Asthma: support in the community.
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Asthma↗
Biomedical subjects
L Norton
Publications and source records attributed to L Norton.
Memorial Sloan-Kettering Cancer Center experience with paclitaxel in the treatment of breast cancer.
Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is the most important new cytotoxic agent to be introduced for the management of breast cancer in many years. During this decade, investigators at Memorial Sloan-Kettering Cancer Center have conducted multiple clinical and laboratory investigations aimed at optimally integrating this agent into therapeutic strategies for breast cancer. These studies address both single-agent and combination regimens in the metastatic and adjuvant settings. This report will review previous results, but focus on active studies and future avenues of research.
Antineoplastic Agents, Phytogenic↗
Memorial Sloan-Kettering Cancer Center experience with paclitaxel in the treatment of breast cancer: from advanced disease to adjuvant therapy.
The novel chemotherapeutic agent paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has received more attention than perhaps any other drug in the past two decades in its development for the treatment of breast cancer. Its unique mechanism of action, demonstrated safety profile, and significant antitumor activity in thousands of patients treated in clinical trials thus far have led to recent US Food and Drug Administration approval of its use against chemotherapy-refractory metastatic breast cancer. This report will summarize the series of clinical investigations with paclitaxel in patients with metastatic breast cancer that have been completed over the past 3 years at Memorial Sloan-Kettering Cancer Center and address present and future avenues of research.
Antineoplastic Combined Chemotherapy Protocols↗
High-dose chemotherapy of breast cancer.
High-dose chemotherapy (HDC) with stem cell autografting produces complete remission (CR) rates far in excess of those reported for lower-dose chemotherapy, or for any form of endocrine manipulation in patients with metastatic breast cancer. In early studies involving patients with resistant disease, HDC produced CR rates of as high as 25%. Most contemporary HDC trials accrue patients who are responding to "conventional" chemotherapy, and hence, few untreated patients have been studied in phase II evaluations. In one case, a CR rate of 54% (25% of which remained durable) was reported. In a randomized trial of high-dose versus conventionally dosed therapy, investigators in South Africa reported complete response rates of 50% and 6% respectively. In trials in which HDC is applied as a form of consolidation therapy following "conventional" chemotherapy, complete remission rates as high as 70% are reported.
Antineoplastic Agents↗
Simultaneous dose escalation and schedule intensification of carboplatin-based chemotherapy using peripheral blood progenitor cells and filgrastim: a phase I trial.
Our purpose was to determine the maximum tolerated dose of, and the minimum interval between treatments with, multiple cycles of carboplatin (CBDCA) rescued with peripheral blood progenitors and filgrastim. Eligible patients had advanced cancers without prior chemotherapy or radiotherapy. The study design involved a sequential cross-over in which patients initially received two or three courses of cyclophosphamide (CPA) at a dose of 3.0 g/m2, supported by filgrastim. Multiple leukaphereses were then performed during the rebound phase of hematological recovery following each CPA-induced nadir to harvest peripheral blood progenitors, which were then reinfused as rescue following each of four courses of CBDCA. We attempted to administer the CBDCA at 14-day intervals. The CBDCA dose (mg/m2/course) was escalated as follows in successive cohorts of patients: Level I, 500; Level II, 800; Level III, 1200; Level IIIa, 1000. Following determination of the maximum tolerated dose of CBDCA administered in this fashion, a subsequent cohort of patients (Level IV) were treated with two courses of high-dose CPA and four courses of the combination of CBDCA (1000 mg/m2) plus CPA (1500 mg/m2). Thirty-one patients were enrolled in the trial. Five patients were removed from study prior to completion of protocol therapy, three due to toxicity and two who developed progressive cancer while on study. The maximum tolerated dose of CBDCA was 1000 mg/m2, with dose-limiting ototoxicity occurring at 1200 mg/m2. The median inter-treatment interval for all cycles was 15 days (range, 12-30). The median intervals between CBDCA courses for each dose level were: Level I, 17 days; Level II, 17 days; Level III, 14 days; Level IIIa, 15 days; Level IV, 16 days. The median dose intensity of the CPA phase was 1493 mg/m2/week. The median (and range) CBDCA dose intensities (measured from the start of CBDCA) for each dose level were: I, 185 (151-222); II, 328 (305-380); III, 567 (512-646); IIIa, 465 (363-481); Level IV, 468 (333-500). Neutropenic fever complicated 35 of 113 CBDCA or CBDCA/CPA courses. Platelet transfusion was required in 51 of 113 courses. One patient had severe epistaxis. There were no treatment-related deaths. Among 27 patients with ovarian cancer who were evaluable for response, there were 5 pathologically documented complete (including 3 of 10 at Level IV) and 16 partial responses. We concluded that peripheral blood progenitors facilitate the simultaneous dose escalation and schedule intensification of carboplatin chemotherapy. The effect is sustained over four courses of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Adult↗
Optimization of conditions for ex vivo expansion of CD34+ cells from patients with stage IV breast cancer.
