1
UI - 11438566
AU - Li CI; Malone KE; Weiss NS; Daling JR
TI - Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.
SO - J Natl Cancer Inst 2001 Jul 4;93(13):1008-13
AD - Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-1024, USA. cili@fhcrc.org
BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.

2
UI - 11438553
AU - Swain SM
TI - Tamoxifen and contralateral breast cancer: the other side.
SO - J Natl Cancer Inst 2001 Jul 4;93(13):963-5

3
UI - 11498214
AU - Cole BF; Gelber RD; Gelber S; Coates AS; Goldhirsch A
TI - Polychemotherapy for early breast cancer: an overview of the randomised clinical trials with quality-adjusted survival analysis.
SO - Lancet 2001 Jul 28;358(9278):277-86
AD - Dartmouth College Medical School, Lebanon, NH, USA. bernard.cole@dartmouth.edu
BACKGROUND: Overview analysis involving 18000 women with breast cancer in 47 randomised trials showed that prolonged chemotherapy significantly reduces the risk of relapse and death compared with no chemotherapy. Here we express the size of the benefit in terms of quality-adjusted survival time gained. METHODS: We used the Q-TWiST method (Quality-adjusted Time Without Symptoms of disease and Toxicity of treatment) to provide treatment comparisons within 10 years' follow-up, incorporating differences in quality of life associated with times patients spend with chemotherapy toxic effects, after relapse, and without symptoms of relapse or toxicity. FINDINGS: Within 10 years' follow-up the benefit of increased relapse-free and overall survival for younger women (<50 years old) who received polychemotherapy balanced the burdens in terms of acute toxic side-effects, especially among women enrolled in trials that did not include tamoxifen. Overall, chemotherapy-treated younger women gained an average of 10.3 months of relapse-free survival and 5.4 months of overall survival within 10 years (p<0.0001 for both) compared with the no-chemotherapy group. Polychemotherapy provided more quality-adjusted time than control across nearly all values of utility weights for time spent undergoing chemotherapy and time after relapse. The range of benefit was from -0.6 to 10.3 months. For older women (50-69 years) overall, polychemotherapy also provided significant benefit compared with no chemotherapy but, compared with younger women, the size of benefit was less and the range of utility-weight values favouring polychemotherapy was smaller. Average gains for older women treated with polychemotherapy (with or without tamoxifen) were 6.8 months of relapse-free survival (p<0.0001) and 2.9 months of overall survival (p=0.0001) within 10 years. The range of quality-adjusted benefit was -3.1 to 6.8 months. For older women with oestrogen-receptor-poor tumours who did not receive tamoxifen (9% of the total), the benefit of polychemotherapy was significant and similar to that observed for younger women. INTERPRETATION: The benefits of adjuvant chemotherapy within 10 years outweigh the burdens especially for younger women (<50 years old) and among older women (50-69 years) to a lesser degree. Additional studies to compare the quality-adjusted survival of chemotherapy plus endocrine therapy versus endocrine therapy alone are required for younger patients with tumours that express steroid-hormone receptors.

4
UI - 11784664
AU - Rodger A
TI - Polychemotherapy for early breast cancer.
SO - Lancet 2001 Dec 22-29;358(9299):2170

5
UI - 12067140
AU - Pienkowski T; Jagiello-Gruszfeld A
TI - Five-day infusion of fluorouracil and vinorelbine for advanced breast cancer patients treated previously with anthracyclines.
SO - Int J Clin Pharmacol Res 2001;21(3-4):111-7
AD - Department of Breast Cancer and Reconstructive Surgery, Maria Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Warsaw, Poland.
Vinorelbine has proven to be effective in pretreated metastatic breast cancer patients. In particular, no cross-resistance with anthracyclines has been demonstrated. Protracted 5-fluorouracil infusion presents a better pharmacological profile than its bolus administration. The aim of this study was to investigate the efficacy and toxicity of the combination of these two antitumor drugs in patients with metastatic breast cancer who had been previously treated with 65 patients were enrolled into the study The most important inclusion criteria were as follows: Karnofsky 70-100, measurable or evaluable disease and normal renal, hepatic, bone marrow and cardiac function. Mean age was 48 years (range: 31-70). Fourteen of the 65 women had already received more than one chemotherapy line. Twenty-three patients had previously been treated with taxanes. Sites of involvement were the lungs in 50% of the patients, the liver in 37%, soft tissue in 72%, bone in 58% and other sites in 32%. Treatment consisted of vinorelbine 25 mg/m2 administered on days 1 and 6 every 21 days and 5-fluorouracil 700 mg/m2/day for 5 consecutive days. The total number of cycles was 340 (mean: five cycles). The treatment was well tolerated. Febrile neutropenia was observed in 4.6% of patients. Fourteen percent of patients experienced grade 3 or 4 neutropenia, and 3% experienced grade 3 thrombocytopenia. Grade 3 stomatitis was observed in 9.2% of patients, grade 3 neurologic toxicity was observed in 1.5%, and grade 3 cardiotoxicity in 4.6%. Grade 3 site reaction occurred in 3% of patients. Sixty patients were evaluated for response. One patient (1.7%) attained complete clinical response and 28 (46.7%) attained partial response. In 22 patients (36.6%) stable disease was documented and nine patients (15%) progressed while on treatment. Median time to progression was 24 weeks, median duration of response was 35 weeks and median overall survival was 41 weeks. Vinorelbine with 5-day infusion of 5-fluorouracil presented high therapeutic activity in breast cancer patients previously treated with anthracyclines, with acceptable toxicity.

