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Background: Patients with liver-only metastatic colorectal cancer (mCRC) who are not candidates for potentially curative resection may become resectable with more aggressive chemotherapy regimens. In this nonrandomized trial, we evaluated folinic acid, 5-fluorouracil (5-FU), oxaliplatin, and irinotecan (FOLFOXIRI) plus the epidermal growth factor receptor inhibitor panitumumab as first-line treatment for KRAS wild-type mCRC with liver-only metastasis., Methods: Patients received FOLFOXIRI (5-FU, 3,200 mg/m(2), 48-hour continuous intravenous (i.v.) infusion; leucovorin, 200 mg/m(2) i.v.; irinotecan, 125 mg/m(2); oxaliplatin, 85 mg/m(2) i.v.) and panitumumab (6 mg/kg i.v.) on day 1 of 14-day cycles. Patients were restaged and evaluated for surgery every four cycles. Planned enrollment was originally 49 patients. The primary endpoint was objective response rate., Results: Fifteen patients (median age: 55 years; 87% male) received a median 6 cycles of treatment (range: 1-33 cycles); 10 patients (67%) were surgical candidates at baseline. Twelve patients were evaluable for clinical response; 9 (60%) achieved partial response. Ten patients underwent surgery; all were complete resections and pathologic partial response. Treatment-related grade 3 adverse events included diarrhea (33%) and rash (20%). Enrollment was halted because of emerging data on expanded KRAS/NRAS mutations beyond the region we initially examined, and the potential for negative interaction with oxaliplatin-based therapy. Eight patients underwent expanded KRAS/NRAS analysis outside exon 2; no additional mutations were found., Conclusion: KRAS/NRAS mutations outside the region tested in this study were recently shown to be associated with inferior survival on similar treatment regimens. Therefore, this trial was stopped early. This regimen remains a viable option for patients with liver-only mCRC in the KRAS/NRAS wild-type population. Enrollment criteria on future studies should include testing for the newly identified mutations., (©AlphaMed Press; the data published online to support this summary is the property of the authors.)

For safe and accurate dose delivery in brachytherapy, associated equipment is subject to commissioning and ongoing quality assurance (QA). Many centres depend on the use of a well-type chamber ('well chamber') for performing brachytherapy dosimetry. Documentation of well chamber commissioning is scarce despite the important role the chamber plays in the whole brachytherapy QA process. An extensive and structured commissioning of the HDR 1000 plus well chamber (Standard Imaging Inc, Middleton WI) for HDR and LDR dosimetry was undertaken at Sir Charles Gairdner Hospital. The methodology and outcomes of this commissioning is documented and presented as a guideline to others involved in brachytherapy. The commissioning tests described include mechanical integrity, leakage current, directional dependence, response, length of uniform response, the influence of insert holders, ion collection efficiency, polarity effect, accuracy of measured air kerma strength (S(K)) or reference air kerma rate (K(R)) and baseline setting (for ongoing constancy checks). For the HDR 1000 plus well chamber, some of the insert holders modify the response curve. The measured sweet length was 2.5 cm which is within 0.5% of that specified by the manufacturer. Correction for polarity was negligible (0.9999) and ion recombination was small (0.9994). Directional dependence was small (less than 0.2%) and leakage current was negligible. The measured K(R) for (192)Ir agreed within 0.11% compared with a second well chamber of similar model and was within 0.5% of that determined via a free-in-air measurement method. Routine constancy checks over a year agreed with the baseline within 0.4%.

