A randomized, placebo-controlled trial (NCIC CTG MAP1) examining the effects of letrozole on mammographic breast density and other end organs in postmenopausal women.

Mammographically detected breast density has been correlated with breast cancer risk. Breast density appears to be influenced by hormonal factors including increasing age, postmenopausal status, number of pregnancies, lower body weight, hormone replacement therapy, and tamoxifen therapy. The aromatase inhibitor letrozole profoundly reduces breast and circulating estrogen levels in postmenopausal women. We hypothesize that letrozole may reduce breast density and report here on its effects on mammographic breast density, bone mineral density (BMD), bone biomarkers, plasma hormone, and serum lipid levels. MAP1 was a multicenter, randomized, double-blind, placebo-controlled, feasibility trial in which postmenopausal women with or without prior invasive breast cancer were randomized in a 2:1 ratio of letrozole (2.5 mg daily) or placebo for 12 months and followed for a total of 24 months. Eligible women had an estimated >25% breast density on baseline mammogram. The primary endpoint was change in percent breast density (PD) between the baseline and 12-month mammograms as estimated by a computer-assisted thresholding program. Baseline and 12-month mammographic density was also assessed in a blinded manner by visual inspection. Secondary endpoints included changes in serum hormones, plasma lipid levels, bone biomarkers, and BMD. Data are available for 67 women (44 on letrozole and 23 on placebo). No significant changes in PD were noted between the treatment arms at either 12 or 24 months. No distinguishable difference in density measurements by visual inspection were noted between baseline and 12-month mammograms. A significant decrease in percentage change in T-score of the femoral neck at 12 months was noted in the letrozole arm without other significant changes in BMD parameters. Lipid values did not differ between treatment groups except for a borderline significant decrease in total cholesterol at 3 months among women treated with letrozole. Letrozole therapy was associated with a significant reduction in mean serum estradiol, estrone, and estrone sulfate levels at 12 months, but not at 24 months. A significant increase in serum IGF-1 levels was also noted in the letrozole group compared to the placebo group at both 12 and 24 months. To conclude, compared with placebo, 12 months of letrozole therapy does not appear to have a significant effect on mammographic PD. Twelve months of letrozole was associated with a decrease of uncertain clinical significance in the T-score of the femoral neck at 12 months which was reversible at 24 months with recovery of estrogen levels. Letrozole therapy was found to increase IGF-1 levels at 12 and 24 months.

A dose escalation trial of adjuvant cyclophosphamide and epirubicin in combination with 5-fluorouracil using G-CSF support for premenopausal women with breast cancer involving four or more positive nodes.

BACKGROUND: Dose-dense and dose-intensive regimens have improved the outcome of breast cancer in high-risk women with operable disease. PATIENTS AND METHODS: Sixty-three premenopausal women with Stage 2, 3 breast cancer and > or =4 positive axillary nodes were treated in three successive cohorts with 70 mg/m(2) of epirubicin, 500 mg/m(2) of 5-fluorouracil and G-CSF every 14 days for 12 cycles. Cyclophosphamide (C) was given at 700 mg/m(2), 900 mg/m(2), and 1100 mg/m(2) doses. Patients were evaluated for dose-limiting toxicities (DLTs) in the first four cycles, the primary endpoint of the trial. RESULTS: No DLTs were seen at C 700 mg/m(2); at C 900 mg/m(2) two of 16 patients experienced febrile neutropenia and poor performance status; at C 1100 mg/m(2), 1 of 31 patients experienced poor performance status. Over 6 months, febrile neutropenia, grade 4 thrombocytopenia, grade 3 anemia and severe fatigue were observed. Clinical congestive heart failure occurred in three patients over 4 years. CONCLUSION: A dose-intense and dose-dense regimen of cyclophosphamide, epirubicin and 5-fluorouracil was delivered with G-CSF without apparent increase in acute toxicity. Cyclophosphamide could be increased to more than twice the standard dose at the cost of more anemia and fatigue.

