Therapy For Advanced Breast Cancer Research Articles

Effective initial therapy of advanced breast cancer with fluorouracil and high-dose, continuous infusion calcium leucovorin.

The use of leucovorin (LV) to modulate fluorouracil (FU)-mediated inhibition of thymidylate synthase has been shown both in vitro and in vivo to improve the antitumor activity of this drug. Based on our previous demonstration that this combination was active in heavily pretreated patients with prior FU exposure, we performed a phase II study of FU and high-dose intravenous calcium LV in patients with advanced breast cancer who had been exposed to no more than one prior chemotherapy regimen. Fifty-one female patients with metastatic breast cancer were entered onto this trial. Patients with metastatic disease limited to soft tissue, lymph nodes, skin, and pulmonary nodules were allowed no prior chemotherapy for advanced disease. Those with metastases in the liver or a lymphangitic pattern on chest x-ray were allowed either a single prior regimen for advanced disease or no therapy for metastatic disease if less than 1 year had elapsed since the completion of adjuvant chemotherapy. FU was given daily for 5 days at 400 mg/m2/d with calcium LV, 500 mg/m2/d, beginning 24 hours before and continuing 12 hours after the first and last FU doses, respectively. The overall objective response rate among 45 eligible patients was 36% (95% confidence interval, 22% to 51%). Fourteen of 31 patients in the soft tissue category responded (45%), and two of 14 in the visceral category experienced an objective response (14%). The median response duration was 5 months. Toxicities were moderate leukopenia and mucositis. FU plus LV is an active first-line regimen with antitumor efficacy comparable to that of the anthracyclines, which warrants further exploration in combination with other agents active in advanced breast cancer. FU plus LV in this schedule is also an excellent alternative for patients with medical contraindications to more intensive combination chemotherapy regimens.

Pharmacokinetics and pharmacodynamics of medroxyprogesterone acetate in advanced breast cancer patients.

Medroxyprogesterone acetate (MPA) is one of the major drugs used in endocrine therapy for advanced breast cancer. However, its optimal dose still has not been clearly established. Response to treatment and drug-related side effects were analyzed as a function of plasma MPA concentrations during prolonged MPA treatment. MPA plasma concentrations were measured (high-performance liquid chromatography [HPLC] assay) at steady state (Css min) in 129 patients (mean age, 63 years; range, 34 to 87) treated by MPA (86% were treated orally exclusively with daily doses ranging from 400 to 2,000 mg). A wide interpatient variability was noted in MPA Css min for the 70 patients who received 1,000 mg/d orally (median, 51 ng/mL; range, 10 to 269 ng/mL). Intrapatient analysis of the evolution of MPA Css min during prolonged treatment showed relative stability of MPA concentrations (mean CV, 20.6%). A weak but significant correlation was demonstrated between oral doses and MPA Css min (P = .016). Thirty-five percent of patients (45 of 129) developed MPA-related side effects that were associated with the highest plasma MPA concentrations; medians were 81 and 32 ng/mL for toxic and nontoxic treatments, respectively (P less than .001). Objective response was assessable in 55 patients who were treated by MPA exclusively. Plasma MPA concentrations were significantly different (P = .025) between patients with progressive disease (PD) (median, 46 ng/mL) and those with complete response (CR), partial response (PR), or stable disease (SD) (median 65 ng/mL). Comparison of CR plus PR versus SD versus PD showed only a tendency toward significant differences in MPA Css min (P = .07). Analysis of toxicity and response as a function of the oral dose did not show any significant relationship. These data suggested an optimal therapeutic window for MPA Css min located within 50 to 70 ng/mL. This study demonstrates that plasma MPA concentration, as opposed to the administered dose, is a determining factor for toxicity and response therapy [corrected].

Endocrine therapy for advanced breast cancer: a review.