Background: Patients with advanced squamous-cell non-small-cell lung cancer (NSCLC) who have disease progression during or after first-line chemotherapy have limited treatment options. This randomized, open-label, international, phase 3 study evaluated the efficacy and safety of nivolumab, a fully human IgG4 programmed death 1 (PD-1) immune-checkpoint-inhibitor antibody, as compared with docetaxel in this patient population., Methods: We randomly assigned 272 patients to receive nivolumab, at a dose of 3 mg per kilogram of body weight every 2 weeks, or docetaxel, at a dose of 75 mg per square meter of body-surface area every 3 weeks. The primary end point was overall survival., Results: The median overall survival was 9.2 months (95% confidence interval [CI], 7.3 to 13.3) with nivolumab versus 6.0 months (95% CI, 5.1 to 7.3) with docetaxel. The risk of death was 41% lower with nivolumab than with docetaxel (hazard ratio, 0.59; 95% CI, 0.44 to 0.79; P<0.001). At 1 year, the overall survival rate was 42% (95% CI, 34 to 50) with nivolumab versus 24% (95% CI, 17 to 31) with docetaxel. The response rate was 20% with nivolumab versus 9% with docetaxel (P=0.008). The median progression-free survival was 3.5 months with nivolumab versus 2.8 months with docetaxel (hazard ratio for death or disease progression, 0.62; 95% CI, 0.47 to 0.81; P<0.001). The expression of the PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit. Treatment-related adverse events of grade 3 or 4 were reported in 7% of the patients in the nivolumab group as compared with 55% of those in the docetaxel group., Conclusions: Among patients with advanced, previously treated squamous-cell NSCLC, overall survival, response rate, and progression-free survival were significantly better with nivolumab than with docetaxel, regardless of PD-L1 expression level. (Funded by Bristol-Myers Squibb; CheckMate 017 ClinicalTrials.gov number, NCT01642004.).

Tritium radiopharmaceuticals are often used in drug development because of their desirable specific activity. The inherent instability of these radioactive tracers often leads to a requirement to purify prior to use. Purification methodologies such as preparative chromatography and solid/liquid extractions often utilize water as a solvent, which is not suitable for long-term storage and necessitates removal. Rotary evaporation has traditionally been utilized for the removal of this unwanted solvent, however, this method has been shown to lead to decomposition of the tritium species in some cases. Centrifugal evaporation is a milder concentration method which has been demonstrated to effectively remove solvents. In this study, we show that centrifugal evaporation leads to effective concentration of tritium samples without the decomposition typically observed by rotary evaporation., (Copyright © 2015 John Wiley & Sons, Ltd.)

Metformin is currently prescribed worldwide to treat type 2 diabetes, and therefore, radiolabeled [(14) C] metformin is often prepared for clinical comparisons of new drug candidates. Prior to using the radiolabeled metformin, the purity needs to be determined to ensure the quality of the material. While typical reversed-phase LC methods are often the first choice for purity analysis, they are not suitable for this determination because the compound is poorly retained under these conditions. Mixed-mode chromatography has been demonstrated to overcome these retention issues, and therefore, this methodology was utilized for the purity determination of radiolabeled metformin., (Copyright © 2015 John Wiley & Sons, Ltd.)

Introduction: PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC)., Methods: Patients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m, carboplatin, area under the curve = 6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed., Results: Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio = 0.85, 90% confidence interval, 0.7-1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms., Conclusions: Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.

Within the World Health Organization 2012-2020 roadmap for control and elimination of schistosomiasis, the scale-up of mass drug administration with praziquantel is set to change the epidemiological landscape across Africa and Arabia. Central in measuring progress is renewed emphasis upon diagnostics which operate at individual, community and environmental levels by assessing reductions in disease, infections and parasite transmission. However, a fundamental tension is revealed between levels for present diagnostic tools, and methods applied in control settings are not necessarily adequate for application in elimination scenarios. Indeed navigating the transition from control to elimination needs careful consideration and planning. In the present context of control, we review current options for diagnosis of schistosomiasis at different levels, highlighting several strengths and weaknesses therein. Future challenges in elimination are raised and we propose that more cost-effective diagnostics and clinical staging algorithms are needed. Using the Kingdom of Saudi Arabia as a contemporary example, embedding new diagnostic methods within the primary care health system is discussed with reference to both urogenital and intestinal schistosomiasis.