6
UI - 11673683
AU - Wolff AC
TI - Systemic therapy.
SO - Curr Opin Oncol 2001 Nov;13(6):436-49
AD - The Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21231-1000, USA. awolff@jhmi.edu
A large body of data on systemic therapy has been presented and published in the past year, including new information on primary risk reduction, patient selection for adjuvant systemic therapy, and anthracycline-analogs. New data on ongoing adjuvant trials (including taxane studies), unpublished updates from the fourth Oxford Overview in Development Conference on Adjuvant Therapy for Breast Cancer. Important new data on anti-estrogen therapy, including aromatase inhibitors and pure antiestrogens, further expand the role of the oldest targeted breast cancer therapy. Trastuzumab and other novel compounds are being investigated as single-agents and in combination with conventional systemic approaches. Discussions on the long-term effects of adjuvant therapy have taken center stage also. These and other important ongoing developments since 2000 are examined in this review article.

7
UI - 11773307
AU - Partridge AH; Burstein HJ; Winer EP
TI - Side effects of chemotherapy and combined chemohormonal therapy in women with early-stage breast cancer.
SO - J Natl Cancer Inst Monogr 2001;(30):135-42
AD - Breast Oncology Center, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02215, USA.
The decision to receive chemotherapy or chemohormonal therapy involves careful consideration of both the potential benefits and possible risks of therapy. There are substantial short- and long-term side effects from chemotherapy. By convention, short-term side effects include those toxic effects encountered during chemotherapy, while long-term side effects include later complications of treatment arising after the conclusion of adjuvant chemotherapy. These side effects vary, depending on the specific agents used in the adjuvant regimen as well as on the dose used and the duration of treatment. There is also considerable variability in side effect profile across individuals. This review will focus on the short- and long-term toxicity seen with the most commonly used adjuvant chemotherapy and chemohormonal therapy regimens.

8
UI - 11817485
AU - Richer MC; Ezer H
TI - Living in it, living with it, and moving on: dimensions of meaning during chemotherapy.
SO - Oncol Nurs Forum 2002 Jan-Feb;29(1):113-9
AD - McGill University Health Center, Montreal, Quebec, Canada. marie-claire.richer@muhc.mcgill.ca
PURPOSE/OBJECTIVE: To explore the meanings assigned to the experience of receiving chemotherapy. DESIGN: Descriptive exploratory. SETTING: An oncology outpatient clinic in a university hospital in Montreal, Quebec, Canada. SAMPLE: Ten women with breast cancer who experienced chemotherapy for the first time. METHODS: Semistructured interview using a grounded theory approach. FINDINGS: Women described three dimensions of their experience with breast cancer and chemotherapy: "living in it," "living with it," and "moving on." Existential and situational meanings were an integral part of their experience. The existential meaning seemed to be present in varying degrees of intensity throughout the treatment, whereas the situational meanings were predominant at the beginning of the treatment phase and became less important as the treatment progressed. CONCLUSIONS: The intrapersonal and interpersonal dimensions of the chemotherapy experience as well as the capacity to move on evolve within a context of both situational and existential meanings. IMPLICATIONS FOR NURSING PRACTICE: The study results suggest the potential value of exploring each woman's inner world of meanings in relation to her sense of self, relationships with others, resources, and coping strategies during treatment for breast cancer. Because existential and situational meanings are an integral part of women's experience, the nurse's role is to create an environment that permits and facilitates dialogue about these dimensions of meaning.

