A phase II prospective multi-institutional trial of adjuvant active specific immunotherapy following curative resection of colorectal cancer hepatic metastases: cancer and leukemia group B study 89903.

BACKGROUND: Patients with curatively resected colorectal cancer hepatic metastases often harbor occult metastatic disease and are at high risk of experiencing recurrence. This patient cohort is ideally suited to test novel therapies such as immunotherapy. We treated patients-post-hepatic resection-with anti-idiotype monoclonal antibody vaccines to the tumor-associated antigens carcinoembryonic antigen (CeaVac) and human milk fat globule (TriAb), both of which are co-expressed in more than 90% of colorectal cancer patients. METHODS: Vaccinations commenced 6-12 weeks post-hepatic resection and consisted of four biweekly treatments of 2 mg CeaVac and TriAb, then monthly treatments for 2 years, then on every other month for 3 years. The primary endpoint was to investigate the proportion of patients recurrence-free at 2 years, and the objective of the study was to demonstrate that at least 58% would be recurrence-free at this time to consider the regimen worthy of further study. RESULTS: Between July 2001 and October 2004, 56 patients were accrued; 52 patients with margin-negative resection were eligible for analysis. Hepatic lobectomy was performed in 56% of patients with a median of one metastasis (range 1-3). Of the 52 eligible patients, 49 were evaluable for the primary end point. Median follow-up was 3.1 years. The proportion of patients recurrence-free at 2 years was 39%, with a lower confidence bound (LCB) of 0.29. Median recurrence-free survival was 16 months. The 2-year overall survival was 94% (95% CI, 0.81, 0.98). Only 10% of patients had documented grade-3 adverse events. CONCLUSIONS: Anti-idiotype monoclonal antibody vaccine therapy with CeaVac and TriAb as an adjuvant to curative resection of colorectal cancer hepatic metastases is well tolerated but did not improve 2-year recurrence-free survival when compared with the expected value of 40% reported for hepatic resection alone.

A comparison of the pharmacokinetics and pharmacodynamics of docetaxel between African-American and Caucasian cancer patients: CALGB 9871.

PURPOSE: Increased clearance of drugs, such as oral cyclosporine, that are CYP3A and/or ABCB1 (P-gp/MDR1) substrates was reported in African-American compared with Caucasian patients. We hypothesized that the pharmacokinetics and pharmacodynamics of docetaxel, an i.v. administered cytotoxic and substrate for CYP3A4, CYP3A5, and ABCB1, would differ between African-American and Caucasian patients. EXPERIMENTAL DESIGN: We investigated population pharmacokinetics and pharmacodynamics and the pharmacogenetics of CYP3A4, CYP3A5, and ABCB1 in African-American and Caucasian cancer patients who received docetaxel 75 or 100 mg/m(2) as a 1-h i.v. infusion. Plasma docetaxel concentrations were measured by high-performance liquid chromatography. Clinical toxicity and absolute neutrophil count (ANC) were monitored on days 8, 15, and 22 postadministration of docetaxel. Using a limited sampling strategy and nonlinear mixed-effects modeling, each patient's docetaxel clearance was estimated. Genotyping for known polymorphisms in CYP3A4, CYP3A5, and ABCB1 was done. RESULTS: We enrolled 109 patients: 40 African-Americans (26 males; 14 females), with a median age of 61 years (range, 29-73), and 69 Caucasians (43 males; 26 females), with a median age of 63 years (range, 38-81). There was no difference in the geometric mean docetaxel clearance between African-American patients [40.3 L/h; 95% confidence interval (95% CI), 19.3-84.1] and Caucasian patients (41.8 L/h; 95% CI, 22.0-79.7; P = 0.6). We observed no difference between African-American and Caucasian patients in the percentage decrease in ANC nor were docetaxel pharmacokinetic parameters related to the genotypes studied. CONCLUSIONS: Docetaxel clearance and its associated myelosuppression were similar in African-American and Caucasian cancer patients.

