The effect of aging on the utilization of chemotherapy for metastatic breast cancer: a population-based study.

Older women (i.e., > or = 65 years of age) receive less adjuvant chemotherapy than younger women, in part because chemotherapy has been less effective in postmenopausal than premenopausal women in clinical trials. Metastatic breast cancer, however, does not respond differently to chemotherapy by age. Therefore, to evaluate further the effect of age on chemotherapy utilization, we conducted a population-based study of the treatment of metastatic breast cancer. Patients (n = 132) were identified by cross-tabulating death certificates from 1984 to 1991 with breast cancer cases in the Washington County Cancer Registry. Treatment information was obtained from the Tumor Registry of the Washington Country Hospital and Hospital medical records. Forty patients (74%) < 65 years old received chemotherapy compared to 11 (42%) 65-74 and 6 (12%) > or = 75 (p < 0.0001). Adjusting for other medical conditions and whether or not the patient saw a medical oncologist, there was still a significant effect of age in patients > or = 75 (p < 0.001) and a trend (p = 0.17) for patients 65-74. The different patterns of chemotherapy utilization were not associated with survival differences. Radiation therapy was also utilized significantly less frequently in older than younger patients, but the age effect was not as pronounced as with chemotherapy. There was no age effect on the utilization of hormonal therapy. Less frequent utilization of chemotherapy in older patients is probably caused by a combination of patient and physician factors and may result in less effective palliation for older patients.

Similar breast cancer cell contamination of single-day peripheral-blood progenitor-cell collections obtained after priming with hematopoietic growth factor alone or after cyclophosphamide followed by growth factor.

PURPOSE: To evaluate tumor-cell contamination of peripheral-blood progenitor-cell (PBPC) collections obtained after priming with granulocyte colony-stimulating factor (G-CSF). PATIENTS AND METHODS: Immunocytochemical (ICC) and tumor clonogenic (TCA) assays were used to analyze tumor-cell contamination of pretreatment peripheral-blood (PB) and bone marrow (BM) samples, and of PBPC collection samples obtained after priming with G-CSF 5 micrograms/kg/d for 5 or 7 days in 38 women with advanced breast cancer undergoing high-dose chemotherapy (HDC). Results were compared with 37 historical control patients who underwent PBPC mobilization with cyclophosphamide (4 g/m2) followed by granulocyte-macrophage colony-stimulating factor (GM-CSF) 5 micrograms/kg/d for 14 days. RESULTS: Before PBPC priming with G-CSF, only one of 37 (3%) PB and four of 36 (11%) BM samples had tumor cells detected by ICC. Tumor-cell contamination of PBPC collections obtained after 5 or 7 days of G-CSF priming was observed in only three of 38 patients (8%). All patients with tumor cells detected in the PBPC collection had stage IV disease. Cells with in vitro clonogenic potential were detected only in the pretreatment BM sample in one patient, and another two patients had ICC- and TCA-positive PBPC samples despite tumor-negative PB and BM before priming. These results are similar to those previously reported for PBPC primed with cyclophosphamide and GM-CSF. CONCLUSION: In patients with advanced breast cancer responsive to cytotoxic chemotherapy, tumor-cell contamination is not increased in PBPC collected after 5 or 7 days priming with G-CSF and appears similar to that seen when PBPC are primed with cyclophosphamide followed by GM-CSF.

Phase I and pharmacologic study of the alkylating agent modulator novobiocin in combination with high-dose chemotherapy for the treatment of metastatic breast cancer.

