Effect of adjuvant tamoxifen on the endometrium in women with breast cancer: a prospective study using office endometrial biopsy.

PURPOSE: To determine the frequency of developing abnormal pathologic changes in the endometria of tamoxifen-treated women. To characterize the type of pathologic changes involved. PATIENTS AND METHODS: Between October 1991 and September 1998, 159 patients initiating tamoxifen therapy for breast cancer confined to the breast and axillary lymph nodes were entered in a prospective study. In this study, office endometrial biopsies (EMBs) were obtained during the initiation of tamoxifen and at 6-month intervals for a 2-year period. Three subsequent annual EMBs were recorded for each patient, amounting to a 5-year surveillance. RESULTS: One hundred fifty-nine patients with a median age of 50 years were entered onto study. Patients were assessable if EMBs were performed at least 1 year after the initiation of tamoxifen treatment. Nine patients (5. 7%) were considered protocol violations. The remaining 111 assessable patients underwent a total of 635 EMBs (mean, 5.8 EMBs), with a median surveillance time of 36 months. Eighty-two (12.9%) of the 635 biopsies revealed tissue insufficient for diagnosis. Fourteen patients (12.6%) underwent dilation and curettage (D&C) for an abnormal EMB, persistent bleeding, or for evaluation of adnexal masses at the time of laparoscopy. Findings at D&C included complex hyperplasia (n = 1), abnormal histiocytes (n = 1), simple hyperplasia (n = 2), polyps (n = 4), endocervical polyp (n = 1), and decidualization (n = 2). Three D&Cs were negative. Three patients have undergone hysterectomy. CONCLUSION: EMB was used to monitor the endometrium in the majority (95%) of breast cancer patients on tamoxifen in this trial, but the utility of routine EMB for screening in tamoxifen-treated women seems limited.

Ninety-six-hour paclitaxel infusion after progression during short taxane exposure: a phase II pharmacokinetic and pharmacodynamic study in metastatic breast cancer.

PURPOSE: A phase II trial of paclitaxel infused over 96 hours in patients with metastatic breast cancer with demonstrated disease progression (PD) during short-infusion taxane treatment was performed to evaluate schedule-dependent activity with prolonged drug exposure. The tolerability of this strategy and its pharmacokinetic profile and pharmacodynamic correlates were also investigated. PATIENTS AND METHODS: Paclitaxel was administered to 26 patients with metastatic breast cancer at 120 to 140 mg/m2 intravenously over 96 hours. Twenty-three patients had demonstrated PD while receiving prior 3-hour paclitaxel, two during 1-hour docetaxel, and one during infusions of docetaxel and then paclitaxel. Twenty-one patients (81%) had no prior response to the short taxane infusion (primary resistance) and five (19%) had prior partial responses (PRs) of brief duration before PD (secondary resistance). Plasma paclitaxel concentrations were assessed at 24, 48, 72, and 96 hours. RESULTS: After delivery of 195 cycles, seven of 26 assessable patients (26.9%; 95% confidence interval, 11.6% to 47.8%) had major objective responses, with a median response duration of 6 months (range, 1 to 13). The predominant toxicities were neutropenia (76% grade > or = 3) and stomatitis (15% grade > or = 3). Despite omission of premedications, no significant hypersensitivity reactions occurred. The median steady-state paclitaxel concentration (Css) in 23 assessable patients was 0.047 mumol/L (range, .023 to .176). Patients who experienced grade 4 neutropenia had significantly decreased paclitaxel clearance and higher Css than those with grade 1 to 3 neutropenia (P < .05). Pretreatment elevation of hepatic transaminases was associated with delayed clearance (P < .01) and increased myelo-suppression and mucosal toxicity. CONCLUSION: Paclitaxel demonstrates activity against metastatic breast cancer when administered over 96 hours to patients with disease that recently had progressed during short taxane exposure. Delayed paclitaxel clearance and consequent increased toxicity occurred in patients with hepatic dysfunction. The activity observed supports preclinical data that suggest variability in efficacy and resistance patterns to paclitaxel based on duration of exposure.

Phase II and pharmacologic study of docetaxel as initial chemotherapy for metastatic breast cancer.

