Phase II study evaluating lapatinib in combination with nab-paclitaxel in HER2-overexpressing metastatic breast cancer patients who have received no more than one prior chemotherapeutic regimen.

Lapatinib, an oral, reversible inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2) tyrosine kinase, has proven antitumor activity in HER2-positive metastatic breast cancer (MBC). Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. This was an open-label, single-arm, multicenter, Phase II study to evaluate the efficacy and safety of nab-paclitaxel plus lapatinib in women with HER2 over-expressing MBC who had received no more than one prior chemotherapeutic regimen. The primary efficacy endpoint was the overall response rate (ORR). This was defined as the percentage of patients having either a complete response (CR) or partial response (PR). Secondary efficacy endpoints included progression-free survival (PFS), overall survival, duration of response (DoR), time to response (TTR), and time to progression (TTP). Investigator-assessed ORR was 53 % (n = 32, 95 % confidence interval (CI): 40.7-66.0) with the majority of patient responses demonstrating a PR (47 %). Four (7 %) patient responses demonstrated a CR, and ten (17 %) a stable disease. The median Kaplan-Meier estimate of investigator-assessed PFS, DoR, TTR, and TTP was 39.7 weeks (95 % CI 34.1-63.9), 48.7 weeks (95 % CI 31.7-57.1), 7.8 weeks (95 % CI 7.4-8.1), and 41 weeks (95 % CI 39.1-64.6), respectively. Lapatinib 1,000 mg with nab-paclitaxel 100 mg/m(2) IV is feasible with manageable and predictable toxicity and an ORR of 53 % comparing favorably with other HER2-based combinations in this setting.

Increasing external beam dose for T1-T2 prostate cancer: effect on risk groups.

PURPOSE: The aim of this study was to investigate effect of increasing dose on risk groups for clinical failure (CF: local failure or distant failure or hormone ablation or PSA>or=25 ng/ml) in patients with T1-T2 prostate cancer treated with external beam radiotherapy. METHODS AND MATERIALS: Patients (n=4,537) were partitioned into nonoverlapping dose ranges, each narrow enough that dose was not a predictor of CF, and risk groups for CF were determined using recursive partitioning analysis (RPA). The same technique was applied to the highest of these dose ranges (70-76 Gy, 1,136 patients) to compare risk groups for CF in this dose range with the conventional risk-group classification. RESULTS: Cutpoints defining low-risk groups in each dose range shifted to higher initial PSA levels and Gleason scores with increasing dose. Risk groups for CF in the dose range 70-76 Gy were not consistent with conventional risk groups. CONCLUSIONS: The conventional classification of risk groups was derived in the early PSA era, when total doses<70 Gy were common, and it is inconsistent with risk groups for patients treated to doses>70 Gy. Risk-group classifications must be continuously re-examined whenever the trend is toward increasing total dose.

Health-related quality of life in men receiving prostate brachytherapy on RTOG 98-05.

PURPOSE: To prospectively assess health-related quality of life (HRQOL) during the first year after treatment with prostate brachytherapy (PB) alone for T1c-2a prostate cancer. MATERIALS AND METHODS: Ninety-eight patients from 24 institutions were eligible and properly entered on this study. All patients were treated with PB alone using I-125 (Oncura Model 6711). The prescription dose was 145 Gy. Three separate health-related quality of life questionnaires (HRQOL) (Functional Assessment of Cancer Therapy-Prostate [FACT-P], Sexual Adjustment Questionnaire [SAQ], and International Prostate Symptom Score [IPSS]) were self-administered before and after PB (baseline; 3, 6, 9, and 12 months after PB). The standard error of the mean (SEM) was used to analyze changes in HRQOL scores over time. Patients who improved greater than the SEM were categorized as improved; patients that declined greater than the SEM were categorized as declined; patients were otherwise categorized as stable. All changes are measured using the pretreatment HRQOL score as baseline. RESULTS: The percentage of men who reported the ability to have an erection decreased from 73% at baseline (65% unassisted, 8% assisted) to 57% at 1 year (36% unassisted, 21% assisted). The rate of urinary incontinence increased to 14% at 6 months but had decreased to 1% at the 12-month follow-up. At 1 year after PB, 80% of men reported decreased sexual functioning according to SAQ scores. More than 60% of men reported decreased urinary function at 12 months compared with baseline. CONCLUSIONS: This article represents the first prospective, multi-institutional study of HRQOL in men treated with PB and demonstrates that patients undergoing PB have a very high overall HRQOL. The rate of incontinence by 1 year after PB is low, but many patients continue to have obstructive symptoms at 1 year. Although 78% of 1-year respondents state that they can achieve an erection with or without assistance, almost 50% report a decrease in sexual function.

