National Cancer Institute®
Last Modified: April 1, 2002
UI - 11735647
AU - Waterhouse D N; Tardi P G; Mayer L D; Bally M B
TI - A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles.
SO - Drug Saf 2001;24(12):903-20
AD - Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada. firstname.lastname@example.org
The anthracycline antibiotic doxorubicin has wide activity against a number of human neoplasms and is used extensively both as a single agent and in combination regimens. In addition to the use of free, unencapsulated doxorubicin, there are two US Food and Drug Administration approved liposomal formulations of doxorubicin currently available, with several additional liposomal formulations being researched either in the laboratory or in clinical trials. The two approved liposomal formulations of doxorubicin have significantly different lipid compositions and loading techniques, which lead to both unique pharmacokinetic and toxicity profiles, distinct from those of the unencapsulated form. This article discusses the toxicities associated with the free form of doxorubicin, as well as those associated with the two most common liposomal formulations, namely Doxil and Myocet. One of the key toxicity issues linked to the use of free doxorubicin is that of both an acute and a chronic form of cardiomyopathy. This is circumvented by the use of liposomal formulations, as these systems tend to sequester the drug away from organs such as the heart, with greater accumulation in liver, spleen and tumours. However, as will be discussed, the liposomal formulations of doxorubicin are not without their own related toxicities, and, in the case of Doxil, may be associated with the unique toxicity of palmar-plantar erythrodysaesthesia. Overall, the use of liposomal doxorubicin allows for a greater lifetime cumulative dose of doxorubicin to be administered, however acute maximal tolerated doses differ significantly, with that of Myocet being essentially equivalent to free doxorubicin, while higher doses of Doxil may be safely administered. This review highlights the differences in both toxicity and pharmacokinetic properties between free doxorubicin and the different liposomal formulations, as have been determined in pre-clinical and clinical testing against a number of different human neoplasms. The need for further testing of the liposomal formulations prior to the replacement of free doxorubicin with liposomal doxorubicin in any established combination therapy regimens, as well as in combination with the newer therapeutics such as monoclonal antibodies is also discussed.
UI - 11759828
AU - Konecny G; Fritz M; Untch M; Lebeau A; Felber M; Lude S; Beryt M; Hepp
TI - H; Slamon D; Pegram M HER-2/neu overexpression and in vitro chemosensitivity to CMF and FEC in primary breast cancer.
SO - Breast Cancer Res Treat 2001 Sep;69(1):53-63
AD - Department of Medicine, UCLA School of Medicine, 90095-1678, USA. email@example.com
Available clinical and experimental data on the effect of HER-2/neu overexpression on chemosensitivity are controversial. It was the purpose of this in vitro study to define the association between HER-2/neu overexpression and the sensitivity to the chemotherapeutic drug combinations of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) and 5-fluorouracil, epirubicin and cyclophosphamide (FEC) of breast cancer cells derived from 140 chemotherapy-naive patients at the time of primary surgery. Both drug combinations were tested at six different concentrations ranging from 6.25-200% peak plasma concentration (PPC). Immunohistochemical detection of HER-2/neu overexpression was performed with the HER-2/neu antibodies, CB11, TAB250 and AO485, in the same tumor specimens. Immunoreactions were determined as negative (0/1+), weakly positive (2+) and strongly positive (3+). However, the antibodies varied in their degrees of sensitivity. Breast cancer samples with strong (3+) HER-2/neu overexpression demonstrated 90% growth inhibition (IC90) at significantly lower PPC values, using the CB11 (p = 0.048), TAB250 (p = 0.007) and AO485 (p < or =0.01) antibodies, and showed 50% growth inhibition (IC50) at significantly lower PPC values, using the CB11 antibody (p = 0.01) compared to their counterparts with lower levels of HER-2/neu expression. When analyzing the group of patients with intermediate and strong HER-2/neu overexpression (2+ and 3+), an association between HER-2/neu overexpression and increased chemosensitivity was seen with the TAB250 (p = 0.044) and AO485 (p = 0.032) antibodies, but not with the CB11 antibody (p =0.8) at the IC90 level. Differences in chemosensitivity between samples with strong HER-2/neu overexpression and those with lower levels were then analyzed separately for CMF and FEC. Both regimens achieved 90% tumor growth inhibition at lower PPC values in samples with strong HER-2/neu overexpression (3+) compared to their counterparts with lower expression levels (AO485 p = 0.011 for CMF, and p = 0.09 for FEC). Cumulative concentration-response plots of tumors responding in vitro with 90% tumor cell inhibition showed a stronger dose dependence for both CMF and FEC among tumor samples with strong HER-2/neu overexpression compared to those with lower levels of expression. In conclusion, the data show that HER-2/neu overexpression was not associated with in vitro drug resistance to CMF or FEC. In contrast, tumors with strong HER-2/neu overexpression demonstrated increased dose-dependent in vitro sensitivity to both the FEC and CMF regimens.