Chemotherapy permits resection of metastatic colorectal cancer: experience from Intergroup N9741.

BACKGROUND: Fluorouracil (5-FU), oxaliplatin and irinotecan combinations improve time to tumor progression (TTP), objective response and overall survival (OS) in patients with metastatic colorectal cancer (MCRC). Here we identify and describe patients treated on Intergroup study N9741 who initially had inoperable MCRC, but who obtained sufficient chemotherapeutic benefit to allow removal of their metastatic disease. PATIENTS AND METHODS: Patient research records in study arms (A) irinotecan/5-FU/leucovorin (LV) (IFL, n = 264), (F) oxaliplatin/5-FU/LV (FOLFOX4, n = 267) and (G) oxaliplatin/irinotecan (IROX, n = 265) were reviewed. TTP and median OS were calculated. RESULTS: Twenty-four (3.3%) of 795 randomized patients underwent curative metastatic disease resection [hepatectomy, 16; radiofrequency-ablation (RFA), six; lung resection, two]. Twenty-two out of 24 (92%) resected patients received an oxaliplatin-based regimen (FOLFOX4, 11; IROX, 11). Seven patients (29.2%) remain disease-free; relapses occurred mainly in the resected organ. Median OS in resected patients is 42.4 months, and median TTP is 18.4 months. All six patients treated with RFA have recurred. Four out of five (80%) patients who received chemotherapy following resection are disease-free. CONCLUSIONS: Resection of metastatic disease after chemotherapy is possible in a small but important subset of patients with MCRC, particularly after receiving an oxaliplatin-based chemotherapy regimen, with encouraging OS and TTP observed in these highly selected patients.

Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA8.

PURPOSE: This phase III study was performed to determine the superiority of doxorubicin (DOX) and vinorelbine (VNB) (arm 1) versus DOX alone (arm 2) in metastatic breast cancer (MBC) for overall survival (OS), time to treatment failure (TTF), toxicity, and quality of life (QOL). PATIENTS AND METHODS: Three hundred three patients were randomized to DOX 50 mg/m(2) intravenously (IV) on day 1 and VNB 25 mg/m(2) IV on days 1 and 8 (arm 1) or DOX 70 mg/m(2) IV on day 1 (arm 2). Both regimens were given every 3 weeks until a cumulative DOX dose of 450 mg/m(2). After 16 of the first 65 randomized patients experienced febrile neutropenia (FN), the doses were reduced to DOX 40 mg/m(2) on day 1 and VNB 20 mg/m(2) on days 1 and 8 versus DOX 60 mg/m(2) on day 1. Eligible patients were vinca alkaloid and anthracycline naive. Chemotherapy was first-line or second-line for MBC. RESULTS: Three patients were ineligible. Thus, 300 patients were assessable for toxicity and to determine time to disease progression (TTP), TTF, and OS. Two hundred eighty-nine patients were assessable for response, and 99 responders were assessable for response duration (RD). The response rates, QOL, and median RD, TTP, and TTF were not significantly different between the arms. Median OS was 13.8 months for arm 1 versus 14.4 months for arm 2 (P =.4). Grade 3 or 4 granulocytopenia was equivalent in both arms but more grade 3/4 neurotoxicity, mild venous toxicity, and FN were seen on arm 1. CONCLUSION: The survival with DOX and VNB is not superior to DOX alone in MBC.

Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To determine the relative efficacy of an intensive cyclophosphamide, epirubicin, and fluorouracil (CEF) adjuvant chemotherapy regimen compared with cyclophosphamide, methotrexate, and fluorouracil (CMF) in node-positive breast cancer. PATIENTS AND METHODS: Premenopausal women with node-positive breast cancer were randomly allocated to receive either cyclophosphamide 100 mg/m2 orally days 1 through 14; methotrexate 40 mg/m2 intravenously (i.v.) days 1 and 8; and fluorouracil 600 mg/m2 i.v. days 1 and 8 or cyclophosphomide 75 mg/m2 orally days 1 through 14; epirubicin 60 mg/m2 i.v. days 1 and 8; and fluorouracil 500 mg/m2 i.v. days 1 and 8. Each cycle was administered monthly for 6 months. Patients administered CEF received antibiotic prophylaxis with cotrimoxazole two tablets twice a day for the duration of chemotherapy. RESULTS: The median follow-up was 59 months. One hundred sixty-nine of the 359 CMF patients developed recurrence compared with 132 of the 351 CEF patients. The corresponding 5-year relapse-free survival rates were 53% and 63%, respectively (P = .009). One hundred seven CMF patients died compared with 85 CEF patients. The corresponding 5-year actuarial survival rates were 70% and 77%, respectively (P = .03). The rate of hospitalization for febrile neutropenia was 1.1% in the CMF group compared with 8.5% in the CEF group. There was one case of congestive heart failure in a patient who received CMF compared with none in the CEF group. Acute leukemia occurred in five patients in the CEF group. CONCLUSION: The results of this trial show the superiority of CEF over CMF in terms of both disease-free and overall survival in premenopausal women with axillary node-positive breast cancer.

Use of dexamethasone and granisetron in the control of delayed emesis for patients who receive highly emetogenic chemotherapy. National Cancer Institute of Canada Clinical Trials Group.

PURPOSE: To evaluate the roles of granisetron and dexamethasone for emesis control on days 2 through 7 after the administration of cisplatin in doses of 50 mg/m2 or greater to patients who had not previously received chemotherapy. PATIENTS AND METHODS: Four hundred thirty-five eligible and assessable patients were randomized to one of two arms in a double-blind fashion: arm A; granisetron 3 mg intravenous (i.v.) plus dexamethasone 10 mg i.v. prechemotherapy followed by granisetron 1 mg orally at 6 and 12 hours, then granisetron 1 mg orally and dexamethasone 8 mg orally twice daily on days 2 through 7 (219 patients); arm B; as in arm A but with placebo substituted for granisetron on days 2 through 7 (216 patients). All patients completed diaries in which episodes of emesis and severity of nausea were recorded. RESULTS: The addition of granisetron on days 2 through 7 had no discernable impact on nausea and vomiting during this period. CONCLUSION: The administration of a 5-hydroxytryptamine3, receptor (5-HT3) antagonist, in this case granisetron, after 24 hours conferred no benefit. This negative result needs to be assessed in light of conflicting literature, but at present it does not appear that the routine use of these drugs in this setting is justified.

Epirubicin, alone or in combination chemotherapy, for metastatic breast cancer. Provincial Breast Cancer Disease Site Group and the Provincial Systemic Treatment Disease Site Group.

GUIDELINE QUESTION: How effective is epirubicin compared with doxorubicin in the treatment of metastatic breast cancer? OBJECTIVE: To make recommendations about the use of epirubicin, particularly compared with doxorubicin, in women with metastatic breast cancer. OUTCOMES: Outcomes of interest are response rate, survival and toxicity. PERSPECTIVE (VALUES): Evidence was reviewed and summarized by a member of the Provincial Systemic Treatment Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative. Drafts of the practice guideline were reviewed and discussed by the Breast Cancer DSG of the Cancer Care Ontario Practice Guidelines Initiative. The 2 DSGs comprise medical oncologists, radiation oncologists, surgeons, epidemiologists, pathologists, nurses, pharmacists, a medical sociologist and a community representative. QUALITY OF EVIDENCE: Thirteen randomized controlled trials (11 published reports and 2 reports in abstract form) were reviewed that compared epirubicin and doxorubicin at equal doses, epirubicin at a higher dose than that of doxorubicin, and epirubicin at escalating doses. BENEFITS: No significant differences were observed in response rate or median survival in the 7 trials comparing equal doses of epirubicin and doxorubicin or in the 3 trials comparing epirubicin at a higher dose than that of doxorubicin. An increased response rate was observed with higher doses of epirubicin in the 3 trials that compared escalating doses; no difference in survival was observed. HARMS: Compared with doxorubicin, epirubicin was associated with less nausea and vomiting (risk ratio [RR] 0.76; 95% confidence interval [CI] 0.63 to 0.92; p = 0.0048), less neutropenia (RR 0.52; 95% CI 0.35 to 0.78; p = 0.0017) and less cardiotoxicity (RR 0.43; 95% CI 0.24 to 0.77; p = 0.0044), including a trend toward fewer episodes of congestive heart failure (RR 0.38; 95% CI 0.14 to 1.04; p = 0.059). PRACTICE GUIDELINE: For the treatment of metastatic breast cancer in which the goal of treatment is palliation, epirubicin (at doses equivalent to doxorubicin) has been shown to be equally efficacious and less toxic than doxorubicin. Doxorubicin, however, is an acceptable alternative. CLINICAL PRACTICE GUIDELINE DATE: Oct. 2, 1997.