Poor response to tuberculosis (TB) therapy might be attributable to subtherapeutic levels in drug-compliant patients. Pharmacokinetic (PK) parameters can be affected by several factors, such as comorbidities or the interaction of TB drugs with food. This study aimed to determine the PK of isoniazid (INH) in a Peruvian TB population under observed daily and twice-weekly (i.e., biweekly) therapy. Isoniazid levels were analyzed at 2 and 6 h after drug intake using liquid chromatography mass spectrometric methods. A total of 107 recruited patients had available PK data; of these 107 patients, 42.1% received biweekly isoniazid. The mean biweekly dose (12.8 mg/kg of body weight/day) was significantly lower than the nominal dose of 15 mg/kg/day (P < 0.001), and this effect was particularly marked in patients with concurrent diabetes and in males. The median maximum plasma concentration (Cmax) and area under the concentration-time curve from 0 to 6 h (AUC0-6) were 2.77 mg/liter and 9.71 mg · h/liter, respectively, for daily administration and 8.74 mg/liter and 37.8 mg · h/liter, respectively, for biweekly administration. There were no differences in the Cmax with respect to gender, diabetes mellitus (DM) status, or HIV status. Food was weakly associated with lower levels of isoniazid during the continuation phase. Overall, 34% of patients during the intensive phase and 33.3% during the continuation phase did not reach the Cmax reference value. However, low levels of INH were not associated with poorer clinical outcomes. In our population, INH exposure was affected by weight-adjusted dose and by food, but comorbidities did not indicate any effect on PK. We were unable to demonstrate a clear relationship between the Cmax and treatment outcome in this data set. Twice-weekly weight-adjusted dosing of INH appears to be quite robust with respect to important potentially influential patient factors under program conditions., (Copyright © 2014 Requena-Méndez et al.)

Introduction: A survey was designed to establish a baseline data set for the current routine practice of high-dose-rate prostate brachytherapy (HDR-PB) in Australia and New Zealand. Existing treatment protocols and clinical implementations are not generally known., Methods: The survey, for the 2010 and 2011 calendar years, collected data including number of patients treated; equipment used; imaging modalities; applicator verification and correction methods; dose prescriptions and normal tissue dose constraints. The number of HDR-PB patients treated was compared with the most recently published prostate cancer incidence data in Australia and in New Zealand. Total biologically equivalent doses in 2.0 Gy fractions (EQD2) were calculated for each prescription regime reported., Results: There were reductions, of 25-60%, in patients treated with HDR-PB from 2010 to 2011 in four departments. Prostate cancer patients are two to six times more likely to be prescribed HDR-PB in Western Australia than elsewhere in the region. There were 12 different treatment prescriptions, with EQD2 doses ranging from 73.5 to 97.6 Gy, among the 18 reported by survey respondents. Normal tissue definition methodology and dose constraints varied, and 13 of 15 departments reported that no particular published external guidelines were followed in full., Conclusion: The high survey response rate, 15 of 17 departments, has provided a representative baseline data set of contemporary HDR-PB practice in Australia and New Zealand that may assist government and professional bodies, such as the Australasian Brachytherapy Group, in formulating recommendations, setting standards and future planning., (© 2013 The Authors. Journal of Medical Imaging and Radiation Oncology © 2013 The Royal Australian and New Zealand College of Radiologists.)

Docetaxel-containing chemotherapy improves disease-free survival (DFS) and overall survival in patients with early stage breast cancer. Bevacizumab improves response rate and DFS in metastatic breast cancer. However, adding antivascular endothelial growth factor therapy to anthracycline-containing chemotherapy may increase cardiotoxicity. This trial evaluates the feasibility of adding bevacizumab to three standard adjuvant docetaxel regimens with a primary endpoint of grade ≥3 congestive heart failure (CHF). Phase IIb, randomized, non-comparative study of women with previously untreated node-positive or high-risk node-negative breast cancer. Human epidermal growth factor receptor 2 (HER2)-negative patients were randomized to: (arm A) doxorubicin + cyclophosphamide followed by docetaxel or (arm B) docetaxel + doxorubicin + cyclophosphamide. HER2-positive patients (arm C) received docetaxel + carboplatin + trastuzumab for 52 weeks. All patients received bevacizumab beginning on day 1 for 52 weeks. Safety data in 212 women (mean age = 53.1 years) show that 1 patient each in arm A (1.3 %) and arm C (1.7 %), and 3 patients in arm B (4.0 %) experienced clinical CHF grade ≥3. A decreased ejection fraction was observed in 1 patient each in arms A and C, and cardiac disorder was observed in 12.8, 22.7, and 8.5 % in arms A, B, and C, respectively. A grade 3/4 treatment-emergent adverse event was reported in 82.1, 84.0, and 52.5 % of participants in arms A, B, and C, respectively. Kaplan-Meier estimates of DFS show rates at 24 months of 85.5, 90.4, and 90.4 % in arms A, B, and C, respectively. Adding bevacizumab to three standard docetaxel-based chemotherapy regimens as adjuvant treatment in patients with node-positive and high-risk node-negative breast cancer resulted in a low rate of clinical CHF grade ≥3. Maintenance bevacizumab monotherapy did not identify any new safety signals. Breast cancer recurrence/relapse, secondary malignancies, and death were uncommon, although the follow-up time in this study was relatively short.

Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m(2) once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3-64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2-5.4 months). Median OS was 8.2 months (95% CI, 5.1-9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer., (© 2013 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Purpose: Low-dose-rate brachytherapy using iodine-125 seeds is a highly efficacious treatment for low-risk prostate cancer. We propose a bioeffect model may be used to target an ablative dose to the tumor with a lower, therapeutic dose to low-risk regions to maintain high rates of tumor control with reduced toxicity. We report on the validation of the model and derivation of the optimal cutpoint value of tumor control probability (TCP) that predicts for freedom from biochemical failure., Methods and Materials: The TCP was calculated from postimplant dosimetry data for 423 prostate cancer patients from three Australian institutions. To apply the model, the prostate was mathematically divided into 12 subsections with tumor characteristics, including a nonuniform distribution of tumor cell density, derived from the literature., Results: When TCP values were above and below 0.62, the 5-year freedom from biochemical failure were 93.7% (95% confidence interval [CI], 90.4, 96.4%) and 88.8% (95% confidence interval, 81.3, 94.5%), respectively (p = 0.004)., Conclusions: Using postimplant dosimetry data, the TCP model was able to predict for freedom from biochemical failure. The cutpoint value that would be used clinically depends on the selection of the model parameters, but the potential for the model to be used in the optimization of treatment planning is demonstrated., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background: The dose of bevacizumab necessary to optimally inhibit tumor angiogenesis in advanced renal cell carcinoma is unknown. In this phase II trial, we evaluated the efficacy and safety of 2 escalated doses of bevacizumab in patients with advanced clear cell renal carcinoma., Patients and Methods: Eligible patients had metastatic or locally advanced unresectable clear cell renal carcinoma. Patients who were previously untreated or who had previously received vascular endothelial growth factor receptor (VEGFR)-targeted therapy were eligible and were considered separately in the efficacy evaluation. Two doses of bevacizumab were evaluated in sequential cohorts: 15 mg/kg every 2 weeks and 15 mg/kg weekly. The initial reevaluation was at 8 weeks; responding and stable patients continued treatment, with reevaluations every 8 weeks until tumor progression or unacceptable toxicity occurred., Results: One hundred nineteen eligible patients were enrolled and received bevacizumab 15 mg/kg every 2 weeks (n = 61) or bevacizumab 15 mg/kg weekly (n = 58). Seventy patients were previously untreated with VEGFR-targeted therapy. In previously untreated patients, the overall response rate was 19%, with a median progression-free survival (PFS) of 7.8 months. Less activity was seen in patients previously treated with VEGFR-targeted agents (overall response rate, 4%; median PFS, 3.7 months). There was no suggestion of any difference in efficacy between the 2 dose levels tested. Both dose levels were tolerated well by most patients, with a spectrum of toxicity typical for bevacizumab. Grade 3/4 proteinuria was more frequent with both of these escalated doses, particularly with 15 mg/kg weekly., Conclusion: Although administration of escalated doses of bevacizumab was feasible in patients with advanced clear cell renal carcinoma, there was no suggestion that these doses were more efficacious than bevacizumab administered at the standard dose of 10 mg/kg every 2 weeks., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Topotecan is currently the only US Federal Drug Administration (FDA)-approved drug for second-line treatment of relapsed small-cell lung cancer (SCLC). We investigated the efficacy and safety of a novel topotecan-bevacizumab combination in treating relapsed SCLC., Patients and Methods: Each 21-day treatment cycle consisted of bevacizumab (15 mg/kg) administration on day 1 and oral topotecan (2.3 mg/m(2)/d) administration on days 1 to 5. Treatment was continued for 8 cycles or until disease progression/toxicity. The primary objective was evaluation of 3-month progression-free survival (PFS). Overall response rate (ORR), duration of response, time to response (TTR), and overall survival (OS) were secondary objectives., Results: The study enrolled 50 patients between July 2008 and May 2010. The 3-month PFS was 65% (95% confidence interval [CI], 49.3%-76.9%), which was promising compared with the historical control of 50% (P = .017) but did not meet the predefined criteria for clinically meaningful improvement. Median PFS was 6.24 months for the sensitive subgroup (progression time from end of previous chemotherapy > 90 days; n = 27) and 2.91 months for the resistant subgroup (progression time ≤ 90 days; n = 23). No patient achieved complete response (CR), and the ORR was 16%. Twenty (40%) patients had stable disease (SD) and 13 (26%) had progressive disease (PD). Median OS, TTR, and duration of response were 7.4, 1.3, and 4.7 months, respectively. The worst reported adverse events (AEs) were grade 1/2 in 11 (22%) patients and grade 3/4/5 in 39 (78%) patients., Conclusion: Improvement in the 3-month PFS after treatment with topotecan-bevacizumab was promising compared with the historical control and justifies additional studies with this regimen., (Copyright © 2013. Published by Elsevier Inc.)