UI - 11759829
AU - Powell B L; Bydder S; Grieu F; Gnanasampanthan G; Elsaleh H; Seshadri R;
TI - Berns E M; Iacopetta B Prognostic value of TP53 gene mutation in adjuvant treated breast cancer patients.
SO - Breast Cancer Res Treat 2001 Sep;69(1):65-8
AD - Department of Surgery, University of Western Australia, Nedlands, Australia.
We investigated the prognostic significance of mutation to the TP53 tumor suppressor gene in a series of 908 breast cancer patients treated with or without adjuvant therapies. The frequency of TP53 mutation detected by single strand conformation polymorphism (SSCP) was 19.4% (176/908) in the overall tumor series. In multivariate analysis, TP53 mutation was independently associated with worse survival in the overall (HR = 2.1, 95% CI [1.5-3.1], P<0.0001), non-adjuvant treated (HR=2.2, 95% CI [1.2-4.2], P=0.017) and adjuvant treated (HR= 2.0, 95% CI [1.3-3.1], P = 0.0009) patients.
UI - 11759820
AU - Fiorentino C; Berruti A; Bottini A; Bodini M; Brizzi MP; Brunelli A;
TI - Marini U; Allevi G; Aguggini S; Tira A; Alquati P; Olivetti L; Dogliotti L Accuracy of mammography and echography versus clinical palpation in the assessment of response to primary chemotherapy in breast cancer patients with operable disease.
SO - Breast Cancer Res Treat 2001 Sep;69(2):143-51
AD - Dipartimento di Radiologia, Azienda Ospedaliera Istituti Ospitalieri Cremona, Italy.
The response to primary chemotherapy is an important prognostic factor in patients with non metastatic breast cancer. In this study we compared the assessment of response performed by clinical palpation to that performed by echography and mammography in 141 out of 157 consecutive breast cancer patients (T2-4, N0-1, M0) submitted to primary chemotherapy. A low relationship was recorded between tumor size assessed clinically and that evaluated by either mammography: Spearman R = 0.38 or echography: R = 0.24, while a greater correlation was found between the tumor dimension obtained by the two imaging techniques (R = 0.62). According to the WHO criteria, the grade of response of breast cancer to primary chemotherapy, showed by mammography and echography, was less marked than the grade of response seen at clinical examination. Residual tumor size assessed clinically depicted a stronger correlation with pathological findings (R = 0.68) than the residual disease assessed by echography (R = 0.29) and mammography (R = 0.33). Post-chemotherapy histology evaluation revealed pathological complete response in three cases (2.1%). Two of these cases were judged as complete responders by clinical palpation but only one was recognized by mammography, and none by echography. Clinical response, but not the response obtained by the two imaging techniques, was a significant predictor for longer disease free survival (p = 0.04). To conclude, physical examination measurements remain the method of choice in evaluating preoperatively the disease response in trials of primary chemotherapy. Prediction of pathological outcome is not improved by echography and mammography.
UI - 11801870
AU - Bentrem DJ; Jordan VC
TI - Role of antiestrogens and aromatase inhibitors in breast cancer treatment.
SO - Curr Opin Obstet Gynecol 2002 Feb;14(1):5-12
AD - Department of Surgery, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Medical School, Chicago, Illinois 60611, USA.
This review explores the recent experience with, and the basis for, the use of selective estrogen receptor modulators to treat and prevent breast cancer. As new agents are unveiled, they will continue to be tested against tamoxifen. A number of new selective estrogen receptor modulators are in clinical development in an attempt to decrease the unwanted effects of tamoxifen. Raloxifene holds the promise of treating osteoporosis with the beneficial side effect of breast cancer prevention. Additionally, two different classes of hormonal agents, the aromatase inhibitors and estrogen receptor down-regulators, which have no estrogen-like properties at any site, appear to be promising new treatments for advanced breast cancer.
UI - 11900209
AU - Jonat W
TI - Goserelin (Zoladex)--its role in early breast cancer in pre- and perimenopausal women.
SO - Br J Cancer 2001 Nov;85 Suppl 2():1-5
AD - Gynaecology and Obstetrics Clinic, University of Kiel, Germany.
