Serum levels of fibronectin and a fibronectin-like DNA-binding protein in patients with various diseases.

The levels of fibronectin and the fibronectin-like, malignant disease-associated DNA-binding protein (MAD-2) were determined in sera from patients with various diseases. The levels of both proteins were elevated in most serum samples from patients with various types of cancer and in some patients with nonmalignant diseases. The highest levels of these proteins were found in patients with carcinomas of the breast and lung. A subset of the lung cancer patients with small cell carcinoma had either normal or depressed marker levels. The levels of fibronectin and MAD-2 varied concordantly in the different patient populations studied, which suggests that the serum levels of the fragment are directly proportional to the total amount of fibronectin in the serum.

Response of plasma histaminase activity to heparin in normal subjects and in patients with small cell carcinoma of the lung.

Plasma histaminase (PH) activity only partially reflected the consistently high activity of histaminase in tumor tissue of patients with small cell carcinoma of the lung (SCC). To determine whether heparin might release histaminase from tumor tissue into the circulation as it does from some normal tissues, we studied the response of PH activity to small doses of heparin in 41 patients with SCC and in 57 normal subjects. In patients with SCC, the initial mean PH activity (2.0 U/m) was not different from that in normal subjects (1.7 U/ml). After heparin administration, the mean PH activity was no different between the 2 groups (patients with SCC, 3.1 U/ml; normal subjects, 3.5 U/ml). In both groups, the higher the initial PH activity, the greater the magnitude of the PH activity response to heparin. This relationship was linear (normal subjects, r = 0.88; patients with SCC, r = 0.91). However, in patients with SCC, the increase in post-heparin PH activity, as related to the basal levels, was significantly less than that in normal subjects (P less than 0.001 by analysis of covariance). The data suggested that heparin did not affect the release of histaminase from tumor tissue into plasma to the same degree as it promoted the enzyme's entry from normal tissue sources. The differences between the groups may enable us to differentiate between selected patients with SCC and normal subjects with borderline high PH activity values.

High-dose chemotherapy with reinfusion of purged autologous bone marrow following dose-intense induction as initial therapy for metastatic breast cancer.

We assessed the toxicity and efficacy of high-dose chemotherapy consolidation with reinfusion of purged autologous bone marrow in women with metastatic breast cancer responding to a dose-intense outpatient regimen. Thirty women with hormone-unresponsive metastatic breast cancer, previously untreated with adjuvant doxorubicin or with any chemotherapy for metastatic disease, were treated with cyclophosphamide, methotrexate, doxorubicin, fluorouracil, vincristine, and leucovorin for 16 weeks. Twenty-four patients responded to therapy; 8 showed a complete response, and 16 showed a partial response. These patients proceeded to the next phase of the protocol, ie, marrow harvest and treatment with 6000 mg/m2 cyclophosphamide and 800 mg/m2 thiotepa given over 4 days. Harvested marrow was purged with 100 micrograms/mL 4-hydroperoxycyclophosphamide, and all patients engrafted satisfactorily. The predominant side effects were myelosuppressive and gastrointestinal, and there were no deaths from toxic effects. Three of the 16 patients who showed a partial response after the outpatient phase of treatment achieved a complete response after high-dose therapy. The partial response seen in two more patients converted to a complete response at all sites except bone. The median time to disease progression for all patients in this study was 13 months, and the median survival was 22 months. Four of the original 30 patients remained without disease progression a median of 27 months from entry into the study. This study indicates that this dose-intense regimen can be safely administered, even with the use of purged marrow, with an acceptable toxicity profile. This approach results in a high response rate in women with metastatic breast cancer and could form the basis for a regimen to be tested in the high-risk adjuvant setting.

Deletion of 3(p14p23) in secondary erythroleukemia arising in long-term survivors of small cell lung cancer.