More than 45,000 women will die of metastatic breast cancer in the United States in 1991. Endocrine therapy remains a major option for treatment of such patients, and results in complete plus partial response rates of 30% with a median duration of approximately one year. Postmenopausal status, increased age, a prolonged disease-free interval, bone and soft tissue metastases, and positive estrogen and progesterone receptors are all associated with an increased response to endocrine therapy. The use of additive hormonal therapy, specifically antiestrogens, progestins, and aromatase inhibitors, have replaced surgical ablative procedures in the majority of patients; response rates to antiestrogen therapy, progestin therapy, and aromatase inhibitors are similar, but antiestrogens have generally been associated with the most favorable therapeutic index. At present, there is no convincing evidence that either combinations of endocrine therapies or endocrine therapy combined with chemotherapy are associated with an improvement in survival for patients with metastatic disease. Future research efforts directed at defining the molecular mechanisms of endocrine activity should facilitate clinical trials of newer and potentially more effective agents. All patients with metastatic breast cancer should be considered for at least one trial of endocrine therapy provided their metastatic disease is not rapidly progressive or life-threatening.

Current controversies in the endocrine therapy of advanced breast cancer.

The response of breast cancer to endocrine therapy depends on depriving the tumor cells of estrogen stimulation of cell division. This may be achieved by blocking estrogen synthesis in the body, using inhibitors of aromatase or by using drugs like tamoxifen, which interfere with the direct effects of estrogen on tumor cells. Current controversies relate to the mechanism for achieving more effective inhibition of estrogen synthesis and for the use of more specific antiestrogenic drugs.

Recent Advances in Hormonal Therapy in Cancer. Symposium proceedings. Amsterdam, The Netherlands, September 15, 1991.

Recent Advances in Hormonal Therapy in Cancer. Symposium proceedings. Amsterdam, The Netherlands, September 15, 1991.

A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer.

One hundred forty-one patients with advanced breast cancer who had not received prior chemotherapy were randomly assigned to receive doxorubicin 60 mg/m2 or epirubicin 90 mg/m2 every 3 weeks. These doses were selected to produce equivalent toxicities. All patients were assessed for toxicity, and 138 patients were assessable for response. After a median of five treatment cycles, 47% (32 of 68) of doxorubicin-treated patients achieved a partial or complete response. Response duration and survival were 10 and 12 months for doxorubicin and 8 and 10 months for epirubicin, respectively. Noncardiac toxicities were similar for both drugs. Of 41 patients receiving doxorubicin who had serial left ventricular ejection fraction assessments, seven sustained a fall of 10% or more, and one patient developed congestive cardiac failure at a cumulative doxorubicin dose of 489 mg/m2. Of 39 patients receiving epirubicin who had serial cardiac assessments, five sustained left ventricular ejection fraction falls of 10% or more and two patients developed congestive cardiac failure at cumulative doses of 178 mg/m2 and 833 mg/m2. These data indicate that an epirubicin dose of 90 mg/m2 produces toxicity equivalent to doxorubicin 60 mg/m2 but does not improve response rates, response duration, or survival in advanced breast cancer.

Weekly Epirubicin Versus Doxorubicin as Second Line Therapy in Advanced Breast Cancer A Randomized Clinical Trial

Forty-nine patients with advanced breast cancer who had failed from first-line cyclophosphamide, methotrexate, and 5-fluorouracil (CMF regimen) chemotherapy, were randomized to treatment with either epirubicin (Epi) or doxorubicin (Dox) at a dose of 20 mg/m2 given intravenously (i.v.) weekly to compare the efficacy and toxicity of these two anthracyclines given in such a schedule. Of 43 evaluable patients 36% (eight of 22) treated with Epi and 38% (eight of 21) treated with Dox achieved a complete plus partial response rate (95% confidence limits 16-56% +/- 20% and 18-58% +/- 20%, respectively). Patients who obtained a major therapeutic response to previous CMF exhibited a significantly higher response rate with both the drugs: seven of eight (87.5%) compared with one of 13 (8%); p less than 0.05 for Epi and six of seven (86%) compared with two of 15 (13%); p less than 0.05 for Dox. The median duration of response was 4.5 months with Epi compared with 7 months with Dox, and the median survival of the two groups of patients were superimposable (12 months with Epi versus 11 months with Dox). The median cumulative dose was 220 mg/m2 (range 160-620) and 240 mg/m2 (range 160-860) for Epi and Dox, respectively. Gastrointestinal and hematological toxicities were moderate for both the drugs, with fewer episodes of nausea and vomiting, stomatitis, and leukopenia following Epi administration. A very low incidence of alopecia was recorded for both the drugs. Regarding cardiac evaluation, no significant differences were evident; however, the only case that developed symptomatic congestive heart failure was in the Dox arm, after a cumulative dose of 820 mg/m2 at 11.5 months. Epi given weekly at low doses preserves efficacy in the treatment of patients with advanced breast cancer, and given at equimolar doses, has a slightly better therapeutic index than the parent compound.