Multiple cycles of high-dose chemotherapy can be hematologically supported by repeated administration of peripheral blood progenitors obtained after mobilization using cytokine alone or in combination with chemotherapy. We have explored the quality of such cells and their potential to undergo ex vivo expansion. Twenty-five leukapheresis samples from 19 patients who had received extensive prior chemotherapy for stage IV breast cancer were subjected to CD34+ cell selection using immunoaffinity columns of immunomagnetic bead separation. Cells were cultured in suspension in the presence of c-kit ligand, interleukin-3, interleukin-6, erythropoietin, and granulocyte colony-stimulating factor. Ten experiments were performed using weekly exchange of media and cytokines (Delta assay). Median myeloid and erythroid progenitors expanded 15-fold at 7 days (range, 7 to 43), 40-fold at 14 days (range, 18 to 470), 46-fold at 21 days (range, 0 to 118), and 21-fold at 28 days (range, 0 to 61). In a system using gas-permeable bags without exchange of media or cytokine, median progenitors expanded 13-fold at 7 days (range, 7 to 36), 14-fold at 10 days (range, 4 to 61), 14-fold at 12 days (range, 3 to 46), and 10-fold at 14 days (range, 1 to 35). Progenitor expansion less than 10-fold occurred in 8% of experiments at day 7, in 17% at day 10, in 43% at day 12, and in 50% at day 14. When autologous plasma, autologous plasma processed (removal of cryoprecipitate, centrifugation, then filtration), or human serum were substituted for 20% fetal calf serum, the ratio of progenitor expansion at 7 days relative to 20% fetal calf serum for 10% human serum, 20% human serum, and 1% autologous plasma processed was 1.01 (range, 0.62 to 1.33), 0.88 (range, 0.61 to 1.20), and 0.96 (range, 0.55 to 1.64), respectively. These findings support the feasibility of ex vivo expansion in a system free of nonhuman proteins of CD34(+)-derived progenitors obtained from the peripheral blood of patients who have received prior chemotherapy.
Animals↗
Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma.
BACKGROUND: Adjuvant chemotherapy is widely used for breast cancer and is known to extend survival. Some clinicians seek a greater survival benefit by increasing the intensity of the dose, whereas others lower it to diminish toxicity. METHODS: The Cancer and Leukemia Group B (CALGB) conducted a randomized trial of different levels of doses and dose intensity (dose per unit of time) of adjuvant chemotherapy in 1572 women with node-positive, stage II breast cancer who were assigned to three treatment groups. One group received 400 mg of cyclophosphamide per square meter of body-surface area and 40 mg of doxorubicin per square meter once every 28 days and 400 mg of fluorouracil per square meter twice every 28 days, for six cycles. Another group received 50 percent higher doses of the three drugs (600 mg, 60 mg, and 600 mg, respectively) but for only four cycles, so that the total dose was identical in these two groups but the dose intensity was higher in the first. The third group of women received half the total dose used in the other two groups and at half the dose intensity used in the second group. RESULTS: After a median of 3.4 years of follow-up, the women treated with a high or moderate dose intensity had significantly longer disease-free survival (P < 0.001) and overall survival (P = 0.004) than those treated with a low dose intensity, in three-way log-rank comparisons. However, the difference in survival between the two groups treated with a moderate or high dose intensity was not significant. These results are consistent with either a dose-response effect or a threshold level of the dose or dose intensity. CONCLUSIONS: The doses of chemotherapy used to treat breast cancer, especially early breast cancer, should not be reduced if the maximal benefit is to be achieved.