Current standard adjuvant therapies for premenopausal women with early breast cancer include ovarian ablation by surgery or irradiation, chemotherapy and tamoxifen. The value of ovarian ablation in prolonging the survival of premenopausal patients with early breast cancer was clearly established by the analyses performed by the Early Breast Cancer Trialists' Collaborative Group in 1996. More recently, the value of ovarian suppression using the luteinizing hormone releasing hormone analogue goserelin as adjuvant therapy in pre-/perimenopausal women with early breast cancer has been confirmed in a series of studies involving over 8000 patients. The results from these studies provide evidence that goserelin, alone or in combination with tamoxifen, is at least as effective as cytotoxic chemotherapy in patients with hormone receptor-positive tumours and is effective when used after adjuvant chemotherapy. The use of goserelin in the management of early breast cancer presents an option which can avoid the side-effects experienced with cytotoxic chemotherapy and may offer unique benefits to premenopausal patients. The consolidation of these emerging results should help in defining the optimal role for goserelin in pre-/perimenopausal patients with early breast cancer.
UI - 11900210
AU - Robertson J F
TI - ICI 182,780 (Fulvestrant)--the first oestrogen receptor down-regulator--current clinical data.
SO - Br J Cancer 2001 Nov;85 Suppl 2():11-4
AD - Department of Surgery, City Hospital Nottingham, UK.
ICI 182,780 (Fulvestrant) is the first in a new class of novel, steroidal, 'pure' antioestrogens--the oestrogen receptor (ER) down-regulators. Its unique mode of action and the absence of partial agonist activity make it a candidate for the treatment of advanced breast cancer in both pre- and postmenopausal women. Tamoxifen has been available for use over the past 25 years. However, its partial agonist activity has been associated with detrimental effects, particularly on the endometrium, and may be associated with the development of tamoxifen resistance. Other antioestrogen agents have previously been unable to demonstrate clinically relevant activity following the development of resistance to tamoxifen. In contrast, the unique mechanism of action of ICI 182,780 results in significant clinical activity in patients failing on tamoxifen therapy. Indeed, phase III clinical trials have demonstrated that ICI 182,780 is at least as effective as the aromatase inhibitor anastrozole in the treatment of postmenopausal patients with advanced disease who have progressed during threatment with prior enocrine therapy. As such, ICI 182,780 will provide a valuable addition to the armamentarium for the treatment of advanced breast cancer.
UI - 11900211
AU - Baum M
TI - A vision for the future?
SO - Br J Cancer 2001 Nov;85 Suppl 2():15-8
AD - Department of Psycho-oncology, University College London Medical School, UK.
Systemic adjuvant therapy is recommended immediately following surgical removal of the primary tumour in the majority of patients with early breast cancer, to prevent the recurrence of distant metastases. Significant progress has been made in the development and evaluation of endocrine therapies for systemic adjuvant therapy. In pre- and perimenopausal women, ovarian ablation has proven to be a valuable treatment option, though not always desirable for young patients. Thus, reversible medical ovarian suppression with a luteinizing hormone releasing hormone agonist, such as goserelin (Zoladex), may provide an attractive alternative for such patients. International trials have indicated that goserelin provides an important addition to the choice of adjuvant therapies now available to pre- and perimenopausal patients. For postmenopausal patients, it is hoped that the ATAC (Arimidex, tamoxifen, alone or in combination) trial will reveal whether or not the benefits of anastrozole (Arimidex) observed in advanced disease, where it has proven to be well tolerated and at least as effective as tamoxifen in recent trials, will translate to the early setting to provide further management options for these patients. On the horizon is yet another exciting endocrine agent, ICI 182,780 (Fulvestrant), which has also been shown to be as effective as anastrozole in advanced disease. In terms of the future, these agents are likely to provide additional valuable treatment choices for early breast cancer across the patient spectrum.
UI - 11900212
AU - Buzdar A U
TI - Anastrozole (Arimidex)--an aromatase inhibitor for the adjuvant setting?
SO - Br J Cancer 2001 Nov;85 Suppl 2():6-10
AD - Department of Breast Medical Oncology, MD Anderson Cancer Center, University of Texas, Houston 77030, USA.