9
UI - 11914638
AU - Boyer CR; Karjian PL; Wahl GM; Pegram M; Neuteboom ST
TI - Nucleoside transport inhibitors, dipyridamole and p-nitrobenzylthioinosine, selectively potentiate the antitumor activity of NB1011.
SO - Anticancer Drugs 2002 Jan;13(1):29-36
AD - NewBiotics, Inc, San Diego, CA 92121, USA.
NB1011, a novel anticancer agent, targets tumor cells expressing high levels of thymidylate synthase (TS). NB1011 is converted intracellularly to bromovinyldeoxyuridine monophosphate (BVdUMP) which competes with the natural substrate, deoxyuridine monophosphate, for binding to TS. Unlike inhibitors, NB1011 becomes a reversible substrate for TS catalysis. Thus, TS retains activity and converts BVdUMP into cytotoxic product(s). In vitro cytotoxicity studies demonstrate NB1011's preferential activity against tumor cells expressing elevated TS protein levels. Additionally, NB1011 has antitumor activity in vivo. To identify drugs which interact synergistically with NB1011, we screened 13 combinations of chemotherapeutic agents with NB1011 in human tumor and normal cells. Dipyridamole and p-nitrobenzylthioinosine (NBMPR), potent inhibitors of equilibrative nucleoside transport, synergized with NB1011 selectively against 5-fluorouracil (5-FU)-resistant H630R10 colon carcinoma cells [combination index (CI)=0.75 and 0.35] and Tomudex-resistant MCF7TDX breast carcinoma cells (CI=0.51 and 0.57), both TS overexpressing cell lines. These agents produced no synergy with NB1011 in Det551 and CCD18co normal cells (CI > 1.1) lacking TS overexpression. Dipyridamole potentiated NB1011's cytotoxicity in medium lacking nucleosides and bases, suggesting a non-salvage-dependent mechanism. We demonstrate that nucleoside transport inhibitors, dipyridamole and NBMPR, show promise for clinically efficacious combination with NB1011.

10
UI - 11914643
AU - Wenzel C; Locker GJ; Schmidinger M; Rudas M; Taucher S; Gnant MF; Jakesz
TI - R; Steger GG Combined analysis of two phase II trials in patients with primary and advanced breast cancer with epidoxorubicin and docetaxel+granulocyte colony stimulating factor.
SO - Anticancer Drugs 2002 Jan;13(1):67-74
AD - Department of Internal Medicine I, Division of Oncology, University Hospital of Vienna, 1090 Vienna, Austria.
Anthracyclines and taxanes are to date the most active cytotoxic agents in the treatment of breast cancer, and a combination of these is therefore considered to result in the highest response rates in the neoadjuvant, as well as in palliative treatment. These two phase II studies aimed to evaluate the feasibility, toxicity and activity of a cytostatic regimen combining epidoxorubicin and docetaxel in outpatient patients suffering from breast cancer. In total, 104 consecutive patients were enrolled in these prospective clinical trials. The chemotherapeutic regimen consisted of epidoxorubicin [75 mg/m2 body surface area (BSA)] and docetaxel (75 mg/m2 BSA) on day 1 accompanied by the administration of granulocyte colony stimulating factor on days 3-10, repeated every 3 weeks (ED+G). Sixty-six patients received ED+G as neoadjuvant and 38 patients as palliative treatment, respectively. Patients received a total of 566 cycles (median: 6 cycles, range: 2-11 cycles) of this therapeutic regimen. Outpatient ED+G was well tolerated. A major response to preoperative ED+G could be demonstrated in 54 of 66 patients (82%) and in 22 of 38 palliative treated patients (58%). We conclude that outpatient ED+G is safe in the neoadjuvant and palliative treatment of patients suffering from breast cancer by showing a favorable side effect and activity profile. Thus, this regimen can be considered for further clinical trials.

