Outcomes not described individually for pts obtaining one-agent sorafenib. Not attained soon after 278 times suggest follow-up. Median (selection). Quality one.PFS and OS for each of the phase 3 trials are represented graphically in Fig. two, alongside with outcomes from Goal, EU-ARCCS, and NA-ARCCS. In which documented, treatment method-emergent AEs transpired in almost all sufferers, and quality three/4 AEs have been witnessed in 36%-70%. General incidences of AEs by line of remedy are challenging to assess due to the fact data have not been reported for four of the seven trials. The incidences of critical AEs was described for a few trials and ranged from 25%-34%. Frequencies of pick AEs taking place in >20% of patients in any phase 3 demo are comprehensive in Desk two. Fatigue, hand-foot pores and skin reaction (HFSR), rash or desquamation, diarrhea, and hypertension had been between the most frequent AEs. Incidences of these AEs are presented graphically in Fig. three [6803].Released data ended up determined for a heterogeneous group of 9 period 2 trials that achieved eligibility criteria for this overview (Desk 3). 1st-line sorafenib was used in three randomized, openlabel research [250]. Median PFS (95% CI) ranged from five.7 (five..4) to 9. (five.fifty.9) months. In a one-arm dose-escalation research in the very first-line setting, clients acquired four hundred mg twice everyday (BID) for four months, and escalated to 600 mg BID for four weeks and lastly to 800 mg BID, with response evaluated at 6 months. The dose-escalation protocol was tolerated by eighteen/sixty seven patients [31,32]. The remaining patients experienced dose escalations and reductions as tolerated throughout the study. General median PFS (95% CI) was 7.4 (six.3.seven) months. Subgroup examination by dose (400, 600, or 800 mg BID) administered to individuals for the longest period showed median PFS (95% CI) of three.seven (1.8.five), seven.four (six.32) and eight.5 (five.64.nine) months, respectively [32]. In three period 2 trials, sorafenib was evaluated as 2nd-line or later on remedy in individuals who experienced failed or progressed right after cytokine remedy [35,36] or in sufferers refractory to sunitinib or bevacizumab [33] (Desk 3). A single examine [34] was a randomized, discontinuation demo in which clients with tumor development or <25% tumor shrinkage during a 12-week run-in period of sorafenib treatment were randomized to receive continued sorafenib or placebo. Thirty-two patients received continued sorafenib efficacy results are presented only for these patients. Safety results are presented for the entire enrolled population (N = 202), 91% of whom received prior interleukin (IL)-2, interferon, or nonspecified systemic anticancer therapy. Median PFS (95% CI) was, respectively, 4.4 (3.6.9) and 5.5 (not reported) months in patients (N = 79) previously treated with VEGF inhibitors [33,34], and 7.4 (6.53.1) and 7.9 (6.40.8) months in patients (N = 165) previously treated with cytokine therapy [35,36]. It should be noted that this particular study technically met inclusion criteria for this systematic review because it was published in 2006. However, efficacy data are reported only up to December 31, 2004. Overall incidences of treatment-emergent AEs were not consistently reported, but ranged from 96%-100% where data are available [31,34,37]. Incidences of treatment-related AEs, where reported, ranged from 95%-97%, and grade 3/4 treatment-related AEs in the same studies ranged from 41%-69% [27,35]. Frequencies of the most common specific AEs are detailed in Table 3.In addition to phase 2, phase 3, and expanded access trials, five small single-arm studies and three patient series reports were identified. Results for these studies are reported in Table 4. As mentioned above, one trial was listed as a phase 3 trial, but because it was not a randomized controlled trial and because only 39 patients were enrolled, it is included with this, more similar sorafenib response rates, PFS, and OS in TARGET, associated expanded access trials, and subsequent phase 3 trials. A) Response rates. B) Median PFS and OS. Data for trials including patients for whom sorafenib was used second line are indicated by stippling. Data were not reported group of studies [60]. Notably, in two of the single-arm trials, median PFS [95% CI] was considerably longer than was seen in any of the phase 2/3 trials (9.5 [not reported] and 14 [01.7] months) [61,62]. These two studies were undertaken entirely in Chinese patients and 91% of the patients had received at least one prior systemic therapy.Generally when a drug is demonstrated to have clinical utility and becomes approved for use, results from a pivotal phase 3 trial, and potentially one or a few earlier phase 2 studies, comprise the body of experience in terms of disease response and management of side effects. These studies therefore have a profound effect on drug labeling and its uptake and use in the incidences of select adverse events in TARGET, associated expanded access trials, and subsequent phase 3 trials. A) Fatigue B) HFSR C) Rash, desquamation D) Diarrhea E) Hypertension. Data for trials including patients for whom sorafenib was used second-line are indicated by