The impact of induction chemotherapy and the associated tumor response on subsequent radiation-related changes in lung function and tumor response.

PURPOSE: To assess the impact of induction chemotherapy, and associated tumor shrinkage, on the subsequent radiation-related changes in pulmonary function and tumor response. METHODS AND MATERIALS: As part of a prospective institutional review board-approved study, 91 evaluable patients treated definitively with thoracic radiation therapy (RT) for unresectable lung cancer were analyzed. The rates of RT-associated pulmonary toxicity and tumor response were compared in the patients with and without pre-RT chemotherapy. In the patients receiving induction chemotherapy, the rates of RT-associated pulmonary toxicity and tumor response were compared in the patients with and without a response (modified Response Evaluation Criteria in Solid Tumor criteria) to the pre-RT chemotherapy. Comparisons of the rates of improvements in pulmonary function tests (PFTs) post-RT, dyspnea requiring steroids, and percent declines in PFTs post-RT were compared in patient subgroups using Fisher's exact test, analysis of variance, and linear or logistic regression. RESULTS: The use of pre-RT chemotherapy appears to increase the rate of radiation-induced pneumonitis (p = 0.009-0.07), but has no consistent impact on changes in PFTs. The degree of induction chemotherapy-associated tumor shrinkage is not associated with the rate of subsequent RT-associated pulmonary toxicity. The degree of tumor response to chemotherapy is not related to the degree of tumor response to RT. CONCLUSIONS: Additional study is needed to better clarify the impact of chemotherapy on radiation-associated disfunction.

Updated assessment of the six-minute walk test as predictor of acute radiation-induced pneumonitis.

PURPOSE: To assess the utility of the 6-minute walk test (6MWT) as a predictor of symptomatic radiation-induced pneumonitis (RP). METHODS: As part of a prospective trial to study radiation-induced lung injury, 53 patients receiving thoracic radiotherapy (RT) underwent a pre-RT 6MWT, pulmonary function tests (PFTs), and had >or=3-month follow-up for prospective assessment of Grade 2 or worse RP (requiring medications or worse). Dosimetric parameters (e.g., the percentage of lung receiving >or=30 Gy) were extracted from the lung dose-volume histogram. The correlations between the 6MWT and PFT results were assessed using Pearson's correlation. The receiver operating characteristic technique was used in patient subgroups to evaluate the predictive capacities for RP of the dosimetric parameters, 6MWT results, and PFT results, or the combination (using discriminant analysis) of all three metrics. ROCKIT software was used to compare the receiver operating characteristic areas between each predictive model. The association of the decline in 6MWT with the development of RP was evaluated using Fisher's exact test. RESULTS: The pre-RT PFT and 6MWT results correlated weakly (r = 0.44-0.57, p or=30 Gy, receiver operating characteristic area 0.73, p = 0.03). Including the PFT or 6MWT results with the percentage of lung receiving >or=30 Gy did not improve the predictions. The predictive abilities of dosimetric-based models improved when the analysis was restricted to those patients whose tumors were not causing regional lung dysfunction. No correlation was found between the decline in the 6MWT result and the RP rate (p = 0.6). CONCLUSION: Although the PFTs and 6MWT are related to each other, the correlation coefficients were weak, suggesting that they could be measuring different physiologic functions. In the present data set, the addition of the PFTs or 6MWT did not increase the ability of the dosimetric parameters to predict for acute symptomatic RP. Additional work is needed to better understand the interaction among the PFT results, exercise tolerance (6MWT), and the risk of RT-induced lung dysfunction.

Prospective assessment of dosimetric/physiologic-based models for predicting radiation pneumonitis.