Purpose: To evaluate the feasibility and efficacy of sorafenib and everolimus in renal cell carcinoma (RCC)., Methods: Patients with advanced RCC and ≤ 1 previous targeted therapy were treated., Results: Maximum tolerated doses were sorafenib 200 mg PO BID, everolimus 35 mg PO once weekly. Dose-limiting toxicity was hand-foot syndrome. The response rate was 13%; median PFS was 5.45 months (95% CI: 3.8-7.6). Skin toxicity, fatigue, hypertension, proteinuria, and mucositis (usually Grade 2) were common., Conclusions: Fifty percent doses of sorafenib and everolimus were required when these drugs were combined. No increase in efficacy was suggested; toxicity was modestly increased.

We describe a patient with mid-facial pain and nasal obstruction due to a nasal septal abscess (NSA) complicating an occult fungal ball of the sphenoid sinus. We highlight the importance of suspecting unusual pathology in patients with NSA and no trauma history.

Objectives: To evaluate the 6-mo overall survival, safety and tolerability of lenalidomide in combination with standard gemcitabine as first-line treatment for patients with metastatic pancreatic cancer., Methods: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas with metastases incurable by surgery/radiation therapy; ECOG PS 0-2; adequate organ function; prophylactic anticoagulation for venous thromboembolic events (VTEs). Patients received lenalidomide 25 mg PO (days 1-21) and gemcitabine 1,000 mg/m ( 2) IV (days 1, 8 and 15) each 28-day cycle, with response evaluations every eight weeks., Results: Between 5/2009-4/2010, 72 patients (median age 64 years; 68% male; 42% ECOG PS 0) were enrolled in this multicenter, community-based study. Six-month OS was 37% (95% CI 26-48%). Median PFS and OS were 2.3 (95% CI 1.9-3.5) and 4.7 (95% CI 3.4-5.7) months, respectively. Eight partial responses (11%) were documented. Thirty-nine patients (54%) experienced thrombocytopenia (2 patients, 3% grade 4). Hematologic toxicities resulted in dose modifications for the majority of patients. Twenty patients (28%) developed VTEs during treatment., Conclusions: The observed 6-month OS (37%) of lenalidomide with gemcitabine does not suggest improvement compared with historical results with gemcitabine alone. Toxicities and dose modifications likely limited dose intensity. Further development of this regimen in pancreas cancer is not recommended.

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.