Adenocarcinoma↗
Symptom prevalence, characteristics and distress in a cancer population.
Despite the importance of symptom control in the cancer population, few studies have systematically assessed the prevalence and characteristics of symptoms or the interactions between various symptom characteristics and other factors related to quality of life (QOL). As part of a validation study of a new symptom assessment instrument, inpatients and outpatients with prostate, colon, breast or ovarian cancer were evaluated using the Memorial Symptom Assessment Scale and other measures of psychological condition, performance status, symptom distress and overall quality of life. The mean age of the 243 evaluable patients was 55.5 years (range 23-86 years); over 60% were women and almost two-thirds had metastatic disease. The Karnofsky Performance Status (KPS) score was < or = 80 in 49.8% and 123 were inpatients at the time of assessment. Across tumour types, 40-80% experienced lack of energy, pain, feeling drowsy, dry mouth, insomnia, or symptoms indicative of psychological distress. Although symptom characteristics were variable, the proportion of patients who described a symptom as relatively intense or frequent always exceeded the proportion who reported it as highly distressing. The mean (+/- SD range) number of symptoms per patient was 11.5 +/- 6.0 (0-25); inpatients had more symptoms than outpatients (13.5 +/- 5.4 vs. 9.7 +/- 6.0, p < 0.002) and those with KPS < or = 80 had more symptoms than those with KPS > 80 (14.8 +/- 5.5 vs. 9.2 +/- 4.9, p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Taxol (paclitaxel): a novel anti-microtubule agent with remarkable anti-neoplastic activity.
Taxol (paclitaxel), an anti-microtubule agent extracted from the needles and bark of the Pacific yew tree Taxus brevifolia, has shown a remarkable anti-neoplastic effect in human cancer in phase I studies and early phase II and III trials thus far conducted. This has been reported primarily in advanced ovarian and breast cancer, although significant activity has also been documented in small-cell and non-small-cell lung cancer, head and neck cancers, and with lower activity in metastatic melanoma. The clinical utilization of Taxol had been previously somewhat restricted by its limited availability, a limitation that has recently been overcome by combined efforts of pharmaceutical, agricultural, and governmental agencies. In this review we shall address the pre-clinical data which have led to the use of Taxol in man, the main clinical results thus far obtained, the toxicities associated with its use, current ongoing trials and future clinical directions of this promising agent.
Animals↗
The Memorial Symptom Assessment Scale: an instrument for the evaluation of symptom prevalence, characteristics and distress.
The Memorial Symptom Assessment Scale (MSAS) is a new patient-rated instrument that was developed to provide multidimensional information about a diverse group of common symptoms. This study evaluated the reliability and validity of the MSAS in the cancer population. Randomly selected inpatients and outpatients (n = 246) with prostate, colon, breast or ovarian cancer were assessed using the MSAS and a battery of measures that independently evaluate phenomena related to quality of life. Symptom prevalence in the 218 evaluable patients ranged from 73.9% for lack of energy to 10.6% for difficulty swallowing. Based on a content analysis, three symptoms were deleted and two were added; the revised scale evaluates 32 physical and psychological symptoms. A factor analysis of variance yielded two factors that distinguished three major symptom groups and several subgroups. The major groups comprised psychological symptoms (PSYCH), high prevalence physical symptoms (PHYS H), and low prevalence physical symptoms (PHYS L). Internal consistency was high in the PHYS H and PSYCH groups (Cronback alpha coefficients of 0.88 and 0.83, respectively), and moderate in the PHYS L group (alpha = 0.58). Although the severity, frequency and distress dimensions were highly intercorrelated, canonical correlations and other analyses demonstrated that multidimensional assessment (frequency and distress) augments information about the impact of symptoms. High correlations with clinical status and quality of life measures support the validity of the MSAS and indicate the utility of several subscale scores, including PSYCH, PHYS, and a brief Global Distress Index. The MSAS is a reliable and valid instrument for the assessment of symptom prevalence, characteristics and distress. It provides a method for comprehensive symptom assessment that may be useful when information about symptoms is desirable, such as clinical trials that incorporate quality of life measures or studies of symptom epidemiology.
