Increased circulating tumor cells (CTCs; five or more CTCs per 7.5 mL of whole blood) are associated with poor prognosis in metastatic breast cancer (MBC). A randomized trial of patients with ...persistent increase in CTCs tested whether changing chemotherapy after one cycle of first-line chemotherapy would improve the primary outcome of overall survival (OS).
Patients with MBC who did not have increased CTCs at baseline remained on initial therapy until progression (arm A). Patients with initially increased CTCs that decreased after 21 days of therapy remained on initial therapy (arm B). Patients with persistently increased CTCs after 21 days of therapy were randomly assigned to continue initial therapy (arm C1) or change to an alternative chemotherapy (arm C2).
Of 595 eligible and evaluable patients, 276 (46%) did not have increased CTCs (arm A). Of those with initially increased CTCs, 31 (10%) were not retested, 165 were assigned to arm B, and 123 were randomly assigned to arm C1 or C2. No difference in median OS was observed between arm C1 and C2 (10.7 and 12.5 months, respectively; P = .98). CTCs were strongly prognostic. Median OS for arms A, B, and C (C1 and C2 combined) were 35 months, 23 months, and 13 months, respectively (P < .001).
This study confirms the prognostic significance of CTCs in patients with MBC receiving first-line chemotherapy. For patients with persistently increased CTCs after 21 days of first-line chemotherapy, early switching to an alternate cytotoxic therapy was not effective in prolonging OS. For this population, there is a need for more effective treatment than standard chemotherapy.
The combination of anastrozole and fulvestrant — which interfere with estrogen signaling by distinct mechanisms — increases progression-free and overall survival as compared with anastrozole alone or ...anastrozole followed by fulvestrant in women with HR-positive breast cancer.
Endocrine therapy plays a central role in the treatment of hormone-receptor (HR)–positive metastatic breast cancer.
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Selective aromatase inhibitors, such as anastrozole, letrozole, and exemestane, lower the estrogen level and are used as first-line endocrine treatments of HR-positive metastatic disease, owing to their superiority over tamoxifen.
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Fulvestrant (Faslodex, AstraZeneca) is an analogue of estradiol that down-regulates the estrogen receptor by disrupting estrogen-receptor dimerization and accelerating degradation of the unstable fulvestrant–estrogen-receptor complex.
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This effect leads to reduced cross-talk between the estrogen receptor and estrogen-independent growth factor signaling, thus delaying resistance to hormone therapy.
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Clinically, fulvestrant at a dose of 250 mg monthly . . .
Summary Background Results from phase II studies in patients with stage IIIA non-small-cell lung cancer with ipsilateral mediastinal nodal metastases (N2) have shown the feasibility of resection ...after concurrent chemotherapy and radiotherapy with promising rates of survival. We therefore did this phase III trial to compare concurrent chemotherapy and radiotherapy followed by resection with standard concurrent chemotherapy and definitive radiotherapy without resection. Methods Patients with stage T1-3pN2M0 non-small-cell lung cancer were randomly assigned in a 1:1 ratio to concurrent induction chemotherapy (two cycles of cisplatin 50 mg/m2 on days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days 1–5 and 29–33) plus radiotherapy (45 Gy) in multiple academic and community hospitals. If no progression, patients in group 1 underwent resection and those in group 2 continued radiotherapy uninterrupted up to 61 Gy. Two additional cycles of cisplatin and etoposide were given in both groups. The primary endpoint was overall survival (OS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov , number NCT00002550. Findings 202 patients (median age 59 years, range 31–77) were assigned to group 1 and 194 (61 years, 32–78) to group 2. Median OS was 23·6 months (IQR 9·0–not reached) in group 1 versus 22·2 months (9·4–52·7) in group 2 (hazard ratio HR 0·87 0·70–1·10; p=0·24). Number of patients alive at 5 years was 37 (point estimate 27%) in group 1 and 24 (point estimate 20%) in group 2 (odds ratio 0·63 0·36–1·10; p=0·10). With N0 status at thoracotomy, the median OS was 34·4 months (IQR 15·7–not reached; 19 point estimate 41% patients alive at 5 years). Progression-free survival (PFS) was better in group 1 than in group 2, median 12·8 months (5·3–42·2) vs 10·5 months (4·8–20·6), HR 0·77 0·62–0·96; p=0·017); the number of patients without disease progression at 5 years was 32 (point estimate 22%) versus 13 (point estimate 11%), respectively. Neutropenia and oesophagitis were the main grade 3 or 4 toxicities associated with chemotherapy plus radiotherapy in group 1 (77 38% and 20 10%, respectively) and group 2 (80 41% and 44 23%, respectively). In group 1, 16 (8%) deaths were treatment related versus four (2%) in group 2. In an exploratory analysis, OS was improved for patients who underwent lobectomy, but not pneumonectomy, versus chemotherapy plus radiotherapy. Interpretation Chemotherapy plus radiotherapy with or without resection (preferably lobectomy) are options for patients with stage IIIA(N2) non-small-cell lung cancer. Funding National Cancer Institute, Canadian Cancer Society, and National Cancer Institute of Canada.