11
UI - 12056098
AU - Tonkin K; Bates M; Lieu D; Arundell E; Williamson T; Zagari M
TI - Dexrazoxane cardioprotection for patients receiving FAC chemotherapy: a pharmacoeconomic evaluation.
SO - Can J Oncol 1996 Nov;6(2):458-73
AD - London Regional Cancer Centre, London, Ontario.
Anthracyclines are among the most effective and commonly-prescribed antitumor agents but have dose-limiting cumulative cardiotoxicity. We performed a pharmacoeconomic evaluation of the ability of dexrazoxane to prevent cardiac-related adverse events in patients with Stage IIIB or IV metastatic breast cancer who were treated with a median of 10 cycles of intravenous FAC (5-fluorouracil, doxorubicin and cyclophosphamide) at doses of 500/50/500 mg/m2 respectively. Dexrazoxane was given at 500 mg/m2 commencing at the seventh cycle of treatment. We determined the cost of each cardiac event prevented and the cost of each additional life-year saved by dexrazoxane use. The cost per cardiac event prevented was CDN $5745 and the cost per additional life-year saved was CDN $2856. With the increasing use of anthracyclines in Stages I and II breast cancer, these favorable clinical and economic results may broaden the range of therapeutic possibilities for anthracyclines in adjuvant and metastatic therapy of breast cancer.

12
UI - 12064322
AU - Carroll-Johnson RM
TI - Reader suggests fuller appreciation of findings.
SO - Oncol Nurs Forum 2002 Jun;29(5):751; discussion 751

13
UI - 9469328
AU - Dombernowsky P; Smith I; Falkson G; Leonard R; Panasci L; Bellmunt J;
TI - Bezwoda W; Gardin G; Gudgeon A; Morgan M; Fornasiero A; Hoffmann W; Michel J; Hatschek T; Tjabbes T; Chaudri HA; Hornberger U; Trunet PF Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate.
SO - J Clin Oncol 1998 Feb;16(2):453-61
PURPOSE: To compare two doses of letrozole and megestrol acetate (MA) as second-line therapy in postmenopausal women with advanced breast cancer previously treated with antiestrogens. PATIENTS AND METHODS: Five hundred fifty-one patients with locally advanced, locoregionally recurrent or metastatic breast cancer were randomly assigned to receive letrozole 2.5 mg (n = 174), letrozole 0.5 mg (n = 188), or MA 160 mg (n = 189) once daily in a double-blind, multicenter trial. Data were analyzed for tumor response and safety variables up to 33 months of follow-up evaluation and for survival up to 45 months. RESULTS: Letrozole 2.5 mg produced a significantly higher overall objective response rate (24%) compared with MA (16%; logistic regression, P = .04) or letrozole 0.5 mg (13%; P = .004). Duration of objective response was significantly longer for letrozole 2.5 mg compared with MA (Cox regression, P = .02). Letrozole 2.5 mg was significantly superior to MA and letrozole 0.5 mg in time to treatment failure (P = .04 and P = .002, respectively). For time to progression, letrozole 2.5 mg was superior to letrozole 0.5 mg (P = .02), but not to MA (P = .07). There was a significant dose effect in overall survival in favor of letrozole 2.5 mg (P = .03) compared with letrozole 0.5 mg. Letrozole was significantly better tolerated than MA with respect to serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain. CONCLUSION: The data show letrozole 2.5 mg once daily to be more effective and better tolerated than MA in the treatment of postmenopausal women with advanced breast cancer previously treated with antiestrogens.

14
UI - 11352951
AU - Mouridsen H; Gershanovich M; Sun Y; Perez-Carrion R; Boni C; Monnier A;
TI - Apffelstaedt J; Smith R; Sleeboom HP; Janicke F; Pluzanska A; Dank M; Becquart D; Bapsy PP; Salminen E; Snyder R; Lassus M; Verbeek JA; Staffler B; Chaudri-Ross HA; Dugan M Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.
SO - J Clin Oncol 2001 May 15;19(10):2596-606
AD - Rigshospitalet, Copenhagen, Denmark.
PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.

15
UI - 11579125
AU - Panasci LC
TI - Aromatase inhibitors: treatment of advanced breast cancer.
SO - J Clin Oncol 2001 Oct 1;19(19):3999-4000

