from 1900 to 1970 was governed by the 'non-science' of anecdotalism and classical inductivism and was marked by the absence of a scientific gestalt. In keeping with the Halstedian concept that breast cancer was a local disease that spread throughout the body by contiguous extension and could be cured by more expansive surgery, the disease was treated with radical surgery. In 1950, however, a new era of enlightenment began to emerge. The awareness that there was a scientific process in which hypotheses generated from laboratory and clinical investigation could be tested by means of randomised clinical trials was a seminal advance, as were findings from studies that laid the groundwork for the modern era of steroid hormone action, including identification of oestrogen receptors. Expanding knowledge regarding tumour cell kinetics, tumour heterogeneity, and technological advances related to mammography and radiation therapy were also to play a role in making possible the advances in therapy that were subsequently to occur. In the past 30 years, as a result of laboratory and clinical investigation, the Halstedian thesis of cancer surgery was displaced by an alternative hypothesis that was supported by findings from subsequent clinical trials. A new paradigm governed surgery for breast cancer, and lumpectomy followed by radiation therapy became accepted practice. A second paradigm that governed the use of adjuvant systemic therapy arose as a result of laboratory and clinical investigation. Treating patients who were free of identifiable metastatic disease with systemic adjuvant therapy because some of them might develop distant disease in the future was a revolutionary departure from prior treatment strategy and became a new exemplar. Not only did the chemotherapy favourably alter the outcome of breast cancer patients, but the anti-oestrogen tamoxifen benefited patients with all stages of the disease. Tamoxifen also reduced the incidence of contralateral breast cancer, as well as tumour in the ipsilateral breast following lumpectomy. The use of preoperative therapy was also found to enhance breast-conserving surgery in women with large tumours, although its value in other circumstances is still being defined. The observation that, as a result of tamoxifen administration, invasive and non-invasive breast cancers can be prevented in women who are at increased risk for such tumours, and the finding that pathological entities such as atypical hyperplasia, lobular carcinoma in situ (LCIS) and intraductal carcinoma (DCIS) can identify women who should be considered candidates for tamoxifen serve as a fitting capstone to the accomplishments of the twentieth century. Breast cancer prevention has now become a reality. Unfortunately, a variety of circumstances have arisen as the result of advances in the understanding and treatment of breast cancer over the last 30 years that threaten to nullify the progress that has been achieved. This distressing phenomenon may be reviewed as a 'paradox of accomplishment'. The numerous uncertainties, issues and questions that have arisen following the report of each advance in treatment, the surfeit of new information that has not yet been integrated into treatment strategies, the undesirable consequences of enhanced tumour detection, a reversion to Halstedianism and anecdotalism, and the uncertainty of therapeutic decision making resulting from the demonstration of small but statistically significant benefits, particularly in patients with good prognosis, need to be addressed. Inappropriate interpretation of those circumstances threatens to deny women with breast cancer and those at high risk for the disease the opportunity to benefit from treatments that have been proven to be of worth. Perhaps the most important accomplishment of the twentieth century relates to the change in the pro

Antineoplastic Agents, Hormonal↗
PubMed1999

Phase II study of first-line LY231514 (multi-targeted antifolate) in patients with locally advanced or metastatic colorectal cancer: an NCIC Clinical Trials Group study.

BACKGROUND: Metastatic colon cancer is difficult to treat with treatment being palliative and with little effect on survival. This trial has evaluated the effects of LY231514 (Multitargeted antifolate (MTA)) given to previously untreated patients with recurrent or metastatic colorectal carcinoma. PATIENTS AND METHODS: All patients were required to have a histological diagnosis of colorectal adenocarcinoma with measurable disease and no prior chemotherapy for metastatic disease. Patients had to have had performance status of 0-2, pretreatment absolute granulocyte count of > or = 1.5 x 10(9)/l and a platelet count of > or = 150 x 10(9)l. Patients received MTA at a dose of 600 mg/m2 by 10 minute infusion on day 1 repeated every 21 days. After the first 9 patients, this dose was reduced down to 500 mg/m2 every 21 days because of toxicity. Doses of MTA were modified depending on nadir counts. RESULTS: Thirty-two eligible patients were enrolled and twenty-nine were evaluable for response. Three patients did not have repeat radiological testing to determine response because they went off study after only one cycle of treatment due to toxicity. In the 29 evaluable patients, there was 1 complete response, 4 partial responses and 14 patients with stable disease. Response rate was 17.2% (95% confidence intervals: 5.8%-35.8%). All responses occurred in the patients receiving a starting dose of MTA 500 mg/m2. Median time to progression for all eligible patients was 3.3 months. The most common toxicities experienced were mild to moderate fever, lethargy, anorexia, nausea, vomiting, stomatitis, abdominal pain, diarrhea, and skin rash. There was one death due to sepsis. CONCLUSION: Single-agent MTA at 500 mg/m2 given every three weeks has modest activity in metastatic colorectal carcinoma.

