John Barstis

Multicenter, Randomized Trial for Stage IIIB or IV Non–Small-Cell Lung Cancer Using Weekly Paclitaxel and Carboplatin Followed by Maintenance Weekly Paclitaxel or Observation

PURPOSE To explore the efficacy and safety of three regimens of weekly paclitaxel plus carboplatin as initial therapy and the feasibility of subsequent maintenance therapy versus observation in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Four hundred one patients were randomly assigned to one of the following arms: arm 1, paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin (area under the curve [AUC] = 6) on day 1; arm 2, paclitaxel 100 mg/m2 and carboplatin (AUC = 2) weekly for 3 of 4 weeks; or arm 3, paclitaxel 150 mg/m2 cycle 1 and 100 mg/m2 cycle 2 and carboplatin (AUC = 2) weekly for 6 of 8 weeks. Patients who responded (n = 130) at week 16 were randomly assigned to either weekly paclitaxel therapy (70 mg/m2, 3 of 4 weeks; n = 65) or observation (n = 65). RESULTS For the 390 assessable patients, the objective response rates observed with initial therapy were 32% for arm 1, 24% for arm 2, and 18% for arm 3. The median time to progression and median survival times were 30 and 49 weeks for arm 1, 21 and 31 weeks for arm 2, and 27 and 40 weeks for arm 3, respectively. The 1-year survival rates were 47% for arm 1, 31% for arm 2, and 41% for arm 3. CONCLUSION Arm 1, paclitaxel 100 mg/m2 weekly for 3 of 4 weeks with carboplatin (AUC = 6) administered on day 1, demonstrates the most favorable therapeutic index in patients with advanced NSCLC.

The reliability of fine-needle aspiration biopsy as the initial diagnostic procedure for palpable masses: a 4-year experience of 730 patients from a community hospital-based outpatient aspiration biopsy clinic.

Fine‐needle aspiration biopsy (FNAB) is a reliable, rapid, minimally invasive alternative to surgical biopsy when it is performed by physician specialists for the diagnosis of palpable masses. FNAB may be under‐utilized in community hospitals in the U.S. because physicians without specialty training commonly provide the service, resulting in less reliable results.

Final Results of a Phase II Trial Evaluating Trastuzumab and Bevacizumab as First Line Treatment of HER2-Amplified Advanced Breast Cancer.

Background: Overexpression of HER2/neu is associated with upregulation of VEGF in human breast cancer cells in vitro. In xenograft models, superior efficacy is observed when anti-HER2 antibody trastuzumab (T) is given in combination with anti-VEGF antibody bevacizumab (B). Results from a phase I study of T + B (Breast Cancer Res Treat. 88:S124, 2004) were sufficiently positive to proceed with phase II testing. The objectives of this phase II study were to more fully determine clinical efficacy and safety of T + B.Methods: Women with normal cardiac function and bidimensionally measurable, HER2-amplified (FISH), metastatic or locally recurrent unresectable breast cancer were eligible. Patients (pts) were excluded if they had received chemotherapy in the metastatic setting, had CNS metastases, proteinuria, >3 different organ sites of metastasis, >50% parenchymal liver metastasis, or symptomatic lung metastases. Prior adjuvant T was allowed if it was discontinued ≥ 1 year before study entry. B (10mg/kg q 2 weeks) + T (4mg/kg loading, then 2mg/kg weekly) IV was given, per the results of phase I testing (above).Results: From 12/2004 to 4/2007, 50 pts were enrolled at 19 US sites. Pt characteristics: median age 58, prior breast surgery-38 (76%), prior radiation-22 (44%), prior (neo)adjuvant chemotherapy-26 (52%), prior anthracyclines-25 (50%), prior taxanes-20 (40%), prior endocrine therapy–23 (46%), visceral metastasis-36 (72%). A median of 6.25 cycles (range 1-34) were administered to pts. Drug-related adverse events (AEs) (all Grade (Gr) 3/4 and any events reported in >10% of patients, NCI-CTC v.2) included hypertension (N= 30: 18 Gr 3/4, 12 Gr 1/2), fever/chills/infusion reaction (N=18: 2 Gr 3/4, 16 Gr 1/2), headache (N=17: 2 Gr 3/4, 15 Gr 1/2), epistaxis (N=17: all Gr 1/2), fatigue (N=15: 1 Gr 3, 14 Gr 1/2), proteinuria (N=12: 4 Gr 3/4, 8 Gr 1/2), AST /ALT increase (N=12, all Gr 1/2), diarrhea (N=10: 1 Gr 3, 9 Gr 1/2), edema (N=6, all Gr 1/2), nail changes (N=6, all Gr 1/2), dyspnea (N=5: 2 Gr 3/4, 3 Gr 1/2), leucopenia (N=5: Gr 3/4=2, Gr 1/2=3), inflammatory demyelination (N=1, Gr 3), hyperglycemia (N=1, Gr 3), hyponatremia (N=1, Gr 3) and irregular menses (N=1, Gr 3). One pt developed a perforated ulcer and 4 weeks later died of sepsis (Gr 5). One Gr 4 cardiac AE was reported at the end of cycle 2 in a pt who had previously received doxorubicin. In addition, there were 9 Gr 2 and 9 Gr 1 cardiac AEs (all asymptomatic). Objective clinical responses (WHO criteria) were documented in 24 pts (48%), including 2 CRs. 15 pts (30%) had stable disease, 6 of which lasted ≥ 6 mos (12%) for a clinical benefit rate of 60%. No pts remain on active study treatment. The median time to progression (TTP) was 9.2 mos (95% CI: 5.4-20.5). No difference in TTP was detected between hormone receptor negative and positive tumor types. Median overall survival was 43.8 months (95% CI: 40.6,NA).Conclusions: These are the final results for the first phase II trial of 2 humanized antibodies given in combination to human subjects. The results show that T + B is clinically feasible and very active despite the absence of chemotherapy in HER2+ advanced breast cancer. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6094.

