Self-reported dietary habits, overall dietary quality and symptomatology of breast cancer survivors: a cross-sectional examination.

Little information is available about the relationship between quality of life of women who have survived breast cancer (specifically, symptoms including those of menopause and depression) and the quality of their diet. In this cross-sectional study, 117 women with known primary breast cancer completed a self-administered food frequency questionnaire (FFQ) reflecting usual diet during the past year, a Survey of Feelings and Attitudes using the Center for Epidemiologic Studies Depression scale (CES-D) and a survey that includes menopausal symptoms among others common to women with a history of breast cancer. When women's responses to the FFQ were scored using the Healthy Eating Index (HEI), most often diets were evaluated as those that 'need improvement' with a mean total HEI score of 67.2. With regard to the CES-D scores, study women averaged 9.5, with 19 women being classified as clinically depressed. HEI and CES-D scores were inversely related (p = -0.22, p = 0.02). A negative correlation was also observed between energy-adjusted calcium intakes and CES-D scores (p = -0.19, p = 0.04). Clinical depressed women had not only lower HEI scores and calcium intakes, but also lower grain and variety scores. Comparisons to national data for disease-free women and that available for those with breast cancer suggest that our study women consumed diets low in energy and dietary variety. Diet quality may be an important factor influencing the manifestation of depressive symptoms in breast cancer survivors or conversely, poorer diet quality may be an outcome of depression.

First-line Herceptin monotherapy in metastatic breast cancer.

The pivotal phase II and III Herceptin trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/ kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg i.v. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for > or =6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase III combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients.

First-line, single-agent Herceptin(R) (trastuzumab) in metastatic breast cancer. a preliminary report.

Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(R) (trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.

First-line, single-agent Herceptin(trastuzumab) in metastatic breast cancer: a preliminary report.

Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.

Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.

PURPOSE: Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. PATIENTS AND METHODS: Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. RESULTS: Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. CONCLUSION: Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Hormone replacement therapy and high S phase in breast cancer.

CONTEXT: Prolonged postmenopausal hormone replacement therapy (HRT) is associated with increased incidence of breast cancer and, paradoxically, reduced breast cancer mortality. The biological rationale for this discrepancy has not been explored. OBJECTIVE: To compare the prognostic characteristics of cancers arising in women who have used HRT with those in women who never have used HRT. DESIGN: Prospective cohort study from December 1989 to November 1996. SETTING: Teaching hospital in a large midwestern metropolitan area. PATIENTS: Cohort of 331 postmenopausal women who presented consecutively with 349 invasive breast cancers. MAIN OUTCOME MEASURES: Estrogen receptor (ER) status (ER positive vs ER negative) and S phase (low vs high) for current HRT users vs never users. RESULTS: The frequency of high S-phase fraction among cancers in women who were using HRT was markedly increased compared with that in women who had never used HRT (adjusted odds ratio [OR], 2.82; 95% confidence interval [CI], 1.04-7.66). However, the greater frequency of high S-phase fraction was limited to women with ER-positive cancers (for HRT users vs never users, OR, 5.25; 95% CI, 1.36-20.28; for ER-negative cancers in HRT users vs never users, OR, 1.08; 95% CI, 0.20-5.86). CONCLUSIONS: Use of HRT appears to stimulate growth of ER-positive but not ER-negative breast cancer as measured by S-phase fraction. The prognostic significance of high S-phase fraction in current HRT users who have ER-positive tumors is unknown.

Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer.

PURPOSE: Adjuvant chemotherapy for breast cancer causes significant changes in ovarian function. More young women survive breast cancer than ever before and they are at risk of the sequelae of early menopause. We attempted to (1) define menopausal status in the setting of adjuvant chemotherapy; (2) define chemotherapy-related amenorrhea (CRA); (3) document rates of permanent amenorrhea, temporary amenorrhea, and oligomenorrhea among different regimens; and (4) analyze variables that influence ovarian function. DESIGN: We reviewed reports of the effects of adjuvant chemotherapy for breast cancer on ovarian function in premenopausal women. We searched Medline and Cancerlit from 1966 to 1995 on the following terms: breast neoplasms; chemotherapy, adjuvant; menstruation disorders; premature menopause, and amenorrhea. Further references were obtained from reports retrieved in the initial search. RESULTS: A uniform definition of menopause and CRA is lacking. The wide range of CRA rates reported in adjuvant chemotherapy trials is a result, at least in part, of this problem. The average CRA rate reported in regimens based on cyclophosphamide, methotrexate, and fluorouracil (CMF) is 68% (95% confidence interval [CI], 66% to 70%), with a range of 20% to 100%. CRA incidence varies with age, cytotoxic agent, and cumulative dose. CONCLUSION: Ovarian damage is the most significant long-term sequela of adjuvant chemotherapy in premenopausal breast cancer survivors. We suggest a common definition of the following important terms: menopausal status, CRA (early and late), temporary CRA, and oligomenorrhea in the setting of adjuvant treatment. With uniform definitions in place, regimens can be more precisely compared with respect to this important complication.