PURPOSE: Resistance to alkylators may potentially be overcome by drugs that inhibits DNA repair, thus improving the efficacy of high-dose chemotherapy. This trial was performed to determine if novobiocin, an agent that inhibits DNA repair, could be given with high-dose alkylators. Study aims were to define the toxicities and maximal-tolerated dose (MTD) of novobiocin and the pharmacokinetics of novobiocin and high-dose cyclophosphamide and thiotepa. PATIENTS AND METHODS: Thirty-eight women with responsive metastatic breast cancer received high-dose cyclophosphamide (3 to 6 g/m2 over 4 days), thiotepa (400 to 800 mg/m2), and novobiocin (0.5 to 5.0 g/d x 7, orally) with autologous marrow support. Toxicity was monitored. The pharmacology of novobiocin, cyclophosphamide, and thiotepa was evaluated. RESULTS: There were no toxic deaths. The MTD of novobiocin was 4 g/d. All seven patients treated at 5 g/d developed grade III/IV mucositis and vomiting. The severity of mucositis correlated with the plasma levels of novobiocin. Other severe toxicities were not observed. Plasma novobiocin levels > or = 100 micrograms/mL, which are associated with reversal of drug resistance in animal models, were consistently seen at dose levels greater than 2 g. The dispositions of cyclophosphamide and thiotepa were not altered by novobiocin. CONCLUSION: Novobiocin may be given with high-dose alkylators in doses that produce plasma levels that augment the activity of these cytotoxics in experimental models. The pharmacology of high-dose cyclophosphamide and thiotepa is unaffected. Novobiocin 4 g/d orally for 7 days is recommended for future study.

Predictive factors for peripheral-blood progenitor-cell collections using a single large-volume leukapheresis after cyclophosphamide and granulocyte-macrophage colony-stimulating factor mobilization.

PURPOSE: (1) To study the ability of mobilized peripheral-blood progenitor cells (PBPC) collected in a single large-volume leukapheresis performed on a predetermined date to accelerate engraftment after high-dose cyclophosphamide and thiotepa; (2) to establish the minimum dose of PBPC associated with early engraftment; and (3) to identify parameters predictive of collection of large numbers of PBPC. PATIENTS AND METHODS: Twenty-three patients with breast cancer received cyclophosphamide (4 g/m2) and granulocyte-macrophage colony-stimulating factor ([GM-CSF] 5 micrograms/kg/d x 15 days) for PBPC mobilization. A single leukapheresis was performed 15 days after cyclophosphamide administration. Then, patients received high-dose cyclophosphamide and thiotepa followed by reinfusion of PBPC and 4-hydroperoxycyclophosphamide (4HC)-purged bone marrow. PBPC concentration was measured in serial peripheral-blood samples and in the leukapheresis product. Correlation analysis between PBPC dose and engraftment and between leukapheresis yield and patient characteristics was attempted. RESULTS: A single leukapheresis processed a median 36 L (range, 24 to 46) blood and collected 5 x 10(6) CD34+ cells/kg (< 0.3 to 24) and 6.2 x 10(5) colony-forming units granulocyte-macrophage (CFU-GM)/kg (< 0.001 to 29). All sixteen patients (70%) reinfused with > or = 2.9 x 10(6) CD34+ cells/kg reached a level of greater than 1,000 leukocytes/microL by day 13 and greater than 50,000 platelets/microL by day 15. All of these patients had a percentage of peripheral-blood CD34+ cells > or = 0.5%, and all but one, a level of greater than 100,000 platelets/microL, on the day of leukapheresis. The bone marrow CD34+ cell percentage at study entry predicted the number of CD34+ cells collected after PBPC mobilization (R2 = .42, P = .002). All patients with > or = 2.5% bone marrow CD34+ cells experienced early engraftment. CONCLUSION: Reinfusion of PBPC collected in a single leukapheresis accelerates engraftment in the majority of patients. Pretreatment bone marrow CD34+ cell content determines PBPC mobilization capacity and may help select hematopoietic rescue strategies.

Absence of breast cancer cells in a single-day peripheral blood progenitor cell collection after priming with cyclophosphamide and granulocyte-macrophage colony-stimulating factor.