Anastrozole (Arimidex) is a third-generation aromatase inhibitor which has been shown to possess superior efficacy and tolerability over established endocrine agents in advanced breast cancer. Inhibition of aromatase prevents the conversion of androgen substrates to oestrogen, its sole source in postmenopausal women, thereby leading to regression of hormone-sensitive breast carcinomas. Clinical pharmacology data indicate that anastrozole is a potent aromatase inhibitor, providing near-maximal suppression of serum and intratumoural oestrogens to below detectable levels. Anastrozole may offer greater selectivity compared with other aromatase inhibitors, being without any intrinsic endocrine effects and with no apparent effect on the synthesis of adrenal steroids. It is well tolerated and has a convenient once-daily dosing regimen, ensuring maximum patient compliance. A major clinical programme has demonstrated that anastrozole is superior to the standard endocrine therapy, tamoxifen, for the first-line treatment of postmenopausal women with hormone-sensitive advanced breast cancer. Its superior efficacy in advanced disease, together with its improved tolerability and convenient dosage, make it a suitable agent to be assessed for the treatment of early breast cancer in postmenopausal women. This was investigated in the largest single adjuvant breast cancer study ever to be carried out, the ATAC (Arimidex, tamoxifen, alone or in combination) trial, which has now completed recruitment, with the first efficacy and safety data awaited.
UI - 11875727
AU - Spielmann M; Tubiana-Hulin M; Namer M; Mansouri H; Bougnoux P;
TI - Tubiana-Mathieu N; Lotz V; Eymard JC Sequential or alternating administration of docetaxel (Taxotere) combined with FEC in metastatic breast cancer: a randomised phase II trial.
SO - Br J Cancer 2002 Mar 4;86(5):692-7
AD - Institut Gustave Roussy, 39-53 rue Camille Desmoulins, 94805 Villejuif, France. firstname.lastname@example.org
The aim of this study, using a Fleming single-stage design, was to explore the efficacy and safety of Taxotere 100 x mg x m(-2) docetaxel and FEC 75 cyclophosphamide 500 mg x m(-2), fluorouracil 500 x mg x m(-2) and epirubicin 75 mg x m(-2), in alternating and sequential schedules for the first-line treatment of metastatic breast cancer. One hundred and thirty-six women were randomly allocated, to one of three treatment regimens: DTX 100 plus FEC 75, alternated for eight courses (ALT); four courses of DTX 100 followed by four courses of FEC 75 (SEQ T); or four courses of FEC 75 followed by four courses of DTX 100 (SEQ F). One hundred and thirty-one women were evaluable for tumour response. Although the treatment outcome was equivalent in the two sequential arms and the alternating regimen (P=0.110, not significant), the response rate was less encouraging in the SEQ F arm (52.3%) than in the other two arms (71.1% for ALT and 70.5% for SEQ T), in which docetaxel was administered first. Time to progression was similar in the ALT, SEQ T and SEQ F arms (9.5, 9.3 and 10.4 months respectively). Grade 3-4 neutropenia was observed in nearly all patients; febrile neutropenia occurred in 9% (ALT), 16% (SEQ T) and 2% (SEQ F) of patients. Few patients (< or =9%) developed grade 3-4 non-haematological toxicities. Relative dose intensity was 97-99% for all regimens. All treatment regimens were active and well tolerated. Copyright 2002 Cancer Research UK
UI - 11875740
AU - Hague S; Manek S; Oehler MK; MacKenzie IZ; Bicknell R; Rees MC
TI - Tamoxifen induction of angiogenic factor expression in endometrium.
SO - Br J Cancer 2002 Mar 4;86(5):761-7
AD - Nuffield Department of Obstetrics and Gynaecology, Women's Centre, John Radcliffe Hospital, Oxford OX3 9DU, UK.
Tamoxifen is the current therapy of choice for patients with oestrogen receptor positive breast cancer, and it is currently under evaluation as a prophylactic for women at high risk of developing the disease. However, tamoxifen is also known to induce proliferative changes in the endometrium increasing the risk of developing endometrial hyperplasia, polyps and carcinoma. Angiogenesis is an intimate part of this process. For this reason, we have examined the expression of several well characterized angiogenic factors, namely, acidic and basic fibroblast growth factor, thymidine phosphorylase, vascular endothelial growth factor and adrenomedullin in both normal and tamoxifen exposed pre- and postmenopausal endometrium. Vascular density and endothelial proliferation index were also quantified. We found increased expression of acidic and basic fibroblast growth factor and adrenomedullin after treatment with tamoxifen mainly in premenopausal tissue. Vascular density was significantly increased in pre- but not post-menopausal endometrium (P=0.0018) following tamoxifen treatment. These results support the notion that angiogenesis is integral to the response to tamoxifen exposure, and is a potential target with which to block these side effects of tamoxifen. Copyright 2002 Cancer Research UK
UI - 11908256
AU - Lavrenkov K; Man S; Geffen DB; Cohen Y
TI - Experience of hormonal therapy with anastrozole for previously treated metastatic breast cancer.