Unresected stage III non-small-cell lung cancer. Provincial Lung Cancer Disease Site Group.

GUIDELINE QUESTIONS: 1) What is the role of different schedules or doses of radiotherapy in patients with unresected, clinical or pathological, stage III non-small-cell lung cancer (NSCLC)? 2) Does chemotherapy combined with radiotherapy provide improved survival compared with radiotherapy alone in patients with unresected NSCLC? OBJECTIVE: To make recommendations about the role of chemotherapy and radiotherapy in the treatment of unresected stage III NSCLC. OUTCOMES: Survival is the primary outcome of interest. Quality of life is a secondary outcome. PERSPECTIVE (VALUES): Evidence was selected and reviewed by 5 members of the Provincial Lung Cancer Disease Site Group (Lung DSG) of the Ontario Cancer Treatment Practice Guidelines Initiative. The Lung DSG comprises medical and radiation oncologists, pathologists, surgeons, epidemiologists, a psychologist and a medical sociologist. No community representative participated in the development of this guideline. QUALITY OF EVIDENCE: Two meta-analyses were available for review. The specific analysis of interest examined the role of combined chemotherapy plus radiotherapy v. radiotherapy alone in locally advanced disease. The first meta-analysis included combined data from 22 randomized controlled (RCTs) involving a total of 3033 patients. The second included combined data from 14 RCTs involving a total of 2589 patients. Also reviewed were 4 RCTs of radiotherapy alone, 1 trial of combined chemotherapy and radiotherapy that was not included in the meta-analysis, 4 abstracts of studies of combined chemotherapy and radiotherapy, and 4 trials examining the role of hyperfractionated radiotherapy. BENEFITS: In the first meta-analysis, an overall benefit was detected at 2 years for the use of combined chemotherapy and radiotherapy. A hazard ratio of 0.90 (p = 0.006), or a 10% reduction in the risk of death, translated into an absolute benefit of 3% at 2 years and 2% at 5 years. A subgroup analysis of cisplatin-based chemotherapy plus radiotherapy versus radiotherapy alone demonstrated a 13% reduction in the risk of death in the combined treatment arm (pooled hazard ratio 0.87, 95% confidence interval [CI] 0.79-0.96), for an absolute benefit of 4% at 2 years. In the second meta-analysis, there was a 13% reduction in the risk of death in the combined therapy arm at 2 years (pooled relative risk [RR] 0.87, 95% CI 0.81-0.94) and a 17% reduction at 3 years (pooled RR 0.83, 95% CI 0.77-0.90). Subgroup analysis of cisplatin-based chemotherapy plus radiotherapy versus radiotherapy alone showed similar results: a 15% reduction in the risk of death in the combined therapy arm at 2 years (pooled RR 0.85, 95% CI 0.79-0.92) and a 19% reduction at 3 years (pooled RR 0.81, 95% CI 0.74-0.88). PRACTICE GUIDELINE: For patients with unresected stage III NSCLC, the combination of cisplatin-based chemotherapy and radical radiotherapy provides a survival benefit compared with radiotherapy alone. This guideline is based on high-quality evidence from 2 meta-analyses of RCTs. Patients with good performance status (Eastern Cooperative Oncology Group [ECOG] 0-1) and minimal weight loss (less than 5% in the preceding 3 months) have been shown to have a survival benefit from treatment with combined chemotherapy and radiotherapy and should be considered for this type of treatment approach (see section V). For these patients, thoracic irradiation of 60 Gy in 30 fractions over 6 weeks, in combination with cisplatin-based chemotherapy, should be recommended as a treatment option. The patient and physician should discuss fully the benefits, limitations and toxic effects of therapy. Patients not meeting these criteria are not candidates for combined therapy; those experiencing symptoms amenable to treatment should receive palliative thoracic irradiation. At this time, hyperfractionated radiotherapy is not recommended outside of the context of a clinical trial. (ABSTRACT TRUNCATED)

