Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer

PURPOSE: To evaluate the efficacy and toxicity of paclitaxel administered as a 1-hour infusion on weekly basis, without interruption, to patients with metastatic breast cancer who had received prior therapy. PATIENTS AND METHODS: Thirty patients with metastatic breast cancer received sustained weekly paclitaxel therapy at an initial dose of 100 mg/m2 until disease progression. Prior therapy included adjuvant only (n=17), metastatic only (n=7), or both (n=6). Eighteen patients had received prior anthracycline therapy, 12 of whom had demonstrated progression of disease within 12 months of it. All patients were assessable for efficacy; 29 patients were assessable for toxicity. Pharmacokinetic studies of paclitaxel were also performed. RESULTS: A total of 469 weekly paclitaxel infusions were administered to 30 patients (median, 14 infusions/patient). The median delivered dose-intensity was 91 mg/m2/wk (range, 80 to 108). The overall response rate was 53% (95% confidence interval [CI], 34% to 72%), with 10% complete responses (CRs) and 43% partial responses (PRs). Median response duration was 7.5 months (range, 2 to 11+). Responses were observed in nine of 18 (50%) patients with prior anthracycline therapy, including six of 12 (50%) with disease progression on anthracycline within 1 year (three of four within 6 months). Therapy was well tolerated and remarkable for a lack of overall and cumulative myelosuppression. Grade 3/4 neutropenia occurred in four patients; febrile neutropenia was not observed. Peripheral neuropathy prohibited dose escalation above 100 mg/m2, and grade 3 neuropathy was observed in two of 21 patients at < or = 100 mg/m2. CONCLUSION: Weekly paclitaxel therapy is active and well tolerated in patients with metastatic breast cancer. Weekly therapy should be considered as a current clinical option for these patients and should be incorporated into future comparative clinical trials.     

The emerging role of photodynamic therapy in the management of Barrett''s oesophagus

BACKGROUND: In the rat, indomethacin causes jejunal villous shortening, microvascular distortion, and blood stasis prior to ulceration. The beta3-adrenoceptor agonist CL316,243 (CL) prevents both the early histological changes and ulceration. AIM: To test the hypothesis that the beta3-adrenoceptor agonist CL316,243 exerts its protective effect by prevention and/or reversal of blood flow changes in the rat jejunum exposed to indomethacin. METHODS: In anaesthetized rats, jejunal villous blood flow was measured in surface capillaries using fluorescence microscopy. Stasis of superficial capillary blood flow was induced by combined topical and i.v. indomethacin (100 microg/mL, 2.8 x 10(-4) M). To examine the effect of CL on blood stasis, CL was applied either i.v. (1 mg/kg) or luminally (100 microg/mL, 2.5 x 10(-5)M) at the onset of stasis. Prophylactic protection was assessed by giving i.v. CL simultaneously with indomethacin. Results were compared with controls which received luminal saline applied at blood stasis. The effect of i.v. CL (1 mg/kg) alone, or luminal CL (100 microg/mL) alone on basal villous blood flow was also examined. The small intestines were perfusion-fixed with 10% formol saline, and removed for histology, n = 5 for all groups. RESULTS: Luminal CL given at stasis reversed indomethacin-induced stasis within 10 min, whereas i.v. CL did not. Pretreatment with i.v. CL prevented the onset of stasis. Basal blood flow was raised slightly only by luminal CL. CONCLUSION: The beta-adrenoceptor agonist CL316,243 can protect against indomethacin-induced blood stasis in rat jejunal villi.     

The role of radiation therapy after local excision of invasive and noninvasive breast cancer

An international survey of health service user fee and exemption policies in 26 low- and middle-income countries assessed whether user fee policies were supported by measures that protect the poor. In particular, it explored whether governments were introducing a package of supportive measures to promote service improvements that benefit disadvantaged groups and tackle differential ability to pay through an effective series of exemptions. The results show that many countries lack policies that promote access for disadvantaged groups within user fee systems and quality improvements such as revenue retention at the health care facility and expenditure guidelines for local managers. More significant policy failures were identified for exemptions: 27 percent of countries had no policy to exempt the poor; in contrast, health workers were exempted in 50 percent of countries. Even when an official policy to exempt the poor existed, there were numerous informational, administrative, economic, and political constraints to effective implementation of these exemptions. The authors argue that user fee policy should be developed more cautiously and in a more informed environment. Fees are likely to exacerbate existing inequities in health care financing unless exemptions policy can effectively reach those unable to pay.     