Adenocarcinoma↗
PubMed1999

Randomized phase II study of high-dose paclitaxel with or without amifostine in patients with metastatic breast cancer.

PURPOSE: To determine whether the neurotoxicity of paclitaxel 250 mg/m(2) given over 3 hours every 3 weeks could be reduced by pretreatment with amifostine 910 mg/m(2). Secondary objectives included comparing myelosuppression, myalgias, and response rates of the two groups. PATIENTS AND METHODS: Forty women with metastatic breast cancer were randomized to receive either paclitaxel alone (arm 1) or paclitaxel preceded by amifostine (arm 2). All were assessable for toxicity, and 37 were assessable for response. At baseline and after each cycle, all patients completed questionnaires for neurologic symptoms and had standardized neurologic examinations, including objective assessments of power and vibration sense. In addition, standard follow-up assessments for other toxicities and tumor response were undertaken. Changes from baseline after courses 1, 2, and 3 were assessed. The sample size was sufficient to detect a 50% improvement in the expected determination in sensory change. RESULTS: There were no differences observed in any of the measures of neurotoxicity. Other toxicity was similar in arms 1 and 2, including hair loss (95% v 90%), neurosensory changes (100% v 100%), fatigue/lethargy (85% v 90%), myalgia (95% v 90%), and grade 4 neutropenia (47% v 60%). Nausea, vomiting, dizziness, hypotension, and sneezing were more common in the amifostine arm. Response rates (22.2% v 36.8%) and paclitaxel pharmacokinetics were not significantly different. CONCLUSION: There was no protection from paclitaxel-related neurotoxicity or hematologic toxicity in this study. These results suggest that the mechanism of action of paclitaxel-related toxic effects is not amenable to the cytoprotective action of amifostine.

Adult↗
PubMed1999

Further evaluation of intensified and increased total dose of cyclophosphamide for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-25.

PURPOSE: In 1989, the National Surgical Adjuvant Breast and Bowel Project initiated the B-22 trial to determine whether intensifying or intensifying and increasing the total dose of cyclophosphamide in a doxorubicin-cyclophosphamide combination would benefit women with primary breast cancer and positive axillary nodes. B-25 was initiated to determine whether further intensifying and increasing the cyclophosphamide dose would yield more favorable results. PATIENTS AND METHODS: Patients (n = 2,548) were randomly assigned to three groups. The dose and intensity of doxorubicin were similar in all groups. Group 1 received four courses, ie, double the dose and intensity of cyclophosphamide given in the B-22 standard therapy group; group 2 received the same dose of cyclophosphamide as in group 1, administered in two courses (intensified); group 3 received double the dose of cyclophosphamide (intensified and increased) given in group 1. All patients received recombinant human granulocyte colony-stimulating factor. Life-table estimates were used to determine disease-free survival (DFS) and overall survival. RESULTS: No significant difference was observed in DFS (P =.20), distant DFS (P =.31), or survival (P =.76) among the three groups. At 5 years, the DFS in groups 1 and 2 (61% v 64%, respectively; P =. 29) was similar to but slightly lower than that in group 3 (61% v 66%, respectively; P = 08). Survival in group 1 was concordant with that in groups 2 (78% v 77%, respectively; P =.71) and 3 (78% v 79%, respectively; P =.86). Grade 4 toxicity was 20%, 34%, and 49% in groups 1, 2, and 3, respectively. Severe infection and septic episodes increased in group 3. The decrease in the amount and intensity of cyclophosphamide and delays in therapy were greatest in courses 3 and 4 in group 3. The incidence of acute myeloid leukemia increased in all groups. CONCLUSION: Because intensifying and increasing cyclophosphamide two or four times that given in standard clinical practice did not substantively improve outcome, such therapy should be reserved for the clinical trial setting.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1999

Phase II trial of N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl and doxorubicin chemotherapy in metastatic breast cancer: A National Cancer Institute of Canada clinical trials group study.