High-Dose Medroxyprogesterone Acetate versus Oophorectomy as First-Line Therapy of Advanced Breast Cancer in Premenopausal Patients

Forty premenopausal patients with advanced breast cancer entered a prospective and randomized study in which high-dose medroxyprogesterone acetate (HD MAP) and oophorectomy (OPX) were compared. All the patients were first treated for advanced disease. Twenty-two patients received HD MAP (1,000 mg b.i.d. p.o.) and 18 patients received OPX. Complete remission (CR) was achieved in 2 (9%) in the HD MAP group and in 2 (11%) in the OPX group for a duration of 20-24 and 30-54 months respectively. Partial remission (PR) was achieved in 10 (45%) patients in the HD MAP group and in 4 (22%) patients in the OPX group for a median duration of 9 and 7 months respectively. The objective response rates (CR + PR) were 55% for the HD MAP group and 33% for the OPX group (p = 0.17). Ten patients who received OPX as first-line treatment received HD MAP when the disease progressed and were evaluable for response: PR was achieved in 6 patients (2 responders and 4 nonresponders to OPX) for a median duration of 5 months. Two out of 4 patients who received OPX at progression after objective response to HD MAP presented PR. HD MAP induced a significant decrease in pain intensity and, compared to OPX, a more frequent improvement was induced in performance status. No difference was observed between the two groups in terms of overall survival. This study shows that HD MAP is an active treatment in premenopausal patients with advanced breast cancer and that it can induce a response in some patients resistant to OPX.

Overview of hormonal therapy in advanced breast cancer.

Hormonal therapy of breast cancer is widely used and effective. Although never curative in advanced disease, significant palliation and durable remissions can be obtained with a wide variety of hormonal manipulations. Historically, surgical ablation was used to reduce endogenous hormone levels, but this invasive procedure has been largely supplanted by drugs that reduce hormone secretion or block steroid hormone activity. A number of such antagonists are available, with tamoxifen probably the most widely used. Response can also be achieved with hormone agonists. Estrogens and androgens or their congeners have about the same level of activity as surgical ablation or drug antagonists (20% to 30% overall response rate). The progestins, another class of agonists, are also effective in the palliation of advanced breast cancer. Megestrol acetate, in part because of its oral formulation, is probably the most commonly used progestational drug for the treatment of breast cancer. Reports of 16 trials involving 1,342 patients show a response rate of 26% in patients with advanced breast cancer treated with megestrol acetate. The drug has proved active in a small number of male patients and, in randomized trials, it has been shown to be comparable with tamoxifen in efficacy (30% response for megestrol acetate v 35% for tamoxifen). Studies are currently under way to evaluate the possibility that high doses of megestrol acetate may increase response rates, and to determine whether weight gain, a well-described effect of this drug, may prove beneficial in cancer treatment.

Endocrine Pharmacology of Antiestrogens as Antitumor Agents*

I. Introduction IN 1958, Lerner and co-workers (1) described the biological properties of the first nonsteroidal antiestrogen MER25 (see Fig. 1). The discovery of this new class of drugs opened up a variety of clinical possibilities (2, 3), but early studies were terminated because of toxic side effects. Another member of this new class of drugs, clomiphene (then known as chloramiphene or MRL41), held the promise of being a potential antifertility agent (4); however, clinical studies demonstrated that ovulation was induced (5). The drug is now available as a profertility agent in subfertile women (6). During the 1960s a range of antiestrogens was synthesized by the pharmaceutical industry for potential applications in gynecology (7, 8). In the main though, these agents were used only to study reproductive endocrinology in the laboratory. However the focus of clinical application slowly changed from the broad market of contraception to the relatively small market of advanced breast cancer therapy.

