A substantial proportion of breast cancer patients develop metastatic disease, with over 450,000 deaths globally per year. Bone is the most common first site of metastatic disease accounting for 40% ...of all first recurrence and 70% of patients with advanced disease develop skeletal involvement. Treatment of bone metastases currently focusses on symptom relief and prevention and treatment of skeletal complications. However, there remains a need for further treatment options for patients with bone metastases. Combining systemic therapy with a bone-targeted agent, such as radium-223, may provide an effective treatment with minimal additional side effects.
CARBON is a UK-based, open-label, multi-centre study which comprises an initial safety phase to establish the feasibility and safety of combining radium-223 given on a 6-weekly schedule in combination with orally administered capecitabine followed by a randomised extension phase to further characterise the safety profile and provide preliminary estimation of efficacy.
The CARBON study is important as the results will be the first to assess radium-223 with chemotherapy in advanced breast cancer. If the results find acceptable rates of toxicity with a decrease in bone turnover markers, further work will be necessary in a phase II/III setting to assess the efficacy and clinical benefit.
ISRCTN, ISRCTN92755158, Registered on 17 February 2016.
To compare the efficacy and safety of orally administered capecitabine (Xeloda; Roche Laboratories, Inc, Nutley, NJ), a novel fluoropyrimidine carbamate designed to mimic continuous fluorouracil ...(5-FU) infusion but with preferential activation at the tumor site, with that of intravenous (IV) 5-FU plus leucovorin (5-FU/LV) as first-line treatment for metastatic colorectal cancer.
We prospectively randomized 602 patients to treatment with capecitabine 1,250 mg/m(2) administered twice daily days 1 to 14 every 3 weeks, or to the 4-weekly Mayo Clinic regimen (5-FU/LV) until disease progression or unacceptable toxicity.
The primary objective, to demonstrate at least equivalent response rates in the two treatment groups, was met. The overall response rate was 18.9% for capecitabine and 15.0% for 5-FU/LV. In the capecitabine and 5-FU/LV groups, respectively, median time to disease progression was 5.2 and 4.7 months (log-rank P =.65); median time to treatment failure was 4.2 and 4.0 months (log-rank P =.89); and median overall survival was 13.2 and 12.1 months (log-rank P =.33). The toxicity profiles of both treatments were typical of fluoropyrimidines. However, capecitabine led to significantly lower incidences (P <.00001) of stomatitis and alopecia, but a higher incidence of cutaneous hand-foot syndrome (P <.00001). Capecitabine also resulted in lower incidences (P <.00001) of grade 3/4 stomatitis and neutropenia, leading to a lower incidence of grade 3/4 neutropenic fever and sepsis. Only grade 3 hand-foot syndrome (P <.00001) and uncomplicated grade 3/4 hyperbilirubinemia (P <.0001) were reported more frequently with capecitabine.
Oral capecitabine achieved an at least equivalent efficacy compared with IV 5-FU/LV. Capecitabine demonstrated clinically meaningful safety advantages and the convenience of an oral agent.
•Lung cancer is the leading cause of cancer mortality worldwide.•Gold standard chemoradiotherapy is not deliverable for the majority of patients.•Radiation-induced DNA damage repair is an actionable ...mechanism of radioresistance.•Careful trial design is essential to elicit maximum impact on therapeutic index.•CONCORDE is a platform study of novel drug/radiotherapy combinations in lung cancer.
Lung cancer is the leading cause of cancer mortality worldwide and most patients are unsuitable for ‘gold standard’ treatment, which is concurrent chemoradiotherapy. CONCORDE is a platform study seeking to establish the toxicity profiles of multiple novel radiosensitisers targeting DNA repair proteins in patients treated with sequential chemoradiotherapy. Time-to-event continual reassessment will facilitate efficient dose-finding.
Purpose and Methods
Our secondary analyses compared survival with eribulin versus capecitabine in various patient subgroups from a phase 3, open-label, randomized study. Eligible women aged ≥18 years ...with advanced/metastatic breast cancer and ≤3 prior chemotherapies (≤2 for advanced/metastatic disease), including an anthracycline and taxane, were randomized 1:1 to intravenous eribulin mesylate 1.4 mg/m2 on days 1 and 8 or twice-daily oral capecitabine 1250 mg/m2 on days 1–14 (21-day cycles).
Results
In the intent-to-treat population (eribulin 554 and capecitabine 548), overall survival appeared longer with eribulin than capecitabine in various subgroups, including patients with human epidermal growth factor receptor 2-negative (15.9 versus 13.5 months, respectively), estrogen receptor-negative (14.4 versus 10.5 months, respectively), and triple-negative (14.4 versus 9.4 months, respectively) disease. Progression-free survival was similar between the treatment arms.