The role of hormone replacement therapy in the risk for breast cancer and total mortality in women with a family history of breast cancer

BACKGROUND: The risks and benefits of hormone replacement therapy (HRT) are of considerable interest and importance, especially in terms of whether they differ among subsets of women. OBJECTIVE: To determine whether HRT is associated with increased risks for breast cancer and total mortality in women with a family history of breast cancer. DESIGN: Prospective cohort study. SETTING: Population-based sample of midwestern post-menopausal women enrolled in an observational study of risk factors for cancer. PARTICIPANTS: Random sample of 41,837 female Iowa residents 55 to 69 years of age. MEASUREMENTS: Incidence rates of and relative risks for breast cancer (n = 1085) and total mortality (n = 2035) through 8 years of follow-up were calculated by using data from the State Health Registry of Iowa and the National Death Index. RESULTS: A family history of breast cancer was reported by 12.2% of the cohort at risk. Among women with a family history of breast cancer, those who currently used HRT and had done so for at least 5 years developed breast cancer at an age-adjusted annual rate of 61 cases per 10,000 person-years (95% CI, 28 to 94 cases); this rate was not statistically significantly higher than the rate in women who had never used HRT (46 cases per 10,000 person-years [CI, 36 to 55 cases]). Among women with a family history, those who used HRT had a significantly lower risk for total mortality than did women who had never used HRT (relative risk, 0.67 [CI, 0.51 to 0.89]), including total cancer-related mortality (relative risk, 0.75 [CI, 0.50 to 1.12]). The age-adjusted annual mortality rate for women using HRT for at least 5 years was 46 deaths per 10,000 person-years (CI, 19 to 74 deaths); this is roughly half the rate seen in women who had never used HRT (80 deaths per 10,000 person-years [CI, 69 to 92 deaths]). CONCLUSIONS: These data suggest that HRT use in women with a family history of breast cancer is not associated with a significantly increased incidence of breast cancer but is associated with a significantly reduced total mortality rate.     

The role of ataxia-telangiectasia heterozygotes in familial breast cancer

The role of ataxia-telangiectasia (AT) heterozygotes in breast cancer has been controversial. We have found previously an overrepresentation (3.4%) of ATM mutations in a subset of 88 selected breast cancer patients with a family history of breast cancer, leukemia, and lymphoma. This prevalence is comparable to the estimated value (3.8%) from epidemiological study. To further examine the possibility that ATM is correlated to breast cancer, we screened for ATM germ-line mutations in another 100 breast cancer patients with a family history of breast cancer. We used the protein truncating test and found one new germ-line mutation. This figure (1%) is consistent with the observed 0.2-1% carrier frequency for AT. We also studied breast tumors from ATM mutants, and three showed retention of both alleles, whereas the fourth showed loss of the mutant allele. We conclude that the contribution of heterozygous ATM mutations to familial breast cancer is minimal. Even if the ATM gene were causative in these cases, it is not likely to act as a tumor suppressor.     

Cost-utility model comparing docetaxel and paclitaxel in advanced breast cancer patients

Relevant data from direct comparisons in clinical trials are not available for economic evaluations of docetaxel and paclitaxel in the management of metastatic breast cancer. A modified Markov model is used to estimate the incremental cost in US$ per quality-adjusted life-year (QALY) for docetaxel versus paclitaxel in managing metastatic breast cancer patients in the US. The model incorporates the latest available clinical trial data (response rates of 47.8% for docetaxel and 25% for paclitaxel, chemotherapy-specific toxicities, time to progression, and 1-year survival) from studies against other comparators. Medical care resources were estimated by US oncologists and costed using US data sources. Utility scores were obtained from 29 US oncology nurses. The base case and subsequent sensitivity analyses show that docetaxel management of advanced breast cancer is more costly per patient but yields higher health benefits than paclitaxel therapy. The cost per QALY gained by docetaxel is $8615, and ranges between $3943 and $9416 in sensitivity analyses. These results confirm those of an earlier model using preliminary data and compare favorably with other cost-utility results in this patient group.     