A highly sensitive and rapid liquid chromatography tandem mass spectrometry (LC-MS/MS) method has been developed to measure the levels of the antitubercular drug rifampicin (RIF) in human plasma and cerebrospinal fluid (CSF). The analyte and internal standard (IS) were isolated from plasma and CSF by a simple organic solvent based precipitation of proteins followed by centrifugation. Detection was carried out by electrospray positive ionization mass spectrometry in the multiple-reaction monitoring (MRM) mode. The assay was linear in the concentration range 25-6400 ng/mL with intra- and inter-day precision of <7% and <8%, respectively. The validated method was applied to the study of RIF pharmacokinetics in human CSF and plasma over 25 h period after a 10 mg/kg oral dose., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Epothilones, a new class of cytotoxic agents, have demonstrated activity in non-small-cell lung cancer (NSCLC). This phase II study examined ixabepilone/carboplatin (cohort A) and ixabepilone/carboplatin/bevacizumab (cohort B) as first-line therapy for patients with advanced NSCLC., Method: Patients were enrolled to either cohort A or B at physician discretion and when eligibility met. Eligible patients had newly diagnosed stage III/IV NSCLC, ECOG PS 0-1, adequate organ function, no active CNS metastases, and, in cohort B, bevacizumab treatment criteria. Both cohorts received ixabepilone 30 mg/m2 and carboplatin AUC=6 IV day 1 every 3-weeks for a maximum of 6 cycles. Patients assigned to cohort B also received bevacizumab 15 mg/kg IV day 1 of each cycle, and could continue single-agent bevacizumab for 6 additional cycles., Results: Eighty-two patients (median age, 63 years; majority stage IV and former smokers) were enrolled from 11/08 to 10/09 (A-42, B-40) and received medians of 4 and 6 cycles, respectively. The ORRs were 29% and 50%. After median follow up of 17.5 months (A) and 15.7 months (B), median progression free survivals were A-5.3 months (95% CI 2.8-8.6) and B-6.7 months (95% CI 5.1-8.4), with median overall survivals of 9.3 months (95% CI 6.4-16.6) 13.2 months (95% CI 8.9-upper limit not reached), respectively. Grade 3/4 toxicity included: anemia (A-10%, B-27%), neutropenia (A-31%, B-48%), thrombocytopenia (A-19%, B-20%), fatigue (A-10%, B-23%), infection (A-5%, B-20%), and hypersensitivity reaction (A-2%, B-5%). There was one treatment-related death, due to hemoptysis in a cohort B patient with squamous histology., Conclusions: Ixabepilone can be safely combined with carboplatin in newly diagnosed patients with advanced NSCLC. The benefits of treatment appear consistent with those achieved with other modern platinum-doublet regimens. The addition of bevacizumab increases toxicities, however, these are largely expected and reversible. The high ORR and OS observed in the bevacizumab-cohort are encouraging, but would require validation in a larger randomized trial of cohort A versus B., (Copyright © 2012. Published by Elsevier Ireland Ltd.)

Purpose: To evaluate the efficacy of bevacizumab (Avastin, Genentech) and erlotinib (Tarceva, Genentech/Roche) when added to preoperative chemoradiation therapy with paclitaxel, carboplatin, and infusional 5-fluorouracil (5-FU) in the treatment of localized cancers of the esophagus or gastroesophageal (GE) junction. The primary endpoint was the pathologic complete response (pCR) rate., Methods: Eligible patients had previously untreated localized squamous cell, adenocarcinoma, or adenosquamous carcinoma of the esophagus or GE junction, and were considered surgical candidates at enrollment. Daily erlotinib (100 mg orally) was administered on days 1-42 of preoperative treatment. Patients received paclitaxel (200 mg/m2 intravenously [IV]), carboplatin (area under the curve [AUC] 5.0 IV), and bevacizumab (15 mg/kg IV) on days 1 and 22, and 5-FU by continuous infusion (225 mg/m2/day IV) on days 1-35, with radiation therapy in 1.8-Gy single fractions, Monday-Friday (to a total of 45 Gy). Those who were deemed surgical candidates proceeded to resection during weeks 12-14., Results: Between February 2007 and September 2009, 62 patients (median age, 64 years; 92% male; 94% adenocarcinoma) were enrolled; 44 patients (71%) completed neoadjuvant treatment and proceeded to surgery. Eighteen patients (29%) achieved pCR, with partial pathologic remission in an additional 22 patients (35%). Common grade 3/4 toxicities included leukopenia (64%), neutropenia (44%), mucositis/stomatitis (42%), diarrhea (27%), and esophagitis (27%). There were 40 instances of treatment-related hospitalization, and 2 postoperative deaths., Conclusions: The addition of bevacizumab and erlotinib to neoadjuvant chemoradiation did not demonstrate survival benefit or improved pCR rate over similar regimens. While the overall rates of toxicity were not increased, targeted agent-specific toxicity was evident. Further study of this specific regimen is not warranted.