PURPOSE: Clinical and 3D dosimetric parameters are associated with symptomatic radiation pneumonitis rates in retrospective studies. Such parameters include: mean lung dose (MLD), radiation (RT) dose to perfused lung (via SPECT), and pre-RT lung function. Based on prior publications, we defined pre-RT criteria hypothesized to be predictive for later development of pneumonitis. We herein prospectively test the predictive abilities of these dosimetric/functional parameters on 2 cohorts of patients from Duke and The Netherlands Cancer Institute (NKI). METHODS AND MATERIALS: For the Duke cohort, 55 eligible patients treated between 1999 and 2005 on a prospective IRB-approved study to monitor RT-induced lung injury were analyzed. A similar group of patients treated at the NKI between 1996 and 2002 were identified. Patients believed to be at high and low risk for pneumonitis were defined based on: (1) MLD; (2) OpRP (sum of predicted perfusion reduction based on regional dose-response curve); and (3) pre-RT DLCO. All doses reflected tissue density heterogeneity. The rates of grade > or =2 pneumonitis in the "presumed" high and low risk groups were compared using Fisher's exact test. RESULTS: In the Duke group, pneumonitis rates in patients prospectively deemed to be at "high" vs. "low" risk are 7 of 20 and 9 of 35, respectively; p = 0.33 one-tailed Fisher's. Similarly, comparable rates for the NKI group are 4 of 21 and 6 of 44, respectively, p = 0.41 one-tailed Fisher's. CONCLUSION: The prospective model appears unable to accurately segregate patients into high vs. low risk groups. However, considered retrospectively, these data are consistent with prior studies suggesting that dosimetric (e.g., MLD) and functional (e.g., PFTs or SPECT) parameters are predictive for RT-induced pneumonitis. Additional work is needed to better identify, and prospectively assess, predictors of RT-induced lung injury.

Radiation-induced narrowing of the tracheobronchial tree: an in-depth analysis.

PURPOSE: Symptomatic narrowing of the tracheobronchial tree is not a common clinical problem after conventional-dose external beam radiation therapy but has been described when higher doses are utilized. This in-depth study quantifies changes in the caliber of the trachea and mainstem bronchi after high-dose external beam radiation therapy (EBRT). METHODS AND MATERIALS: As part of an IRB-approved prospective clinical trial to assess for radiation-induced lung injury, patients with thoracic malignancies had pre- and serial post-RT CT scans in the radiation oncology department. This report focuses on 18 enrolled patients who received high-dose (> or = 73.6 Gy) EBRT for NSCLC. The caliber of the trachea, right mainstem bronchus, and left mainstem bronchus were measured utilizing three-dimensional coordinates in axial and coronal planes such that multiple measurements were made of each structure. The decrease in airway caliber was tested for significance using a one-sided Wilcoxon matched-pairs signed-ranks test. The correlation between airway caliber changes, dose, and follow-up interval was tested using the Spearman rank correlation coefficient and the effect of chemotherapy on airway narrowing was evaluated with a one-sided exact Wilcoxon rank sum test. RESULTS: There was no significant narrowing of the trachea for all dose and time points. There were significant decreases in the caliber of both mainstem bronchi on axial measurements (p = 0.07 and 0.005 for right and left mainstem bronchi, respectively). Decrease in airway caliber ranged from 6 to 57% and appeared to be dose dependent (p = 0.08), progressed with increasing time post-RT (p = 0.04), and was worse in patients who also received chemotherapy (p = 0.04). CONCLUSION: High-dose EBRT (> or = 73.6 Gy) appears to cause narrowing of the mainstem bronchi as early as 3 months post radiation therapy. Additional study is needed to assess the impact of such narrowing on RT-induced pulmonary symptoms.

Impact of hospital procedure volume on surgical operation and long-term outcomes in high-risk curatively resected rectal cancer: findings from the Intergroup 0114 Study.