Comparison of conventional-dose vs high-dose conformal radiation therapy in clinically localized adenocarcinoma of the prostate: a randomized controlled trial.

CONTEXT: Clinically localized prostate cancer is very prevalent among US men, but recurrence after treatment with conventional radiation therapy is common. OBJECTIVE: To evaluate the hypothesis that increasing the radiation dose delivered to men with clinically localized prostate cancer improves disease outcome. DESIGN, SETTING, AND PATIENTS: Randomized controlled trial of 393 patients with stage T1b through T2b prostate cancer and prostate-specific antigen (PSA) levels less than 15 ng/mL randomized between January 1996 and December 1999 and treated at 2 US academic institutions. Median age was 67 years and median PSA level was 6.3 ng/mL. Median follow-up was 5.5 (range, 1.2-8.2) years. INTERVENTION: Patients were randomized to receive external beam radiation to a total dose of either 70.2 Gy (conventional dose) or 79.2 Gy (high dose). This was delivered using a combination of conformal photon and proton beams. MAIN OUTCOME MEASURE: Increasing PSA level (ie, biochemical failure) 5 years after treatment. RESULTS: The proportions of men free from biochemical failure at 5 years were 78.8% [corrected] (95% confidence interval, 73.1%-84.6%) [corrected] for conventional-dose and 91.3% [corrected] (95% confidence interval, 87.2%-95.4%) [corrected] for high-dose therapy (P<.001), a 59% [corrected] reduction in the risk of failure. The advantage to high-dose therapy was statistically significant [corrected] in both the low-risk subgroup [corrected] (risk reduction, 84% [P<.001]) [corrected] There has been no significant difference in overall survival rates between the treatment groups. Only 1% of patients receiving conventional-dose and 2% receiving high-dose radiation experienced acute urinary or rectal morbidity of Radiation Therapy Oncology Group (RTOG) grade 3 or greater. So far, only 2% and 1%, respectively, have experienced late morbidity of RTOG grade 3 or greater. CONCLUSIONS: Men with clinically localized prostate cancer have a lower risk of biochemical failure if they receive high-dose rather than conventional-dose conformal radiation. This advantage was achieved without any associated increase in RTOG grade 3 acute or late urinary or rectal morbidity.

Randomized trial of lapatinib versus placebo added to paclitaxel in the treatment of human epidermal growth factor receptor 2-overexpressing metastatic breast cancer.