Treatment of Elderly Non–small Cell Lung Cancer Patients with Three Different Schedules of Weekly Paclitaxel in Combination with Carboplatin: Subanalysis of a Randomized Trial

Background: Administration of paclitaxel on a weekly schedule in combination with carboplatin is associated with a lower incidence of neuropathy and myelosuppression. The authors conducted subgroup analysis of their randomized phase II study of three different schedules of weekly paclitaxel with carboplatin to determine the efficacy of each regimen in elderly patients (aged ≥ 70 years) with advanced non–small-cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC were randomized to one of three different weekly paclitaxel/carboplatin regimens. After four cycles of chemotherapy, those with objective response or stable disease were randomized to weekly paclitaxel or observation as maintenance therapy. Four hundred three patients were enrolled in the study, of whom 111 (28%) were aged 70 years or older. Results: The treatment regimen of weekly paclitaxel (100 mg/m2 for 3 of 4 weeks) and carboplatin (area under the curve = 6 mg/ml/min once every 4 weeks) (arm 1) was associated with the best therapeutic index overall. The median survival and 1-year survival rates were 11.3 months and 50% for patients in the ≥70 years cohort versus 11.2 months and 46% for the <70 years cohort in arm 1. Efficacy results were comparable between the two groups in the other arms as well. Grade 4 neutropenia and febrile neutropenia occurred in 13.6% and 2.3% in the ≥70 years cohort compared with 4.5% and 1.1% in the <70 years cohort in arm 1. Conclusion: The weekly regimen of paclitaxel administered in combination with carboplatin is tolerated well by elderly NSCLC patients and has comparable efficacy with younger patients.

Breast‐Conservation Treatment Outcomes: A Community Hospital’s Experience

Abstract:  In the United States, the majority of early breast cancer patients choose breast‐conserving treatment in the community setting, yet there is a paucity of literature describing outcomes. In this paper, we describe our experience with breast‐conserving treatment in a small community hospital. Our hospital tumor registry was used to identify breast cancer cases diagnosed at our hospital between 1997 and 2003. We limited our study to those women with initial attempts at breast‐conserving surgery (BCS) who had follow‐up oncology treatment at on‐campus affiliated oncological services. We looked at factors that influence survival for early stage 0–II disease such as tumor and patient characteristics, completeness of local surgical tumor excision, and adjuvant treatment. We also evaluated the percentage of cases in which the initial BCS did not achieve adequate surgical oncological results and the number and type of subsequent surgeries that were required to achieve this goal. There were 185 cases with a median patient age of 55 and a median follow‐up time of 53 months. Most tumors were stage 0–I (68%) or stage II (23%). A single surgery was deemed sufficient to achieve the desired oncological outcome in 54% of cases; the remaining cases (46%) required additional surgeries. A final margin of 5 mm or greater was successfully achieved in 81% of cases. Ninety‐two percent of the patients underwent radiotherapy, 65% received hormonal therapy, and 49% underwent chemotherapy. One hundred and sixty one patients had successful breast‐conserving surgeries (87%) and 24 patients (13%) ultimately required mastectomy. There were four loco‐regional recurrences and 19 deaths during the study period. Our disease‐free survival rate for early‐stage cancer (stage 0–II) was 91% at 5 years. Our study shows that high‐quality patient outcomes for breast‐conserving treatment can be achieved in the community setting.