A randomized trial of paracentesis plus intraperitoneal tumor necrosis factor-alpha versus paracentesis alone in patients with symptomatic ascites from recurrent ovarian carcinoma.

PURPOSE: Previous phase I and II studies of intraperitoneal recombinant human tumor necrosis factor-alpha (rhTNF-alpha) suggested a high degree of efficacy in reducing or eliminating ascitic fluid. To more accurately determine the efficacy of this agent, the role of paracentesis versus paracentesis plus intraperitoneal rhTNF-alpha was studied in a randomized trial. PATIENTS AND METHODS: Thirty-nine patients with symptomatic ascites with a volume of > 1000 ml from recurrent epithelial ovarian carcinoma or primary peritoneal carcinoma, which was refractory to standard therapy, were randomized either to receive 0.06 mg/m2 rhTNF-alpha (Knoll, Canada) (the dose determined optimal from phase I and II studies) intraperitoneally after drainage of fluid or to receive drainage alone. A maximum of three treatments were given at weekly intervals. Eighteen patients were randomized to receive rhTNF-alpha. RESULTS: None of 18 evaluable rhTNF-alpha patients had either a complete response (CR) (no clinical evidence of ascites and < 400 ml of fluid on ultrasound) or a partial response (PR) (asymptomatic ascites and < or = 1000 ml of fluid ultrasound). There were no CRs or PRs in the 17 evaluable patients who received drainage alone. The intraperitoneal infusion of rhTNF-alpha was generally well tolerated. Moderate to severe toxicity consisted of pain/discomfort in 42.1%, fever/chills in 36.9%, nausea/vomiting in 10.5%, edema in 10.5%, and hypotension in 5.3% of patients receiving rhTNF-alpha. CONCLUSION: rhTNF-alpha, as given in this study, was not effective in preventing recurrence of ascites in this patient population.

Use of palliative end points to evaluate the effects of mitoxantrone and low-dose prednisone in patients with hormonally resistant prostate cancer.

PURPOSE: This phase II study was designed to assess the effects of mitoxantrone with prednisone in patients with metastatic prostate cancer who had progressed on hormonal therapy. The methods of assessment included quality-of-life analyses, pain indices, analgesic scores, and the National Prostatic Cancer Project (NPCP) criteria. PATIENTS AND METHODS: Patients received mitoxantrone 12 mg/m2 intravenously every 3 weeks plus prednisone 10 mg orally daily. All had a castrate serum testosterone and Eastern Cooperation Oncology Group (ECOG) performance status < or = 3, and had not received prior chemotherapy. Every 3 weeks, analgesic intake was scored, and a present pain intensity (PPI) record and visual analog scale (VAS) describing pain were collected. Every 6 weeks, the European Organization for Research and Treatment of Cancer (EORTC) core quality-of-life questionnaire plus a prostate-specific module were completed. A palliative response was defined as a decrease in analgesic score by > or = 50% or a decrease in PPI by > or = two integers without any increase in the other. RESULTS: Twenty-seven patients were entered onto the study. Nine of 25 (36%) assessable patients achieved a palliative response maintained for > or = two cycles (range, two to eight or more). Improvements in mean PPI and VAS pain scores after each cycle of therapy (P < .05) were seen. Quality-of-life analysis showed improvements in social and emotional functioning, and in pain and anorexia. Using NPCP criteria, one patient achieved a partial response (PR) and 12 had stable disease; one of seven patients with measurable disease had a PR. No serious nonhematologic toxicity was experienced, and there were no episodes of febrile neutropenia. CONCLUSION: Mitoxantrone with low-dose prednisone is a well-tolerated treatment regimen that has some beneficial effects on disease-related symptoms and quality of life for patients with advanced prostate cancer.