Tandem peripheral blood progenitor cell transplants as initial therapy for metastatic breast cancer.

PURPOSE: To investigate the use of two sequential courses of high-dose chemotherapy and peripheral blood progenitor cell (PBPC) transplant as initial therapy for patients with untreated metastatic breast cancer. The goal of the study was to maximize treatment intensity through the use of two non-cross-resistant regimens, each equal in intensity to that used in single transplants. METHODS: PBPC were collected after a course of granulocyte colony-stimulating factor (G-CSF) only or of cyclophosphamide, etoposide, and G-CSF. The first transplant regimen consisted of thiotepa (600 mg/m2), cyclophosphamide (6000 mg/m2), and carboplatin (800 mg/m2). After recovery from the first transplant, responding patients received a second course of therapy consisting of busulfan (16 mg/kg) and etoposide (60 mg/kg). RESULTS: Forty-four patients were enrolled. Five patients did not proceed to transplantation due to tumor progression during PBPC mobilization. Five patients achieved complete response after the first transplant, and 14 were in complete remission at the end of the therapy. Six patients remain free of disease after a median followup of 22 months (range 12-27+ months). The 2-year event-free survival for complete responders is 25.4% (standard error 14.4%). Engraftment was prompt, with a median of 8 and 13 days, respectively, to reach a neutrophil count of 500/mm3 and a platelet count of 50,000/mm3. As a result of the gastrointestinal toxicity of the first course, the median interval between transplants was 68 days. The toxicities of the second transplant course were principally hepatic and muco-cutaneous. Hepatic veno-occlusive disease occurred in 12 patients and was a contributor to the death of three. CONCLUSIONS: Rapid hematologic recovery achieved with PBPC made possible the administration of two courses of high-dose chemotherapy without compromising the intensity of either transplant regimen. The adverse effects of the second course, however, were substantially higher than predicted. The outcome of patients achieving a complete response is promising. Overall, the antitumor benefit of this approach in patients with previously untreated metastatic disease was not superior to that achieved with single transplants in patients responding to standard-dose chemotherapy.

Should multicentric disease be an absolute contraindication to the use of breast-conserving therapy?

PURPOSE: Multicentric cancer is present in a large proportion of mastectomies performed as treatment of breast cancer; it has been considered a contraindication to breast conservation. METHODS AND MATERIALS: We reviewed the records of our patients with Stage I or II breast cancer treated with breast conserving surgery and radiation therapy over a 13-year period. Twenty-seven patients had two or more nodules of grossly visible cancer separated by histologically normal breast tissue. All patients had grossly negative margins of excision; however, four patients had microscopically positive margins. Nine patients had positive axillary nodes. All patients received radiation therapy to the breast postoperatively, with a median dose of 50.4 Gy in 28 fractions; 11 patients also received a boost dose of 6-20 Gy to the tumor bed. Eleven patients were given adjuvant chemotherapy and one patient was given adjuvant tamoxifen. RESULTS: With a median follow-up of 53 months, only one patient has relapsed in the breast (3.7%); that patient relapsed in multiple distant sites at the same time. Three patients have died of disseminated disease; the actuarial survival and disease-free survival rates at 4 years are 89%. CONCLUSION: Breast conservation may be considered for patients with multicentric breast cancer discovered at the time of histologic examination. For patients with multicentric disease detected prior to surgery, breast conserving therapy may be appropriate as long as: (1) all clinically and radiographically apparent abnormalities are removed, (2) clear margins of resection are achieved, and (3) there is no extensive intraductal component.

Treatment of metastatic breast cancer with a split-course high-dose chemotherapy regimen and autologous bone marrow transplantation.