Cytogenetic studies were done on the leukemia cells of two patients with small cell lung cancer (SCLC) who developed erythroleukemia (acute nonlymphocytic leukemia, French-American-British M6) after combined modality chemotherapy and radiotherapy for their lung cancer. Surprisingly, both erythroleukemias exhibited the del(3)(p14p23) predominantly found in SCLC. In four other patients who had secondary erythroleukemias associated with other cancers, no deletions of 3p were found. These findings could be accounted for by one of three possible mechanisms: (a) an inherited recessive gene (anti-oncogene or tumor suppressor gene) in this region of 3p was uncovered by the combined modality therapy, (b) an inherited predisposition to damage of both chromosomes at 3p14 leads to SCLC and erythroleukemia after exposure to carcinogens and/or chemotherapy-radiotherapy, or (c) the finding of lineage specificity for the 3p deletion with the presence of the 3p deletion in SCLC and erythroleukemia suggests a common bone marrow precursor.

Justification for evaluating new anticancer drugs in selected untreated patients with extensive-stage small-cell lung cancer: an Eastern Cooperative Oncology Group randomized study.

BACKGROUND: Studies have shown that response to a given chemotherapy in previously untreated patients with extensive-stage small-cell lung cancer is superior to that in patients previously treated with other regimens. This finding raises the question of whether it is necessary and ethical to study the effects of new anticancer agents in untreated patients. Such studies appear to be the best test for drug development, but there has been no evaluation of whether survival of untreated patients, whose cancer is sensitive to established drugs, is adversely affected in trials of new drugs. PURPOSE: This randomized study of untreated patients with extensive-stage small-cell lung cancer was designed (a) to compare the survival of patients treated with either effective standard chemotherapy or an investigational anticancer drug as initial therapy and (b) to evaluate response rates and toxic effects of such therapies. METHODS: Eighty-six patients were randomly assigned to receive, as initial therapy, either the standard CAV regimen--cyclophosphamide (1000 mg/m2), doxorubicin (50 mg/m2), and vincristine (1.4 mg/m2) every 3 weeks--or the phase II drug menogaril (200 mg/m2) every 4 weeks. Treatment after induction therapy varied, depending on patient response, but nonresponders and those with disease progression received salvage chemotherapy--etoposide (120 mg/m2 on days 1, 2, and 3) and cisplatin (60 mg/m2 on day 1), repeated every 3 weeks. RESULTS: Of the 43 patients on CAV, 42% responded (eight complete responses and 10 partial responses); 5% of the 43 on menogaril responded (two partial responses) (P = .0001). Twelve (22%) of 54 patients responded to salvage chemotherapy (five complete responses and seven partial responses). Within 3 months from start of treatment, twelve patients died--3 patients in the CAV group and nine patients in the menogaril group (P = .12). The estimated median survival was 37 weeks with menogaril and 45 weeks with CAV (P = .28). At 6 months, survival was 76.7% for the CAV group and 67.4% for the menogaril group. At 12 months, survival rates were 24.4% and 27.9%, respectively. Confidence intervals (95%) for the differences between the proportions surviving in the two groups were -9%-28% at 6 months and -25%-14% at 12 months. Use of CAV resulted in significantly higher occurrence of severe and life-threatening treatment-related complications (P = .002). CONCLUSION: The confidence intervals for the differences in survival are too wide to conclude that evaluation of a new drug in untreated patients with extensive-stage small-cell lung cancer is or is not harmful. The data do suggest, however, that use of this study design may have no adverse effect on survival.

Sixteen-week dose-intense chemotherapy in the adjuvant treatment of breast cancer.