stippling. Data were not reported community. Over time, clinical experience in management of dose- and course- limiting acute and chronic side effects typically matures, with positive impacts for both the patient experience and disease outcomes. However, information on the collective experience may not be readily available to the practitioner. Sorafenib was approved for the treatment of RCC in 2005 after favorable PFS results were obtained in the pivotal TARGET trial. Since that time, a large number of studies using sorafenib in RCC therapy have been undertaken. The number of publications initially identified (2411) represents a dauntingly broad experience. The availability of published data from these studies provides an important opportunity to comprehensively evaluate how the safety and efficacy experience with this drug may have evolved. To that end, we have systematically reviewed the published literature for clinical studies conducted since 2005 that included the use of single-agent sorafenib for RCC. In all, we identified 30 studies in which 2182 patients were treated with sorafenib. Among these, 1575 were treated in randomized controlled phase 3 trials. It is important to note that even among phase 3 trials, comparisons with TARGET should be undertaken with caution. Differences in trial design, patient baseline characteristics (including proportion of patients with higher-risk characteristics) duration of treatment and follow-up and reported endpoints have precluded quantitative comparisons or meta-analysis. There is no comprehensive patientlevel database that spans those experiences, and no practical way to re-analyze response or toxicity assessments. Whereas TARGET was a double-blind, placebo-controlled trial, all of the phase 3 trials (Table 2) identified in this review were open-label studies where the comparator arm was another targeted agent. Overall survival was the primary end-point in TARGET and PFS was the primary endpoint in the other seven phase 3 trials. Although it is not the intent of this review to provide a comparison with other agents, it is interesting to note that where reported, OS in sorafenib- treated patients was either similar to[58,61,86], or superior to[80][1] comparator agents. Among the identified trials, patients differed with respect to baseline characteristics, perhaps most profoundly by MSKCC score and line of treatment. A recent retrospective review of control (comparator) arm data derived from clinical trials in RCC suggests that the characteristics of RCC patients at baseline have consistently improved over time and proposes that these differences may result from increased use of palliative nephrectomy, advances in surgical techniques, and earlier diagnosis [108]. The diversity of reported trial designs reflects not only evolving approaches in standard of care for RCC, but also the desire to further evaluate the role of sequential treatment for patients whose disease progresses during treatment with targeted agents that were unavailable at the time sorafenib was approved. In the TARGET trial, patients' tumors must have progressed after one systemic treatment within the previous 8 months. Sorafenib was used exclusively second-line for three other phase 3 trials. In contrast to TARGET, prior treatment in these trials consisted largely, if not entirely, of targeted non-cytokine therapies. As summarized in Table 2 and Fig. 2, patients treated in the second-line setting appeared to have shorter PFS than in the 3 trials where patients were treated first-line with sorafenib, a finding that is in keeping with the trend towards poorer MSKCC score in the second-line trials. While the major impacts of risk-group, disease features,and line-of-treatment preclude a quantitative comparison, more contemporary data are generally similar to that seen in TARGET. Disappointingly, safety data were inconsistently reported among the trials. Overall incidences of AEs were reported for five of the seven phase 3 trials included Serious AEs were reported for only three studies. Incidences of grade 3/4 AEs varied substantially. In TARGET, overall incidences of AEs were reported only if they were considered treatment related. These and other factors, such as differing duration of treatment, preclude a meta-analysis with statistical characterization trends. Specific treatment-emergent AEs reported in all phase 3 trials included in this review were largely similar to TARGET. However, whereas grade 3 HFSR was observed in 6% of patients in TARGET [1], it was reported in 15% patients in five of the more recent phase 3 trials [68,70,74,76,78,79,83]. Similarly, grade 3/4 hypertension occurred in 4% of patients in TARGET [1] and in 11%-18% in four of the more recent trials [70,74,75,779,103] (Fig. 3). One may speculate that some practice-related factors may be responsible for this. In more recent trials, increased familiarity with the use of sorafenib and its side effects may have reduced the frequencies of dose interruptions and reductions, resulting in overall higher dose intensity over the course of treatment. However, due to inconsistent reporting of dose intensities, this notion cannot be substantiated based on the reported data. As a bottom line for the clinician, the HSFR and