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Biomedical subjects

Larry Norton

Publications and source records attributed to Larry Norton.

59 records · Page 4Linked to original sources
PubMed1995

Rapidly cycled courses of high-dose alkylating agents supported by filgrastim and peripheral blood progenitor cells in patients with metastatic breast cancer.

Our purpose was to determine the feasibility of a regimen of multiple, rapidly cycled courses of high-dose alkylating agents, including paired courses of escalating doses of thiotepa, supported by peripheral blood progenitor cells and filgrastim, in patients with responding stage IV breast cancer. The regimen consisted of two courses of cyclophosphamide (3.0 g/m2/course) followed by two courses of thiotepa (500-700 mg/m2/course). All courses were supported by filgrastim. Leukaphereses were performed after each cyclophosphamide course to harvest peripheral blood progenitors (PBPs) for use as rescue following thiotepa administration. The planned interval for all courses was 14 days. Forty-two patients were enrolled. Thirty-eight received all four courses, and four did not receive the second thiotepa cycle due to poor PBP mobilization. The maximum dose of thiotepa that was administered was 700 mg/m2 x 2. At this dose, one patient developed encephalopathy, which resolved over several weeks. The median number of days to an absolute neutrophil count of 0.5 x 10(9)/liter after PBP reinfusion for cycles 1 and 2 of thiotepa were 9 (range, 7-16) and 9 (range, 8-13) days, respectively. The corresponding values for platelet recovery to >20 x 10(9)/liter were 11 (range, 8-39) and 12 (range, 10-28) days, respectively. There were no treatment-related deaths. Hospitalization was required following 28 of 84 cyclophosphamide courses and 76 of 80 thiotepa courses. Four patients developed grade III-IV mucositis. The median interval between courses of treatment was 15 (range, 13-29) days. Of 19 patients who entered the protocol with measurable disease in partial response from prior therapy, 8 (42%) achieved complete response following the high-dose therapy. Nine (21%) of 42 remain progression free at a median follow-up of 28 (range, 20-32) months. Therefore, we concluded that the administration of multiple, rapidly cycled courses of high-dose alkylating agents is feasible.

Adult↗
PubMedDate not supplied

Radiation pneumonitis in breast cancer patients treated with taxanes: does sequential radiation therapy lower the risk?

Taxanes are now routinely used in conjunction with radiation therapy (RT) as adjuvant therapy for breast cancer. Recent publications have reported several cases of radiation pneumonitis (RP) in patients receiving RT and taxane chemotherapy, thus raising concern as to the safety of this combination. To decrease the potential risk of RP, we sequenced RT after taxane chemotherapy with a target interval of 3-4 weeks in two consecutive institutional breast protocols. Forty patients were treated on two adjuvant systemic protocols consisting of modified radical mastectomy (n = 9) or breast-conserving surgery (n = 31), followed by adjuvant doxorubicin, cyclophosphamide, and a sequential taxane (ACT), followed by RT. All patients had either node-positive or high-risk node-negative breast cancer and were treated between October 2000 and September 2002. Postmastectomy, a median dose of 5040 cGy was delivered to the chest wall. After breast-conserving surgery, a median dose of 4680 cGy was delivered to the breast plus a 1400 cGy boost to the surgical cavity. Information regarding RP was gathered retrospectively by reviewing patient records. With a median follow-up of 28 months (range 6-42 months), no cases of clinical RP were identified and no local failures had occurred. The median time interval for all patients between the completion of chemotherapy and the initiation of RT was 34 days (range 5-70 days). At the latest follow-up, 2 patients were diagnosed with metastatic disease and 38 patients were without evidence of disease. Sequencing of RT after taxane therapy with a target interval of 3-4 weeks does not appear to result in increased pulmonary toxicity and is associated with good local control.

Adult↗
PubMedDate not supplied

Conceptual and practical implications of breast tissue geometry: toward a more effective, less toxic therapy.

Mathematics provides greater understanding of the complex process of tumorigenesis. Based on the Gompertzian phenomenon and the Norton-Simon hypothesis, enhanced cell kill can be obtained through a greater chemotherapy dose rate. Results from the 1995 Bonadonna et al. study and the CALGB/Intergroup C9741 study demonstrated that patients in the dose-dense arms had significantly longer disease-free survival and overall survival. Because of the demonstrated applicability of Gompertzian kinetics, attention has been turned to the etiology of the Gompertzian curve. Breast tumor dimensions, as with all tissue dimensions in biology, can be calculated by fractals. A less cell-dense tissue usually has a lower fractal dimension than a tissue with more cells (i.e., a higher cell density is usually due to a higher fractal dimension). Density is the number of cells divided by the tissue volume. When allowed to grow, the density of a tissue with a lower fractal dimension drops quickly. However, a tumor, since it has a higher fractal mass dimension, maintains a high density as it grows bigger, resulting in a more rapid growth rate and a larger final size. Fractal dimensions of infiltrating ductal adenocarcinomas of the breast are high (i.e., 2.98), which results in a very dense tissue compared with normal breast tissue (with a fractal dimension of about 2.25). As expected, the higher fractal dimension results in a high rate of growth. The reason for this high fractal dimension is that breast cancer can be considered as a conglomerate of many small Gompertzian tumors, each of which has a high cell density and hence ratio of mitosis to apoptosis. In mathematical terms, each component of the conglomerate can be considered a small metastasis in itself. Thus, the primary tumor is composed of multiple self-metastases that form around a seed from the tumor to itself. Conventional thinking is that cancers metastasize because they are large, but in fact it may be that they are large because they are self-metastatic. Many genes are associated with the biology of metastasis; these include: A) obligatory cancer genes (most of which regulate mitosis and mitotic rate); B) genes relating to self-metastasis and growth of tumors at local sites, conferring the ability to invade and grow with high cell density; and C) genes that relate to the ability of the cancer to metastasize to distant areas. Additionally, fibroblasts may send out abnormal growth signals causing abnormal breast tissue growth. Consequently, we are not only dealing with abnormal cancer cells, but also with the tissue that surrounds them, or the microenvironment, that is, the "Smith-Bissell" model. These new insights may lead us to change the thrust of our attack from genes involved in mitosis to those involved in metastasis, including metastasis to self, and to use and further improve dose-dense regimens.

Antineoplastic Agents↗
PubMedDate not supplied

Screening chest imaging studies are not effective in the follow-up of breast cancer patients.

PURPOSE: To determine the utility of chest imaging after adjuvant therapy for breast cancer in detection of recurrent disease. PATIENTS AND METHODS: This is a retrospective review of 786 patients diagnosed with early stage breast cancer between 1996-1998 at Memorial Sloan Kettering Cancer Center. 250 of these patients had a chest radiograph or CT scan performed greater that one year after their original diagnosis. Patients were stratified as to whether the chest imaging study was ordered for screening or to evaluate symptoms. RESULTS: 533 chest imaging studies were performed: 397 (74%) chest radiographs and 136 (26%) CT scans. Ten (4%) patients developed metastatic breast cancer. Two patients (0.8%) were found to have metastatic disease by chest radiographs: one (0.4%) was symptomatic and one was not. The remaining eight patients had a negative chest x-ray within one year. No patients were found to have metastatic disease by chest CT. A 2nd primary cancer was found in three patients (1.2%) all of whom had a negative chest x-ray in the past year. There were 20 abnormal radiology studies: 2 true positive (2/20 = 10%) and 18 false positive (18/20 = 90%). CONCLUSIONS: Within this duration of follow-up, we conclude that chest imaging is of limited value for asymptomatic patients with a history of breast cancer and has a high false positive rate.

Breast Neoplasms↗