16
UI - 11895893
AU - Cohen MH; Johnson JR; Li N; Chen G; Pazdur R
TI - Approval summary: letrozole in the treatment of postmenopausal women with advanced breast cancer.
SO - Clin Cancer Res 2002 Mar;8(3):665-9
AD - Division of Oncology Drug Products (HFD-150), Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 20857, USA. cohenm@cder.fda.gov
Letrozole (Femara; Novartis Pharmaceuticals Corp., East Hanover, NJ) is a nonsteroidal inhibitor of aromatase enzyme complex. It inhibits the peripheral conversion of circulating androgens to estrogens. In postmenopausal women, letrozole decreases plasma concentrations of estradiol, estrone, and estrone sulfate by 75-95% from baseline with maximal suppression achieved within 2-3 days of treatment initiation. Suppression is dose related, with doses of >or=0.5 mg giving estrone and estrone sulfate values that were often below assay detection limits. At clinically used dosage, letrozole does not impair adrenal synthesis of glucocorticoids or aldosterone. In 1998, letrozole was approved by the United States Food and Drug Administration (FDA) for the treatment of advanced breast cancer in postmenopausal women, with hormone receptor positive or unknown breast cancer, who had failed one prior antiestrogen treatment (i.e., for "second-line" treatment). Approval was based on two randomized trials comparing tumor RRs of patients receiving 0.5 mg of letrozole, 2.5 mg of letrozole, and either megestrol acetate (MA) or aminoglutethimide. In the megestrol trial, 2.5 mg/day letrozole was superior to 0.5 mg of letrozole and MA (RRs 24, 13, and 16%, respectively), whereas in the aminoglutethimide trial, there was no significant difference in 2.5 mg of letrozole and 0.5 mg of letrozole RRs (20 and 17%). There was a trend toward RR superiority of 2.5 mg of letrozole over aminoglutethimide (P = 0.06). Letrozole (2.5 mg) was the dose chosen for comparison with tamoxifen in the first-line setting. In postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer was submitted to the FDA. A single double-blind, double dummy, randomized, and multicenter trial compared 2.5 mg of letrozole to 20 mg of tamoxifen (456 patients/arm). Letrozole was superior to tamoxifen with regard to time to progression (TTP) and objective response rate (RR). The median TTP for letrozole treatment was 9.9 months [95% confidence interval (CI) 9.1-12.2] versus 6.2 months (95% CI 5.8-8.5) for tamoxifen, P = 0.0001, hazard ratio 0.713, (95% CI 0.61-0.84). RR was 32% for letrozole versus 21% for tamoxifen (odds ratio 1.74, 95% CI 1.29-2.34, P = 0.0003). Preliminary survival data (survival data are still blinded) indicate that letrozole is unlikely to be worse than tamoxifen. Both treatments were similarly tolerated. On the basis of these results, the United States FDA approved letrozole tablets, 2.5 mg/day, for first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer. The manufacturer made a commitment to provide updated information on survival.

17
UI - 11895894
AU - Toppmeyer D; Seidman AD; Pollak M; Russell C; Tkaczuk K; Verma S;
TI - Overmoyer B; Garg V; Ette E; Harding MW; Demetri GD Safety and efficacy of the multidrug resistance inhibitor Incel (biricodar; VX-710) in combination with paclitaxel for advanced breast cancer refractory to paclitaxel.
SO - Clin Cancer Res 2002 Mar;8(3):670-8
AD - Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, USA.
PURPOSE: VX-710 (biricodar, Incel) restores drug sensitivity to P-glycoprotein (MDR1) and multidrug resistance-associated protein (MRP1)-expressing cells. This Phase II study evaluated the safety/tolerability, pharmacokinetics, and efficacy of VX-710 plus paclitaxel in women with locally advanced or metastatic breast cancer who were refractory to prior paclitaxel therapy. EXPERIMENTAL DESIGN: Eligible patients had paclitaxel-refractory disease defined as progressive disease after a minimum of two cycles of paclitaxel (weekly or 3-week schedule) or relapsed/progressive disease within 6 months of prior paclitaxel therapy. Patients received 80 mg/m(2) paclitaxel over 3 h starting 4 h after initiation of a 24-h continuous i.v. infusion of 120 mg/m(2)/h VX-710. Cycles were repeated every 3 weeks. RESULTS: Thirty-seven patients received study treatment and 35 were evaluable for response. VX-710 + paclitaxel therapy was generally well tolerated. Myelosuppression was the principal toxicity, with a median nadir ANC cycle 1 of 0.76 x 10(9) cells/liter and a 40% overall incidence of Grade 4 neutropenia. Nonhematological side effects (asthenia, paresthesia, headache, myalgia, nausea, and diarrhea) were generally mild to moderate and reversible. Paclitaxel AUC (16.8 +/- 5.0 microg x h/ml) and clearance (5.1 +/- 1.3 liters/h/m(2)) during the first treatment cycle were comparable with standard 175 mg/m(2) paclitaxel administered in a 3-h schedule. Four patients achieved partial responses (three of the four had progressive disease on prior paclitaxel) with a mean response duration of 5.5 months. CONCLUSIONS: The 11.4% (4 of 35) objective response rate observed in this study suggests that VX-710 can resensitize a subgroup of paclitaxel-refractory patients to paclitaxel. The safety and pharmacokinetics of the VX-710/pacitaxel regimen support further evaluation in breast cancer patients with initial paclitaxel therapy to prevent emergence of the MDR phenotype in recurrent disease.