SO - Isr Med Assoc J 2002 Mar;4(3):176-7
AD - Department of Oncology, Soroka University Medical Center, Beer Sheva, Israel. email@example.com
BACKGROUND: Recent years have brought significant progress to the development of hormonal therapies for the treatment of breast cancer. Several new agents have been approved for the treatment of breast cancer in the metastatic setting, among which is the new non-steroidal aromatase inhibitor, anastrozole, introduced for clinical use in Israel duration of patients treated with anastrozole for metastatic breast cancer, who had previously received at least one line of hormonal therapy. METHODS: Anastrozole was administered to 37 patients with metastatic breast cancer. The median age was 64 years. Estrogen receptor was positive in 20 patients, negative in 10 and unknown in 7. All patients were previously treated with tamoxifen in the adjuvant setting or as first-line hormonal therapy for metastatic disease. Anastrozole was given orally, 1 mg/day. Response was evaluated 2 months after the initiation of treatment and reevaluated every 2 months. Therapy was given until disease progression. Ten ER-negative patients were excluded from the final analysis. RESULTS: Twenty-seven patients were eligible for response and toxicity analysis. The median follow-up was 20 months. One patient (3.7%) achieved complete response and remains free of disease 28 months after start of therapy. No partial responses were seen. Twenty patients (74%) had stable disease. Two year actuarial survival was 57%. Median survival was 26.5 months after starting therapy and median progression-free survival was 11 months. The toxicity was mild: one patient (3.7%) complained of weight gain and one patient (3.7%) had mild fatigue. CONCLUSION: Although the response rate was low, hormonal therapy with anastrozole seems to be beneficial in terms of disease stabilization, freedom from progression, and overall survival without serious toxicity.
UI - 11915733
AU - Miyamoto H; Yoshida S; Imatomi M; Saitoh T; Nakata A
TI - [Successful treatment of advanced recurent breast cancer using DMpC therapy as maintenance therapy]
SO - Gan To Kagaku Ryoho 2002 Mar;29(3):427-9
AD - Dept. of Surgery, OE Kyohdoh Hospital. felt swelling and numbness of her left lower jaw. As a result of bone biopsy and scintigraphy, multiple bone metastasis was diagnosed. After 6 cycles of CMF therapy, the swelling and numbness of the left lower jaw were reduced, but atelectasis of the left lung upper lobe appeared. After 10 cycles of paclitaxel therapy, atelectasis and bone metastasis were reduced. Daily oral chemoendocrine combination therapy, DMpC therapy (5'-DFUR 800 mg/day + CPA 100 mg/day + MPA 800 mg/day) was continued for 12 months. No recurrent signs and serious side effects were observed during DMpC therapy.
UI - 11902499
AU - Leyland-Jones B
TI - Trastuzumab: hopes and realities.
SO - Lancet Oncol 2002 Mar;3(3):137-44
AD - Department of Oncology, McGill University, Montreal, Quebec Canada. firstname.lastname@example.org
Despite improvements in care of patients with breast cancer, up to half develop refractory or resistant disease. There is therefore a need for new, modified anticancer therapies with greater effectiveness, tolerability to patients, and tumour specificity. Trastuzumab (Herceptin) is the first clinically available oncogene-targeted therapeutic agent for treatment of solid tumours. Clinical trials in patients positive for HER2 (human epidermal-growth-factor receptor 2) show that trastuzumab is effective and well tolerated; as a single-agent second-line or third-line treatment, the drug produced durable tumour responses. First-line trastuzumab in combination with chemotherapy, particularly paclitaxel, significantly improved time to disease progression, duration of response, and time to treatment failure. Combination therapy resulted in a 25% improvement in overall survival compared with chemotherapy alone. Patients with HER2 gene amplification, high overexpression of HER2 (3+ on immunohisto-chemistry), or both features, obtained the greatest clinical benefit. Trastuzumab is the first monoclonal antibody with efficacy in breast cancer and the first gene-product-targeted therapy to produce a significant survival advantage in this disease. Trastuzumab is likely to find its ultimate role in the adjuvant setting. Its development provides a model for the integration of other gene-targeted therapies into breast-cancer management to improve survival and quality of life.
UI - 10760830
AU - Schmoor C; Bastert G; Dunst J; Bojar H; Christmann D; Unbehaun V;
TI - Tummers G; Bauer W; Sauerbrei W; Schumacher M Randomized trial on the effect of radiotherapy in addition to 6 cycles CMF in node-positive breast-cancer patients. The German Breast-Cancer Study Group.