The effect of priming on occult tumor cell involvement of peripheral blood (PB) and PB progenitor cell (PBPC) collections is poorly characterized. Using sensitive immunocytochemistry (ICC) and tumor clonogenic assays (TCA) specific for epithelial-derived tumor cells, hematopoietic specimens were analyzed for PBPC and occult tumor cell involvement in 28 patients with chemotherapy-sensitive stage IIIB or IV breast cancer. Before PBPC priming, tumor was detected by ICC in PB of 1 of 23 (4%) patients and in bone marrow (BM) harvests of 4 of 27 (15%) patients. Fifteen days after cyclophosphamide and granulocyte-macrophage colony-stimulating factor (GM-CSF) priming, 2 of 28 (7%) patients had ICC-positive PBPC collections. The median amplification of CD34+ PBPC during this time was over 19-fold (range, < 1 to 199). One patient had pretreatment tumor involvement of both PB and BM. One patient grew tumor colonies in TCA; the PB and BM were ICC- and TCA-positive, but the PBPC collection was ICC-positive and TCA-negative. After cytoreduction with conventional-dose chemotherapy, patients with advanced breast cancer and histologically negative BM biopsy specimens have rare tumor cell involvement of PB and BM. Despite effective PBPC priming with cyclophosphamide and GM-CSF, clonogenic breast cancer cells were not found in the PBPC collection performed on day 15.

Large-volume leukapheresis using regional citrate anticoagulation to collect peripheral blood progenitor cells.

The use of peripheral blood progenitor cells (PBPC) for hematopoietic rescue after high-dose chemotherapy is limited by the number of leukaphereses required to collect an adequate number of hematopoietic progenitors. To optimize the collection of PBPC, we evaluated a single large-volume leukapheresis protocol with citrate anticoagulation. A group of 23 patients received cyclophosphamide (4 g/m2) and GM-CSF (5 micrograms/kg/day for 15 days) as PBPC mobilization, with a single outpatient 6 h leukapheresis performed on the COBE Spectra 15 days later. Citrate (0.190 mmol/ml) was infused at 1.2 ml/L of blood/minute with a whole blood to citrate ratio between 17:1 and 25:1. Calcium chloride (50 mM) was administered at a citrate to calcium molar ratio between 10:1 and 5:1 to prevent hypocalcemia. A median 36.6 L (range 24.4-46.4) blood was processed using 338 mM citrate (269-473) and 50 mM calcium (25-75). A median 5 x 10(6) CD34+ cells/kg (< 0.3-24) and 6.2 x 10(5) CFU-GM/kg (< 0.001-29) were collected, representing 5.6 and 5.9 more PBPC, respectively, than were in circulation at the initiation of leukapheresis. We conclude that a 6 h large-volume leukapheresis following cyclophosphamide and GM-CSF mobilization is safe, can recruit hematopoietic progenitors into the circulatory compartment, and allows the collection of high numbers of PBPC in a single procedure.

Bone marrow micrometastases in chemotherapy-responsive advanced breast cancer: effect of ex vivo purging with 4-hydroperoxycyclophosphamide.

Tumor contamination of hematopoietic stem cell grafts may influence the outcome of breast cancer patients treated with high-dose chemotherapy. The goals of this study were: (a) to evaluate the prevalence of tumor contamination of bone marrow (BM) harvests in patients responding to systemic chemotherapy; (b) to evaluate reduction of BM tumor contamination by ex vivo purging with 4-hydroperoxycyclophosphamide (4HC); and (c) to compare the tumor contamination of peripheral blood progenitor cell collections and BM in advanced-stage breast cancer patients designated for peripheral blood progenitor cell infusion. We evaluated pre- and post-4HC purge BM specimens from 20 patients for tumor contamination using immunocytochemistry and for in vitro growth potential of tumor cells using a tumor cell clonogenic assay. Pre-4HC purge BM specimens from 15 of 20 (75%) patients were immunocytochemistry and tumor cell clonogenic assay negative. The remaining 5 BM specimens were immunocytochemistry positive, but only 3 of 5 specimens were tumor cell clonogenic assay positive. In vitro tumor colony growth was not observed in any post-4HC purge BM specimens. We also evaluated nine patients with bone or BM metastases from the start of induction chemotherapy. We found less tumor involvement of peripheral blood progenitor cell collections than of simultaneously obtained bone marrow aspirates. We conclude that bone marrow micrometastases occur with low frequency in women with chemotherapy-sensitive breast cancer and that ex vivo purging with 4HC may render tumor cells nonviable.