PURPOSE: Because docetaxel (Taxotere, RP 56976; Rhone-Poulenc Rorer, Antony, France) appeared to be active against breast cancer in phase I trials, we performed this phase II study. PATIENTS AND METHODS: Thirty-seven patients with measurable disease were enrolled. Only prior hormone therapy was allowed, as was adjuvant chemotherapy completed > or = 12 months earlier. Docetaxel 100 mg/m2 was administered over 1 hour every 21 days. Diphenhydramine hydrochloride and/or corticosteroid premedication was added after hypersensitivity-like reactions (HSRs) were seen in two of the first six patients. Pharmacokinetic studies were performed during cycle 1 for correlation with toxicity. RESULTS: Thirty-seven patients were assessable. Nineteen (51%) required dose reductions, usually for neutropenic fever. The median nadir WBC count was 1.4 x 10(3)/microL. HSRs were noted in 20 patients (54%). At a median cumulative dose of 297 mg/m2 (range, 99.6 to 424.5 mg/m2), 30 patients (81%) developed fluid retention, for which 11 (30%) subsequently stopped treatment. The first-cycle plasma area under the concentration-time curve (AUC) did not correlate with toxicity, although an ineligible patient with hepatic metastases (pretreatment bilirubin level 1.8 mg/dL) had an elevated AUC and died of toxicity. Responses were seen at all sites. On an intent-to-treat basis, there were two (5%) complete responses (CRs) and 18 (49%) partial responses (PRs). The overall response proportion (CRs plus PRs) was 54% (95% confidence interval, 37% to 71%). The median time to response was 12 weeks (range, 3 to 15) and the median duration was 26 weeks (range, 10 to 58+). CONCLUSION: Docetaxel is active for metastatic breast cancer. Neutropenia and fluid retention are dose-limiting. The AUC did not predict toxicity, but caution is warranted when treating patients with liver dysfunction. An understanding of the pathophysiology of the fluid retention may facilitate prevention. Frequent HSR may warrant prophylactic premedication.

Paclitaxel as second and subsequent therapy for metastatic breast cancer: activity independent of prior anthracycline response.

PURPOSE: Two phase II clinical trials were performed to determine efficacy and tolerability of paclitaxel (Taxol; Bristol-Myers Squibb Co, Wallingford, CT) and granulocyte colony-stimulating factor ([G-CSF] Neupogen; Amgen, Inc, Thousand Oaks, CA) as second or subsequent therapy for metastatic breast cancer. PATIENTS AND METHODS: Paclitaxel plus G-CSF was administered as a second stage IV regimen to 25 patients with metastatic breast cancer at a dose of 250 mg/m2 intravenously over 24 hours. Fifty-two patients received paclitoxel plus G-CSF at 200 mg/m2 as a third or subsequent regimen (no restriction on number of prior regimens or on prior high-dose chemotherapy). All patients had received prior anthracycline treatment, and ultimately had progressive bidimensionally measurable disease. RESULTS: Twenty-five of 76 patients (32.8%) had a major objective response (95% confidence interval [CI], 14% to 37%). The median duration of response was 7 months (range, 1 to 20+). Responses were as likely in patients with disease demonstrated to be unresponsive to anthracycline, ie, de novo resistance (11 of 37, or 30%) as in those with disease that once exhibited anthracycline sensitivity, ie, acquired resistance, (10 of 31, or 32%). G-CSF administration was associated with febrile neutropenic episodes in 36 of 402 cycles (9%) in 16 of 76 patients (21%). CONCLUSION: Paclitaxel's clinically significant activity against metastatic breast cancer extends to patients with many prior chemotherapy regimens. The lack of impact of prior doxorubicin therapy on the likelihood of subsequent response to paclitaxel suggests an important role for this agent in the treatment of refractory metastatic breast cancer.

Conditioned emotional distress in women receiving chemotherapy for breast cancer.

This study investigated whether women undergoing outpatient chemotherapy for breast cancer can develop classically conditioned emotional distress. Women scheduled to begin chemotherapy were randomly assigned either to an experimental group (exposed to a distinctive stimulus before each chemotherapy infusion) or a control group. After repeated infusions of chemotherapy, patients' responses to the distinctive stimulus were assessed in a location not associated with chemotherapy administration. At the test trial, experimental group patients showed evidence of increased emotional distress (self-reported on a visual analog scale) after the presentation of the distinctive stimulus, whereas control group patients did not. Post hoc analyses indicated that these increases in distress were not secondary to other conditioned responses (e.g., nausea, taste aversion). Thus, results supported the hypothesis that the pairing of a distinctive stimulus with chemotherapy would result in the development of a conditioned emotional response.

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.

Paclitaxel and recombinant human granulocyte colony-stimulating factor as initial chemotherapy for metastatic breast cancer.