hypertension issues seem more frequent in the current experience--an active management plan to mitigate remains an ongoing consideration. Higher incidences of grade 3 HFSR and grade 3 hypertension were also reported in several of the phase 2 trials, although qualitative differences (treatment-emergent vs treatment-related AEs) and inconsistent reporting preclude determining the number of trials in which these occurred. Even with these rather small differences, it appears that the safety profile of sorafenib observed in the variety of patient populations and treatment settings studied is consistent with that observed in the TARGET trial, with no new signals. For comprehensiveness, we included phase 2 and smaller trials in this review. Five of the phase 2 trials were randomized, and the remaining studies, including smaller trials and patient series listed in Table 4, were single arm. In addition to the limitations discussed above for the phase 3 trials, inherent potential bias in these trials should be considered when interpreting the results. Nonetheless, these trials may offer important insights. However, it is important to note that results reported for all of these studies may differ from those observed in daily clinical practice. Similarly, trends or absence of changes in reported prospective trials are not conclusively demonstrative of changes in daily clinical practice. For example, among the seven phase 3 trials included in this review, none enrolled more than 25% of Asian patients. One phase 2 trial [35] enrolled exclusively Japanese patients and two smaller trials [61,62] and a patient series [58] report results in Chinese patients. PFS in these studies appeared longer than in TARGET or any other trial reported here (single-agent sorafenib results were not reported for the patient series). Yang et al. considered ethnic background as an important factor leading to these differences [61]. However, disease control rates and OS (where reported) did not show corresponding differences. These studies in Asian patients enrolled fewer than 100 patients each and did not include a control (non-Asian) population additional studies would be necessary to clarify these findings. Incidences of AEs in Asian patients were similar to those observed in TARGET with the exception that grade 3 HFSR was higher in the smaller studies (Table 4), and treatment-related grade 3/4 hypertension was seen in 17% of patients in the phase 2 trial (Table 3). Understanding how ethnic features affect sorafenib efficacy or side effects remains a challenge. In this review, we have comprehensively collected publications that describe the use of single-agent sorafenib in prospective studies in patients with RCC. The data are focused on the sorafenib experience, rather than comparative efficacy, with the goal of obtaining a broadened perspective on what to expect as medical practices evolve, beyond the database of the original pivotal trial. While the randomized controlled phase 3 trials likely provide the most robust information, important additional information may be gleaned from the inclusion of phase 2 and smaller studies, particularly as they may provide historical context or describe less well-represented populations. Comparisons among the included trials should be made with due caution as study design, patient populations, tumor characteristics, and prior drug exposure vary dramatically. Differences of patient characteristics a priori may be more important than differences of treatment plans. Notwithstanding the diversity of trial designs in this review, in examining the primary endpoints of this study, PFS and safety, we have observed no profound differences from the results observed in TARGET.Progress in breast cancer prevention is currently limited by our lack of biological markers to identify which women will respond to prevention therapies. Tamoxifen (Tam), a selective estrogen receptor modulator, is the most widely used treatment for estrogen receptor (ER)+ breast cancer. Tam treatment is approved for the prevention of breast cancer in pre-menopausal women, but it only reduces the risk of developing ER+ breast cancer by approximately 50% and does not prevent ER- breast cancer [1]. The increased risk of stroke, pulmonary emboli, cardiac events, endometrial cancer, and unwanted side effects (e.g., hot flashes, fatigue, depression, weight gain, and decreased libido) have decreased the acceptance of Tam among patients, particularly in the chemoprevention setting. Thus, there is a critical need to identify the women who are most likely to benefit from risk reducing strategies, and improve breast cancer prevention with novel prevention strategies. Inhibition of ER transcriptional activity is considered the predominate effect of Tam in invasive breast cancer however, not all of Tam's effects can be directly attributed to inhibition of ER. Tam is clinically effective in treatment of tumors that do not express ER [2]. Tam has a wide variety of ER-independent pharmacological activities including stimulation of transforming growth factor-beta, blockade of various chloride channels [3], inhibition of protein kinase C [4], and antagonism of calmodulin activity [5].
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