Des Ilegbodu

Randomized Phase III Study of Trastuzumab, Paclitaxel, and Carboplatin Compared With Trastuzumab and Paclitaxel in Women With HER-2–Overexpressing Metastatic Breast Cancer

PURPOSE This randomized, multicenter, phase III trial evaluated the efficacy and safety of trastuzumab and paclitaxel with or without carboplatin as first-line therapy for women with HER-2-overexpressing metastatic breast cancer (MBC). PATIENTS AND METHODS HER-2 overexpression was defined as immunohistochemical staining scores of 2+ or 3+. Between November 1998 and May 2002, 196 women with HER-2-overexpressing MBC were randomly assigned to six cycles of either trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 every 3 weeks (TP), or trastuzumab 4 mg/kg loading dose plus 2 mg/kg weekly thereafter with paclitaxel 175 mg/m2 and carboplatin area under the time-concentration curve = 6 every 3 weeks (TPC) followed by weekly trastuzumab alone. RESULTS Baseline characteristics of the 196 patients were well balanced between study arms. Objective response rate (ORR) was 52% (95% CI, 42% to 62%) for TPC versus 36% (95% CI, 26% to 46%) for TP (P = .04). Median progression-free survival (PFS) was 10.7 months for TPC and 7.1 months for TP (hazard ratio [HR], 0.66; 95% CI, 0.59 to 0.73; P = .03). Improved clinical outcomes with TPC were most evident in HER-2 3+ patients, with an ORR of 57% (95% CI, 45% to 70%) v 36% (95% CI, 25% to 48%; P = .03) and median PFS of 13.8 v 7.6 months (P = .005) for TPC and TP, respectively (HR, 0.55; 95% CI, 0.46 to 0.64). Both regimens were well tolerated, and febrile neutropenia and neurotoxicity occurred infrequently; grade 4 neutropenia occurred more frequently with TPC (P < .01). CONCLUSION The addition of carboplatin to paclitaxel and trastuzumab improved ORR and PFS in women with HER-2-overexpressing MBC. This well-tolerated regimen represents a new therapeutic option.

Phase II Trial of Capecitabine and Weekly Paclitaxel As First-Line Therapy for Metastatic Breast Cancer

PURPOSE The taxanes and capecitabine have synergistic antitumor activity in preclinical models. This trial was designed to determine the efficacy and tolerability of weekly paclitaxel plus capecitabine as first-line treatment for metastatic breast cancer (MBC). PATIENTS AND METHODS Participants had histologically proven breast cancer, with measurable metastatic disease by Response Evaluation Criteria in Solid Tumors Group. Exclusion criteria included prior taxane therapy or any prior capecitabine or infusional fluorouracil. Participants received capecitabine 825 mg/m2/dose orally bid (1,650 mg/m2/d) for days 1 to 14. Paclitaxel 80 mg/m2 was administered intravenously weekly on days 1 and 8. Cycles were repeated every 3 weeks. Responders (complete or partial) or those with stable disease were treated until progression of disease or intolerable toxicity. RESULTS Fifty-five women were enrolled; 94% received study therapy as first-line treatment for MBC. In the intent-to-treat population, objective responses (partial) were achieved in 30 patients (55%; 95% CI, 40% to 69%), and six additional patients had stable disease for 6 months or longer (clinical benefit rate of 65%). The median duration of response was 10 months (range, 2.5 to 18.7 months). Dose modifications and reductions were common, particularly for capecitabine, leading to a delivered dose-intensity of 75% for capecitabine and 91% for paclitaxel. The most frequent grade 3 to 4 treatment-related adverse events were hand-foot skin reaction (n = 10); neutropenia (n = 7); fatigue (n = 4); and leukopenia, diarrhea, and pain (n = 3 each). CONCLUSION Capecitabine in combination with weekly paclitaxel is an active and tolerable regimen as first-line therapy for women with MBC.

Comparison of Menopausal Symptoms During the First Year of Adjuvant Therapy With Either Exemestane or Tamoxifen in Early Breast Cancer: Report of a Tamoxifen Exemestane Adjuvant Multicenter Trial Substudy

PURPOSE Hormonal breast cancer treatment increases menopausal symptoms in women. This study investigated differences between the symptoms associated with either adjuvant tamoxifen or exemestane. PATIENTS AND METHODS Ten common symptoms were assessed by self-report questionnaire administered to 1,614 consecutive patients at baseline and every 3 months during the first year of a double-blind, randomized trial of postmenopausal women with early hormone receptor-positive breast cancer. Symptoms were categorized as none, mild, moderate, or severe. A hot flash score was calculated at each time point. Symptoms were analyzed by repeated-measures analysis of variance. Each time period was tested repeatedly against the baseline; an overall P value was assigned for each reported symptom. RESULTS Compliance was excellent, with 7,286 questionnaires analyzed. Baseline symptom prevalence ranged from 2% (vaginal bleeding) to 60% to 70% (bone/muscle aches and low energy). There were no significant differences in vaginal bleeding, mood alteration, or low energy. Patients receiving tamoxifen had significantly more vaginal discharge (P < .0001). Exemestane patients reported more bone/muscle aches (P < .0001), vaginal dryness (P = .0004), and difficulty sleeping (P = .03). In both groups, the hot flash score peaked at 3 months and decreased thereafter. At 12 months, patients receiving tamoxifen had a significantly higher mean hot flash score (P = .03), with daily hot flashes increasing from baseline by 33% compared with a 7% increase from baseline with exemestane. CONCLUSION At 12 months, exemestane was associated with fewer hot flashes and less vaginal discharge than tamoxifen, but with more vaginal dryness, bone/muscle aches, and difficulty sleeping. Symptoms were common in both groups.