Fifty-three women with breast cancer were treated with a new 16-week dose-intense, chemotherapy regimen. Patients with operable breast cancer with 10 or more histologically positive axillary nodes were treated with this five-drug regimen that incorporated the concepts of weekly chemotherapy, sequential administration of antimetabolites, and continuous infusion of fluorouracil (5-FU). The chemotherapy regimen consisted of eight cycles (each of 2 wk duration) of 100 mg of cyclophosphamide/m2 orally on days 1-7, 40 mg of doxorubicin/m2 intravenous (IV) on day 1, 100 mg of methotrexate/m2 IV on day 1 with 10 mg of leucovorin rescue/m2 every 6 hours for six oral doses on day 2, 1 mg of vincristine IV on day 1, and 600 mg of 5-FU/m2 IV at hour 20 over 2 hours. A continuous infusion of 300 mg of 5-FU/m2 per day was given IV on days 8-9 of each 2-week cycle. The doses and schedule of drug administration were designed to minimize dosage reduction and treatment delay. At a median follow-up of 17 months, there have been eight relapses in the 53 patients. The actuarial 3-year disease-free survival is 80% (95% confidence interval, 62% to 90%). The major side effects were attributable to myelosuppression. Absolute neutrophil counts less than 250/microL were noted in 12 (23%) patients; seven patients (13%) required hospitalization for management of neutropenic fever. No treatment-related deaths occurred. Ninety-four percent of the planned doses were administered, and only 5% of the courses were delayed because of toxic reactions. The encouraging therapeutic data, manageable side effects, and our ability to deliver over 90% of the planned doses provide the rationale for a phase III comparison of this new dose-intense regimen and standard chemotherapy in patients with operable disease and positive axillary nodes.

Levels of hypoxia-inducible factor-1 alpha during breast carcinogenesis.

BACKGROUND: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases. In this report, we investigated whether the level of HIF-1 alpha is increased during carcinogenesis in breast tissue and is associated with other tumor biomarkers. METHODS: Paraffin-embedded clinical specimens from five pathologic stages of breast tumorigenesis and from normal breast tissue were used. HIF-1 alpha protein and the biomarkers vascular endothelial growth factor (VEGF), HER-2/neu, p53, Ki-67, and estrogen receptor (ER) were identified immunohistochemically, and microvessel density (a measure of angiogenesis) was determined. Associations among levels of HIF-1 alpha and these biomarkers were tested statistically. All statistical tests are two-sided. RESULTS: The frequency of HIF-1 alpha-positive cells in a specimen increased with the specimen's pathologic stage (P<.001, chi(2) test for trend) as follows: normal breast tissue (0 specimens with > or = 1% HIF-1 alpha-positive cells in 10 specimens tested), ductal hyperplastic lesions (0 in 10), well-differentiated ductal carcinomas in situ (DCIS) (11 in 20), well-differentiated invasive breast cancers (12 in 20), poorly differentiated DCIS (17 in 20), and poorly differentiated invasive carcinomas (20 in 20). Increased levels of HIF-1 alpha were statistically significantly associated with high proliferation and increased expression of VEGF and ER proteins. In DCIS lesions, increased levels of HIF-1 alpha were statistically significantly associated with increased microvessel density. HIF-1alpha showed a borderline association with HER-2/neu but no association with p53. CONCLUSIONS: The level of HIF-1 alpha increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1 alpha are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1 alpha are potentially associated with more aggressive tumors.

Predictive value of regression rates following chemotherapy of small cell carcinoma of the lung.

Tumor volumes measured at the time of initial therapy, during the 28 days following treatment, and following subsequent courses of therapy for 29 patients with small cell carcinoma of the lung were determined from serially measurable roentgenographic lesions. Tumor-halving times were calculated following initial therapy, and the proportions of pretreatment tumor volumes were evaluated within 28 days after initial therapy for 26 patients. Pretreatment tumor volumes ranged from 22.5 to 485 cu cm, with a median of 87 cu cm, a log mean of 83 cu cm, and a linear mean of 113 cu cm. The tumor-halving times ranged from 4 to 86 days, with a median of 12 days, a log mean of 12 days, and a linear mean of 16 days. The reduction of tumor volume expressed as a proportion of pretreatment volume following therapy ranged between 0.02 and 0.65, with a median value of 0.22, a log mean of 0.18, and a linear mean of 0.26. Using the linear mean of 0.26 as a discriminant for survival analysis, patients with less than 0.26 had a median duration of survival of 12 months, which was significantly longer (p = 0.035) than the median survival of 8 months for patients with greater than 0.26. Tumor-halving time of 16 days was also able to separate the survival durations of 12 months of those less than 16 days compared to 8 months for greater than 16 days (p = 0.0429). Tumor regression rate, determined from two consecutive tumor volume measurements, was correlated with the tumor volume (r = 0.677; p less than 0.0001); and volume dependency of the tumor regression rate, as specified in Gompertzian kinetics, was demonstrated.