Opposite effects of estrogen and the progestin R5020 on cell proliferation and GCDFP-15 expression in ZR-75-1 human breast cancer cells

We have recently demonstrated that physiological concentrations of androgens cause a marked inhibition of basal and 17β-estradiol (E 2)-induced cell growth in ZR-75-1 human breast cancer cells. Moreover, these steroids exert effects on GCDFP-15 (gross cystic disease fluid protein-15) expression that are opposite to their above-indicated actions on cell proliferation. The synthetic progestin R5020 (17,21-dimethyl-19-nor-4,9-pregnadiene-3,20-dione), on the other hand, causes a potent inhibition of E 2-induced ZR-75-1 cell growth. In order to further characterize the hormonal regulation of GCDFP-15 expression and to better understand the antagonism between progestin and estrogen action in breast cancer cells, we have studied the effect of R5020 on both GCDFP-15 expression and cell growth in ZR-75-1 cells. After a 10-day incubation, the 4-fold stimulatory effect of 1 nM E 2 on cell growth was 60% decreased by maximal effective concentrations of R5020 (> 1 nM) while, in the absence of E 2, R5020 had no effect. The mitogenic action of E 2 was accompanied by a 75% inhibition of GCDFP-15 secretion while nanomolar concentrations of R5020 induced 1.4- and 5.2-fold increases in GCDFP-15 secretion in control and E 2-treated ZR-75-1 cells, respectively. While E 2 caused a marked inhibition of GCDFP-15 mRNA levels, R5020 induced a maximal 2- to 3-fold increase (above control) in GCDFP-15 mRNA accumulation in cells simultaneously incubated with E 2. In the presence of E 2, the effect of R5020 on cell growth and GCDFP-15 secretion was 70–90% blocked by concomitant exposure to the antihormone RU486 while simultaneous exposure to the pure antiandrogen OH-flutamide exerted a small but significant interference with the antiestrogenic effect of R5020 on these two parameters. The present data show that in the presence of E 2, R5020 exerts a potent stimulatory effect on GCDFP-15 expression which is primarily mediated through specific interaction with the progesterone receptor with a minor role of the androgen receptor. In analogy with our previous observations with androgens and estrogens, the effects of the progestin R5020 on GCDFP-15 expression are opposite to their action on cell growth. Such data also suggest that the glycoprotein GCDFP-15 could well be a good biochemical marker to follow the response to androgens and/or progestins as well as antiestrogens in the therapy of advanced breast cancer.

Regulation of Progesterone-Binding Breast Cyst Protein GCDFP-24 Secretion by Estrogens and Androgens in Human Breast Cancer Cells: A New Marker of Steroid Action in Breast Cancer*

We have previously demonstrated that androgens are potent inhibitors of breast cancer cell proliferation under both basal and estrogen-induced incubation conditions, while they suppress expression of the estrogen and progesterone receptors. To better understand the mechanisms responsible for the antagonism between androgens and estrogens in breast cancer and to obtain a new tumor marker for the actions of these two steroids, we have investigated the effects of androgens and estrogens on expression of the major protein found in human breast gross cystic disease fluid, namely GCDFP-24. This study was performed in ZR-75-1 and MCF-7 human breast cancer cells. After a 9-day incubation period, physiological concentrations of 17 beta-estradiol stimulated proliferation of ZR-75-1 and MCF-7 cells by 2- to 3.5-fold while simultaneously exerting a marked 70-90% inhibition of GCDFP-24 secretion. The estrogenic effects on GCDFP-24 secretion and cell proliferation were both competitively blocked by simultaneous incubation with the new steroidal pure antiestrogen EM-139. On the other hand, a maximal concentration (10 nM) of the nonaromatizable androgen dihydrotestosterone decreased by 50% the proliferation of ZR-75-1 cells; the half-maximal inhibitory effect was exerted at 0.01 nM. The androgen exerted a 3- to 4-fold stimulatory effect on GCDFP-24 secretion at an EC50 value of 0.01 nM. The effect of dihydrotestosterone on these parameters was competitively blocked by simultaneous incubation with the pure antiandrogen OH-flutamide. The present data show that the effects of estrogens and androgens in ZR-75-1 cells on GCDFP-24 secretion and cell growth are opposite. Similarly, in MCF-7 cells, estrogens stimulate cell growth, while GCDFP-24 secretion is inhibited. The present data also suggest that GCDFP-24 could well be a good biochemical marker for monitoring the response to androgenic and antiestrogenic compounds in the therapy of advanced breast cancer.