Adult↗
Immunohistochemical detection of cathepsin D in T2N0M0 breast carcinoma.
Recent studies have reported significant but inconsistent correlations between tumor cathepsin D (CD) concentration and prognosis in breast carcinoma. To investigate the tissue distribution and a prognostic utility of CD in breast carcinoma, 159 cases of T2N0M0 breast carcinoma with a minimum of 10 years' follow-up were studied for CD expression by immunohistochemistry. This group of patients was chosen for study because of current interest in prognostic markers for stage I breast carcinoma and the likelihood that there would be sufficient recurrences in this group to detect significant differences. Seventy-two carcinomas (45%) showed prominent staining of cells composing the tumor. Neoplastic cell staining for CD correlated with well-differentiated architecture, and lack of neoplastic cell CD expression correlated with high nuclear grade and the medullary carcinoma category. Stromal cell (primarily histiocyte) staining in carcinomas was the major contributor to CD expression in 67 of the 159 cases (42%). Intense intratumoral stromal cell staining correlated with absence of estrogen receptors and the medullary carcinoma subtype. There was no significant correlation between disease-free or overall survival and (a) intensity of overall staining for CD, (b) staining of carcinoma cells alone, or (c) staining of nonneoplastic cells within the region of the carcinoma. These results show that a significant proportion of CD activity detected within a tumor by immunohistochemistry may be contributed by nonneoplastic cells, and there is no significant correlation between survival and immunohistochemical detection of CD in T2N0M0 breast cancer.
Analysis of Variance↗
Taxol (paclitaxel) plus recombinant human granulocyte colony-stimulating factor in the treatment of metastatic breast cancer.
We treated 28 patients who had no prior chemotherapy for stage IV breast cancer and 51 patients with extensive prior exposure to other chemotherapeutic agents with a 24-hour infusion of Taxol (paclitaxel) as a single agent. Prophylactic recombinant human granulocyte colony-stimulating factor was administered routinely to ameliorate the anticipated dose-limiting toxicity of neutropenia. Nonhematologic toxicity was mild to moderate in most cases. Taxol was more active in patients with chemotherapy-naive stage IV disease, but activity was also observed in extensively treated patients as well. There is a strong clinical suggestion of at least partial noncross-resistance with doxorubicin. Taxol is a very promising agent for the treatment of metastatic breast cancer; its optimal application in this disease will be the subject of future trials.
Adult↗
Re: "We may be lost, but we're sure makin' good time".
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Breast Neoplasms↗
Factors affecting the mobilization of primitive and committed hematopoietic progenitors into the peripheral blood of cancer patients.