PURPOSE: A phase II study of Taxol (paclitaxel; Bristol-Myers Squibb Co, Princeton, NJ) as initial chemotherapy for metastatic breast cancer was conducted. Recombinant human granulocyte colony-stimulating factor (rhG-CSF) was used to ameliorate myelosuppression, the anticipated dose-limiting toxicity. PATIENTS AND METHODS: Twenty-eight patients with bidimensionally measurable breast cancer who had not received prior chemotherapy for metastatic disease were treated. Taxol was administered at 250 mg/m2 as a continuous 24-hour intravenous (i.v.) infusion every 21 days. rhG-CSF was administered at 5 micrograms/kg/d subcutaneously on days 3 through 10. RESULTS: Objective responses were observed in 16 of 26 assessable patients (62%; 95% confidence interval, 41% to 80%). There were three (12%) complete responses (CRs) and 13 (50%) partial responses (PRs). Ten of 16 patients (63%) who had received prior adjuvant chemotherapy responded, which included one CR and four PRs among eight patients who had received prior doxorubicin-containing therapy. Responses were observed in all sites of metastatic disease. The median time to first objective response was 5 weeks (range, 1 to 14). Administration of rhG-CSF was associated with a short duration of neutropenia (median, 2 days with absolute neutrophil count < 500 cells/microL). Eight of 26 patients (31%) who received more than one course received subsequent therapy without dose reduction. One hundred seventy-eight cycles of treatment were administered, with a median of six cycles per patient (range, one to 19). Eight courses (4.5%) were associated with admissions for neutropenic fever. Twenty-two patients (79%) did not require admission for neutropenic fever. Treatment was well tolerated. Adverse effects included generalized alopecia in all patients. Myalgias, arthralgias, and peripheral neuropathy were mild. No hypersensitivity reactions and no cardiac toxicity were observed. CONCLUSION: Taxol is highly active as initial chemotherapy for metastatic breast cancer. Administration of rhG-CSF reduced the incidence, depth, and duration of neutropenia, compared with published prior experience. Further studies of Taxol in breast cancer, including combinations with other active agents, are clearly warranted.

Preliminary experience with paclitaxel (Taxol) plus recombinant human granulocyte colony-stimulating factor in the treatment of breast cancer.

Single-agent paclitaxel (TAXOL) was administered to 79 patients with stage IV breast cancer. Twenty-eight patients had no prior chemotherapy (for metastatic disease), and 51 patients had extensive exposure to other chemotherapeutic agents before beginning the 24-hour paclitaxel infusion. Routine use of recombinant human granulocyte colony-stimulating factor helped to ameliorate neutropenia, the dose-limiting toxicity, in some cases. Other toxicity was generally mild to moderate. Paclitaxel was more active in patients whose stage IV disease had not yet been exposed to chemotherapy, but activity was seen in the patients previously treated extensively as well. There is a strong clinical suggestion of non-cross-resistance with doxorubicin. In one case, an excellent response in previously irradiated skin was seen. Paclitaxel is a very promising agent for the treatment of metastatic breast cancer.

Taxol plus recombinant human granulocyte-colony stimulating factor as initial and as salvage chemotherapy for metastatic breast cancer: a preliminary report.

Twenty-eight patients received Taxol as their first chemotherapy for stage IV breast cancer. An additional 51 patients with extensive prior exposure to other chemotherapeutic agents received Taxol as salvage therapy. We found significant activity for the drug in both situations, as well as a strong clinical suggestion of non-cross-resistance with doxorubicin. An excellent response in previously irradiated skin was noted in one case. The routine use of recombinant human granulocyte-colony stimulating factor seemed to ameliorate some of the dose-limiting toxicity of neutropenia. Other toxicity was mild to moderate in most cases. With further development, Taxol should play a significant role in the systemic management of breast cancer.

An experimental analysis of classically conditioned nausea during cancer chemotherapy.

This study investigated classical conditioning in women undergoing outpatient adjuvant chemotherapy for breast cancer. Breast cancer chemotherapy outpatients were randomly assigned either to an Experimental Group (exposed to a distinctive stimulus before each infusion of chemotherapy) or to a Control Group. After repeated infusions of chemotherapy, patients' responses to the experimental stimulus were assessed in a location not associated with chemotherapy. Experimental Group patients had increased nausea (self-reported on a visual analog scale) following the presentation of the experimental stimulus at this test trial, whereas Control Group patients did not. Two other measures of nausea corroborated these results. Post hoc statistical analyses confirmed predictions based on conditioning theory. This conditioning model of anticipatory nausea bears witness to the relevance of classical conditioning in clinical medicine.

Effective chemotherapy for melanoma after treatment with interleukin-2.