Experience of the Belgian Society of Medical Oncology with single-administration 5 g/m2 ifosfamide with mesna as second- or third-line therapy in advanced breast cancer

In an ongoing phase II trial conducted in advanced breast cancer, we tested a therapy schedule consisting of continuous, 24-h infusion of 5 g/m2 ifosfamide (IFO) in 3 1 dextrose saline with mesna (MSN), repeated every 3 weeks until disease progression. Since September 1988, 16 heavily pretreated patients with advanced disease (11 with visceral lesions) considered refractory to standard chemotherapy (regimens always including cyclophosphamide) have been included. Objective partial remissions were observed in two cases (one in liver and one in soft-tissue and pleural lesions), and disease stabilization for at least 3 months occurred in four cases. No treatment-related death was recorded and tolerance was judged to be excellent (six cases) or acceptable in all instances. The haematological toxicity consisted mainly of transient leucopenia (nadirs evaluated by WHO scale as grade 3 in 43% and grade 4 in 29%), sometimes associated with thrombocytopenia (grade 3 in 7% and grade 4 in 7%). Other side effects included nausea and/or vomiting (grade 3-4 in 33%); worsening of preexisting alopecia (five cases); haemorrhagic cystitis (one case); mild, transient somnolence (two cases); and moderate fluid retention (two cases). We concluded that infusion of 5 g/m2 IFO over 24 h with MSN rescue might represent an acceptable second- or third-line salvage regimen. Close monitoring of haematological and renal function parameters is recommended. A larger number of patients will be treated in a continuation of this study to evaluate the true response rate within narrower confidence limits.

A phase II trial of mitomycin C and 5-fluorouracil as second-line therapy in advanced breast cancer

Fifty-five patients who had relapsed or progressed from chemotherapy for advanced disease were treated with mitomycin C and 5-FU on a 6 weekly regimen. After a median of 2 cycles of therapy the overall response rate was 12% with no complete responses. Significant leucopenia but no thrombocytopenia was seen and despite the low overall response rate the regimen was tolerable and did produce responses in patients primarily resistant to Adriamycin combination chemotherapy. Low overall activity indicates the need for more effective second line treatment.

Ifosfamide/etoposide and mesna uroprotection in advanced breast cancer

The object of the study was to evaluate the effectiveness of ifosfamide/etoposide and mesna therapy in advanced breast cancer. A total of 44 patients with breast cancer were included in the trial. Eligibility criteria included measurable, refractory disease; prior anthracycline therapy (or its contraindication); a life expectancy of at least 3 months; and adequate hepatic, renal, CNS and bone marrow function. All patients were less than or equal to 70 years of age and had a Karnofsky performance status of greater than or equal to 50%. There were 36 evaluable cases. Sites of metastatic disease included bone (19), skin (18), liver (9), lung (14), lymph node (19), and miscellaneous (7). Treatment consisted of 1,500 mg/m2 ifosfamide given i.v. on days 1-5, 120 mg/m2 etoposide given i.v. on days 1-3, and 400 mg i.v. mesna given with and at 4 and 8 h after ifosfamide. Cycles were repeated every 28 days. Initial doses were reduced by 25% or 50% in patients who had previously undergone both chemotherapy and radiotherapy. A median of 4 cycles (range, 2-8) were given. The myelotoxicity was marked: WHO grades 3/4 leukopenia (n = 37), grades 3/4 thrombocytopenia (n = 12), and grades 2/3 anemia (n = 13). Due to myelotoxicity, dose reduction or prolongation of treatment-free intervals was necessary in 28 cases. Alopecia was seen in 35 patients and CNS toxicity, in 8. Partial remission (PR) was obtained in five cases and complete remission (CR), in three. Sites of response included the lung (5), skin (4), lymph node (5), and peritoneum (1). The duration of response was 4 (n = 2) and 8 (n = 1) months for CR and 2 (n = 2), 6 (n = 2), and 10 (n = 1) months for PR. We conclude that the ifosfamide/etoposide and mesna regimen is effective, but its myelotoxicity is treatment-limiting.