PURPOSE: Prior studies have demonstrated superior outcomes after a curative surgical resection of rectal cancer at hospitals where the volume of such surgeries is high. However, because these studies often lack detailed information on tumor and treatment characteristics as well as cancer recurrence, the true nature of this relation remains uncertain. PATIENTS AND METHODS: We studied a nested cohort of 1,330 patients with stage II and stage III rectal cancer participating in a multicenter, adjuvant chemoradiotherapy trial. We analyzed differences in rates of sphincter-preserving operations, overall survival, and cancer recurrence by hospital surgical volume. RESULTS: We observed a significant difference in the rates of abdominoperineal resections across tertiles of hospital procedure volume (46.3% for patients resected at low-volume, 41.3% at medium-volume, and 31.8% at high-volume hospitals; P <.0001), even after adjustment for tumor distance from the anal verge. However, this higher rate of sphincter-sparing operations at high-volume centers was not accompanied by any increase in recurrence rates. Hospital surgical volume did not predict overall, disease-free, recurrence-free, or local recurrence-free survival. However, among patients who did not complete the planned adjuvant chemoradiotherapy (270 patients), those who underwent surgery at low-volume hospitals had a significant increase in cancer recurrence (adjusted hazard ratio, 1.94; 95% CI, 1.01 to 3.72; P =.04 for the trend) and a nonsignificant trend toward increased overall mortality (P =.08) and local recurrence (P =.10). In contrast, no significant volume-outcome relation was noted among patients who did complete postoperative therapy. CONCLUSION: Using prospectively recorded data, we found that hospital surgical volume had no significant effect on rectal cancer recurrence or survival when patients completed standard adjuvant therapy. Sphincter-preserving surgery was more commonly performed at high-volume centers.

Impact of body mass index on outcomes and treatment-related toxicity in patients with stage II and III rectal cancer: findings from Intergroup Trial 0114.

PURPOSE: To study the relationship between body mass index (BMI) and rates of sphincter-preserving operations, overall survival, cancer recurrence, and treatment-related toxicities in patients with rectal cancer. PATIENTS AND METHODS: We evaluated a nested cohort of 1,688 patients with stage II and III rectal cancer participating in a randomized trial of postoperative fluorouracil-based chemotherapy and radiation therapy. RESULTS: Obese patients were more likely to undergo an abdominoperineal resection (APR) than normal-weight patients (odds ratio, 1.77; 95% CI, 1.27 to 2.46). When analyzed by sex, increasing adiposity in men was a strong predictor of having an APR (P <.0001). Obese men with rectal cancer were also more likely than normal-weight men to have a local recurrence (hazard ratio [HR], 1.61; 95% CI, 1.00 to 2.59). In contrast, obesity was not predictive of cancer recurrence in women, nor was BMI predictive of overall mortality in either men or women. Underweight patients had an increased risk of death (HR, 1.43; 95% CI, 1.08 to 1.89) compared with normal-weight patients but no increase in cancer recurrences. Among all study participants, obese patients had a significantly lower rate of grade 3 to 4 leukopenia, neutropenia, and stomatitis and a lower rate of any grade 3 or worse toxicity when compared with normal-weight individuals. CONCLUSION: Increasing BMI in male patients with rectal cancer is associated with a decreased likelihood of sphincter preservation and a higher chance of local recurrence. For both men and women, overweight and obese patients experience less toxicity associated with adjuvant chemoradiotherapy, suggesting that actual body weight dosing of fluorouracil for obese patients is justified.

A phase I trial of escalating doses of trastuzumab combined with daily subcutaneous interleukin 2: report of cancer and leukemia group B 9661.

PURPOSE: The purpose of this study was to determine the toxicity of escalating doses of trastuzumab when combined with a fixed dose regimen of interleukin (IL)-2. EXPERIMENTAL DESIGN: Eligible patients had nonhematological malignancies for which standard therapy did not exist or was no longer effective and had tumors that overexpressed HER2. IL-2 was initially administered at a dose of 1.25 million IU/m(2) (low dose) s.c. daily except for 3 days every 2 weeks, when it was given at a dose of 15 million IU/m(2) (intermediate dose). These doses were reduced to 1.0 million and 12 million IU/m(2) after the first 18 patients. Trastuzumab was administered i.v. just before the first intermediate IL-2 dose and was escalated in cohorts of six or more patients from 1 mg/kg every 2 weeks to 8 mg/kg weekly. In vitro cytotoxicity testing was performed with patient peripheral blood mononuclear cells and HER2-overexpressing cell lines. RESULTS: Forty-five patients were treated. Dose-related toxicity from trastuzumab was not observed. IL-2-related toxicities such as fever, chills, and fatigue were less common with the reduced doses of IL-2. There were two grade 3 and three grade 4 pulmonary reactions. Four major responses were observed, all in breast cancer patients treated with trastuzumab doses of at least 4.0 mg/kg. Although IL-2 produced expansion of natural killer cell subsets, there was no correlation between in vitro cytotoxicity and clinical response. CONCLUSIONS: A regimen of IL-2 combined with trastuzumab is feasible, and response numbers are encouraging. Further testing of this regimen is warranted if the pulmonary toxicity can be ameliorated.