18
UI - 11895898
AU - Petros WP; Broadwater G; Berry D; Jones RB; Vredenburgh JJ; Gilbert CJ;
TI - Gibbs JP; Colvin OM; Peters WP Association of high-dose cyclophosphamide, cisplatin, and carmustine pharmacokinetics with survival, toxicity, and dosing weight in patients with primary breast cancer.
SO - Clin Cancer Res 2002 Mar;8(3):698-705
AD - Bone Marrow Transplant Program, Duke University Medical Center, Durham, North Carolina 27710, USA. wpetros@hsc.wvu.edu
This report investigates relationships between the pharmacokinetics and pharmacodynamics of high-dose alkylators used for the treatment of primary breast cancer. Eighty-five women with primary breast cancer involving >or=10 lymph nodes received four cycles of standard-dose chemotherapy followed by a high-dose regimen consisting of: cyclophosphamide (1875 mg/m(2) once daily x 3), cisplatin (165 mg/m(2) given over 72 h), carmustine (600 mg/m(2)), and stem cell transplantation. Dosages were attenuated in patients whose body weight exceeded their calculated ideal weight by >20%. Pharmacokinetics of the high-dose chemotherapeutic agents were evaluated in each patient by collection and analysis of serial blood samples. Area under the concentration time curve (AUC) for cyclophosphamide and carmustine was highly variable (>10-fold inter-patient range) with coefficients of variation > 50%, in contrast to cisplatin exposures (2-fold range; coefficient of variation 12%). The dosing method for overweight patients resulted in significantly lower systemic exposure to cisplatin (P = 0.035). The parent cyclophosphamide clearance on the 1st day of administration was significantly higher in patients who experienced acute cardiac toxicity (n = 5; P = 0.011), whereas carmustine disposition was not found to be different in those developing pulmonary toxicity (n = 25; P = 0.96). Kaplan-Meier analysis (median follow-up of 5.9 years) demonstrated that patients with lower cyclophosphamide AUC (faster parent drug clearance to potentially cytotoxic compounds) survived longer (P = 0.031). Inter-individual differences in the pharmacokinetic disposition of high-dose chemotherapy may explain variability in both response and toxicity. Prospective strategies, which attempt to individualize AUC, should be evaluated in this setting.

19
UI - 12048744
AU - Anonymous
TI - Research will help chemotherapy patients avoid memory loss.
SO - W V Med J 2002 Mar-Apr;98(2):78

20
UI - 12066455
AU - Brink S
TI - Breast cancer face-off.
SO - US News World Rep 2002 Jun 3;132(19):54

21
UI - 11731525
AU - Cocconi G
TI - False shortening of time to progression in letrozole 2.5-mg dose?
SO - J Clin Oncol 2001 Dec 1;19(23):4353; discussion 4354-5

22
UI - 12050317
AU - Sciuto R; Pasqualoni R; Bergomi S; Petrilli G; Vici P; Belli F; Botti C;
TI - Mottolese M; Maini CL Prognostic value of (99m)Tc-sestamibi washout in predicting response of locally advanced breast cancer to neoadjuvant chemotherapy.
SO - J Nucl Med 2002 Jun;43(6):745-51
AD - Department of Nuclear Medicine, Regina Elena Cancer Institute, Rome, Italy. sciuto@ifo.it
This study evaluated the role of (99m)Tc-sestamibi washout in the prediction of pathologic tumor response to neoadjuvant chemotherapy in 30 patients with locally advanced breast cancer. METHODS: Two (99m)Tc-sestamibi studies were performed before and after chemotherapy for each patient. Early (10 min) and delayed (240 min) planar breast views were acquired after a 740-MBq (99m)Tc-sestamibi intravenous injection, and the washout rate (WOR) was computed. All patients underwent radical mastectomy with pathologic evaluation of the residual tumor size. RESULTS: The pretherapy (99m)Tc-sestamibi WOR ranged from 14% to 92% (mean +/- SD, 50% +/- 18%). At pathologic examination, 15 patients showed no tumor response to chemotherapy and 15 patients showed an objective response to chemotherapy. The pretherapy (99m)Tc-sestamibi study predicted chemoresistance (WOR > 45%) in 18 of 30 patients and no chemoresistance (WOR < or = 45%) in 12 of 30 patients. When the WOR cutoff was set at >45%, the prognostic performance of the test was indicated by a sensitivity of 100%; a specificity of 80%; positive and negative predictive values of 83% and 100%, respectively; and a likelihood ratio of 5. The repeatability of the test was good, with 80%-93% interreader agreement (kappa = 0.57-0.85). Posttherapy (99m)Tc-sestamibi studies confirmed the pretherapy study prediction in 29 of 30 patients. CONCLUSION: (99m)Tc-Sestamibi WOR is a reliable test for predicting tumor response to neoadjuvant chemotherapy. In fact, negative findings (WOR < or = 45%) rule out chemoresistance and positive findings (WOR > 45%) indicate a high risk of chemoresistance.