Randomized phase III study of trastuzumab, paclitaxel, and carboplatin versus trastuzumab and paclitaxel in women with HER-2 overexpressing metastatic breast cancer: An update including survival

573 Purpose: This randomized multicenter phase III trial evaluated the efficacy and safety of trastuzumab with paclitaxel 175 mg/m2 and carboplatin AUC=6 (TPC) versus trastuzumab with paclitaxel 175 mg/m2 (TP) in women with HER-2 overexpressing metastatic breast cancer. METHODS Between November 1998 and May 2002, 196 patients (pts) with HER-2 overexpression of 2+ or 3+ by immunohistochemistry were randomized; 188 were eligible; 93 pts received TPC and 95 pts received TP. In both arms, chemotherapy was delivered every 3 weeks for at least 6 cycles and weekly trastuzumab until progression. RESULTS Overall response (OR) and time to progression (TTP) were significantly improved with TPC compared to TP; OR for TPC was 52%, compared to 36% for TP (P = .04). Median TTP was 11.9 months for TPC and 6.8 months for TP (P = .02). This improvement was greater in HER2 3+ pts, with OR of 57% versus 37% (P = .03), and median TTP of 14.6 months vs 6.9 months (P = .006), for TPC and TP, respectively. There was a trend in the overall survival in favor of TPC of 42.1 months compared to TP with 33.3 months (P= 0.27); in IHC 3+ patients median OS of 42.1 months for TPC vs 30.6 months for TP (P=0.11). Therapy was well tolerated on both arms of the study. Grade 3/4 neutropenia and thrombocytopenia were more common with TPC, as expected. There was no difference in fever/neutropenia, neuropathy, fatigue, and other toxicities between study arms. There was one case of congestive heart failure, seen in the TP arm. CONCLUSION The addition of carboplatin to paclitaxel and trastuzumab significantly improved response rate and TTP in pts with a trend to improved overall survival with HER-2 overexpressing metastatic breast cancer. Treatment was well tolerated. Supported by Bristol-Myers Squibb, Plainsboro, NJ. and Genentech, South San Francisco, CA, USA [Table: see text].

The Effect of Tamoxifen or Exemestane on Bone Mineral Density During the First 2 Years of Adjuvant Treatment of Postmenopausal Women with Early Breast Cancer

BACKGROUND Adjuvant therapy with aromatase inhibitors is associated with increased bone loss in postmenopausal women with breast cancer. We assessed changes in bone mineral density (BMD) from baseline to 24 months in patients receiving either tamoxifen (T) or exemestane (E). PATIENTS AND METHODS A total of 578 women randomly assigned to T 20 mg per day orally or E 25 mg/day orally enrolled in this substudy; baseline, 12-month, and 24-month BMD measurements of the femur and lumbar spine by dual-energy x-ray absorptiometry were planned. Women receiving bone antiresorptive agents were excluded. Mean BMD changes from baseline to 12 and 24 months were tested between the treatment groups using 2-sample t tests and both g/cm2 (as percent changes) and T scores (as differences from baseline). RESULTS A total of 167 women with all 3 imaging studies were evaluable and form the basis of this report (T=89, E=78). Using T scores, the mean difference from baseline was significant between the 2 groups at 12 months at both the spine (P=.0002) and the hip (P=.0004), and at 24 months only at the hip (P=.02). CONCLUSION More bone loss occurred during the first 12 months of treatment with E compared with T, but by 2 years the differences were less apparent and bone loss with E had slowed.

Results of a Phase II Study of Weekly Paclitaxel Plus Carboplatin in Patients With Extensive Small-Cell Lung Cancer With Eastern Cooperative Oncology Group Performance Status of 2, or Age ≥ 70 Years

PURPOSE To determine the 1-year survival, response rate (RR), time to progression (TTP), and safety of weekly paclitaxel plus carboplatin (PC) in patients with extensive small-cell lung cancer (ESCLC) with an Eastern Cooperative Performance Status performance status (PS) of 2 or an age > or = 70 years. PATIENTS AND METHODS Patients were treated with PC (paclitaxel 80 mg/m(2) and carboplatin area under the curve = 2) by intravenous infusion on days 1, 8, and 15 of every 4-week cycle for up to six cycles. RESULTS Between July 2000 and December 2001, 77 eligible patients (50.6% were male, 97.4% were white, 44.2% had PS of 2, with median age of 74 years) with ESCLC were enrolled. Among the 66 patients who were assessable for response, 25 responded to treatment (one complete response and 24 partial responses), for an objective RR of 38%. There were eight cases of stable disease (12.1%) and 33 cases of progressive disease (50%). The median survival was 7.2 months (range, < 1 to 24.4 months), and the estimated 1-year survival rate was 30%. The median TTP was 3.5 months (range, < 1 to 21.2 months), and the estimated 1-year progression-free survival rate was 8%. The median duration of response was 4.5 months (range, 1.6 to 17.5 months). One death (sepsis) was possibly related to the study drugs. Grades 3 and 4 toxicities experienced by > or = 5% of patients included neutropenia (22.1%), fatigue (8.6%), anemia (5.2%), and nausea/vomiting (5.2%). CONCLUSION This regimen produced relatively few toxicities (only two of the 66 assessable patients received fewer than two cycles because of toxicity), and both the median and 1-year survival were similar to other regimens. This regimen may be a preferable treatment choice for patients with ESCLC who have a poor PS or who are aged > or = 70 years.