SO - Int J Cancer 2000 May 1;86(3):408-15
AD - Institute of Medical Biometry and Medical Informatics, University of Freiburg, Freiburg, Germany. email@example.com
In 1984 the GBSG started a multicenter randomized trial to compare the effectiveness of 6 cycles of cyclophosphamide, methotrexate and fluorouracil (CMF) with or without radiotherapy (RT) as adjuvant treatment in node-positive breast-cancer patients treated by mastectomy. During 5 years, 199 patients were randomized. After a median follow-up of about 9 years, the treatment groups 6 x CMF and 6 x CMF + RT were compared regarding time to recurrence and death. As the first event of failure, we observed locoregional recurrence in 22 patients, distant metastases in 66 patients, a secondary malignancy in 9 patients and death without previous event in 5 patients. For event-free survival (EFS), no significant difference was observed [relative risk (RR) 6 x CMF + RT vs. 6 x CMF 0.82, 95% confidence interval (CI) 0.55-1.21]. Event-specific analysis showed a significant decreased risk after radiotherapy for locoregional recurrence. The risk for distant metastases was estimated as slightly decreased and the risk for secondary malignancy and for death without previous event was estimated as increased in treatment group 6 x CMF + RT in comparison with treatment group 6 x CMF, but these effects were not significant. For overall survival (OS) and breast-cancer-specific survival (BCS), no significant treatment effect could be demonstrated. There is a beneficial effect of radiotherapy on locoregional recurrence. For EFS and BCS, a tendency in favour of radiotherapy is observed, but this is not significant; for OS, no difference can be demonstrated, but the power of the study is too low to detect small treatment effects. Copyright 2000 Wiley-Liss, Inc.
UI - 11900215
AU - Bajetta E; Procopio G; Ferrari L; Martinetti A; Zilembo N; Catena L; Alu
TI - M; Della TS; Alberti D; Buzzoni R A randomized, multicenter prospective trial assessing long-acting release octreotide pamoate plus tamoxifen as a first line therapy for advanced breast carcinoma.
SO - Cancer 2002 Jan 15;94(2):299-304
AD - Medical Oncology Unit B, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, Italy. firstname.lastname@example.org
BACKGROUND: Long-acting release octreotide pamoate (OP-LAR) is a synthetic octapeptide that can be administered monthly and whose activity is similar to that of endogenous somatostatin. In vitro and in vivo data suggest that OP-LAR may act as a growth inhibitor or a modulator of growth stimulatory peptides. The potential mechanisms of action of somatostatin analogues in breast carcinoma include the suppression of insulin-like growth factor-1 (a putative tumor growth factor) and the binding to the somatostatin receptors expressed by breast carcinoma cells in order to induce apoptosis. METHODS: This Phase III, multicenter, randomized, double-blind, placebo-controlled trial involved 203 patients (13% premenopausal and 87% postmenopausal) with locally recurrent (but unsuitable for local treatment) or metastatic breast carcinoma, 199 of whom were actually treated (99 patients with OP-LAR and 100 patients with placebo). All patients received TAM and were estrogen and/or progesteron receptor positive (receptor positivity was an eligibility criterion), and all had measurable or evaluable disease. Any patients who had received previous chemotherapy not given in an adjuvant or neoadjuvant setting were excluded. RESULTS: At the time of the interim analysis, the tumor response rates (RR) were 20.2% (9 complete responses [CR] and 11 partial responses [PR]) in the OP-LAR arm and 21% (11 CRs and 10 PRs) in the placebo arm, and the median time to progression (TTP) was 25.0 and 26.9 weeks (P = 0.62), respectively. The adverse events experienced by 10% or more of the patients and attributed to octreotide were gastrointestinal in nature: diarrhea (53%), nausea (16%), and abdominal pain (11%). CONCLUSIONS: Because of the similar RR and TTP in both arms, the trial was stopped at the interim analysis. The current data confirm there is no indication for adding somatostatin analogues to TAM in advanced breast carcinoma.
UI - 11899785
AU - Hartman AR; Fleming GF; Dillon JJ
TI - Meta-analysis of adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy in postmenopausal women with estrogen receptor-positive, node-positive breast cancer.
SO - Clin Breast Cancer 2001 Jul;2(2):138-43; discussion 144
AD - Department of Oncology, Stanford University Medical Center, Palo Alto, CA, USA.