23
UI - 12065558
AU - O'Shaughnessy J; Miles D; Vukelja S; Moiseyenko V; Ayoub JP; Cervantes
TI - G; Fumoleau P; Jones S; Lui WY; Mauriac L; Twelves C; Van Hazel G; Verma S; Leonard R Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.
SO - J Clin Oncol 2002 Jun 15;20(12):2812-23
AD - Baylor-Sammons Cancer Center, Dallas, TX 75246, USA. joyce.o'shaughnessey@usoncology.com
PURPOSE: Docetaxel and capecitabine, a tumor-activated oral fluoropyrimidine, show high single-agent efficacy in metastatic breast cancer (MBC) and synergy in preclinical studies. This international phase III trial compared efficacy and tolerability of capecitabine/docetaxel therapy with single-agent docetaxel in anthracycline-pretreated patients with MBC. PATIENTS AND METHODS: Patients were randomized to 21-day cycles of oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 plus docetaxel 75 mg/m(2) on day 1 (n = 255) or to docetaxel 100 mg/m(2) on day 1 (n = 256). RESULTS: Capecitabine/docetaxel resulted in significantly superior efficacy in time to disease progression (TTP) (hazard ratio, 0.652; 95% confidence interval [CI], 0.545 to 0.780; P =.0001; median, 6.1 v 4.2 months), overall survival (hazard ratio, 0.775; 95% CI, 0.634 to 0.947; P =.0126; median, 14.5 v 11.5 months), and objective tumor response rate (42% v 30%, P =.006) compared with docetaxel. Gastrointestinal side effects and hand-foot syndrome were more common with combination therapy, whereas myalgia, arthralgia, and neutropenic fever/sepsis were more common with single-agent docetaxel. More grade 3 adverse events occurred with combination therapy (71% v 49%, respectively), whereas grade 4 events were slightly more common with docetaxel (31% v 25% with combination). CONCLUSION: The significantly superior TTP and survival achieved with the addition of capecitabine to docetaxel 75 mg/m(2), with the manageable toxicity profile, indicate that this combination provides clear benefits over single-agent docetaxel 100 mg/m(2). Docetaxel/capecitabine therapy is an important treatment option for women with anthracycline-pretreated MBC.

24
UI - 12065569
AU - Lawrence G; Crawford J; Sherman F
TI - Evaluating neoadjuvant chemotherapy in breast cancer.
SO - J Clin Oncol 2002 Jun 15;20(12):2905-6; discussion 2906-7

25
UI - 12088260
AU - Tekin K; Kocaoglu H; Bayar S
TI - Long-term survival after regional chemotherapy for liver metastases from breast cancer. A case report.
SO - Tumori 2002 Mar-Apr;88(2):167-9
AD - Department of General Surgery, Faculty of Medicine, Pamukkale University, Denizli, Turkey. koraytekin@hotmail.com
The prognosis of patients with liver metastases from breast cancer has to be regarded as rather unfavorable. A 45-year-old woman with cancer of the left breast and multiple simultaneous liver metastases was initially treated with cyclophosphamide, methotrexate, and 5-fluorouracil. After two treatment cycles a sonogram of the left breast revealed reduction of the tumor size and she underwent a modified radical mastectomy and hepatic artery catheterization. There was no change in the multiple lesions of the liver on abdominal ultrasonography. One week later a regional chemotherapy regimen was given through a hepatic arterial catheter with subcutaneous implanted reservoir. After completion of the seventh course of chemotherapy, ultrasonography revealed that the there has been no relapse during the seven-year follow-up period. In conclusion, we suggest that intra-arterial regional chemotherapy may have an important role to play in the management of breast cancer patients with isolated liver metastases.