The Canadian experience with intensive fluorouracil, epirubicin and cyclophosphamide in patients with early stage breast cancer.

A multicentre dose-finding pilot study was conducted to determine an intensive regimen of fluorouracil (F), epirubicin (E) plus cyclophosphamide (C) [FEC] that was tolerable and acceptable to patients with node-positive operable (n = 266) or locally advanced (n = 22) breast cancer. Consecutive patients were treated with fluorouracil and epirubicin administered intravenously on days 1 and 8, in addition to cyclophosphamide orally for 14 days. Chemotherapy cycles were repeated at monthly intervals for 6 months, and dosages were increased according to a predetermined protocol. End-points were hospital admissions due to febrile neutropenia and changes in cardiac function as assessed by radionuclide angiography. The first 46 patients were treated with doses of F = 375 mg/m2, E = 50 mg/m2 and C = 75 mg/m2 (level 1), then 42 patients received F = 500 mg/m2, E = 50 mg/m2 and C = 75 mg/m2 (level 2), 69 patients received F = 500 mg/m2, E = 60 mg/m2 and C = 75 mg/m2 (level 3), and 42 patients received F = 500 mg/m2, E = 70 mg/m2 and C = 75 mg/m2 with concurrent antibiotics (level 4). Rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4) [p = 0.002]. Accrual to level 4 was discontinued according to study protocol and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between dosage levels 3 and 3a was statistically significant (p = 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

A pilot study of intensive cyclophosphamide, epirubicin and fluorouracil in patients with axillary node positive or locally advanced breast cancer.

A multicentre pilot study has been conducted to determine an intensive regimen of cyclophosphamide, epirubicin, and fluorouracil which was tolerable and acceptable to patients with node positive breast cancer. Consecutive patients with operable axillary node positive breast cancer (T1-3, N1-2, M0), 266 patients, or locally advanced breast cancer (T4), 22 patients, were treated with cyclophosphamide post-operatively for 14 days and epirubicin and fluorouracil, both intravenously on days 1 and 8. Each cycle was repeated monthly for 6 months. Dosages were increased according to predetermined guidelines. Outcome measures were admission to hospital for febrile neutropenia and change in cardiac function as assessed by radionuclide angiography. The first 46 patients were treated at the doses of cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2, fluorouracil = 375 mg/m2 (level 1), then 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 50 mg/m2 and fluorouracil = 500 mg/m2 (level 2), 69 patients at cyclophosphamide = 75 mg/m2, epirubicin = 60 mg/m2, and fluorouracil = 500 mg/m2 (level 3), and 42 patients at cyclophosphamide = 75 mg/m2, epirubicin = 70 mg/m2, and fluorouracil = 500 mg/m2 with concurrent antibiotics (level 4). The rates of febrile neutropenia were 8.7% (level 1), 7.1% (level 2), 18.8% (level 3), and 31% (level 4), respectively, P = 0.002. Accrual to level 4 was discontinued according to study guidelines and a further 89 patients were recruited at level 3 dosages with antibiotic prophylaxis (level 3a), resulting in a 5.6% rate of febrile neutropenia. The difference in febrile neutropenia rates between levels 3 and 3a was statistically significant. There were no toxic deaths and 2 cases of heart failure. In conclusion, through a careful dose-finding study in patients with operable or locally advanced breast cancer, an intensive epirubicin-containing adjuvant regimen has been established which is presently being compared with standard CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy in a randomised trial. In addition, this study suggests that antibiotic prophylaxis reduces the risk of febrile neutropenia in breast cancer patients receiving intensive chemotherapy.

