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Biomedical subjects

K I Pritchard

Publications and source records attributed to K I Pritchard.

At least 19 recordsLinked to original sources
PubMed2006

Trends in endocrine therapy and chemotherapy for early breast cancer: a focus on the premenopausal patient.

PURPOSE: The majority of breast cancers are diagnosed at an early stage, and treatment is focused on cure and prolonging disease-free survival. Local therapy (surgery and/or radiation treatment) is standard, along with systemic adjuvant therapy that may effectively prevent or delay relapse and death in early-stage disease. In premenopausal women, adjuvant therapeutic approaches include combination cytotoxic chemotherapy and endocrine therapy. Cyclophosphamide, methotrexate and 5-fluorouracil (CMF) was the established chemotherapy regimen; however, newer regimens have more recently been introduced that may offer some benefit over CMF including anthracycline-containing regimens [e.g. cyclophosphamide, epirubicin and 5-fluorouracil (CEF)], and taxane-containing regimens. For women with oestrogen receptor (ER)-positive disease, a second option is endocrine therapy that aims to suppress mitogenic oestrogen signalling. Until recently, 5 years of tamoxifen was regarded as the standard adjuvant endocrine treatment in ER-positive disease. Ovarian ablation is also effective in premenopausal women, and can be achieved by surgery, radiotherapy, or via the use of a luteinising hormone-releasing hormone analogue such as goserelin. Combining tamoxifen and goserelin treatment provides more effective oestrogen blockade than either drug alone. However, as the third-generation aromatase inhibitors (AIs) have demonstrated improved efficacy over tamoxifen in postmenopausal women with early and advanced disease, combination treatment with goserelin plus an AI may provide optimal oestrogen blockade in premenopausal patients. CONCLUSIONS: This review assesses the relative merits of chemotherapeutic and endocrine approaches for the treatment of early breast cancer, and summarises relevant ongoing clinical trials, with an emphasis on the premenopausal setting.

Antineoplastic Agents, Hormonal↗
PubMed2006

The extended adjuvant NCIC CTG MA.17 trials: initial and rerandomization studies.

Based upon the results of the NCIC CTG MA.17 trial, letrozole has become the only approved aromatase inhibitor (AI) in the extended adjuvant treatment setting following 5 years of tamoxifen therapy. In this trial, the AI letrozole decreased the overall risk of breast cancer recurrence by 42% compared with placebo in postmenopausal women completing 5 years of tamoxifen. The benefit of letrozole exceeded the expected difference after median follow-up of more than 2 years and led to the unblinding of the trial. The 30-month updated analyses found a 4.8%, 4-year disease-free survival improvement overall, an improvement in distant disease-free recurrence in both node-negative and node-positive patients, and a survival benefit for node-positive patients. Generally well tolerated, letrozole caused some adverse events including arthralgias and osteoporosis. However, results from the Zometa-Femara adjuvant synergy trial (Z-FAST) suggest that zoledronic acid, when used concomitantly with letrozole, is able to manage bone loss in postmenopausal women with early breast cancer.

Aromatase Inhibitors↗
PubMed2005

Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer.

PURPOSE: This randomized, controlled, multicenter, open-label, phase III study compared docetaxel versus paclitaxel in patients with advanced breast cancer that had progressed after an anthracycline-containing chemotherapy regimen. PATIENTS AND METHODS: Patients (n = 449) were randomly assigned to receive either docetaxel 100 mg/m2 (n = 225) or paclitaxel 175 mg/m2 (n = 224) on day 1, every 21 days until tumor progression, unacceptable toxicity, or withdrawal of consent. RESULTS: In the intent-to-treat population, both the median overall survival (OS, 15.4 v 12.7 months; hazard ratio [HR], 1.41; 95% CI, 1.15 to 1.73; P = .03) and the median time to progression (TTP, 5.7 months v 3.6 months; HR, 1.64; 95% CI, 1.33 to 2.02; P < .0001) for docetaxel were significantly longer than for paclitaxel, and the overall response rate (ORR, 32% v 25%; P = .10) was higher for docetaxel. These results were confirmed by multivariate analyses. The incidence of treatment-related hematologic and nonhematologic toxicities was greater for docetaxel than for paclitaxel; however, quality-of-life scores were not statistically different between treatment groups over time. CONCLUSION: Docetaxel was superior to paclitaxel in terms of OS and TTP. ORR was higher for docetaxel. Hematologic and nonhematologic toxicities occurred more frequently in the docetaxel group. The global quality-of-life scores were similar for both agents over time.

Adenocarcinoma↗
PubMed2003

Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study.