Postmenopausal women with early breast cancer who have undergone successful initial therapy receive five years of treatment with tamoxifen, an antagonist of the estrogen receptor. This ...placebo-controlled trial investigated whether the administration of letrozole, an aromatase inhibitor, after five years of tamoxifen therapy is beneficial. The trial was stopped because of a statistically significant reduction in the rate of breast-cancer–related events in the letrozole group as compared with the placebo group.
This trial was stopped after an interim analysis.
The risk of a recurrence of breast cancer continues for an indefinite period after surgery, radiation, and medical therapy.
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Since the growth of breast cancer depends on the action of estrogen,
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long-term reductions in the risk of recurrence have been achieved by antagonizing the activity of estrogen with the selective estrogen-receptor modulator tamoxifen in women with hormone-receptor–positive tumors.
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The postoperative administration of tamoxifen for five years reduces the risk of recurrence by 47 percent and reduces the risk of death by 26 percent.
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However, in a trial conducted by the National Surgical Adjuvant Breast and Bowel Project . . .
Background: Most recurrences in women with breast cancer receiving 5 years of adjuvant tamoxifen occur after 5 years. The MA.17 trial, which was designed to determine whether extended adjuvant ...therapy with the aromatase inhibitor letrozole after tamoxifen reduces the risk of such late recurrences, was stopped early after an interim analysis showed that letrozole improved disease-free survival. This report presents updated findings from the trial. Methods: Postmenopausal women completing 5 years of tamoxifen treatment were randomly assigned to a planned 5 years of letrozole (n = 2593) or placebo (n = 2594). The primary endpoint was disease-free survival (DFS); secondary endpoints included distant disease-free survival, overall survival, incidence of contralateral tumors, and toxic effects. Survival was examined using Kaplan–Meier analysis and log-rank tests. Planned subgroup analyses included those by axillary lymph node status. All statistical tests were two-sided. Results: After a median follow-up of 30 months (range = 1.5–61.4 months), women in the letrozole arm had statistically significantly better DFS and distant DFS than women in the placebo arm (DFS: hazard ratio HR for recurrence or contralateral breast cancer = 0.58, 95% confidence interval CI = 0.45 to 0.76; P<.001; distant DFS: HR = 0.60, 95% CI = 0.43 to 0.84; P = .002). Overall survival was the same in both arms (HR for death from any cause = 0.82, 95% CI = 0.57 to 1.19; P = .3). However, among lymph node–positive patients, overall survival was statistically significantly improved with letrozole (HR = 0.61, 95% CI = 0.38 to 0.98; P = .04). The incidence of contralateral breast cancer was lower in women receiving letrozole, but the difference was not statistically significant. Women receiving letrozole experienced more hormonally related side effects than those receiving placebo, but the incidences of bone fractures and cardiovascular events were the same. Conclusion: Letrozole after tamoxifen is well-tolerated and improves both disease-free and distant disease–free survival but not overall survival, except in node-positive patients.
In node-positive breast cancer, adjuvant doxorubicin plus cyclophosphamide followed by docetaxel was associated with significantly better disease-free survival than the three drugs together or ...doxorubicin–docetaxel. Premenopausal women who became amenorrheic as a consequence of treatment had significantly improved overall and disease-free survival, regardless of their treatment or the hormone-receptor status of their tumor.
In node-positive breast cancer, adjuvant doxorubicin plus cyclophosphamide followed by docetaxel was associated with significantly better disease-free survival than the three drugs together or doxorubicin–docetaxel. Premenopausal women who became amenorrheic as a consequence of treatment had significantly improved overall and disease-free survival.
Chemotherapy regimens that combine anthracyclines and taxanes with other agents such as cyclophosphamide result in improved disease-free and overall survival among women with operable lymph-node–positive breast cancer.
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The contribution of cyclophosphamide to these regimens has not been defined. Initial evaluations of taxanes in the adjuvant setting used a sequential approach of administration after completion of the anthracycline-based regimen. Phase 3 trials in advanced breast cancer have shown superiority with a doxorubicin–docetaxel combination as compared with doxorubicin–cyclophosphamide and with doxorubicin, cyclophosphamide, and docetaxel (ACT, also known as the TAC regimen), and as compared with fluorouracil, doxorubicin, and cyclophosphamide.
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These . . .