Rapid hematopoietic reconstitution following peripheral blood progenitor cell (PBPC) autotransplantation is thought to result from reinfusion of committed progenitor cells. This has raised concern that PBPC autografts might be rich in committed hematopoietic progentors responsible for early engraftment, but deficient in more primitive progenitors required for long-term hematopoietic reconstitution. The granulomonocytic colony-forming unit (CFU-GM) assay measures committed progenitors responsive to a single species of colony-stimulating activity such as granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas the pre-CFU assay identifies more primitive progenitors by measuring interleukin-3 (IL-3) and kit ligand (KL) induced generation of secondary CFU-GM from CD34+, 4-hydroperoxycyclophosphamide resistant progenitors that require multiple cytokine stimuli. Paired bone marrow (BM) and PBPC samples from 17 breast and ovarian cancer patients participating in four separate clinical trials were compared in these assay systems. In seven of nine patients, PBPC autografts mobilized with cyclophosphamide rebound and G-CSF compared favorably with paired BM autografts in both committed and primitive progenitor capacity. Failure to mobilize substantial primitive progenitor cell numbers occurred in two of nine patients undergoing this mobilization regimen and could not have been predicted by either circulating CFU-GM or CD34+ cell number. Prior myelosuppressive treatment experiences reduced peripheral progenitor yields somewhat, but still allowed for the collection of PBPC autografts which compared favorably with BM autografts in total CFU-GM and Pre-CFU. Mobilization of PBPC with G-CSF or GM-CSF alone in patients who had received prior myelosuppressive therapies produced autografts which were relatively deficient in committed progenitors, but absolutely deficient in primitive progenitors. We conclude that optimization of patient characteristics and mobilization parameters can achieve PBPC autografts rich in both the primitive and committed hematopoietic progenitor cells.
Adult↗
Salvage chemotherapy of breast cancer.
Stage IV breast cancer (metastatic foci beyond the axillary lymph nodes) initially may respond well to systemic salvage therapy with hormonal or chemotherapy drugs. Hormonal therapy is preferred because of its lower toxicity. Patients who eventually relapse after response to first-line hormone therapy may benefit from different hormonal treatments, but the probability (and duration) of response declines with each episode of progression. Chemotherapy is a rational option for patients whose cancers are hormone resistant, for those whose tumors lack hormone receptors, and for those who have rapidly growing visceral tumors. Doxorubicin achieves the highest response rates among the commonly used chemotherapy drugs, but cumulative doses above 500 mg/m2 may cause cardiomyopathy. Of the newer agents, paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) has been approved for use in anthracycline-resistant disease. Randomized trials have shown that increasing the dose intensity (ie, the amount of drug delivered per unit of time) overcomes some drug resistance. Most regimens used to treat stage IV disease are variations of the standard cyclophosphamide/methotrexate/5-fluorouracil (CMF) and cyclophosphamide/doxorubicin/5-fluorouracil (CAF) combinations. Single-agent treatment with doxorubicin or paclitaxel at maximum dose intensities produces response rates comparable with the best combination treatments. The use of untested drug combinations is regrettable and should be avoided. The specific treatment goal in responding patients (to reduce cancer symptoms or to reduce chemotherapy-related toxicity) should determine the need for continuous or intermittent drug administration. When first-line chemotherapy fails, a variety of single agents and combinations may be used, including paclitaxel, mitomycin/vinblastine, 5-fluorouracil, and cisplatin with etoposide or another agent. Future investigations should focus on the possibility of high complete response rates in ideal candidates using regimens that consist of very high chemotherapy doses with hematopoietic support or on new therapies that disrupt some step in the cellular processes of breast cancer.
Antineoplastic Agents↗
Use of ultrasound to guide radiation boost planning following lumpectomy for carcinoma of the breast.