Phase I trial of interferon gamma to potentiate cyclosporine-induced graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

PURPOSE: We investigated if interferon gamma (IFN-gamma) could augment cyclosporine (CSA)-induced graft-versus-host disease (GVHD) following autologous bone marrow transplant in women with metastatic breast cancer and defined the toxicities of this therapy. PATIENTS AND METHODS: Thirty-six women with advanced breast cancer were treated with CSA 2.5 mg/kg daily for 28 days and IFN-gamma 0.025 mg/m2 subcutaneously (SC) every other day, days 7 to 28 following autologous bone marrow transplantation and monitored for induction and severity of GVHD and toxicity of therapy. RESULTS: GVHD was induced in 56% of patients. The severity of GVHD was greater than in a historic control population treated with CSA alone. Stage III rash was seen in 36% of patients, compared with 3% in the historic control population. Fourteen of 36 patients required therapy with topical corticosteroids and two of 36 required systemic treatment. Only three of 31 historic controls needed topical corticosteroids and no patient was treated systemically. There was no severe visceral GVHD. Hematopoietic recovery was not delayed. There were three toxic deaths. CONCLUSION: CSA-induced GVHD can be safely augmented by IFN-gamma in women treated with high-dose alkylating agents and autologous bone marrow transplantation. There is little evidence of increased toxicity. Evidence of antitumor efficacy awaits further investigation.

Sixteen week dose intense chemotherapy for inoperable, locally advanced breast cancer.

Up to 15% of women with breast cancer have locally advanced disease at diagnosis. The poor response of these patients to local therapy alone and the frequent development of disseminated disease suggest that early intensive systemic therapy may benefit these women. Twenty-four patients with non-metastatic, locally advanced, primarily inflammatory, inoperable breast cancer were treated with a 16-week dose-intense chemotherapy regimen as induction therapy. Treatment consisted of 8 repetitive 2-week cycles consisting of 100 mg/m2 cyclophosphamide orally D1-7, 40 mg/m2 doxorubicin intravenously (IV) D1, 1 mg vincristine IV D1, 100 mg/m2 methotrexate IV D1, 10 mg/m2 leucovorin every 6 hours for six oral doses D2-3, and 600 mg/m2 5-FU IV over 2 hours D2. A continuous infusion of 300 mg/m2 5-FU per day was given IV D8-9 of each 2-week cycle. After induction all patients had at least a partial clinical response and were operable; 9/24 (37%) achieved a clinical complete response. All patients underwent at least a simple mastectomy. Pathologic examination revealed no evidence of gross macroscopic tumor in 11/24 patients (46%) and no evidence of microscopic disease in 4/24 patients (17%). Seven of 24 patients (29%) had no microscopic disease in the breast. At a median follow-up of 45 months, there have been 10 relapses in the 24 patients treated with this induction regimen. The actuarial relapse-free survival at 5 years is 58%. Actuarial overall survival at 5 years is 75%. We conclude that this regimen is safe and well-tolerated and that the results of this therapy are sufficiently promising to warrant further study of this regimen in patients with locally advanced breast cancer.

Administration of human recombinant granulocyte colony-stimulating factor (filgrastim) accelerates granulocyte recovery following high-dose chemotherapy and autologous marrow transplantation with 4-hydroperoxycyclophosphamide-purged marrow in women with metastatic breast cancer.