Cancer and leukemia group B (CALGB) 89805: phase II chemoradiation trial using gemcitabine in patients with locoregional adenocarcinoma of the pancreas.

PURPOSE: Determine the safety and efficacy of twice weekly gemcitabine and concurrent radiation to the upper abdomen followed by weekly gemcitabine in patients with surgically staged, locally advanced pancreatic cancer. METHODS: Patients with surgically staged, locally advanced, nonmetastatic adenocarcinoma of the pancreas were treated with intravenous gemcitabine administered twice weekly (40 mg/m2/d) for 5 wk concurrent with upper abdominal radiation (50.4 Gy in 180 cGy daily fractions over 5.5 wk). At the completion of the chemoradiation, patients without disease progression were given gemcitabine (1000 mg/m2) weekly for five cycles. Each cycle consisted of 3 wk of treatment followed by 1 wk without treatment. Disease progression and response were assessed at 6- to 8-wk intervals. RESULTS: From February through December 1999, 43 patients were entered into this phase II trial, 39 of whom were evaluable for treatment response. The median age was 59 yr (range: 39-84 yr); there were 18 males (47%) in the study. Grade III and IV hematologic toxicity occurred in 48 and 21% of patients, respectively, and was primarily leukocytopenia and neutropenia. Grade III and IV gastrointestinal toxicities occurred in 31 and 10% of patients, respectively. There was one death attributed to sepsis. The concurrent gemcitabine and radiation portion of the study was completed without treatment interruptions in 56% of patients. The overall median survival was 8.2 mo and the median survival in the 44% of patients demonstrating a sustained CA-19-9 response was 13.5 mo. Only six patients experienced local regional progression as their first site of failure. Two patients (5%) were still alive at 35 and 41 mo posttreatment. CONCLUSIONS: These results confirm the feasibility of twice weekly gemcitabine and radiation for the treatment of pancreatic cancer. Although this treatment strategy produced good local regional control, this did not result in a survival advantage. Stratifying patients by performance status and CA-19-9 response in future trials may be of value.

Regional lung density changes after radiation therapy for tumors in and around thorax.

PURPOSE: To study the temporal nature of regional lung density changes and to assess whether the dose-dependent nature of these changes is associated with patient- and treatment-associated factors. METHODS AND MATERIALS: Between 1991 and 2004, 118 patients with interpretable pre- and post-radiation therapy (RT) chest computed tomography (CT) scans were evaluated. Changes in regional lung density were related to regional dose to define a dose-response curve (DRC) for RT-induced lung injury using three-dimensional planning tools and image fusion. Multiple post-RT follow-up CT scans were evaluated by fitting linear-quadratic models of density changes on dose with time as the covariate. Various patient- and treatment-related factors were examined as well. RESULTS: There was a dose-dependent increase in regional lung density at nearly all post-RT follow-up intervals. The population volume-weighted changes evolved over the initial 6-month period after RT and reached a plateau thereafter (p < 0.001). On univariate analysis, patient age greater than 65 years (p = 0.003) and/or the use of pre-RT surgery (p < 0.001) were associated with significantly greater changes in CT density at both 6 and 12 months after RT, but the magnitude of this effect was modest. CONCLUSIONS: There appears to be a temporal nature for the dose-dependent increases in lung density. Nondosimetric clinical factors tend to have no, or a modest, impact on these changes.