Successful treatment with DL-alpha-difluoromethylornithine in established human small cell variant lung carcinoma implants in athymic mice.

We report that p.o. administration of DL-alpha-difluoromethylornithine (DFMO), a specific inhibitor of polyamine biosynthesis, markedly inhibits the growth of established implants of cultured human small cell lung carcinoma (SCC) in athymic (nude) mice. Human SCC tumor cells, from a cell line which exhibited cell death in culture in the presence of DFMO, were inoculated s.c. into athymic mice. The tumors were permitted to grow until they became palpable (0.05 cu cm, 3- to 5-mm-diameter nodules). The animals were then randomized into control, and early (low tumor burden) and late (high tumor burden) treatment groups which received 3% DFMO in the drinking water (5.0 g/kg/day). The tumors in the untreated control group grew to a size of 29 cu cm by 9 weeks, and these animals had a median survival of 9 weeks. The late treatment group began DFMO treatment 3 weeks after clinical tumor engraftment, when mean tumor size was 1.5 cu cm (1.2- to 1.5-cm-diameter nodules). Tumor growth was inhibited by 60% (11.4 cu cm) by Week 9 and survival was prolonged, with 83% survival at 10 weeks and a 56% increase in median survival to 14 weeks (p less than 0.05). The early treatment group received the same dose of DFMO beginning 1 week after tumor engraftment, when their mean tumor size was 0.1 cu cm (4- to 6-mm-diameter nodules). The early DFMO group had a 99% inhibition in tumor growth (0.3 cu cm) (p less than 0.05). Survival was also prolonged compared to the untreated controls, with 83% survival at 10 weeks and a median survival of 15 weeks (p less than 0.05). In both the early- and late-DFMO-treatment groups, no significant clinical toxicities were observed in the first 10 weeks, during which antitumor therapeutic effects were seen. DFMO may have a potential role in the treatment of sensitive human tumors such as SCC. The data suggest that DFMO may be most useful clinically in patients with SCC who have a low tumor burden. Thus, DFMO might be an important tool to produce long-term maintenance of initial clinical remissions induced by combination chemotherapy.

Long-term maintenance therapy of established human small cell variant lung carcinoma implants in athymic mice with a cyclic regimen of difluoromethylornithine.

We report that cyclic p.o. administration of alpha-difluoromethylornithine (DFMO), an inhibitor of polyamine biosynthesis, is an effective long-term (1-year) maintenance therapy for established implants of cultured human small cell lung carcinoma in athymic (nude) mice. Human small cell lung carcinoma cells, from a line which exhibited cell death in culture in the presence of DFMO, were inoculated into athymic mice and permitted to grow to palpable tumors (3-5-mm nodules with mean volume of 0.04 cm3). The animals were then randomized into untreated, continuous treatment and cyclic (3 weeks of 4 beginning 1 week after 8 weeks continuous) treatment groups. Treatment consisted of 3% DFMO in the drinking water (5.1 g/kg/day). The tumors in the untreated group grew to 27 cm3 by 8 weeks and the animals had a median survival of 7.6 weeks. Tumor growth was inhibited by 99% (0.3 cm3) in the continuous treatment group in comparison to untreated controls. Survival was prolonged with 93% survival at 10 weeks and a 101% increase in median survival to 15.3 weeks (P less than 0.05). The cyclic DFMO group had a 98.3% inhibition in tumor growth for longer than 1 year (0.56 cm3; P less than 0.05). Survival was also markedly prolonged compared to the untreated group with 100% survival up to 24 weeks and a median survival of 54.3 weeks (P less than 0.05). No significant toxicities were observed in the first 10 weeks of DFMO treatment even though antitumor effects were observed. With continuous DFMO treatment, the animals eventually became debilitated and developed marked weight loss and thrombocytopenia; by 20 weeks, mortality was 79%. With cyclic therapy, the animals resumed weight gain, recovered from thrombocytopenia and, at 20 weeks, had 0% mortality. By 55 weeks, mortality was 50% which, however, was not significantly different (P approximately 0.50) from mortality of a control group of nontumorous, athymic mice that had weekly body weight and skin fold measurements concurrently with the experimental, tumor-bearing animals. Thus, the observed mortality is ascribable to continuous encroachment on the normally sterile environment. These data suggest a role for DFMO in long-term therapy of sensitive human tumors such as small cell lung carcinoma, especially in patients with a low tumor burden. Furthermore, a cyclic regimen might be an important tool in maintaining clinical remissions induced by conventional combination chemotherapy.