26
UI - 12067682
AU - O'Regan RM; Jordan VC
TI - The evolution of tamoxifen therapy in breast cancer: selective oestrogen-receptor modulators and downregulators.
SO - Lancet Oncol 2002 Apr;3(4):207-14
AD - Robert H Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL 60611, USA.
Tamoxifen is the most widely used hormonal treatment for all stages of breast cancer and has been approved for the prevention of breast cancer in high-risk women. The observation that tamoxifen acts as an antioestrogen on the breast but has paradoxical oestrogenic effects on bones and lipids heralded the development of the selective oestrogen-receptor modulators (SERM). Raloxifene, another of these drugs, is being used to prevent osteoporosis in postmenopausal women, but it seems, like tamoxifen, to prevent breast cancer. The molecular basis for these target-site-specific actions remains unclear but may involve the relative expressions of coregulatory proteins in target tissues. Several new SERM agents are in clinical development in an attempt to decrease the unwanted effects. Furthermore, two different classes of hormonal agents, the aromatase inhibitors and oestrogen-receptor downregulators, which have no oestrogen-like properties at any site, are promising new treatments for breast cancer.

27
UI - 11899369
AU - Camp-Sorrell D
TI - Unusual port presentation.
SO - Clin J Oncol Nurs 2001 May-Jun;5(3):115-6
AD - Central Alabama Hematology Oncology Associates Alabaster, USA.

28
UI - 12090973
AU - Ravdin P
TI - Aromatase inhibitors for the endocrine adjuvant treatment of breast cancer.
SO - Lancet 2002 Jun 22;359(9324):2126-7
AD - Department of Medical Oncology, University of Texas Health Science Center, San Antonio, TX 98284-7884, USA. peter@oncology.uthscsa.edu

29
UI - 12090977
AU - The ATAC Trialists' Group. Arimidex, tamoxifen alone or in combination.
TI - Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial.
SO - Lancet 2002 Jun 22;359(9324):2131-9
BACKGROUND: In the adjuvant setting, tamoxifen is the established treatment for postmenopausal women with hormone-sensitive breast cancer. However, it is associated with several side-effects including endometrial cancer and thromboembolic disorders. We aimed to compare the safety and efficacy outcomes of tamoxifen with those of anastrozole alone and the combination of anastrozole plus tamoxifen for 5 years. METHODS: Participants were postmenopausal patients with invasive operable breast cancer who had completed primary therapy and were eligible to receive adjuvant hormonal therapy. The primary endpoints were disease-free survival and occurrence of adverse events. Analysis for efficacy was by intention to treat. FINDINGS: 9366 patients were recruited, of whom 3125 were randomly assigned anastrozole, 3116 tamoxifen, and 3125 combination. Median follow-up was 33.3 months. 7839 (84%) patients were known to be hormone-receptor-positive. Disease-free survival at 3 years was 89.4% on anastrozole and 87.4% on tamoxifen (hazard ratio 0.83 [95% CI 0.71-0.96], p=0.013). Results with the combination were not significantly different from those with tamoxifen alone (87.2%, 1.02 [0.89-1.18], p=0.8). The improvement in disease-free survival with anastrozole was seen in the subgroup of hormone-receptor-positive patients, but not the receptor-negative patients. Incidence of contralateral breast cancer was significantly lower with anastrozole than with tamoxifen (odds ratio 0.42 [0.22-0.79], p=0.007). Anastrozole was significantly better tolerated than tamoxifen with respect to endometrial cancer (p=0.02), vaginal bleeding and discharge (p<0.0001 for both), cerebrovascular events (p=0.0006), venous thromboembolic events (p=0.0006), and hot flushes (p<0.0001). Tamoxifen was significantly better tolerated than anastrozole with respect to musculoskeletal disorders and fractures (p<0.0001 for both). INTERPRETATION: Anastrozole is an effective and well tolerated endocrine option for the treatment of postmenopausal patients with hormone-sensitive early breast cancer. Longer follow-up is required before a final benefit:risk assessment can be made.

30
UI - 11824880
AU - Bashey A; Sundaram S; Corringham S; Jones V; Lancaster D; Silva-Gietzen
TI - J; Law P; Ball ED Use of capecitabine as first-line therapy in patients with metastatic breast cancer relapsing after high-dose chemotherapy and autologous stem cell support.

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