Multivitamin use is not associated with cancer recurrence or survival in patients with stage III colon cancer: findings from CALGB 89803.

PURPOSE: Multivitamin use is widespread in the United States, especially among patients with cancer. However, the influence of multivitamin supplementation on cancer recurrence and death after a curative resection of colon cancer is unknown. PATIENTS AND METHODS: We conducted a prospective, observational study of 1,038 patients with stage III colon cancer enrolled in a randomized adjuvant chemotherapy trial. Patients reported on multivitamin use during and 6 months after adjuvant chemotherapy. Patients were observed until March 2009 for disease recurrence and death. To minimize bias by occult recurrence, we excluded patients who recurred or died within 90 days of their multivitamin assessment. RESULTS: Among 1,038 patients, 518 (49.9%) reported multivitamin use during adjuvant chemotherapy. Compared with nonusers, the multivariate hazard ratio (HR) for disease-free survival was 0.94 (95% CI, 0.77 to 1.15) for patients who used multivitamins. Similarly, multivitamin use during adjuvant chemotherapy was not significantly associated with recurrence-free survival (multivariate HR, 0.93; 95% CI, 0.75 to 1.15) or overall survival (multivariate HR 0.92; 95% CI, 0.74 to 1.16). Multivitamin use reported 6 months after completion of adjuvant chemotherapy was also not associated with improved patient outcome, and consistent use both during and following adjuvant therapy conferred no benefit. Neither an increasing number of tablets nor increasing duration of use before cancer diagnosis was associated with cancer recurrence or mortality. Multivitamin use also did not improve the rates of grade 3 and higher GI toxicity. CONCLUSION: Multivitamin use during and after adjuvant chemotherapy was not significantly associated with improved outcomes in patients with stage III colon cancer.

Randomized phase II study of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in patients with metastatic pancreatic cancer: CALGB 89904.

PURPOSE: The relative value of gemcitabine-based combination chemotherapy therapy and prolonged infusions of gemcitabine in patients with advanced pancreatic cancer remains controversial. We explored the efficacy and toxicity of gemcitabine administered at a fixed dose rate or in combination with cisplatin, docetaxel, or irinotecan in a multi-institutional, randomized, phase II study. PATIENTS AND METHODS: Patients with metastatic pancreatic cancer were randomly assigned to one of the following four regimens: gemcitabine 1,000 mg/m(2) on days 1, 8, and 15 with cisplatin 50 mg/m(2) on days 1 and 15 (arm A); gemcitabine 1,500 mg/m(2) at a rate of 10 mg/m(2)/min on days 1, 8, and 15 (arm B); gemcitabine 1,000 mg/m(2) with docetaxel 40 mg/m(2) on days 1 and 8 (arm C); or gemcitabine 1,000 mg/m(2) with irinotecan 100 mg/m(2) on days 1 and 8 (arm D). Patients were observed for response, toxicity, and survival. Results Two hundred fifty-nine patients were enrolled onto the study, of whom 245 were eligible and received treatment. Anticipated rates of myelosuppression, fatigue, and expected regimen-specific toxicities were observed. The overall tumor response rates were 12% to 14%, and the median overall survival times were 6.4 to 7.1 months among the four regimens. CONCLUSION: Gemcitabine/cisplatin, fixed dose rate gemcitabine, gemcitabine/docetaxel, and gemcitabine/irinotecan have similar antitumor activity in metastatic pancreatic cancer. In light of recent negative randomized studies directly comparing several of these regimens with standard gemcitabine, none of these approaches can be recommended for routine use in patients with this disease.

Association between RT-induced changes in lung tissue density and global lung function.