PURPOSE: To determine if sonographic localization of the breast lumpectomy site is feasible and useful in boost planning. METHODS AND MATERIALS: The operative beds following lumpectomy were localized by ultrasound in 22 patients (15-infiltrating ductal, 7-ductal carcinoma in situ; size: .4-2.0 cm). Twelve patients had two ultrasound examinations on different days for a total of 34 examinations. Twenty-one patients had their course of boost electron therapy planned using ultrasound to guide field placement. While the patient was in the treatment position, the surgical scar was placed at the machine's isocenter. With the electron cone in place, the ultrasound transducer was placed within the cone on top of the surgical scar. The biopsy site was localized and the light field maneuvered so that it's central axis would follow the axis of the transducer, transecting both the scar and biopsy site. RESULTS: The operative bed was highly visible in 26 ultrasound examinations, visible in 7, and subtly visible in 1. Every biopsy site showed some hypoechoic area but most appeared as the mixed hypoechoic pattern. Ultrasound appearances were mixed or mostly hypoechoic (28), anechoic with irregular walls (4), and echoic (hypoechoic compared to parenchyma) (2). In two cases the surgeon placed surgical clips in the operative bed, and in both cases several of these clips could be identified at the margins of the operative bed as hyperechoic foci with shadowing. The mean depth of the operative bed was 21 mm (range 17-36 mm). In 12 patients, two ultrasound examinations were performed on different days, and the mean depth difference between these scans was 2 mm with a range of 0-5 mm. Among patients with two scans we found that both the location and appearance of the operative bed was highly reproducible. CONCLUSION: Ultrasound can successfully be used to localize the biopsy site and facilitate boost field placement in patients treated with lumpectomy and radiation.
Biopsy↗
Kinetic concepts in the treatment of breast cancer.
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Antineoplastic Combined Chemotherapy Protocols↗
Phase I trial of granulocyte-macrophage colony-stimulating factor plus high-dose cyclophosphamide given every 2 weeks: a Cancer and Leukemia Group B study.
BACKGROUND: Chemotherapy-induced myelosuppression often limits escalation of cancer chemotherapy doses. Cyclophosphamide, an alkylating agent, is an ideal candidate for dose escalation: A log-linear relationship between cell kill and dose has been demonstrated, and the drug spares hematopoietic stem cells. In addition, studies suggest that granulocyte-macrophage colony-stimulating factor (GM-CSF) can enhance the ability to achieve optimal dose intensity as well as ameliorating chemotherapy-induced myelosuppression. PURPOSE: The purpose of this study was to determine the maximum tolerated dose and the toxic effects of cyclophosphamide administered every 2 weeks with GM-CSF support. METHODS: For this trial by the Cancer and Leukemia Group B (CALGB), cohorts of patients were treated with cyclophosphamide as a 1-hour intravenous infusion every 14 days; GM-CSF was given subcutaneously on days 3-10. Four dose levels of cyclophosphamide (1.5, 3.0, 4.5, and 6.0 g/m2) and three dose levels of GM-CSF (2.5, 5.0, and 10.0 micrograms/kg per day) were evaluated. There was no dose escalation in individual patients. Fifty-one patients with solid tumors who had CALGB performance status 0 or 1 and minimal prior radiotherapy were eligible for analysis. Drug clearance and area under the curve for plasma drug concentration x time (AUC) were estimated at completion of the infusion and at 4 and 24 hours after the start of the infusion. RESULTS: Ninety-five courses of therapy were analyzed. Treatment with cyclophosphamide at 3.0 g/m2 or more resulted in neutropenia (absolute neutrophil counts < 100/microL) in all cycles of therapy. At those doses, blood cell count recovery adequate for re-treatment occurred in 67%-85% of cycles (median, 16 days). Doses of 6.0 g/m2 were associated with the greatest degree of myelosuppression and frequent hospitalization (88% of cycles); requirements for blood transfusion prohibited further dose escalation. Nonhematologic toxic effects were tolerable, with two episodes of reversible cardiotoxicity and four episodes of hemorrhagic cystitis that precluded further therapy. Degree of myelosuppression was not correlated with cyclophosphamide AUC or clearance. CONCLUSIONS: The recommended phase II dose of cyclophosphamide is 4.5 g/m2 administered every 2 weeks with GM-CSF given at 5.0 micrograms/kg per day of GM-CSF. Our results suggest that, with GM-CSF support, high cumulative doses of cyclophosphamide can be given to achieve optimal dose intensity, with reproducible blood cell count recovery and without the need for autologous bone marrow transplantation. IMPLICATIONS: Phase II studies of this intensive regimen in malignant diseases sensitive to alkylating agents are currently being done in CALGB.
Adult↗