Free trial of femara

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Prospectively planned analyses of the intent-to-treat population showed that letrozole significantly improved overall survival OS compared with tamoxifen over the first 24 months of the trial. An exploratory analysis of patients, who did not cross over, indicated a median OS benefit of 14 months for letrozole compared with tamoxifen. The treatment goals for advanced or metastatic breast cancer MBC are to delay disease progression and to prolong survival [ 1 , 2 ] and to optimize patient care in terms of ameliorating symptoms, thereby improving or maintaining quality of life [ 3 — 5 ].

Although treatment may include surgery and radiation therapy for the treatment of locally advanced tumors or isolated metastases, systemic therapies endocrine, cytotoxic, biologic, and palliative are the foundation of disease management [ 6 , 7 ].

Systemic therapy for patients with advanced breast cancer should be tailored according to specific tumor biology, particularly with respect to hormone receptor HR and human epidermal growth factor receptor 2 HER2 status, the growth rate of disease, presence of visceral metastases, history of prior therapy and response, susceptibility to treatment-related toxicity, and individual patient preference [ 7 — 14 ].

Systemic therapy can prolong survival and enhance patient quality of life but is not curative [ 1 ]. Consequently, minimally toxic endocrine therapies are generally preferred to cytotoxic therapy as initial therapy for patients with hormone-responsive tumors [ 6 , 15 ]. Since the s, endocrine therapy with tamoxifen was well established as a standard first-line treatment for post-menopausal women with advanced breast cancer, even though estrogen receptor ER expression was not always used routinely to select patients for endocrine therapy [ 16 — 18 ].

The first-generation aromatase inhibitor aminoglutethimide or a progestin such as megestrol acetate has provided a reasonable second-line alternative [ 19 — 22 ]. Furthermore, the short median time to treatment failure TTF , in the range 6—8 months, demonstrates a relatively rapid emergence of resistance in patients initially sensitive to tamoxifen [ 19 , 27 ].

However, the majority of patients who develop acquired tamoxifen resistance still express ER at the time of progression [ 37 , 38 ] and may respond to alternative endocrine therapies [ 39 ]. The third-generation aromatase inhibitors letrozole, anastrozole, and exemestane were developed in the search for more effective therapeutic alternatives to tamoxifen.

Aromatase inhibitors prevent estrogen synthesis by potently inhibiting the aromatase enzyme, which converts androgens to estrogen [ 40 ]. Unlike tamoxifen, the aromatase inhibitors do not have any partial estrogen-agonist activity [ 41 ] and are less susceptible to the emergence of resistance associated with long-term estrogen deprivation [ 42 ]. The development and mechanism of action of aromatase inhibitors is described in detail in the article by Dr.

Bhatnagar in this supplement. The initial randomized controlled trials of third-generation aromatase inhibitors were conducted in patients with advanced breast cancer in whom tamoxifen had failed i. Letrozole, anastrozole, and exemestane all demonstrated evidence of clinical superiority to megestrol acetate in the second-line setting [ 43 — 47 ]. Thus, the individual trials demonstrate a trend or even a significant difference in favor of the third-generation aromatase inhibitors in one or more efficacy end points; in addition, the aromatase inhibitors were shown to be associated with improved tolerability versus comparator endocrine therapy in these randomized trials.

One trial demonstrated a significantly higher ORR for letrozole 2. In this trial, low-dose letrozole 0. However, in another similarly designed trial with letrozole versus megestrol acetate, overall response rates with the two doses of letrozole 0. Differences in the distribution of baseline variables may explain the different outcomes in the two trials in terms of the superiority of letrozole over megestrol acetate according to dose [ 48 ].

Letrozole was significantly better tolerated than megestrol acetate, specifically in terms of serious adverse experiences, discontinuation due to poor tolerability, cardiovascular side effects, and weight gain [ 45 ]. Third-generation aromatase inhibitors have demonstrated greater potency and selectivity than the first-generation compound aminoglutethimide [ 49 ]. Two doses of the most potent aromatase inhibitor letrozole 2.