PURPOSE: To assess the association between radiotherapy (RT)-induced changes in computed tomography (CT)-defined lung tissue density and pulmonary function tests (PFTs). METHODS AND MATERIALS: Patients undergoing incidental partial lung RT were prospectively assessed for global (PFTs) and regional (CT and single photon emission CT [SPECT]) lung function before and, serially, after RT. The percent reductions in the PFT and the average changes in lung density were compared (Pearson correlations) in the overall group and subgroups stratified according to various clinical factors. Comparisons were also made between the CT- and SPECT-based computations using the Mann-Whitney U test. RESULTS: Between 1991 and 2004, 343 patients were enrolled in this study. Of these, 111 patients had a total of 203 concurrent post-RT evaluations of changes in lung density and PFTs available for the analyses, and 81 patients had a total of 141 concurrent post-RT SPECT images. The average increases in lung density were related to the percent reductions in the PFTs, albeit with modest correlation coefficients (range, 0.20-0.43). The analyses also indicated that the association between lung density and PFT changes is essentially equivalent to the corresponding association with SPECT-defined lung perfusion. CONCLUSION: We found a weak quantitative association between the degree of increase in lung density as defined by CT and the percent reduction in the PFTs.

Phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal dysfunction: CALGB 60301.

PURPOSE: We sought to characterize the pharmacokinetics (PK) and determine a tolerable dose of oral sorafenib in patients with hepatic or renal dysfunction. PATIENTS AND METHODS: Patients were assigned to one of nine cohorts: cohort 1, bilirubin < or = upper limit of normal (ULN) and AST < or = ULN and creatinine clearance (CC) > or = 60 mL/min; cohort 2, bilirubin more than ULN but < or = 1.5x ULN and/or AST more than ULN; cohort 3, CC between 40 and 59 mL/min; cohort 4, bilirubin more than 1.5x ULN to < or = 3x ULN (any AST); cohort 5, CC between 20 and 39 mL/min; cohort 6, bilirubin more than 3x ULN to 10x ULN (any AST); cohort 7, CC less than 20 mL/min; cohort 8, albumin less than 2.5 mg/dL (any bilirubin/AST); and cohort 9, hemodialysis. Sorafenib was administered as a 400-mg dose on day 1 for PK, and continuous daily dosing started on day 8. RESULTS: Of 150 registered patients, 138 patients were treated. With the exception of cohorts 6 and 7, at least 12 patients per cohort were assessable, and the dose level with prospectively defined dose-limiting toxicity in less than one third of patients by day 29 was considered tolerable. No significant associations between the sorafenib PK and cohort were found. CONCLUSION: We recommend the following empiric sorafenib starting doses by cohort: cohort 1, 400 mg twice a day; cohort 2, 400 mg twice a day; cohort 3, 400 mg twice a day; cohort 4, 200 mg twice a day; cohort 5, 200 mg twice a day; cohort 6, not even 200 mg every third day tolerable; cohort 7, not defined; cohort 8, 200 mg each day; and cohort 9, 200 mg each day.

Prospective assessment of radiotherapy-associated cardiac toxicity in breast cancer patients: analysis of data 3 to 6 years after treatment.

BACKGROUND: Radiation therapy (RT) to the left breast/chest wall has been linked with cardiac dysfunction. Previously, the authors identified cardiac perfusion defects in approximately 50% to 60% of patients 0.5 to 2 years post-RT. In the current study, they assessed the persistence of these defects 3 to 6 years post-RT. METHODS: From 1998 to 2006, 160 patients with left-sided breast cancer were enrolled onto an Institutional Review Board-approved, prospective study. All patients received tangential photons to the left breast/chest wall. Patients had pre-RT and serial post-RT single-photon emission computed tomography (SPECT) scans to assess changes in regional cardiac perfusion, wall motion, and ejection fraction (EF). Forty-four patients had SPECT scans 3 to 6 years post-RT and were evaluable for the current analysis. RESULTS: The overall incidence of perfusion defects at 3 years, 4 years, 5 years, and 6 years was 52% (11 of 21 patients), 71% (17 of 24 patients), 67% (12 of 18 patients), and 57% (4 of 7 patients), respectively. The rate of abnormal SPECT scans 3 to 6 years post-RT in patients who had scans at 0.5 to 2 years that were either all abnormal, intermittently abnormal, or all normal was 80%, 67%, and 63%, respectively. The incidence of wall motion abnormalities in patients with or without perfusion defects 3 to 6 years post-RT was low and did not differ statistically (17% vs 7.1%, respectively; P = .65), as was the incidence of reductions in EF of >/=5% (27% vs 36%, respectively; P = .72). CONCLUSIONS: The results from this study indicated that RT-induced perfusion defects may persist or initially may appear 3 to 6 years post-RT in a high percentage of patients. However, these defects were not associated with changes in regional wall motion or EF. Additional study will be needed to determine the clinical relevance of these defects. In the meantime, the authors believe that every effort should be made to minimize incidental irradiation of the heart while maintaining adequate coverage of target volumes.