Twenty patients with biopsy-proven metastatic malignant melanoma, previously treated with interleukin-2 (IL-2), received combination chemotherapy for progressive disease. Treatment included carmustine, cisplatin, dacarbazine, and tamoxifen (BCDT). Nausea was the most common toxicity (100%) and usually was mild. Persistent thrombocytopenia was the most frequent toxicity limiting further treatment. Eleven patients (55%) had an objective partial response, three patients (15%) had a minor response, and six patients (30%) had no change or progressive disease in response to this treatment. These results were comparable to the high response rates (21 of 40, 53%) achieved with BCDT in previously untreated patients with melanoma. It was concluded that prior therapy using IL-2 does not significantly alter the response rate of metastatic melanoma to BCDT, thus suggesting that immunomodulators (e.g., IL-2) and chemotherapeutic agents are not cross-resistant treatments.

Association of interleukin-2 therapy with staphylococcal bacteremia.

The authors prospectively monitored patients undergoing leukapheresis for peripheral stem cell harvesting (PSCH) or lymphokine activated killer (LAK) cell generation for 3 weeks after catheter placement for evidence of local or systemic infections. Over a 1-year period, 16 patients underwent leukapheresis for PSCH in preparation for autologous bone marrow transplantation (ABMT). The original catheters remained in place an average of 20 days without any documented infections. Seventeen patients underwent leukapheresis as part of a low-dose interleukin-2 (IL-2) treatment for LAK cell generation, and their catheters remained in place an average of 20.2 days with three documented episodes of bacteremia (18%). Eight patients treated with high-dose IL-2 also underwent leukapheresis for LAK cell generation and their catheters remained in place an average of 12 days with three documented episodes of bacteremia (38%). In all cases of bacteremia, Staphylococcus species were isolated from the blood. The IL-2 exposure level was associated with the risk of bacteremia (P = 0.01). Other potential risk factors (e.g., number of pheresis procedures, complement level, serum immunoglobulin levels, absolute neutrophil count) were not related to this risk.

Design of combination biotherapy studies: future goals and challenges.

The recent large-scale production of biomodulators, also known as biologic response modifiers, made possible through recombinant DNA technology, offers the potential for significant advances in the treatment of cancer. The antitumor activity of these agents, such as interferons, interleukins, and tumor necrosis factor, have generated enthusiasm for further investigation. In an effort to improve response rates, combinations of these agents both with and without conventional therapies are currently being examined. Clinical trials have been conducted with various therapeutic combinations, including a biomodulator plus chemotherapy, combinations of different biomodulators, a biomodulator with concomitant chemotherapy and radiation, and multiple combinations of chemotherapies and biomodulators. These approaches are promising and some limited successes have been reported; however, the goal of increased anticancer activity without greater toxicities or antagonism between various agents is not always achieved. Synergism among active agents is not necessarily assured and quite unexpected and unpredictable toxicities have been noted. The studies to date suggest that important new therapies will emerge, but many questions have to be answered before the specific roles of these new treatments are defined.

Evaluation of Leu-M5 (CD11c) in hairy cell leukemia by the alkaline phosphatase anti-alkaline phosphatase technique.

The concomitant presence of B antigens and of the antigen recognized by the monoclonal antibody Leu-M5 (CD11c) on neoplastic lymphoid cells has been reported to be largely restricted to hairy cell leukemia (HCL). The authors studied Leu-M5 reactivity of neoplastic cells from 59 patients whose specimens were referred with a stated diagnosis of HCL by using the alkaline phosphatase anti-alkaline phosphatase technique on peripheral blood (PB) and bone marrow (BM) specimens. Tartrate-resistant acid phosphatase (AcP-T) activity was also studied. In 49 patients, HCL had been confirmed previously by BM biopsy, and specimens were evaluated for disease status during or after therapy with interferon (IFN) or 2'-deoxycoformycin. The remaining ten patients were newly referred for confirmation of the diagnosis of HCL before therapy. In all 55 patients in whom the BM biopsy demonstrated HCL, virtually every leukemic cell was Leu-M5 reactive, and the reaction proved, in some cases, to be helpful in the detection of small numbers of hairy cells in PB or BM preparations. AcP-T reactivity was demonstrated in the neoplastic cells of 52 of these 55 patients, including all but 3 of those receiving IFN, and was helpful in confirming persistent leukemia when interpretation of BM biopsy sections was difficult because the numbers of hairy cells were small. However, in four of the ten newly referred patients, BM biopsy showed features of splenic lymphoma with villous lymphocytes, rather than HCL. The neoplastic cells of these four patients were of B-cell origin and in three were Leu-M5 reactive. The authors' study indicates that Leu-M5 is present in nearly all hairy cells, but its presence in conjunction with other B-cell markers is not specific for HCL.