PURPOSE: To compare the efficacy of a standard anthracycline-based regimen to a dose-intensified anthracycline regimen in locally advanced breast cancer. PATIENTS AND METHODS: Locally advanced breast cancer patients were randomly assigned onto a study comparing cyclophosphamide (C; 75 mg/m(2) orally days 1 to 14), epirubicin (E; 60 mg/m(2) intravenously [IV] days 1, 8), and fluorouracil (F; 500 mg/m(2) IV days 1, 8) six cycles every 28 days versus E (120 mg/m(2) IV day 1), C (830 mg/m(2) IV day 1), and granulocyte colony-stimulating factor (filgrastim; 5 micro g/kg/d subcutaneously days 2 to 13) six cycles every 14 days. The study was designed to detect a 15% improvement; that is, from 50% to 65% in median progression-free survival (PFS) in favor of the dose-intensified regimen. RESULTS: A total of 448 patients were enrolled over a period of 3 years. The median dose intensity delivered for C and E reached, respectively, 85% and 87% of that planned in the CEF arm and 96% and 95% of that planned in the EC arm. The dose-intensified arm was slightly more emetogenic and generated more grade 3 to 4 anemia but less febrile neutropenia episodes. After a median follow-up of 5.5 years, 277 events have been reported. The median PFS was 34 and 33.7 months for CEF and EC, respectively (P =.68), and the 5-year survival rate was 53% and 51% for CEF and EC, respectively (P =.94). CONCLUSION: Dose-intensified EC does not provide a measurable therapeutic benefit over CEF as neoadjuvant chemotherapy for unselected locally advanced breast cancer patients.

Adolescent↗
PubMed2003

Hormone replacement therapy after treatment for breast cancer: physicians' attitudes towards randomized trials.

PURPOSE: Physician support is required for successful patient recruitment to a large randomized controlled trial (RCT) designed to determine the safety and benefits of short-term hormone replacement therapy (HRT) after breast cancer (BC). METHODS: A survey was mailed to 1899 Canadian gynaecologists, family physicians, medical, radiation and surgical oncologists to assess willingness to refer patients to an RCT of HRT after BC. RESULTS: Of 538 physicians, 420 (78%) reported that they would be willing to refer a woman after BC to an RCT of HRT versus placebo. Variables predicting willingness to refer included: support for HRT in well women (p = 0.04) and after BC (p = 0.0001); support for clinical trials (p = 0.0001); ongoing BC trials at the physicians' institution (p = 0.003); currently prescribing HRT to women after BC (p = 0.03); and beneficial results in ongoing RCTs of HRT in well women (p = 0.02). CONCLUSIONS: An RCT of short-term HRT after BC may be feasible among Canadian physicians.

Antineoplastic Agents, Hormonal↗
PubMed2003

Oestrogen receptor downregulation: an opportunity for extending the window of endocrine therapy in advanced breast cancer.

BACKGROUND: Advanced breast cancer is largely incurable and current treatment modalities are aimed towards restricting tumour growth, prolonging survival, palliating symptoms and maintaining quality of life (QoL). The development of breast cancer is strongly influenced by endogenous oestrogens (and other growth factors), leading to a strong focus on the development of antioestrogenic compounds for the treatment of hormone-sensitive advanced disease. DESIGN: This is a review of current endocrine therapies available for postmenopausal women with advanced breast cancer, examining the likely impact of newer agents on treatment strategies. RESULTS: In postmenopausal women, current treatment options include tamoxifen, aromatase inhibitors (AIs) and megestrol acetate. Fulvestrant ('Faslodex') is a new, well-tolerated, oestrogen receptor antagonist that has no known agonist effect and is at least as effective as the AI anastrozole for the treatment of postmenopausal patients with metastatic or advanced breast cancer who have progressed on prior endocrine therapy. Fulvestrant maintains QoL throughout successful treatment. CONCLUSIONS: Fulvestrant represents a new treatment option for postmenopausal women with advanced disease. New agents that appear to lack cross-resistance with existing treatments may be used to extend the time period during which endocrine therapy may be employed before the need for cytotoxic chemotherapy.

Aged↗
PubMed2001

A comparison of four treatment strategies for ductal carcinoma in situ using decision analysis.