The potential role of somatostatin analogues in breast cancer treatment

Existing treatments for breast cancer are helpful for many patients, but treatment failure remains a common event, and there is a strong clinical need to improve upon current therapies. Somatostatin analogues have been evaluated for antineoplastic activity in model systems over the past decade, and encouraging results have been obtained (reviewed in [1, 2]). This has led to suggestions to test these agents clinically in the treatment of breast cancer patients, and a program of clinical trials has recently been initiated. This review will describe aspects of research in this area.     

The role of neoadjuvant therapy in surgically resectable esophageal cancer

OBJECTIVE: To determine the effect of neoadjuvant therapy (NT) (preoperative chemotherapy, radiation therapy, or both) in surgically resectable esophageal cancer. DESIGN: A retrospective review over a 20-year period. SETTING: A tertiary academic medical center. PARTICIPANTS: All patients undergoing surgical resection for esophageal cancer (N = 316) over this time period. MAIN OUTCOME MEASURES: Perioperative morbidity and mortality, local and distant recurrences, and overall survival. RESULTS: Patients undergoing NT (n = 106) had prognostic factors similar to those treated with surgery alone (n = 210). No increase was noted in surgical morbidity with NT (anastomotic leaks, reoperation rates, complications, or extended hospital stays). Overall survival was not improved by NT (median survival, 14 months) except in the subset of patients (11/83) who responded completely (100% histological necrosis) to preoperative chemotherapy (median survival, 79.2 months; P < .02). Complete response to radiation therapy alone was not associated with improved survival. Partial necrosis of the primary tumor was seen in 13 (15%) of 83 patients but conferred no survival advantage. Complete response to preoperative chemotherapy was associated with squamous cell pathological features and excellent performance status as measured by preanesthesia evaluation. CONCLUSIONS: The addition of NT did not increase perioperative morbidity or mortality. Only the subset of patients who had a complete response to preoperative chemotherapy showed a survival advantage. Excellent performance status and squamous cell pathological features were associated with an increased chance of complete pathological response following preoperative chemotherapy.     

Systemic therapy for breast cancer

Currently available information suggests that the optimal duration of adjuvant therapy for breast cancer patients with no involved axillary nodes is 5 years, though controversy about this recommendation persists. In postmenopausal patients, disease-free survival appears to be improved by the addition of combination chemotherapy to tamoxifen. Recently reported studies indicate that there is no benefit to dose escalation of cyclophosphamide in adjuvant therapy and that the risk of secondary leukemia may be increased. The combination of paclitaxel and doxorubicin has been reported in single-institution studies to produce high response rates but may also be cardiotoxic. Recent reports indicate that a pharmacokinetic interaction between these two drugs may cause these clinical findings. New agents that may be of utility in the management of advanced or primary breast cancer include novel hormonal agents, notably the aromatase inhibitors, and the bisphosphonates.     

Gene therapy for breast cancer

Gene therapy for breast cancer is still in the very early stages of development. Many of the molecular strategies that have been proposed are also being developed for other cancers. Their application to breast cancer, however, needs to address several issues specific to this disease such as the widespread nature of metastases, the indolent growth of the tumor cells, and the production by the tumor of immunosuppressive agents. Nonetheless, these approaches appear promising, particularly those that employ a combination of strategies. Gene therapies that affect the biology of breast cancer cells or regulate host immune mechanisms have been most successful and may be paired with existing therapies for breast cancer.     