PURPOSE: This multicenter phase II trial investigated the efficacy and toxicity of a combination of the novel intracellular histamine antagonist, N,N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine.HCl (DPPE), and doxorubicin in patients with anthracycline-naïve metastatic breast cancer. Preclinical models and early single institutional studies suggested DPPE could potentiate the cytotoxicity of doxorubicin. PATIENTS AND METHODS: Forty-two women, 32 to 77 years old (median, 59 years), with anthracycline-naïve metastatic breast cancer were treated. Patients may have had one previous regimen of nonanthracycline chemotherapy, either in the adjuvant or metastatic disease treatment setting. DPPE (6 mg/kg) was administered as an 80 minute intravenous infusion with doxorubicin (60 mg/m(2)) given intravenously over the last 20 minutes of the DPPE infusion. Patients were premedicated with an antiemetic and sedating regimen. The DPPE/doxorubicin treatment was given every 21 days for a maximum of seven cycles. RESULTS: All 42 patients were assessable. Overall, toxicity was comparable to that expected with doxorubicin alone, with the exception of DPPE-related motion sickness, mild hallucinations, and cerebellar signs at the time of the infusion. These CNS side effects were manageable in an ambulatory care setting, improved with subsequent cycles of treatment, and did not usually require hospitalization. Four patients developed febrile neutropenia. Thirty-five patients received four or more cycles of chemotherapy. The overall response rate was 52.5% (95% confidence interval, 36% to 68%), with 9.5% complete responses (n = 4), 43% partial responses (n = 18), and 38% of patients with stable disease (n = 16). CONCLUSION: The antitumour effects of DPPE/doxorubicin the 52.5% response rate seems encouraging, particularly in consideration of the fact that a recently reported randomized National Cancer Institute of Canada Clinical Trials Group trial using single-agent doxorubicin 60 mg/m(2) in one of the treatment arms achieved a 31% response rate. Thus, a randomized phase III trial of doxorubicin versus doxorubicin plus DPPE is being conducted in this clinical setting.

Adult↗
PubMed1999

Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04.

PURPOSE: To compare the efficacy of leucovorin-modulated fluorouracil (FU+LV) with that of fluorouracil and levamisole (FU+LEV) or with the combination of FU+LV and levamisole (FU+LV+LEV). PATIENTS AND METHODS: Between July 1989 and December 1990, 2,151 patients with Dukes' B (stage II) and Dukes' C (stage III) carcinoma of the colon were entered onto National Surgical Adjuvant Breast and Bowl Project protocol C-04. Patients were randomly assigned to receive FU+LV (weekly regimen), FU + LEV, or the combination of FU+LV+LEV. The average time on study was 86 months. RESULTS: A pairwise comparison between patients treated with FU+LV or FU+LEV disclosed a prolongation in disease-free survival (DFS) in favor of the FU+LV group (65% v 60%; P =.04); there was a small prolongation in overall survival that was of borderline significance (74% v 70%; P =.07). There was no difference in the pairwise comparison between patients who received FU+LV or FU+LV+LEV for either DFS (65% v 64%; P =.67) or overall survival (74% v 73%; P =.99). There was no interaction between Dukes' stage and the effect of treatment. CONCLUSION: In patients with Dukes' B and C carcinoma of the colon, treatment with FU+LV seems to confer a small DFS advantage and a borderline prolongation in overall survival when compared with treatment with FU+LEV. The addition of LEV to FU+LV does not provide any additional benefit over and above that achieved with FU+LV. These findings support the use of adjuvant FU+LV as an acceptable therapeutic standard in patients with Dukes' B and C carcinoma of the colon.

Aged↗
PubMed1999

Multitargeted antifolate LY231514 as first-line chemotherapy for patients with advanced non-small-cell lung cancer: A phase II study. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the efficacy and safety of the multitargeted antifolate LY231514 (MTA) in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with measurable, advanced NSCLC who had not received previous chemotherapy for advanced disease were considered for this study. Eligible patients who gave written informed consent initially received MTA 600 mg/m(2) intravenously (IV) for 10 minutes every 3 weeks. After three patients received treatment at this dose, the dose was reduced to 500 mg/m(2) IV at the same infusion time and frequency because of toxicity seen in this study and another Canadian MTA trial in colorectal cancer. Patients received up to four cycles after complete or partial remission or six cycles after stable disease was documented. RESULTS: Thirty-three patients were accrued onto the study. All were assessable for toxicity, and 30 patients were assessable for response. All but one patient had an Eastern Cooperative Oncology Group performance status score of 0 or 1, 18 patients (55%) had adenocarcinoma, and nine patients (27%) had squamous cell carcinoma. Twenty-five patients (76%) had stage IV disease, and the remainder had stage IIIB disease at trial entry. Seven patients experienced a confirmed partial response and no complete responses were seen; thus, the overall response rate was 23.3% (95% confidence interval, 9.9% to 42.3%). The median duration of response was 3.1 months (range, 2. 3 to 13.5 months) after a median follow-up period of 7.9 months. Four (67%) of six patients with stage IIIB disease and three (12.5%) of 24 with stage IV disease responded to treatment. Four patients (13.3%) experienced febrile neutropenia and 13 (39%) experienced grade 3 or 4 neutropenia, whereas only one patient (3%) developed grade 4 thrombocytopenia. Nonhematologic toxicity was generally mild or moderate, but 39% of patients developed a grade 3 skin rash. Most other toxicities comprised grade 1 or 2 stomatitis, diarrhea, lethargy, and anorexia. Ten patients stopped protocol therapy because of toxicity. CONCLUSION: MTA seems to have clinically meaningful activity as a single agent against advanced NSCLC. Toxicity is generally mild and tolerable. Further study of this agent in combination with cisplatin and other active drugs is warranted in this disease.