Phase I and pharmacokinetic study of erlotinib for solid tumors in patients with hepatic or renal dysfunction: CALGB 60101.

PURPOSE: We investigated dose and pharmacokinetics of erlotinib in patients with hepatic dysfunction or renal dysfunction. PATIENTS AND METHODS: Patients were assigned to one of three cohorts: cohort 1, AST > or = 3x upper limit of normal; cohort 2, direct bilirubin of 1 to 7 mg/dL; and cohort 3, creatinine of 1.6 to 5.0 mg/dL. Cohort 1a was amended for albumin less than 2.5 g/dL. Erlotinib was administered orally daily to groups of at least three assessable patients in escalating doses of 50, 75, 100, and 150 mg, starting with 50 mg in hepatic dysfunction patients and 75 mg in renal dysfunction patients. RESULTS: Between December 2001 and May 2005, 55 patients were accrued. The distribution of assessable patients was: two of three in cohort 1, three of three in cohort 1a, 16 of 30 in cohort 2, and 18 of 18 in cohort 3. Dose-limiting toxicity (DLT) consisted of elevation of both total and direct bilirubin 1.5x baseline in three patients (cohort 1: one of five patients at 50 mg; cohort 2: two of six patients at 100 mg). In cohort 2, one of seven patients had DLT at 75 mg. No DLT was encountered in cohort 3 with 12 patients at 150 mg. Apparent oral clearance (mean +/- standard deviation) was cohort dependent as follows: 1.9 +/- 0.2 L/h in cohort 1; 3.7 +/- 4.7 L/h in cohort 1a; 2.4 +/- 1.1 L/h in cohort 2; and 4.5 +/- 2.7 L/h in cohort 3 (Kruskal-Wallis, P < .017). CONCLUSION: Patients with renal dysfunction tolerate 150 mg of erlotinib daily and seem to have an erlotinib clearance similar to patients without organ dysfunction. Patients with hepatic dysfunction should be treated at a reduced dose (ie, 75 mg daily) consistent with their reduced clearance.

Is there an increased risk of local recurrence under the heart block in patients with left-sided breast cancer?

UNLABELLED: Tangential radiotherapy for left-sided breast cancer may be cardiotoxic. Shaping the field with a heart block reduces cardiac exposure but may under-dose the breast and/or chest wall. We compared the incidence and location of local recurrences in patients irradiated with and without a heart block. METHODS AND MATERIALS: Between 1994 and 1998, 180 patients irradiated to the left breast and/or chest wall were retrospectively reviewed. The local recurrence rates in patients treated with and without a heart block were compared using a 2-tailed Fisher exact test. An in-depth dosimetric analysis was performed in 23 patients to assess the percentage of breast tissue under-dosed by inclusion of the heart block. RESULTS: Overall, the local recurrence rates in patients with or without a heart block were similar. In postlumpectomy patients with inferiorly located tumors, the rates of local recurrence with and without a heart block were 2 of 6 patients versus 0 of 19 patients, respectively. In the dosimetric analysis, the average percentage of breast tissue under-dosed by the inclusion of a heart block was 2.8% (range, 0%-11%). DISCUSSION: A heart block is a reasonable method to limit cardiac dose but should be used cautiously following a lumpectomy in patients with inferiorly located tumors. Additional study with larger numbers of patients is warranted.