BACKGROUND: The goals of the current study were to compare four treatment approaches in the management of ductal carcinoma in situ (DCIS), to determine the conditions where mastectomy may be preferred to breast-conserving therapy (BCT), and to determine conditions where the addition of tamoxifen produces better results than BCT alone. METHODS: A decision analysis model was used to compare four treatment approaches after local excision for DCIS: mastectomy, irradiation, irradiation plus adjuvant tamoxifen, or observation. The model weighed the potential benefits of each treatment approach (reduction of ipsilateral and/or contralateral breast carcinoma) against the potential risks of treatment-related toxicities. In addition, the model adjusted for the potential detrimental impact of local recurrence or treatment-related toxicity on health-related quality of life (HRQOL). Base-case estimates were obtained from published randomized trial data. One-way and two-way sensitivity analyses were performed. RESULTS: According to the model, the optimal treatment for DCIS was strongly dependent on the individual's risk of local recurrence and the patient's attitudes toward mastectomy. Mastectomy was preferred in patients whose estimated 10-year risk of local recurrence was > 15%, provided that mastectomy resulted in a very low reduction in quality of life (i.e., utility estimate > 0.97). Conditions where the addition of tamoxifen was preferred to breast-conserving therapy alone included the following: estimated 10-year risk of local recurrence > 38%, estimated 10-year risk of developing a contralateral breast carcinoma > 6%, or a significant decrement in HRQOL associated with the development of an invasive local recurrence or salvage mastectomy (utility estimates < 0.85). CONCLUSION: Based on this quality-adjusted model, BCT appeared to be the preferred treatment for DCIS. The most important determinants of optimal management for DCIS included the risk of local recurrence and the utility of mastectomy. Formal evaluation of utilities in the context of DCIS and more accurate determination of the risk of recurrence are required.

Antineoplastic Agents, Hormonal↗
PubMed2001

The role of hormone replacement therapy in women with a previous diagnosis of breast cancer and a review of possible alternatives.

Estrogen replacement therapy either with (HRT) or without (ERT) accompanying progesterone is routinely offered to well women at the time of menopause, in order to relieve vasomotor symptoms, (hot flashes), reduce urogenital atrophy and reduce the risks of cardiovascular disease, osteoporosis and perhaps colon cancer and Alzheimer's disease. It is generally felt however, that women with a previous diagnosis of breast cancer are not suitable candidates for such therapy since either estrogen or progesterone may be associated with an increased risk of cancer recurrence. There are however, a variety of approaches to menopausal therapy in such women. A careful history must first be taken in order to identify the symptoms or conditions of concern. Vasomotor symptoms can be reduced by the use of other medications such as the antidepressant venlafaxine (Effexor). Estring, a vaginal estrogen ring can be used to reduce genitourinary symptoms, with little systemic estrogen absorption. Osteoporosis can be prevented or treated with calcium supplements, exercise, improved diet, bisphosphonates and/or selective estrogen receptor modulators (SERMs) while cardiovascular risk can be reduced by diet and exercise, as well as the appropriate use of lipid lowering and antihypertensive medications.

Alzheimer Disease↗
PubMed2001

Breast cancer prevention with selective estrogen receptor modulators: a perspective.

Chemoprevention for breast cancer is both old and new. It has long been appreciated that early ovarian ablation dramatically reduces the incidence of breast cancer in premenopausal women. It was subsequently demonstrated, in the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview, that tamoxifen results in a 40% or greater reduction in the incidence of contralateral breast cancer. Now, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has shown a similar reduction in a randomized trial [Breast Cancer Prevention Trial (BCPT)] comparing tamoxifen and placebo in women aged 35 years or over at increased risk of developing breast cancer because of age, family history, or other factors. In this trial, the incidences of both ductal carcinoma in situ (DCIS) and invasive cancer were reduced. Reduction in incidence was similar over all years of the study and in all subgroups of high-risk women. However, all of the reduction was confined to estrogen receptor (ER)-positive tumors. Raloxifene, a newer selective estrogen receptor modulator (SERM) originally developed for osteoporosis, also appears to have a major preventive effect on breast cancer incidence. Limitations in the design and patient population of raloxifene trials, however, have made it difficult to as yet recommend raloxifene for risk reduction of breast cancer. The randomized Study of Tamoxifen and Raloxifene (STAR) study, which will compare raloxifene to tamoxifen in over 20,000 postmenopausal women at increased risk of breast cancer, as well as ongoing and proposed placebo-controlled studies of tamoxifen, the aromatase inhibitor anastrazole, and other antiestrogens in high- or average-risk postmenopausal women, will provide further results on optimal prevention strategies.

Breast Neoplasms↗
PubMed2001

Hormone replacement in women with a history of breast cancer.