PURPOSE: Lapatinib is an oral small-molecule tyrosine kinase inhibitor of both epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2). This study is designed to test whether the addition of lapatinib to paclitaxel improves overall survival (OS) compared with placebo plus paclitaxel in patients with HER2-overexpressing metastatic breast cancer (MBC). PATIENTS AND METHODS: This phase III, randomized, double-blind study assessed the efficacy and safety of lapatinib plus paclitaxel compared with placebo plus paclitaxel in patients with newly diagnosed HER2-positive MBC. The primary end point was OS. Secondary end points included progression-free survival (PFS), overall response rate (ORR), clinical benefit rate, and safety. RESULTS: The addition of lapatinib to paclitaxel significantly improved OS versus paclitaxel (treatment hazard ratio [HR], 0.74; 95% CI, 0.58 to 0.94; P = .0124); median OS was 27.8 versus 20.5 months, respectively. Median PFS was prolonged by 3.2 months, from 6.5 months with placebo plus paclitaxel to 9.7 months with lapatinib plus paclitaxel (HR, 0.52; 95% CI, 0.42 to 0.64; stratified log-rank P < .001). ORR was significantly higher with lapatinib plus paclitaxel compared with placebo plus paclitaxel (69% v 50%, respectively; P < .001). The incidence of grades 3 and 4 diarrhea and neutropenia was higher in the lapatinib plus paclitaxel arm. Only 4% of patients in this group reported febrile neutropenia. Cardiac events were low grade, asymptomatic, and mostly reversible. The incidence of hepatic events was similar in both arms. There were no fatal adverse events in the lapatinib plus paclitaxel arm. CONCLUSION: This trial demonstrated that lapatinib combined with paclitaxel offers a significant and clinically meaningful survival advantage over paclitaxel alone in patients with HER2-positive MBC.

Phase II study of predictive biomarker profiles for response targeting human epidermal growth factor receptor 2 (HER-2) in advanced inflammatory breast cancer with lapatinib monotherapy.

PURPOSE: Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Lapatinib, an oral reversible inhibitor of epidermal growth factor receptor (EGFR) and human EGFR 2 (HER-2), demonstrated clinical activity in four of five IBC patients in phase I trials. We conducted a phase II trial to confirm the sensitivity of IBC to lapatinib, to determine whether response is HER-2 or EGFR dependent, and to elucidate a molecular signature predictive of lapatinib sensitivity. PATIENTS AND METHODS: Our open-label multicenter phase II trial (EGF103009) assessed clinical activity and safety of lapatinib monotherapy in patients with recurrent or anthracycline-refractory IBC. Patients were assigned to cohorts A (HER-2-overexpressing [HER-2+]) or B(HER-2-/EGFR+) and fresh pretreatment tumor biopsies were collected. RESULTS: Forty-five patients (30 in cohort A; 15 in cohort B) received lapatinib 1,500 mg once daily continuously. Clinical presentation and biomarker analyses demonstrated a tumor molecular signature consistent with IBC. Lapatinib was generally well tolerated, with primarily grade 1/2 skin and GI toxicities. Fifteen patients (50%) in cohort A had clinical responses to lapatinib in skin and/or measurable disease (according to Response Evaluation Criteria in Solid Tumors) compared with one patient in cohort B. Within cohort A, phosphorylated (p) HER-3 and lack of p53 expression predicted for response to lapatinib (P < .05). Tumors coexpressing pHER-2 and pHER-3 were more likely to respond to lapatinib (nine of 10 v four of 14; P = .0045). Prior trastuzumab therapy and loss of phosphate and tensin homolog 10 (PTEN) did not preclude response to lapatinib. CONCLUSION: Lapatinib is well tolerated with clinical activity in heavily pretreated HER-2+, but not EGFR+/HER-2-, IBC. In this study, coexpression of pHER-2 and pHER-3 in tumors seems to predict for a favorable response to lapatinib. These findings warrant further investigation of lapatinib monotherapy or combination therapy in HER-2+ IBC.

Measurement of plasma-derived substance P: biological, methodological, and statistical considerations.

The undecapeptide substance P (SP) is a member of the tachykinin family of neurotransmitters, which has a pivotal role in the regulation of inflammatory and immune responses. One of the major barriers to the study of the in vivo role of SP in a number of immune disorders is the accurate measurement of SP in fluids. This is reflected in the variability of reported SP levels in serum and plasma of humans in both healthy and diseased states. This study was initiated in order to identify sources of variability by the comparative evaluation of the influences of sample preparation and analytical detection methods on the measurement of SP in plasma. The results indicate that sample preparation (peptide extraction versus no extraction) and the choice of analytical method for SP quantitation may yield significantly different values and may contribute to the variability in SP values reported in the literature. These results further emphasize the need for careful consideration in the selection of methods for SP quantitation, as well as caution in the interpretation and comparison of data reported in the literature.