Adult↗
PubMed1999

Health-related quality of life and tamoxifen in breast cancer prevention: a report from the National Surgical Adjuvant Breast and Bowel Project P-1 Study.

PURPOSE: This is the initial report from the health-related quality of life (HRQL) component of the National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial. This report provides an overview of HRQL findings, comparing tamoxifen and placebo groups, and advice to clinicians counseling women about the use of tamoxifen in a prevention setting. PATIENTS AND METHODS: This report covers the baseline and the first 36 months of follow-up data on 11,064 women recruited over the first 24 months of the study. Findings are presented from the Center for Epidemiological Studies-Depression Scale (CES-D), the Medical Outcomes Study 36-Item Short Form Health Status Survey (MOS SF-36) and sexual functioning scale, and a symptom checklist. RESULTS: No differences were found between placebo and tamoxifen groups for the proportion of participants scoring above a clinically significant level on the CES-D. No differences were found between groups for the MOS SF-36 summary physical and mental scores. The mean number of symptoms reported was consistently higher in the tamoxifen group and was associated with vasomotor and gynecologic symptoms. Significant increases were found in the proportion of women on tamoxifen reporting problems of sexual functioning at a definite or serious level, although overall rates of sexual activity remained similar. CONCLUSION: Women need to be informed of the increased frequency of vasomotor and gynecologic symptoms and problems of sexual functioning associated with tamoxifen use. Weight gain and depression, two clinical problems anecdotally associated with tamoxifen treatment, were not increased in frequency in this trial in healthy women, which is good news that also needs to be communicated.

Adult↗
PubMed1999

Low grade glioma: a measuring radiographic response to radiotherapy.

PURPOSE: We set out to determine the rate of response of low-grade (WHO Grade II) gliomas to radiotherapy and analyze the relationship between radiographic response, symptom control and patient survival. METHODS: Patients were eligible for this study if they had received radiotherapy for pathologically confirmed, residual, supratentorial low-grade astrocytoma, oligodendroglioma, or mixed glioma, and imaging studies (baseline and follow-up) were available for review. Percent change in tumor size and rate and timing of response were determined by maximum linear measurement, area measurement, volume measurement using an ellipsoid model, and volume measurement by image segmentation. For each method, response to radiotherapy was defined firstly as a > or = 50% decrease in tumor size (partial response), and secondly as a decrease equivalent to a 50% area decrease (normalized partial response). Relationships between radiographic response, clinical improvement and progression-free survival were analyzed using a Cox Proportional Hazard's model. RESULTS: Twenty-one patients in a database (13 male, 8 female; ages 22-66 years) met the eligibility criteria. Twenty were imaged by computed tomography, 18 had an astrocytoma and 15 were irradiated soon after surgery. Responses were common and not felt to be due to a steroid effect. Use of normalized response criteria improved agreement between assessment of response as determined by the 4 methods. Median time to maximum radiographic improvement was 2.8 months (range, 1.5-11). Sixteen patients (76%) were improved neurologically, the median time to progression was 4.8 years and the 5-year progression-free survival rate was 43%. We did not detect a statistically significant association between response (as measured by any method), symptomatology and progression-free survival. CONCLUSIONS: Low-grade gliomas are moderately radioresponsive. Use of volume measurement may over-estimate the number of partial responses unless a volume reduction equivalent to a 50% area decrease is used to define response. The best way to measure response remains uncertain because neither visual, area, nor volume changes confidently predicted clinical outcomes.

Adult↗