The effect of systemic adjuvant chemotherapy on local breast recurrence in node positive breast cancer patients treated by lumpectomy without radiation.

A randomised trial has previously been repeated in which 437 women with node positive breast cancer received either a 12-week chemohormonal regimen consisting of cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, adriamycin and tamoxifen or 36 weeks of CMFVP. The present analysis concerns the local recurrence rates for the 122 lumpectomy patients who did not receive breast irradiation. The cumulative rate of local breast recurrence was greater in the 12-week than the 36-week group, P = 0.02. Similarly, in the lumpectomy patients, the cumulative rate of distant recurrence was greater in the 12-week than the 36-week group, P = 0.04. In conclusion, our results suggest that adjuvant chemotherapy impacts on local breast recurrence in a similar manner to other sites in Stage II breast cancer patients treated by lumpectomy without radiation. Despite the use of a conventional 36-week adjuvant chemotherapy regimen, the local breast recurrence rate was substantial.

A randomized, double-blinded study comparing six doses of batanopride (BMY-25801) with methylprednisolone in patients receiving moderately emetogenic chemotherapy.

Several agents in a new class of antiemetic compounds, 5-hydroxytryptamine (5-HT3) antagonists, have shown promise as effective antiemetics with fewer side effects than metoclopramide. One of these agents, batanopride, produced no severe toxicity at doses that prevented emesis due to chemotherapy in early Phase I trials. We conducted a randomized, double-blinded, 7 arm clinical trial to: (1) identify the presence of a dose-response for complete protection from emesis, and (2) compare batanopride with a standard antiemetic, methylprednisolone if a dose-response was found not to exist. Prior to chemotherapy, six patient groups each received a single intravenous dose of batanopride ranging from 0.2 to 6.0 mg/kg whereas a seventh group received methylprednisolone 250 mg intravenously. Chemotherapy-naïve cancer patients scheduled to receive moderately emetogenic chemotherapy were eligible. Primary treatment outcomes that were recorded and analyzed included the number of episodes of emesis, the time to the first episode of emesis as well as the frequency and severity of nausea. Two hundred and eight patients accrued between April 1989 and February 1990 were evaluable for response. A significant dose-response effect for complete protection from emesis was not seen over the first 24 hours after chemotherapy (p = 0.102). However, a linear dose-response effect for time to first emesis was evident in a multivariate analysis (p = 0.029). While the highest batanopride dose group was associated with a higher complete protection rate (CPR) than the control group, this group also exhibited a higher incidence of diarrhea (p = 0.013), hypotension, and electrocardiographic abnormalities.(ABSTRACT TRUNCATED AT 250 WORDS)

A randomized trial comparing 12 weeks versus 36 weeks of adjuvant chemotherapy in stage II breast cancer.

A randomized trial has been performed in which women with axillary node-positive breast cancer were allocated to either a short intensive 12-week chemohormonal treatment consisting of cyclophosphamide, methotrexate, fluorouracil, vincristine, prednisone, Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH), and tamoxifen (CMFVP plus AT) or 36 weeks of CMFVP. The median follow-up is 37 months. Of the 222 women randomized to the 12-week treatment, 113 (50.9%) have experienced either recurrence or death as compared with 90 patients (41.9%) in the 36-week treatment group. The corresponding 3-year relapse-free survivals are 55% and 64%, respectively, P = .003. Fifty-nine (26.6%) of the patients in the 12-week group have died compared with 46 (21.4%) of the 36-week group. The corresponding 3-year survival rates are 78% and 85%, respectively, P = .04. A Cox regression analysis showed an associated increased risk ratio for recurrence or death of 1.7, P = .003, and for death of 1.8, P = .017 in the 12-week treatment group compared with the 36-week group. Thus, this 12-week regimen of adjuvant chemohormonal therapy is inadequate treatment for women with axillary node-positive breast cancer; possible explanations for this inferiority are its shorter duration and/or a negative interaction of tamoxifen on the chemotherapy.