Stem cell contamination by tumor is common in many diseases for which autologous bone marrow transplantation is used. In in vitro models chemotherapeutic purging reduces contamination and may have an impact on clinical outcome. Purging, however, delays engraftment. Little is known about the ability of granulocyte colony-stimulating factor (G-CSF) to accelerate myelopoiesis after purged autologous bone marrow transplantation. We treated 22 women with metastatic breast cancer with high-dose cyclophosphamide and thiotepa and, following the infusion of 4-hydroperoxycyclophosphamide-purged marrow, administered G-CSF, 16 micrograms/kg daily, from day 0 to engraftment. Results were compared with a control population of 24 women with breast cancer who received identical chemotherapy and purged marrow but not growth factor. Neutrophil recovery was accelerated in the G-CSF-treated population. An absolute neutrophil count of 500 was reached in 19 days compared with 29 for the historic controls. The median number of days febrile was reduced (8 versus 5.5) as were the number of days of hospitalization from marrow infusion (33 versus 25). There was no difference in the number of days on antibiotics or time to last platelet transfusion. G-CSF was administered without any notable toxicity. G-CSF accelerates myelopoiesis following the infusion of 4-hydroperoxycyclophosphamide-purged autologous marrow and shortens hospitalization.

Phase I trial of intravenous cyclosporine to induce graft-versus-host disease in women undergoing autologous bone marrow transplantation for breast cancer.

PURPOSE: We investigated if graft-versus-host disease (GVHD), which is associated with an antitumor effect, could be induced in women with advanced breast cancer by treatment with cyclosporine (CSA) following reinfusion of purged autologous marrow after treatment with high-dose chemotherapy and defined the toxicities of this approach. PATIENTS AND METHODS: Fifty-one women with advanced breast cancer responding to therapy were treated with escalating doses of CSA (1.0, 2.5, or 3.75 mg/kg/d) for 28 days following high-dose chemotherapy and autologous bone marrow transplantation and monitored for induction of GVHD and toxicity of therapy. RESULTS: GVHD was induced in a dose-dependent fashion in 14%, 68%, and 92% of patients at each dose level, respectively, a median of 15 days following autologous marrow reinfusion. GVHD was clinically mild and limited to skin. Toxicity was acceptable, with two deaths within 50 days of marrow reinfusion. Statistically significant increases in maximum creatinine and bilirubin levels were seen at all dose levels when compared with similarly treated historic controls who did not receive CSA. Time to last platelet transfusion was significantly delayed in patients treated at the highest dose. CONCLUSION: GVHD can be safely induced by treatment with CSA in women with advanced breast cancer who are receiving high-dose alkylating agents and autologous bone marrow transplantation. The toxicity of this approach is acceptable. Evidence of antitumor efficacy awaits further investigation.

Breast self-examination proficiency and training effects: women at increased risk of breast cancer.

While breast self-examination (BSE) frequency has received extensive research attention, proficiency has been less frequently addressed. Moreover, BSE proficiency among women at increased risk has not been adequately examined. Assessment of BSE proficiency is critical in determining the value of BSE with mammography and clinical breast examination in the early detection of breast cancer. BSE proficiency was assessed in 101 first-degree relatives of breast cancer patients. Participants were stratified by BSE frequency and randomized to one of two training techniques (MammaCare or concentric circle). BSE performance was assessed at baseline and at three follow-up visits at 4-month intervals. Proficiency was assessed by verbal description, a projected grid observational method, and lump detection ability on two breast models. BSE frequency was also assessed, in addition to BSE confidence, knowledge of breast cancer, risk perception, and worry related to breast cancer development. At baseline, proficiency was poor and correlations were not significant across assessment modalities. Significant improvement occurred on self-report measures, lump detection ability (true positives) on both models, and the projected grid. Improvement occurred across both training groups by the first follow-up, with no changes at subsequent visits. Both training techniques significantly improved BSE proficiency and were viewed positively by participants.