Estrogen used alone (estrogen replacement therapy [ERT]) or with the addition of progesterone (hormone replacement therapy [HRT]) is known to be effective in reducing menopausal symptoms including hot flashes, vaginal dryness and urinary symptoms. It has been traditionally contraindicated, however, in women with a previous diagnosis of breast cancer because of fear that it may increase the risk of recurrence. There are considerable basic scientific data but little methodologically strong observational data and none from randomized studies concerning the use of ERT in women with a prior diagnosis of breast cancer. From our knowledge of the physiology of breast cancer, however, estrogen and/or progestational agents should be used with caution in women with a previous diagnosis of breast cancer. There are currently many alternatives to ERT/HRT in the prevention of menopausal symptoms such as vitamin E, clonidine and selective serotonin reuptake inhibitor antidepressants such as venlafaxine. There are also a variety of other approaches to the prevention of osteoporosis and cardiovascular disease including bisphosphonates, diet, and exercise; and diet, exercise, and statins, respectively. Other suggested beneficial effects of estrogen such as colon cancer prevention can be approached by the use of aspirin or the non-steroidals. Several trials of ERT/HRT used for 2 years versus no therapy in menopausal women with a previous diagnosis of breast cancer are ongoing in Europe and Britain, and should give us stronger data as to the role of HRT in this setting.

Breast Neoplasms↗
PubMed2001

The role of tamoxifen and aromatase inhibitors/inactivators in postmenopausal patients.

The traditional hormonal cascade of the 1970s and 1980s used tamoxifen followed by megestrol acetate and subsequently by aminoglutethimide. In the 1990s, however, three trials of third-generation aromatase inhibitors (AIs) compared with megestrol acetate and two trials of third-generation AIs compared with aminoglutethimide showed improved efficacy and decreased toxicity for the newer AIs. Thus, the hormonal cascade changed in the late 1990s, to one in which tamoxifen, followed by a third-generation AI, followed by megestrol acetate, seemed more suitable. Now, however, several trials comparing anastrozole, letrozole, and exemestane to tamoxifen as first-line hormonal agents for metastatic breast cancer have shown that these drugs are at least equivalent and perhaps superior to tamoxifen in that setting in terms of response rate and time to progression. Results from 1021 patients randomized to receive anastrozole versus tamoxifen showed a slightly improved overall response rate (RR; 29% versus 26%), slightly improved clinical benefit (CB; 57% versus 52%), and a significantly improved time to progression (TTP; 8.5 months versus 7.0 months) in favor of anastrozole. In 907 women randomized to treatment with letrozole versus tamoxifen, significantly improved RR (30% versus 20%), CB (49% versus 38%), and TTP (9.4 months versus 6 months) have all been shown for those treated with letrozole. In addition, a randomized Phase II trial of 121 patients has shown nonsignificant benefits in favor of exemestane (RR 41% versus 14%; CB 56% versus 42%; TTP not available). To date, none of these trials has demonstrated any overall survival benefit. Additional follow-up in regard to survival in the trial of tamoxifen versus letrozole and an expanded Phase III trial of tamoxifen versus exemestane are ongoing.

Antineoplastic Agents, Hormonal↗
PubMed2000

Current and future directions in medical therapy for breast carcinoma: endocrine treatment.

Endocrine therapy remains a mainstay of treatment for breast carcinoma in both adjuvant and metastatic settings. The choice of endocrine therapy is guided by the presence and degree of expression of estrogen receptor (ER) and progesterone receptor (PgR) as well as by clinical parameters. Adjuvant tamoxifen (TAM) given for 5 years is accepted standard therapy for postmenopausal ER and/or PgR positive (+ve) women. In premenopausal women, 5 years of TAM given alone has similar effects, but is used less frequently because chemotherapy has been regarded as a standard even in ER and PgR +ve women. Recent literature has demonstrated the equivalence or superiority of (Zoladex [ZOL], Zeneca Pharmaceuticals, Wilmington, DE) goserelin acetate plus TAM to cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) chemotherapy in premenopausal ER and PgR +ve women. This, together with older data showing equivalence or superiority of ovarian ablation (OA) to CMF chemotherapy in the same setting, as well as accumulating data suggesting benefit from the addition of ZOL, OA, and/or TAM to chemotherapy in the premenopausal adjuvant setting, has raised issues regarding whether ZOL, OA, and/or TAM can substitute for chemotherapy or should always be added to it for premenopausal receptor +ve women. In the metastatic setting, the second-generation aromatase inhibitors (AI) clearly have moved into position as second-line therapy after TAM. Recent data have shown equivalence and perhaps some superiority to TAM by at least one AI (anastrazole [AN]) in first-line metastatic treatment. The results of adjuvant studies comparing TAM, AN, and TAM + AN in the adjuvant setting will be awaited with great interest. In the interim, the development of other SERMS (raloxifene, EM 850) and of pure antiestrogens may provide new and exciting approaches in the metastatic, adjuvant, and preventive settings.

Breast Neoplasms↗