Carcinoembryonic antigen for monitoring patients with small cell carcinoma of the lung during treatment.

Carcinoembryonic antigen (CEA) was measured at specific intervals in the plasma of 56 patients with small cell carcinoma of the lung. Of these patients, 47 had serial analyses for varying periods during their illness, 42 had pretreatment CEA levels, and 17 of the latter patients had determinations throughout the entire course of their disease. Pretreatment CEA levels were elevated above 2.5 ng/ml for 74% of the 42 patients and above 5.0 ng/ml for 48%. Although exceptions were noted, in general, a direct relationship was found between pretreatment CEA levels and extent of disease or tumor burden. Initial stage of disease, however, was more predictive of survival than was the pretreatment CEA level. With response to therapy, a corresponding decrease in CEA levels occurred for patients with an elevated pretreatment level. For those patients with a pretreatment CEA level below 5.0 ng/ml, an immediate slight increase in level was often seen associated with response and followed by a subsequent fall after one month. A rising CEA level was usually found with recurrence or progression of disease after initial response and occurred frequently prior to clinical evidence of progression. In combination with careful clinical evaluation, serial CEA measurements can aid in assessing tumor changes associated with treatment in patients with small cell carcinoma of the lung particularly at the times of recurrence or disease progression following a partial or complete response.

Activities of L-dopa decarboxylase and diamine oxidase (histaminase) in human lung cancers and decarboxylase as a marker for small (oat) cell cancer in cell culture.

The neuroendocrine [amine precursor uptake (decarboxylase)] properties of small (oat) cell lung cancer (SCC) have suggested that this neoplasm may have a separate histogensis from the other major types of human lung tumors. We now report that a key element of this concept, L-dopa decarboxylase activity, is present in surgical and autopsy tissues from all forms of lung cancer. Values are highest in SCC lesions; however, lung adenocarcinoma tissues can have considerable activity, and values overlap those for SCC and fall between values for SCC and large cell and squamous cell carcinoma. The distribution of diamine oxidase activity is identical except that even more overlap occurs between the major tumor types. These data may provide further evidence that SCC and other human lung cancers could share a common origin in the bronchial mucosa. In cell cuture, the distribution of the two enzyme activities is different. The average L-dopa decarboxylase activity is much higher (seven separate culture lines) than in the in vivo specimens, and it completely separates these cell lines from non-SCC lung tumors (four lines). Diamine oxidase is generally low in both SCC cells and non-SCC cells in culture and does not separate the various cell types. L-Dopa decarboxylase activity thus does appear to be a valuabe marker for separating SCC cells from other lung cancer cells in vitro.

Phase I and pharmacokinetic study of brequinar sodium (NSC 368390).