Radiation therapy and breast cancer

OBJECTIVE: To evaluate the benefits of a policy of performing screening blood tests in new patients with arterial disease referred to the vascular outpatients department. METHODS: Clinical audit over a 12-month period of all new referrals with arterial disease to the vascular outpatients department at the Leicester General Hospital. RESULTS: Two hundred and seventy-two patients had at least one blood test performed at their outpatient visit. All of these patients had a full blood count performed, of which 21 results (21%) were abnormal. Further investigation of patients with abnormal results revealed one case of bladder cancer, one case of leukaemia and one patient with polycythaemia. Urea and electrolytes were measured in 269 patients (99%). Of these, 26 (10%) were expectedly abnormal in patients with known renal impairment. A further 27 patients (10%) were identified to have some degree of unrecognised renal impairment. Serum non-fasting glucose was measured in 252 patients (93%). There were 11 unexpectedly raised results, but further investigation of these patients only diagnosed one of these patients as diabetic. Serum cholesterol was measured in 201 patients (74%). One hundred and thirty-two patients (66%) had an abnormally raised serum cholesterol level. Of these, only 12 patients (6%) were known to have hyperlipidaemia. CONCLUSIONS: Screening new patients with arterial disease in vascular outpatients does identify significant abnormalities, in particular renal impairment and hyperlipidaemia. Correction of these abnormalities may reduce the morbidity associated with contrast induced nephrotoxic acute renal failure, and also contribute to secondary prevention of vascular events associated with raised lipids.     

The role of international agencies in emerging infections

Emergent and resurgent infections have no respect for national borders. Surveillance programmes, policies and practices, educational activities and control initiatives all require international leadership, multinational funding, and the ability to transcend national barriers if we are to prevent and control these infections. Society seems to expect us to organise ourselves to do this job well without building "impossible to maintain" barriers to the flow of people or goods. As a result, we must determine how international organisations, including United Nations agencies, international societies, and academic groups in universities, can work together with national organisations to achieve effective surveillance, ongoing education, important research and control initiatives to prevent infections from becoming an ever-increasing global threat to our security.     

The role of cell communication in the pathogenesis of breast cancer]

OBJECTIVE: The aim of the study is to analyse long-term results of patients with small cell lung cancer (SCLC) treated at the same institution according to a prospective study including surgery, chemotherapy, and radiotherapy. METHODS: From 1981 to 1995, 104 patients with a proven histology of SCLC underwent surgery, chemotherapy, and radiotherapy. Fifty-one patients with operable stage I or II lesion received surgical resection followed by adjuvant chemotherapy and radiotherapy. Fifty-three patients with proved SCLC and clinical stage III received induction chemotherapy followed by surgery and radiotherapy. All patients received from four to six courses of chemotherapy and 36 had prophylactic cranial irradiation (PCI). All patients had follow-up for at least 1 year, and survival time was calculated from the date of the diagnosis until death or most recent follow-up. RESULTS: Ninety-six patients were male and eight female. We performed 29 pneumonectomies, eight bilobectomies, 66 lobectomies and one no resection. Regarding the clinical stage, 35 patients (33.6%) had stage I, 16 patients (15.4%) had stage II and 53 (51%) had stage III. Post-operative pathologic staging revealed stage I in 37 patients (35.6%), stage II in nine patients (8.6%), stage III in 45 patients (43.3%), and in 13 patients (12.5%) there was no more tumor. The 30-day mortality was 2% (two patients). Fourteen patients (13.4%) had post-operative complications. Fifty-one patients (49%) had a relapse. The median follow-up was 55 months. Twenty-six patients remain alive and 78 patients have died. The overall 5-year survival rate was 32%, with an estimate median survival time of 28 months; according to the pathologic stage, the survival data were 52.2%, 30% and 15.3% for stage I, II and III, respectively (P < 0.001). The 5-year survival was 41% in patients without SCLC after chemotherapy. CONCLUSION: As with non-small cell lung cancer, survival following surgery and chemotherapy clearly correlates with the stage. At present, it is not clear whether surgery is truly effective for patients with SCLC. In our experience, the complete elimination of small cell lung cancer is associated with an improvement in survival (41% at 5 years).