Conflicting results have been published regarding the efficacy of adjuvant cyclophosphamide/methotrexate/5-fluorouracil (CMF)-type chemotherapy in postmenopausal, estrogen receptor (ER)-positive women. The Oxford overview suggests real but limited benefit of any chemotherapy in this group of patients but avoids analyzing smaller subsets. We wished to better quantitate the benefit of adding CMF to tamoxifen in postmenopausal ER-positive women with tumor involvement of axillary lymph nodes. Six randomized studies comparing CMF plus tamoxifen to tomoxifen alone in postmenopausal, ER-positive, node-positive women have been published since 1992. They include 2368 patients. We performed a meta-analysis of 6 endpoints: survival, disease-free survival, locoregional recurrence, distant recurrence, contralateral breast recurrence, and thromboembolic complications. There was a statistically significant increase in disease-free survival from the addition of CMF-type chemotherapy to tamoxifen in this population; the absolute risk of relapse was reduced by 5.5% at 5 years. Effects of locoregional recurrence were greater than those on overall recurrence. No significant survival benefit was observed.
UI - 11899382
AU - Spielmann M; Martin M; Namer M; duBois A; Unger C; Dodwell DJ
TI - Activity of pemetrexed (ALIMTA, multitargeted antifolate, LY231514) in metastatic breast cancer patients previously treated with an anthracycline and a taxane: an interim analysis.
SO - Clin Breast Cancer 2001 Apr;2(1):47-51
As many breast cancer patients receive adjuvant chemotherapy using anthracyclines or anthracenediones and taxanes, more therapeutic options are needed for subsequent lines of therapy. Pemetrexed (ALIMTA, multitargeted antifolate, LY231514) is a novel antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis. This paper reports on a subset analysis of a phase II clinical trial of pemetrexed in heavily pretreated metastatic breast cancer (MBC) patients. Patients were required to have received prior first-line anthracycline therapy for metastatic disease. Prior adjuvant chemotherapy and prior taxanes were allowed. A substantial subset of the study population (31 of 72 patients, 43%) had also received a taxane in the metastatic setting. All patients were treated with pemetrexed, 600 mg/m2 by intravenous infusion, once every 21 days. In the study subset, 23 of 31 (74%) patients were anthracyclines failures (progression > 30 days following treatment), and eight (26%) patients were anthracyclines refractory (progression during or < or = 30 days of treatment). The median age was 55 years (range, 30-75 years) and the median World Health Organization performance status was 0. Metastases were present in the liver (61%), lung (29%), bone (6%), and soft tissue (19%). The overall response rate for this subset was 26%, with one complete response, seven partial responses, and 13 (42%) patients with stable disease. The median duration of response was 5.4 months and median survival was 12.8 months. Pemetrexed was well tolerated by patients in the study. This post hoc analysis suggests promising activity in MBC patients previously treated with both anthracyclines and taxanes. An ongoing trial is prospectively evaluating activity in this same population.
UI - 11899351
AU - Smorenburg CH; Bontenbal M; Verweij J
TI - Capecitabine in breast cancer: current status.
SO - Clin Breast Cancer 2001 Jan;1(4):288-93; discussion 294
AD - Rotterdam Cancer Institute (Daniel den Hoed Kliniek), University Hospital Rotterdam, Rotterdam, The Netherlands. email@example.com
Anthracyclines, together with taxanes, are at present the most active agents in metastatic breast cancer, while single-agent, bolus 5-fluorouracil (5-FU) is not very active in this setting. In view of encouraging results and tolerable toxicity of continuous infusion of 5-FU in gastrointestinal cancer, innovative oral 5-FU agents such as capecitabine have been developed. Capecitabine is a prodrug that is converted into the active compound 5-FU preferentially at the tumor site. An intermittent dosing schedule of capecitabine twice daily at a dose of 2510 mg/m2/day on days 1-14 in a 3-week cycle appeared to be feasible and resulted in a high dose intensity. A large phase II study investigating capecitabine in 135 advanced breast cancer patients, pretreated with anthracyclines and taxanes, observed three complete and 24 partial responses (response rate, 20%), with a mean duration of 8.0 months. Preliminary results of a study comparing capecitabine with paclitaxel in 42 breast cancer patients failing anthracyclines indicate that the efficacy of capecitabine is comparable to that of paclitaxel, with response rates of 36% and 21%, respectively. Another study reported a response rate of 25% for capecitabine as first-line therapy for advanced breast cancer in women aged > or = 55 years, which tended to be better than combination chemotherapy with cyclophosphamide/methotrexate/5-FU. In all studies, capecitabine side effects were mainly mild, and treatment-related grade 3/4 toxicity consisted of diarrhea (8%-11%), nausea (4%-11%), hand-foot syndrome (10%-18%), neutropenia (3%-20%), and bilirubin elevation (6%). Capecitabine is clearly an active agent for the treatment of breast cancer. It is currently registered in various countries for use in third-line treatment of metastatic disease. Its further role will have to be defined from data of randomized phase III studies.