Brequinar sodium is a quinoline carboxylic acid derivative that has shown antitumor activity in a number of in vivo murine and human tumor xenograft models. Its mechanism of action is blockade of de novo pyrimidine biosynthesis by inhibition of dihydroorotic acid dehydrogenase. In vitro and in vivo studies demonstrate the superiority of prolonged drug exposure in achieving tumor growth inhibition. This phase I study evaluated the administration of brequinar sodium by short, daily i.v. infusion for 5 days repeated every 4 weeks. Fifty-four subjects were enrolled in the study and received drug in doses ranging from 36-300 mg/m2. The dose-limiting toxicities were mucositis and diffuse skin rash. Other toxicities included myelosuppression, nausea, vomiting, malaise, and burning at the infusion site. The maximum tolerated dose on the "daily times 5" schedule was 300 mg/m2. The recommended phase II dose is 250 mg/m2. Pharmacokinetic analysis of the day 1 drug clearance curves in 51 subjects showed slight nonlinearity in the relationship between dose and area under the clearance curve (AUC). The dose versus AUC relationship was well described using a Michaelis-Menten model of brequinar elimination kinetics with Vmax = 45 (micrograms/ml)/h and Km = 123 micrograms. Analysis of the day 5 drug clearance curves revealed a diminution in Vmax to 30 (micrograms/ml)/h. As a consequence of the reduction in Vmax brequinar plasma concentrations on day 5 were higher than predicted from day 1 drug kinetics. Pharmacodynamic analysis of the day 1 kinetic parameters and the toxicities occurring during the first cycle of drug therapy revealed significant correlations between mucositis and dose, AUC, and peak brequinar concentration; between leukopenia and AUC and peak drug concentration; and between thrombocytopenia and beta elimination rate.

Doctor-patient communication about breast cancer adjuvant therapy.

Candidates for breast cancer adjuvant therapy must not only grapple with the concept of micrometastatic disease, but often must consider the benefits and risks of clinical trials and alternatives. We studied 100 consecutive patient-physician encounters about adjuvant therapy to determine how well we informed patients about benefits and risks and how clearly we recommended treatment. Evaluation included observation and audiorecording of encounters, patient- and physician-completed questionnaires, and patient interviews. Patient-physician agreement on the benefits and risks of adjuvant therapy was poor. Sixty percent of patients overestimated their chance of cure by 20% or more compared with the physician. Poor agreement was partially explained by the observation that patients and physicians exchanged little specific information. Furthermore, decision-making was compressed. Although this was the first meeting with a medical oncologist for 79 patients (79%), 82 (82%) made final decisions about treatment by the end of the meeting. Physicians clearly identified their recommended treatment. Patients generally followed the physician's recommendation, except when clinical trials were recommended. Only 45% of trial-eligible patients chose to participate in offered trials. Physician recommendations of clinical trials were not as effectively communicated as nontrial treatments. Nonstandard adjuvant regimens, similar to the experimental arm of some ongoing randomized trials, were recommended to 30% of patients, especially those with a poor prognosis. In essence, physicians acted as if the trial question was answered, thereby diminishing enthusiasm for the trial. The widespread recommendation of nonstandard regimens similar or identical to the experimental arms in ongoing trials suggests a serious lack of consensus on what questions to ask in clinical trials and whether or not those questions have been answered.

Anxiety levels in patients randomized to adjuvant therapy versus observation for early breast cancer.

We studied anxiety levels in 68 patients who had been randomized to adjuvant chemotherapy v observation on two Eastern Cooperative Oncology Group (ECOG) protocols. All subjects were women who had undergone total or modified radical mastectomy for breast cancer. Immediately before breast protocol randomization and again 3, 6, and 12 months later, patients completed two self-report measures: the State-Trait Anxiety Inventory and the SCL-90. There were no consistent trends in anxiety levels over time. At each test point, patients under observation displayed higher anxiety scores than did patients receiving adjuvant therapy, but these differences failed to attain statistical significance. Power calculations indicate that these results rule out the possibility of major differences in anxiety levels among patients randomized to observation v adjuvant therapy, but a larger patient sample is required before a definitive statement can be made about smaller differences.