Myelopathy after radiation therapy and chemotherapy with capecitabine and gemcitabine.

This article describes a woman with metastatic upper gastrointestinal cancer who developed thoracic myelopathy unexpectedly after standard dosage and fractionation radiotherapy. She also was receiving capecitabine and gemcitabine concomitantly. There are few reported cases of chemotherapy potentiation of spinal cord radiation toxicity. These agents are known radiosensitizers, making it likely that they contributed to this adverse outcome. As these agents are increasingly incorporated into clinical trials of combined therapy, caution will be necessary in both trial design and clinical management.

Abstract 1385: Molecular changes in breast tumors following bevacizumab-based treatment: Final analysis of a randomized neoadjuvant study of bevacizumab or placebo, followed by chemotherapy with or without bevacizumab, in patients with stage II or III breast cancer

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Background: Bevacizumab (bev) has been widely studied in breast cancer (BC), yet no randomized trial in BC has reported in vivo molecular effects of bev on human tumor tissue. We conducted a trial to evaluate the safety, clinical & molecular effects of neoadjuvant chemotherapy plus bev for locally advanced BC. Methods: 90 pts were randomized (2:1:2:1) to 1 of 4 arms: Arm A: TAC (docetaxel, T: 75 mg/m2, doxorubicin, A: 50 mg/m2, cyclophosphamide, C: 500 mg/m2) + low dose bev (7.5 mg/kg); Arm B: TAC + low dose placebo (P); Arm C: TAC + standard dose bev (15 mg/kg); Arm D: TAC + Std-P. A run-in cycle of bev or P was followed by 6 cycles of TAC plus P or bev. Tumor biopsies pre- and 7-10 days post-run-in with bev or P were taken. Unblinding occurred post surgery (Sx): Arms A/C received maintenance bev to complete 52 wks, Arms B/D received no further P. Eligible patients were females with >3 cm, HER2(-) BC. Endpoints included safety and pathologic complete response (pCR) in breast & lymph nodes. To assess the effects of VEGF pathway inhibition on tumor vasculature, PCR analysis using the fluidigm array platform was performed on RNA from the pre- and post-run in samples to evaluate expression of 67 genes known to play a defined role in VEGF signaling. Results: 28 pts were assigned to Arm A, 30 to Arm C, and 32 to Arms B/D. 12 pts came off Tx before surgery (Arm A:2, Arm C:6, Arms B/D:4) and 78 received all Tx, underwent Sx and are evaluable for pCR. Two pts (6%) in Arms B/D, 5 pts (18%) in Arm A and 10 pts (33%) in Arm C had wound healing complications. 17% of pts in Arm C had Gr 3 (N=4) or Gr 4 (N=1) heart failure, none in Arms A/B/D. The pCR rate in evaluable patients was 18% (14/78): 5 (19%) Arm A, 3 (13%) Arm C, 6 (21%) Arms B/D. 45 samples (20 from Arms B/D and 25 from bev arms) were included in the pair-wise analysis to identify 6 genes that were differentially expressed. Bev resulted in a decrease in expression of Dll4, Cox2, Fibronectin (FN_EIIIB), angiopoietin 2 (Angpt2) and ESM1. In addition, upregulation of the cytokine, stromal derived growth factor (SDF1) was observed. Notably, genes such as CD31 or VE-cadherin were not appreciably differentially expressed. Of the genes that were downregulated, Dll4 and Angpt2 represent genes enriched in endothelial tip cells, which guide the migration of newly formed blood vessels. The decrease in these genes likely represents the effect of bev on reducing immature, growing vasculature in the tumor. Conclusions: This trial enabled the clinical and molecular evaluation of breast cancer tumor tissue pre and post-bev. Clinically, bev was associated with more wound healing and heart failure events and similar pCR rates compared to P. Tumor expression analysis for genes in the angiogenesis pathway supports the preclinical hypothesis that bev may primarily target immature tumor vasculature. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1385. doi:1538-7445.AM2012-1385