Addition of verapamil and tamoxifen to the initial chemotherapy of small cell lung cancer. A phase I/II study.

Based on experimental observations that verapamil and tamoxifen reverse multiple drug resistance, the authors investigated the feasibility of combining both agents with the initial chemotherapy of extensive small cell lung cancer. Overall, in a consecutive series of 58 patients the most important toxicity was myelosuppression, and there was a 24% rate of severe infections. Therapeutic results included 24% complete and 34% partial response rates, median time to disease progression of 32 weeks, and median survival of 46 weeks. In three consecutive cohorts of patients the dose of either tamoxifen or verapamil were escalated by 25% and 33%, respectively. The cohort of patients receiving verapamil 360 mg/day and tamoxifen 100 mg/day (level 2) had slightly more toxicity but also more responses than the other groups. Therefore, the authors recommend that these doses be used in controlled trials to confirm the promising results of their study.

Quality of life in stage II breast cancer: an instrument for clinical trials.

A questionnaire has been developed for use as an outcome measure in clinical trials of adjuvant chemotherapy in women with stage II breast cancer. The selection of items for this Breast Cancer Chemotherapy Questionnaire (BCQ) was based on the problems and experiences felt to be most important by women undergoing adjuvant chemotherapy. The BCQ consists of 30 questions that focus on loss of attractiveness, fatigue, physical symptoms, inconvenience, emotional distress, and feelings of hope and support from others. The BCQ, other instruments that evaluate quality-of-life (Spitzer, Karnofsky, and Rand), and patient and physician global assessments were administered serially to 418 patients taking part in a randomized trial comparing a 12-week regimen and a 36-week regimen of adjuvant chemotherapy. The validity of the BCQ is supported by its correlation with the Rand Emotional (r = .58), Rand Physical (r = .60), and Spitzer (r = .62) questionnaires. The BCQ correlated more strongly with global ratings of both physical and emotional function by the patients and their physicians than the other instruments. A comparison of the quality-of-life outcomes of patients in the two treatment groups in the period beyond 3 months after initiation of treatment, when one group had completed the treatment course and the other was still on treatment, revealed that the BCQ and Karnofsky were the only instruments able to demonstrate differences between the groups (P less than .0001). Hence, the BCQ is a valid and responsive method of assessing treatment-related morbidity in patients receiving adjuvant chemotherapy for stage II breast cancer.

Enhancement of the viscosity of mucin by serum albumin.

The interaction of serum albumin with a model epithelial mucin from pig stomach was explored by rotary viscometry. During 30 min of incubation of human serum albumin(20mg/ml) and pig gastric mucin (8mg/ml) in iso-osmotic buffers at 37 degrees C, the solution became markedly viscous. Viscosity enhancement was proportional to albumin concentration (2-40mg/ml), was most pronounced under conditions of low shear rate (less than 45S-1), and was considerably greater than the additive or multiplicative viscosity values calculated from albumin or mucin solutions measured separately. The viscous mucin-albumin complex was destroyed by high shear rates (greater than 90S-1), but slowly re-formed under zero shear conditions. Elevation of pH (7 to 9), ionic strength (0.1 to 1.0), and addition of disodium EDTA (5mM) did not cause marked or specific alterations in the viscosity of the mixture, suggesting that electrostatic interactions probably do not stabilize mucin-albumin complexes. Urea (7M) and heating (35 to 55 degrees C) caused a major increase in the viscosity of mucin and mucin-albumin mixtures, suggesting that rupture of hydrogen bonds, unfolding and partial denaturation of mucin promotes greater intertangling (possibly hydrophobic interactions) between mucin and albumin molecules. The implications of mucin-albumin interaction in diseases associated with mucus obstruction are briefly discussed.