Conclusions
Patients with advanced/metastatic breast cancer and human epidermal growth factor receptor 2-, estrogen receptor-, or triple-negative disease may gain particular benefit from eribulin as first-, second-, and third-line chemotherapies.
Trial Registration (Primary Study)
This study reports the subgroup analyses of eribulin versus capecitabine from a phase 3, open-label, randomized study (www.clinicaltrials.gov; ClinicalTrials.gov identifier: NCT00337103).
Purpose: The expression and activation of the Ras/Raf-1/mitogen-activated protein kinase (MAPK) pathway plays an important role in
the development and progression of cancer, and may influence ...response to treatments such as tamoxifen and chemotherapy. In
this study we investigated whether the expression and activation of the key components of this pathway influenced clinical
outcome, to test the hypothesis that activation of the MAPK pathway drives resistance to tamoxifen and chemotherapy in women
with breast cancer.
Experimental Design: Breast tumors from patients at the Glasgow Royal Infirmary and others treated within the BR9601 trial were analyzed for expression
of the three Ras isoforms, total Raf-1, active and inactive forms of Raf-1 pRaf(ser338) and pRaf(ser259), respectively,
MAPK, and phospho-MAPK using an immunohistochemical approach. Analyses were done with respect to disease free-survival and
overall survival.
Results: Expression and activation of the Ras pathway was associated with loss of benefit from treatment with tamoxifen but not chemotherapy.
Overexpression of pRaf(ser338) was associated with shortened disease-free and overall survival time in univariate analyses.
Multivariate analysis suggested pRaf(ser338) was independent of known prognostic markers in predicting outcome following tamoxifen
treatment ( P = 0.03).
Conclusion: This study suggests that activation of the Ras pathway predicts for poor outcome on tamoxifen but not chemotherapy, and identifies
pRaf(ser338) as a potential marker of resistance to estrogen receptor–targeted therapy. In addition, it suggests that expression
of pRaf(ser338) could identify patients for whom tamoxifen alone is insufficient adjuvant systemic therapy, but for whom the
addition of chemotherapy may be of benefit.
The X-ACT (Xeloda® in Adjuvant Colon Cancer Therapy) trial compared the efficacy and safety of the oral fluoropyrimidine capecitabine with bolus 5-fluorouracil (5-FU)/leucovorin (LV; Mayo Clinic ...regimen) as adjuvant therapy for stage III colon cancer. A total of 1987 patients were enrolled at 164 centers worldwide. Disease-free survival (primary study endpoint) in the capecitabine arm was at least equivalent to that in the 5-FU/LV arm; the upper limit of the hazard ratio was significantly (
P < 0.001) below the predefined margins for noninferiority. Capecitabine was also associated with significantly fewer fluoropyrimidine-related grade 3/4 adverse events (AEs;
P < 0.001) and fewer AE-related hospital admissions/days than 5-FU/LV. Pharmacoeconomic analyses performed in several countries show that the savings in direct costs (drug administration and AE-related costs) associated with capecitabine versus 5-FU/LV offset the acquisition costs of the drug. Furthermore, capecitabine reduces patient travel time and costs, making it a ‘dominant” strategy (ie, less costly and more effective) in the adjuvant setting. In conclusion, efficacy, safety, convenience, and cost findings from the X-ACT trial show that capecitabine offers at least equivalent clinical benefit compared with bolus 5-FU/LV and can replace intravenous 5-FU/LV in the adjuvant treatment of stage III colon cancer. The X-ACT trial has not only helped to better define the role of capecitabine but has also broadened the options available to patients with early-stage disease to include a uniquely effective oral outpatient treatment.
•There remains an unmet need for treatment of bone metastases in breast cancer.•We explored the safety and preliminary efficacy of capecitabine in combination with radium-223.•The combination was ...safe at the commonly used doses in the corresponding monotherapies.•No efficacy signals were seen at the radium-223 dose used, that might suggest greater efficacy of the combination over capecitabine.
Approximately 70% of patients with metastatic breast cancer (MBC) develop bone metastases. Despite advances in systemic treatment options and the use of bone targeted agents in the management of bone metastases to reduce skeletal morbidity, there remains an unmet need for further treatment options. Radium-223 (Ra223) is an alpha-emitting radiopharmaceutical that is preferentially taken up into bone at sites of increased osteoblastic activity where it emits high-energy, short-range alpha-particles that could provide a targeted anti-tumour effect on bone metastases. Here we evaluate the safety, feasibility and efficacy findings of the combination of Ra223 with capecitabine chemotherapy in patients with MBC with bone involvement.