The addition of fulvestrant to anastrozole in postmenopausal women with hormone-receptor–positive metastatic breast cancer led to significantly longer progression-free survival (median, 15 months) ...and overall survival (median, 50 months) than anastrozole alone (13.5 and 42 months, respectively) when given as first-line endocrine therapy.
Traditional treatment for superior sulcus non-small-cell lung cancers (SS NSCLC), radiation plus surgery, yields a 50% rate of complete resection and a 30% 5-year survival. On the basis of improved ...outcomes in other subsets of stage III NSCLC, this trial tested the feasibility of induction chemoradiotherapy for SS NSCLC.
Patients with T3-4, N0-1 SS NSCLC received two cycles of cisplatin and etoposide concurrently with radiation (45 Gy). Patients with stable or responding disease underwent thoracotomy. All patients received two more cycles of chemotherapy. Survival was calculated by the Kaplan-Meier method and prognostic factors were assessed by Cox regression analysis.
From April 1995 to November 1999, 110 eligible patients (76 men, 34 women) were entered onto the study (78 T3, 32 T4 tumors). Induction therapy was completed by 104 (95%) patients. Of 95 patients eligible for surgery, 88 (80%) underwent thoracotomy, two (1.8%) died postoperatively, and 83 (76%) had complete resection. Pathologic complete response (CR) or minimal microscopic disease was seen in 61 (56%) resection specimens. Five-year survival was 44% for all patients and 54% after complete resection, with no difference between T3 and T4 tumors. Pathologic CR led to better survival than when any residual disease was present (P = .02). Disease progression occurred mainly in distant sites.
This combined-modality approach is feasible and is associated with high rates of complete resection and pathologic CR in both T3 and T4 tumors. Local control and overall survival seem markedly improved relative to previous studies of radiation plus resection.
To prospectively evaluate the effectiveness, safety, and clinical benefits of once-weekly epoetin alfa therapy as an adjunct to chemotherapy in anemic cancer patients.
A total of 3,012 patients with ...nonmyeloid malignancies who received chemotherapy were enrolled onto this multicenter, open-label, nonrandomized study conducted in 600 United States community-based practices. Patients received epoetin alfa 40,000 U once weekly, which could be increased to 60,000 U once weekly after 4 weeks dependent on hemoglobin response. Treatment was continued for a maximum of 16 weeks.
Among the 2,964 patients assessable for efficacy, epoetin alfa therapy resulted in significant increases in hemoglobin levels, decreases in transfusion requirements, and improvements in functional status and fatigue as assessed by the linear analog scale assessment (energy level, ability to perform daily activities, and overall quality of life) and the anemia subscale of the Functional Assessment of Cancer Therapy-Anemia questionnaire. Improvements in quality-of-life parameters correlated significantly (P <.001) with increased hemoglobin levels. The direct relationship between hemoglobin and quality-of-life improvement was sustained during the 16-week study period, which is similar to findings of large community-based trials of three-times-weekly dosing. Once-weekly epoetin alfa was well tolerated, with most adverse events attributed to the underlying disease or concomitant chemotherapy.
The results from this large, prospective, community-based trial suggest that once-weekly epoetin alfa therapy increases hemoglobin levels, decreases transfusion requirements, and improves quality of life in patients with cancer and anemia who undergo concomitant chemotherapy. Based on the results of this study, the clinical benefits and the adverse event profile of once-weekly epoetin alfa therapy in community-based practice are similar to those observed in the historical experience with the three-times-weekly dosage schedule.
This randomized trial was designed to determine whether paclitaxel plus carboplatin (PC) offered a survival advantage over vinorelbine plus cisplatin (VC) for patients with advanced non--small-cell ...lung cancer. Secondary objectives were to compare toxicity, tolerability, quality of life (QOL), and resource utilization.
Two hundred two patients received VC (vinorelbine 25 mg/m(2)/wk and cisplatin 100 mg/m(2)/d, day 1 every 28 days) and 206 patients received PC (paclitaxel 225 mg/m(2) over 3 hours with carboplatin area under the curve of 6, day 1 every 21 days). Patients completed QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization forms were completed at five time points through 24 months.
Patient characteristics were similar between the groups. The objective response rate was 28% in the VC arm and 25% in the PC arm. Median survival was 8 months in both arms, with 1-year survival rates of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P =.002) and neutropenia (P =.008) occurred more frequently on the VC arm. Grade 3 nausea and vomiting were higher on the VC arm (P =.001, P =.007), and grade 3 peripheral neuropathy was higher on the PC arm (P <.001). More patients on the VC arm discontinued therapy because of toxicity (P =.001). No difference in QOL was observed. Overall costs on the PC arm were higher than on the VC arm because of drug costs.
PC is equally efficacious as VC for the treatment of advanced non--small-cell lung cancer. PC is less toxic and better tolerated but more expensive than VC. New treatment strategies should be pursued.
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