Letrozole 2. Letrozole has also been compared with anastrozole in a randomized, unblinded trial in the second-line setting in patients with MBC. The trial showed that letrozole was associated with a statistically higher ORR than anastrozole Both letrozole and anastrozole were well tolerated, and a similar incidence of adverse events was observed in the two groups.

These studies generated the hypothesis that letrozole might have superior efficacy to tamoxifen as first-line therapy for advanced breast cancer. A large clinical trial Femara Study PO25 was therefore conducted to compare the efficacy and tolerability of letrozole with those of tamoxifen as first-line therapy in post-menopausal women with advanced breast cancer [ 52 ].

This review will describe the results of the PO25 trial, highlighting the evidence for the superiority of letrozole over tamoxifen as first-line endocrine therapy in this setting. The Femara Study PO25 was the largest phase 3 trial conducted in the advanced breast cancer setting [ 52 , 53 ].

To achieve the recruitment target, the trial was conducted in centers in 29 countries. Local ethics review boards approved the protocol, and all patients gave written informed consent before study enrollment.

Patients were randomized to receive letrozole 2. Patients were permitted to cross over from 1 treatment arm to the other in a double-blind fashion if their first-line treatment was discontinued because of progressive disease or for any other reason Fig.

Patients in whom endocrine therapy was discontinued were subsequently treated as clinically indicated, using chemotherapy, trastuzumab, and bisphosphonates. The crossover design was an integral part of the study, and it probably affected the assessment of OS. Post-menopausal women with advanced breast cancer, defined as stage IIIB locally advanced disease, locoregionally recurrent disease that was not amenable to surgery or radiotherapy, or metastatic disease, were eligible for inclusion in the trial.

All patients presented with measurable or assessable tumors and were candidates for endocrine therapy. One prior chemotherapy regimen for the treatment of metastatic disease was permitted, but recurrence during or within 12 months of adjuvant antiestrogen therapy and any prior endocrine therapy for advanced breast cancer precluded enrollment.

The primary end point was TTP, defined as the interval between date of randomization and the earliest date of disease progression. ORR was defined as the proportion of patients who achieved a complete response CR or a partial response PR , confirmed by a second evaluation 1—3 months later. The duration of overall response was defined for patients with CR or PR, as the interval between date of randomization and the earliest date of disease progression. The rate of clinical benefit was defined as proportion of patients who achieved CR or PR or who stabilized NC for at least 24 weeks; the duration of clinical benefit was defined for patients who achieved CR or PR or NC as the interval between date of randomization and the earliest date of disease progression.

TTF was defined as the interval between date of randomization and the earliest date of disease progression, withdrawal, lost to follow-up, or death. TTR was defined for CR or PR patients as the interval between randomization and the earliest documentation of response, and TTC was defined as the total duration of endocrine therapy. The duration of OS was defined as the interval between randomization and death for any reason.

Exploratory analyses of OS were performed. The first analysis included all patients with censoring at crossover, whereas the second included only patients with no crossover. The characteristics of the patients included in the intent-to-treat ITT population were well balanced between the letrozole and tamoxifen arms. The median age of the patients was 65 years range 31—96 years in the letrozole arm and 64 years range 31—93 years in the tamoxifen arm.

The majority of patients of treated with adjuvant tamoxifen received at least 2 years of therapy, and the treatment-free interval between stopping adjuvant therapy and entering the study was more than 2 years in of patients. Of the patients included in the ITT efficacy population, crossed over to the other treatment arm, 75 continued on first-line therapy without progression, and the remainder terminated first-line treatment without crossover Fig.

Letrozole was superior to tamoxifen for all primary and secondary efficacy end points, including a prospectively planned survival analysis at 1- and 2-year follow-up [ 53 ].

In the primary efficacy analysis, the median TTP was significantly longer with letrozole than with tamoxifen 9. The hazard ratio of 0. Time to progression at median follow-up of 32 months for patients on first-line letrozole versus tamoxifen.

Reprinted from ref. Patients tend to tolerate the side effects of ribociclib very well, Dr. Burris said. Hortobagyi reported, and none had any clinical problems associated with it. But Dr. Burris said he hopes this thinking will now change. Because of his long involvement in clinical trials of ribociclib and the consistency of the survival data from these trials, Dr. Burris said that he tends to favor it for many of his patients.

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