Effect of patients' expectations of benefit with standard breast cancer adjuvant chemotherapy on participation in a randomized clinical trial: a clinical vignette study.

Patients frequently overestimate the benefit of standard breast cancer adjuvant therapy. This is due in part to vague doctor-patient communication. To examine how the doctor's description and patient's expectations of the benefit of standard therapy affect clinical trial participation, we randomized 282 female cancer patients to one of two versions of a clinical vignette describing a choice between standard cyclophosphamide, methotrexate, and fluorouracil (5FU) (CMF) and a randomized trial comparing CMF with cyclophosphamide, doxorubicin, and 5FU (CAF). The vignettes differed only on whether results with CMF were described verbally or numerically in terms of disease-free survival (DFS). After selecting CMF or the trial, patients estimated their 10-year DFS with CMF. Patients were randomized 3:1 to the verbal vignette. The trial was selected by 110 of 210 (52.4%) verbal vignette patients versus 25 of 72 (34.7%) numeric vignette patients (P = .01). Estimates of 10-year DFS with CMF varied considerably; many were inaccurate. When patients in the verbal vignette group were divided into thirds according to DFS estimate, 22 of 64 (34.4%) in the top third selected the trial versus 38 of 64 (59.4%) and 38 of 65 (58.5%) in the middle and bottom third, respectively (P = .005). Younger age, college education, and previous participation in a trial also predicted trial selection. Multivariate logistic regression suggested that the benefit expected from CMF was more important than how benefit was described in treatment selection. Assuring realistic patient expectations of standard adjuvant therapy benefit is likely to be important during discussion of clinical trials.

Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: an intergroup study.

PURPOSE: To compare 1 year of therapy with continuous cyclophosphamide, methotrexate, fluorouracil (5-FU), vincristine, and prednisone (CMFVP) with a short course of treatment with a doxorubicin-based regimen in the postsurgical adjuvant treatment of patients with hormone receptor-negative, node-positive breast cancer. PATIENTS AND METHODS: Five-hundred thirty-one eligible women with hormone receptor-negative, node-positive breast cancer were randomized to receive either 1 year of therapy with CMFVP or 20 weeks of therapy with four 5-week courses of treatment with 5-FU, doxorubicin, cyclophosphamide, and methotrexate (FAC-M). RESULTS: At a median follow-up time of 4.9 years, the two treatment arms cannot be demonstrated to be different with respect to overall survival (stratified log-rank, P = .27). The 5-year survival rate is 64% on the CMFVP arm and 61% on the FAC-M arm. CMFVP produces marginally superior disease-free survival (P = .06). The estimated 5-year disease-free survival rate is 55% for patients treated with CMFVP as opposed to 50% for patients treated with FAC-M. CONCLUSION: Neither regimen was shown to be superior in terms of overall survival. Because the disease-free survival produced by CMFVP is marginally superior to that produced by FAC-M, we do not recommend FAC-M for further investigation or for routine use. Possible implications of this study are discussed in the context of other adjuvant chemotherapy trials.

Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study.

PURPOSE: To determine whether the addition of surgical ovariectomy to standard chemotherapy prolongs disease-free survival (DFS) and overall survival in premenopausal patients with estrogen receptor (ER)-positive operable breast cancer with positive axillary nodes. PATIENTS AND METHODS: Three hundred fourteen premenopausal patients with ER-positive, node-positive breast cancer were enrolled between July 1979 and July 1989. Patients were stratified according to number of involved nodes and type of primary surgery and randomized to receive either of the following: (1) cyclophosphamide 60 mg/m2/d by mouth for 1 year, methotrexate 15 mg/m2 intravenously (i.v.) weekly for 1 year, fluorouracil (5-FU) 400 mg/m2 i.v. weekly for 1 year, vincristine .625 mg/m2 i.v. weekly for the first 10 weeks, and prednisone weeks 1 to 10 with doses decreasing from 30 mg/m2 to 2.5 mg/m2 (CMFVP); or (2) bilateral ovariectomy followed by CMFVP. RESULTS: The median follow-up time is 7.7 years and the maximum 13.2 years. Treatment arms are not significantly different with respect to either survival or DFS (one-sided log-rank, P = .55 and .70, respectively). The 7-year survival rate is 71% on the CMFVP arm and 73% on CMFVP plus ovariectomy. No significant differences were observed in node or receptor level subsets. CONCLUSION: We conclude that, in this study, the addition of ovariectomy did not improve results over chemotherapy alone in the treatment of premenopausal women with node-positive, ER-positive, operable breast cancer. Our sample size was too small to detect a small improvement. The death hazards ratio of CMFVP/CMFVP plus ovariectomy was 1.22 (95% confidence interval [CI], .79 to 1.89).