CARBON is a multi-centre, open-label phase IB/IIA study evaluating the combination of Ra223 (55 kBq/kg day 1 given on 6 weekly schedule) and capecitabine (1000 mg/m2 bd days 4–17 every 21 days) in patients with bone metastases from MBC (± other disease sites). Other eligibility criteria included ECOG performance status 0–2, ≤2 lines of chemotherapy for MBC and current bisphosphonate or denosumab use for ≥ 6 weeks. The phase IB part of the trial (6 patients) was conducted to provide preliminary feasibility and safety of capecitabine + Ra223. Thereafter, 28 patients were randomised (2:1) to capecitabine + Ra223 or capecitabine alone to further characterise the safety profile and evaluate efficacy, the primary efficacy endpoint being the bone turnover marker (urinary n-telopeptide of type I collagen) change from baseline to end of cycle 5 and secondary endpoints of time to first symptomatic skeletal event, and disease progression at extra-skeletal and bone disease.
In addition to bone metastases, 10/23 44% and 13/23 57% capecitabine + Ra223 and 2/11 18% and 9/11 82% capecitabine alone patients had soft tissue and visceral disease sites respectively. More capecitabine + Ra223 patients had received prior chemotherapy for MBC: 11/23 48% vs 2/11 18%. The analysis populations comprise 34 patients (23 capecitabine + Ra223, 11 capecitabine); 2 patients randomised to capecitabine + Ra223 received capecitabine alone and are included in the capecitabine arm. Median number of cycles received was 8.5 in capecitabine + Ra223 (range 3–12) and 12 in the capecitabine arm (range 1–12). 94/95 prescribed Ra223 cycles were administered. No dose limiting toxicities were seen in phase IB and no patients developed grade ≥ III diarrhoea. Gastrointestinal, haematological and palmer-planter erthyrodysesthesia adverse events were similar in both arms. Although formal statistical comparisons were not made, changes in bone turnover markers, the times to extra-skeletal progression and bone disease progression, and the frequency of symptomatic skeletal events were similar across the two treatment arms.
Capecitabine + Ra223 at the planned dose was safe and feasible in MBC patients with bone metastases. However, no efficacy signals were seen that might suggest greater efficacy of the combination over capecitabine alone clinically or biochemically.
In a pivotal phase 3 study (Study 305), eribulin mesylate improved overall survival (OS) in patients with previously treated metastatic breast cancer (MBC) compared with treatment of physician's ...choice (TPC). This post hoc, pooled subgroup analysis of two phase 3 studies (Study 305 and Study 301) reports the influence of the number of prior chemotherapy regimens (0‐6) on OS in patients with locally advanced/MBC randomized to eribulin versus TPC/capecitabine. Patients with ≤ 3 prior chemotherapies for locally advanced/MBC had longer median OS with eribulin (15.3 months) versus control (13.2 months; hazard ratio, 0.858; P = .01).
Ninety-four common genetic variants are confirmed to be associated with breast cancer. This study tested the hypothesis that breast cancer susceptibility variants may also be associated with ...chemotherapy-induced toxicity through shared mechanistic pathways such as DNA damage response, an association that, to our knowledge, has not been previously investigated. The study included breast cancer patients who received neoadjuvant/adjuvant chemotherapy from the Pharmacogenetic SNPs (PGSNPS) study. For each patient, a breast cancer polygenic risk score was created from the 94 breast cancer risk variants, all of which were genotyped or successfully imputed in PGSNPS. Logistic regression was performed to test the association with two clinically important toxicities: taxane- related neuropathy (n = 1279) and chemotherapy-induced neutropenia (n = 1676). This study was well powered (≥96%) to detect associations between polygenic risk score and chemotherapy toxicity. Patients with high breast cancer risk scores experienced less neutropenia compared to those with low risk scores (adjusted p-value = 0.06). Exploratory functional pathway analysis was performed and no functional pathways driving this trend were identified. Polygenic risk was not associated with taxane neuropathy (adjusted p-value = 0.48). These results suggest that breast cancer patients with high genetic risk of breast cancer, conferred by common variants, can safely receive standard chemotherapy without increased risk of taxane-related sensory neuropathy or chemotherapy-induced neutropenia and may experience less neutropenia. As neutropenia has previously been associated with improved survival and may reflect drug efficacy, these patients may be less likely to benefit from standard chemotherapy treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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