UI - 11899352
AU - Geisler J; Lonning PE
TI - Resistance to endocrine therapy of breast cancer: recent advances and tomorrow's challenges.
SO - Clin Breast Cancer 2001 Jan;1(4):297-308; discussion 309
AD - Department of Oncology, Haukeland University Hospital, Bergen, Norway.
The role of endocrine therapy in early as well as advanced breast cancer cannot be overrated. Long-term tamoxifen exposure (5 years) in the adjuvant setting has been shown to be effective not only in improving relapse-free and overall survival but also in reducing the incidence of contralateral cancers. Promising results have been achieved in breast cancer prevention with use of antiestrogens. Novel aromatase inhibitors and inactivators have been found superior to conventional treatment in metastatic disease and are currently being evaluated in the adjuvant setting to improve relapse-free and overall survival. If potential health hazards from estrogen deprivation with regard to cardiovascular disease as well as bone metabolism can be addressed, adjuvant endocrine therapy may include such drugs in the future. However, while endocrine therapy of breast cancer has become more and more important in the clinic, the major problems in hormonal therapy are primary and acquired resistance to endocrine manipulations. The causes for endocrine resistance and possible ways to delay or avoid this phenomenon are only allusively understood. Elucidation of the mechanisms underlying endocrine resistance in vivo represents the key to improve our treatment strategies. Due to intense use of in vitro models and animal systems, many potential mechanisms of endocrine resistance have been described; however, our understanding of the problem of drug resistance in vivo remains limited. Hopefully, ongoing programs on translational research in the neoadjuvant, adjuvant, and palliative settings will provide information that will improve our understanding of the biology of endocrine resistance in vivo and, thus, provide us with a better rationale to improve early as well as late endocrine therapy in breast cancer patients. The present publication summarizes the state of the art with respect to endocrine resistance.
UI - 11899388
AU - Sparano JA
TI - Taxanes for breast cancer: an evidence-based review of randomized phase II and phase III trials.
SO - Clin Breast Cancer 2000 Apr;1(1):32-40; discussion 41-2
AD - Albert Einstein Comprehensive Cancer Center, Montefiore Medical Center-Weiler, Division South, Room 52, Bronx, New York 10461, USA. firstname.lastname@example.org
The taxanes paclitaxel and docetaxel have an important role in the treatment of breast cancer, and numerous randomized trials have evaluated their efficacy for this indication. A systematic, evidence-based review was performed, which included all randomized, controlled trials evaluating taxanes for the treatment of early-or advanced-stage breast cancer that were identified in CANCERLIT and MEDLINE searches. The primary objectives of this review were to determine the dose and schedule for each taxane that was associated with the most favorable therapeutic index, and to determine whether (and under what circumstances) the taxanes improved survival. The search revealed 18 randomized phase II (n = 1) or phase III (n = 17) trials. For metastatic breast cancer, the dose and schedule associated with the most favorable therapeutic index for paclitaxel was 175 mg/m2 given as a 3-hour infusion every 3 weeks, and docetaxel was 60-100 mg/m2 given as a 1-hour infusion every 3 weeks. Survival was improved under the following circumstances: (1) when 4 cycles of paclitaxel (175 mg/m2 every 3 weeks) was given following 4 cycles of conventional doxorubicin-cyclophosphamide for axillary node-positive operable breast cancer, (2) when trastuzumab was added to paclitaxel as first-line therapy for metastatic breast cancer that overexpressed HER2/neu, and (3) when docetaxel was given as second-line therapy for anthracycline-resistant disease. Although a survival benefit was found for taxanes as a component of first-line therapy in two of six trials, the interpretation of both positive trials was confounded by a lack of crossover to taxane therapy in those who were initially randomized to receive standard therapy. The taxanes improve survival in patients with early-stage breast cancer and selected patients with metastatic breast cancer. Further research is necessary in order to identify the efficacy of docetaxel relative to paclitaxel, the optimal dose of docetaxel, the role of weekly taxane therapy, the role of trastuzumab plus taxanes in early-stage disease, and whether taxanes are more effective when given concomitantly or sequentially in patients with early-stage disease.