Phase II study of goserelin for patients with postmenopausal metastatic breast cancer.

PURPOSE: To determine the response rate of postmenopausal breast cancer patients to the gonadotropin-releasing hormone (GN-RH) agonist, Zoladex (goserelin; ICI Pharma, Wilmington, DE). PATIENTS AND METHODS: A multi-institutional single-agent trial in postmenopausal patients was conducted. Serum levels of follicle-stimulating hormone (FSH), testosterone, and estradiol were requested before and after Zoladex treatment. RESULTS: For estrogen receptor-positive (ER+) patients, the response rate was 11%, with one complete response (CR) and three partial responses (PRs) among 36 eligible patients. Responses were of short duration. There were no responses among 16 estrogen receptor-negative (ER-) patients. CONCLUSION: GN-RH agonists have activity in ER+ postmenopausal patients, but response rates are not as high as with other available endocrine therapies and the duration of response is short.

Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial.

PURPOSE: A randomized trial was performed in premenopausal postoperative women with ipsilateral axillary node-positive (N+) breast carcinoma and known estrogen receptor (ER) status to assess the efficacy of an Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH)-based induction regimen and 5 or more years of tamoxifen (Tam). PATIENTS AND METHODS: Patients received 12 28-day cycles of cyclophosphamide 100 mg/m2 orally days 1 to 14, methotrexate 40 mg/m2 intravenously (IV) days 1 and 8, fluorouracil 600 mg/m2 IV days 1 and 8, prednisone 40 mg/m2 orally days 1 to 14, and Tam 10 mg orally twice daily (CMFPT), or the same regimen plus halotestin 10 mg orally twice daily (CMFPTH) alternating monthly with 22-day cycles of vinblastine 4.5 mg/m2 IV day 1, Adriamycin 45 mg/m2 IV day 1, thiotepa 12 mg/m2 IV day 1, halotestin, and Tam (ALTER). Prednisone in the ALTER regimen was stopped after the second CMFPTH cycle. After 12 cycles, patients were again randomized to stop or continue Tam. After 5 years, patients on Tam were again randomized to continue or stop Tam; the results from this randomization are still coded. Among 533 analyzed induction cases, 263 received CMFPT and 270 ALTER. Among 396 analyzed maintenance cases, 201 continued Tam and 195 were observed. Pretreatment characteristics were balanced among treatments. The median follow-up times are 5.1 years for induction and 4.1 years for maintenance. RESULTS: The time to relapse (TTR) was superior for the ALTER regimen (P = .04) and for the maintenance Tam (P = .05). Overall survival comparisons between the regimens are not statistically different. A longer TTR was associated with decreasing nodal involvement, ER+ status, and increasing age. The favorable effects of decreasing nodal involvement and ER+ status carried over to survival; a progesterone receptor-positive (PgR+) status and decreasing tumor size were also associated with longer survival. Development of amenorrhea was associated with improved TTR and survival. Toxicity was similar for the two induction regimens and for the two maintenance regimens. Overall relapse patterns were similar among the induction regimens, but continuing Tam led to fewer locoregional relapses. CONCLUSION: The results suggest significant overall TTR therapeutic benefits of an Adriamycin-containing alternating induction regimen and of continuing maintenance Tam therapy for at least 5 years.