PURPOSE: We investigated the role of high-dose chemotherapy and autologous bone marrow transplantation (ABMT) as the initial systemic treatment in patients with hormone-unresponsive metastatic breast cancer. We studied a regimen involving a split-course schedule using sequential administration of two pairs of alkylating agents separated by 5 days of rest. The rest period was intended to provide time for recovery from the treatment-immediate adverse effects, thereby allowing further dose escalation. PATIENTS AND METHODS: The treatment consisted of thiotepa 225 to 300 mg/m2/d (days - 11 to -9), cisplatin 50 to 100 mg/m2/d (days - 11 and -3), and cyclophosphamide 60 mg/kg/d (days - 3 and -2). Dose escalation was performed in the initial 15 patients before reaching dose-limiting toxicities. When feasible, responding patients received posttransplant irradiation to sites of residual or prior bulky disease. Patients with bone marrow or CNS involvement, prior pelvic irradiation, or age greater than 55 years were excluded. RESULTS: Thirty-nine patients with measurable or assessable tumor were enrolled: 23 with visceral metastases, 11 with only soft tissue disease, and five with skeletal involvement. Twenty-five patients had received no chemotherapy for metastatic disease before transplantation. The dose-limiting toxicities of this therapy were renal and gastrointestinal. Six patients died from complications: four of a fungal infection and two of hemorrhage. A complete response was achieved in 14 patients (36%), three of whom are free of disease at 79+, 55+, and 40+ months after transplantation. Ten of 25 patients not treated with standard-dose chemotherapy for metastatic disease achieved a complete response (40%). The three patients in continuous remission were in the untreated relapse group. CONCLUSION: This single high-dose treatment achieved a relatively high complete response rate in patients with metastatic breast cancer and may have cured some of them. On the other hand, the split-course dose schedule as tested here did not permit significant dose-intensification.

Sequential transplants using mobilized peripheral blood progenitor cells.

Modest success has been achieved with the use of high-dose cytotoxic therapy and bone marrow transplantation in solid tumors. Patient outcome can potentially be improved with further intensification of the therapy. The rapid hematologic recovery achieved with mobilized peripheral blood progenitor cells (PBPC) may reduce the toxicity of transplantation enabling the use of sequential courses of myeloablative therapy. We report on 42 patients with solid tumors enrolled in a tandem transplant protocol involving the use of PBPC mobilized with cyclophosphamide (4 g/m2), etoposide (1 g/m2), and granulocyte-colony-stimulating factor (G-CSF: 10 micrograms/kg/day). This regimen significantly increased the number of circulating progenitor cells; only 1-2 aphereses were sufficient to collect 2.5 x 10(8)/kg mononuclear cells, our goal for each transplant course. The median number of circulating colony-forming units (CFU) and CD34+ cells obtained for each transplant course were 70.3 x 10(4)/kg, and 11.7 x 10(6)/kg, respectively. There was a significant correlation between the numbers of CD34+ cells and CFU measured in the apheresis product (r = 0.49, P = .003). The first transplant regimen given to 38 patients consisted of thiotepa, carboplatin, and cyclophosphamide. The second transplant regimen given to 29 patients consisted of busulfan and etoposide. Hematologic recovery was comparable after each of the two transplant courses. The median time to neutrophil recovery over 0.5 x 10(9)/L and to platelet transfusion independence was 9 and 8 days, respectively. There was no difference in engraftment rates after transplant with PBPC only (n = 28 courses) compared to transplant with PBPC plus bone marrow (n = 39 courses).(ABSTRACT TRUNCATED AT 250 WORDS)

Breast cancer and fenretinide, an analogue of vitamin A.

Preclinical studies make fenretinide attractive for prevention and treatment of breast cancer. It inhibits mammary gland end bud formation in developing animals. Carcinogen-induced mammary cancer is suppressed by fenretinide, both at early and late stages of carcinogenesis, in young and mature rats. Fenretinide causes regression of invasive rat mammary cancer. Cytostatic activity has been demonstrated against human breast cancer cell lines. Autocrine stimulation of human breast cancer cell lines by tgf-alpha, insulin-like growth factors I and II is significantly abrogated by fenretinide. The human half-life is 24 hours. Absorption is markedly affected by meal content. Serum levels of 1 mM are achieved at doses of 200 mg/day. This dose significantly suppresses serum IGF-I levels in women. This concentration is capable of suppressing human breast cancer growth in vitro. A 3-day drug holiday is given each month in order to restore serum retinol levels. Under these circumstances, fenretinide is well tolerated. A phase III trial evaluating the efficacy of fenretinide for breast cancer prevention in high-risk women has been completed. Tamoxifen enhances the effectiveness of fenretinide in carcinogenesis models. The combination can be safely administered to women. A phase III adjuvant trial of tamoxifen, with or without fenretinide will be conducted in the United States.