How to Improve Cytotoxic Therapy in Advanced Breast Cancer

The optimal cytotoxic treatment of patients with advanced breast cancer is so far not defined. Median survival after first metastatic manifestation is approximately 18 months. No direct evidence for a survival improvement after the introduction of cytotoxic therapy has been published. Major effects have been made to improve treatment efficacy through manipulations of doses, schedules and combinations of known cytotoxic drugs. Three months is probably too short a treatment period. Alternating non-cross resistant regimens offer no advantage over sequential therapy. A dose-response relationship clearly exists in breast cancer, but the higher response rates have not been transformed into a survival benefit. Treatment of advanced breast cancer is palliative, and if, furthermore, we have actually reached a plateau where no further improvement in survival is possible, we will have to evaluate every new treatment modality carefully according to quantity as well as quality of life.

Principles of Therapy in Advanced Breast Cancer

Advanced breast cancer represents a common clinical problem faced by medical oncologists, internists, surgeons, and radiation oncologists. The medical oncologist or internist is usually the patient's primary physician and is responsible for coordinating the multiple disciplines to optimize the therapeutic management. In the case of locally advanced (stage III) breast cancer, there are far fewer prospective clinical trials on which to base management decisions than are available in the metastatic disease setting. The primary cancer care physician's responsibility is particularly great for coordination of the multidisciplinary approach and integration of medical oncology, radiation oncology, and surgical treatment modalities, however. In the case of metastatic breast cancer, an understanding of the importance of certain clinical factors (that is, hormonal receptors, performance score, disease-free interval, sites and extent of metastasis, and tempo of disease) is crucial to the development of the therapeutic plan in the individual patient. Although entry on a state-of-the-art clinical trial is the appropriate goal, this is not always possible, and an understanding of therapeutic options is essential. Palliation is the key word in the management of metastatic breast cancer, and hormonal therapy is generally the most appropriate course unless the patient is not a hormonal candidate because of sites, extent, or tempo of disease, or because of the known lack of hormonal receptors. Of particular importance is attention to sites of bone metastasis where appropriate radiation therapy and/or surgical intervention can relieve pain or prevent a devastating fracture with resultant loss of mobility and decrease in quality of life.

Mitoxantrone is useful for palliative therapy of advanced breast cancer

Mitoxantrone is useful for palliative therapy of advanced breast cancer

Mitoxantrone—A Useful Palliative Therapy in Advanced Breast Cancer

We have treated 76 patients with advanced breast cancer with single-agent mitoxantrone: all had previously received hormone therapy and 30 patients had also received prior chemotherapy. The overall response rate at 6 months was 15%, with a further 22% having static disease. Responding and static patients had similar survival curves and were grouped together as patients with "stable disease." Patients with stable disease had a significantly longer survival than patients with progressive disease (p less than 0.001); the median difference in survival was 9 months.

Immunocytochemical determination of the estrogen-regulated protein Mr, 24,000 in primary breast cancer and response to endocrine therapy

Monoclonal antibodies against an estrogen-regulated M r 24,000 cytosol protein (p 24) were used for immunocytochemical localization of p 24 in formalin-fixed paraffin-embedded specimens from the primary tumor in 103 patients who received endocrine therapy for advanced breast cancer. Sixty-one per cent of the tumors showed p 24-positive staining, and this correlated well with the presence of estrogen receptor (ER) ( P = 0.00017, chi-square test). Response to endocrine therapy was obtained in 43% of the patients. A statistically significant association between p 24 status and response could not be established, while response and ER status were highly correlated ( P = 0.0000029, chi-square = 21.6). Discrimination between ER-positive responders and ER-positive non-responders was not possible using p 24 staining.