Phase I/II trial of tamoxifen with or without fenretinide, an analog of vitamin A, in women with metastatic breast cancer.

PURPOSE: Considerable attention has been focused on the chemopreventive properties of fenretinide against carcinogen-induced rodent mammary cancer. Less is known about its direct antitumor effects. The combination of tamoxifen and fenretinide is more effective than tamoxifen or fenretinide alone in prevention of rat mammary cancer. However, the combined toxicity of tamoxifen plus fenretinide in humans is unknown. Therefore, we performed a phase I/II trial in women with estrogen receptor (ER)-positive or progesterone receptor (PR)-positive, previously untreated metastatic breast cancer. PATIENTS AND METHODS: Groups of three patients received tamoxifen 20 mg/d, or tamoxifen plus fenretinide 100, 200, 300, or 400 mg/d. Patients who received fenretinide enjoyed a 3-day "drug holiday" every 4 weeks. Serum levels of fenretinide and its major metabolites were monitored. Patients were monitored for known toxicities of tamoxifen and vitamin A analogs, as well as for response. RESULTS: There were no significant adverse effects on renal, hepatic, hematologic, or lipid values. Nyctalopia, photophobia, cheilitis, and pruritus were not observed. Improvement or stabilization of disease occurred in 12 of 15 patients. CONCLUSION: We conclude that tamoxifen administered with fenretinide is nontoxic. Phase III trials of tamoxifen versus tamoxifen plus fenretinide are warranted.

Phase II trial of spirogermanium in advanced non-small cell lung cancer. An Illinois Cancer Council Study.

A phase II trial of spirogermanium was conducted in advanced previously untreated non-small cell lung cancer patients. The drug was given by intravenous infusion 3 times per week for 2 weeks, twice per week for the next 2 weeks, and then weekly. Starting dose was 125 mg/m2, and dose escalation of 25 mg/m2 per week was required in the absence of toxicity to a maximum dose of 200 mg/m2 per infusion. Fifteen eligible patients were treated, and no objective responses were seen. Primary toxicity was neurologic and reversible after withdrawal of the drug. We conclude that spirogermanium is not active against non-small cell lung cancer in the dosage used in this study.

Phase II trial of fludarabine phosphate in advanced renal cell carcinoma: an Illinois Cancer Council Study.

Fludarabine Phosphate (FP), the 2-fluoro, 5'phosphate derivative of adenosine arabinoside (ara-A), was studied in 18 patients with advanced renal cell carcinoma. These patients had measurable disease and had not received chemotherapy. FP was administered at a loading dose of 20 mg/m2 followed by a 48-hour infusion at 30 mg/m2/day given every 21 days. There were no complete or partial responses seen. Toxicity was mainly hematologic, with leukopenia most commonly observed. FP given in this manner had no activity in advanced renal cell carcinoma.

Primary culture of squamous head and neck cancer with and without 3T3 fibroblasts and effect of clinical tumor characteristics on growth in vitro.

Twenty-one tumors from patients with squamous cell carcinoma of the head and neck (SCC H/N) were cultured with and without 3T3 fibroblasts in order to determine whether, on the basis of improved tissue culture medium, 3T3 cells could be deleted without altering growth and cloning efficiency. Thirty-five additional primary SCC H/N specimens, cultured in the presence of 3T3 fibroblasts, were studied to assess the effect of tumor differentiation, site of primary tumor, and site of specimen procurement on growth. The authors conclude that 3T3 cells remain essential for optimal growth and cloning efficiency. Also, 3T3 cells improved the number of successful cultures by 33% to 100% depending on the plating density, and cloning efficiency was improved by 50% in the presence of 3T3 cells. Growth did not correlate with tumor differentiation or site of origin of the tumor specimen. Culture of specimens from the primary site resulted in growth significantly more frequently than culture of specimens obtained from metastatic neck nodes.