The growing role of nurse practitioners (NPs) in today's demanding health-care system has allowed for a more comprehensive and complementary approach to patient care. Within the past few years, NPs have expanded their role to include invasive procedures. Limited research in the utilization of NPs has suggested equality among procedures performed by NPs when compared with those conducted by their physician counterparts. Nurse practitioners and their colleagues need to take an active role in developing protocols to train practitioners and assess their procedural competency. We suggest such a guideline for training NPs to perform invasive procedures and to confirm procedural competency, using bone marrow biopsies and aspirates as an example. Future research should be directed not only at the overall quality of biopsies obtained, but also toward patient satisfaction scores in procedures performed by NPs.

Purpose: To assess safety and efficacy of folinic acid, 5-fluorouracil, gemcitabine (FFG) and folinic acid, fluorouracil, oxaliplatin (FOLFOX4) regimens with added bevacizumab as first-line treatment in patients with advanced colorectal cancer (CRC)., Patients and Methods: Patients with Stage III unresectable or Stage IV adenocarcinoma of the colon or rectum were randomly assigned to either FFG weekly for 6 weeks of an 8-week cycle or FOLFOX4 every 2 weeks. After FDA approval, bevacizumab 5 mg/kg was added every 2 weeks. Treatment continued until disease progression. Planned enrollment was 190 patients. Primary endpoint was overall response rate (ORR); secondary endpoints included evaluation of adverse events, time to progression (TTP), and overall survival (OS). Disease Control Rate (DCR; % of patients with complete or partial responses or stable disease) was a post hoc analysis., Results: The trial was stopped prematurely due to low enrollment. Of 84 enrolled patients (42 to each arm), 36 patients (18 in each arm) received bevacizumab. ORR was greater (P = .002) for FOLFOX4 (17/42; 40.5%) than for FFG (4/42; 9.5%); however, TTP, OS, and DCR results were not statistically different comparing FOLFOX4 and FFG. Peripheral neuropathy was more frequent (P = <.001) with FOLFOX4 (18/42; 42.9%) than with FFG (1/42; 2.4%)., Conclusions: FFG and FOLFOX4 were generally well tolerated. Based on ORR, FOLFOX4 was superior to FFG. However, differences in TTP and OS comparing regimens were inconclusive. General use of gemcitabine as a biomodulator of 5-fluorouracil in CRC cannot be recommended at this time and the regimen remains investigational.

Purpose: To assess time to progression (TTP) in elderly patients with previously untreated nonsquamous non-small cell lung cancer treated with pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab., Methods: Eligible patients were aged 70 years or older with newly diagnosed stage IIIB/IV nonsquamous non-small cell lung cancer; Eastern Cooperative Oncology Group performance status 0 to 1; adequate organ function; and no active central nervous system metastasis. Patients were randomized 1:1 to cohort A (pemetrexed 500 mg/m2 IV, gemcitabine 1500 mg/m2 IV, and bevacizumab 10 mg/kg IV; days 1 and 15 of 28-day cycles) or cohort B (pemetrexed 500 mg/m2 IV, carboplatin area under the concentration-time curve =5 IV, and bevacizumab 15 mg/kg IV; day 1 of 21-day cycles). After six cycles, stable/responding patients continued bevacizumab until disease progression., Results: Between March 2007 and December 2009, 110 patients (median age, 76 years; 88% stage IV) were treated for medians of 2.5 cycles (cohort A) and 6 cycles (cohort B). Overall response rate was 35% in both cohorts, with stable disease rates of 33% (A) and 45% (B). TTP by cohort was 4.7 and 10.2 months with median OS 7.5 and 14.8 months, respectively. Severe toxicities included the following: neutropenia (A, 51% and B, 45%), fatigue (A, 36% and B, 18%), anemia (A, 22% and B, 7%), infection (A, 25% and B, 7%), thrombocytopenia (A, 11% and B, 31%), and thromboembolism (A, 7% and B, 7%). Three potential treatment-related deaths occurred in cohort A (sepsis, thrombocytopenia, and myocardial infarction) and two in B (sepsis and pulmonary hemorrhage)., Conclusions: Treatment with pemetrexed/carboplatin/bevacizumab was associated with improved TTP and OS in this elderly population and should be further evaluated. Treatment-related toxicities were expected and usually manageable, although deaths occurred with both regimens.

Measurements of backscatter correction factors for intra operative (IOBT) HDR brachytherapy applicators were made using Centre for Medical Radiation Physics (CMRP), MOSFET devices. In clinical use there is an absence of backscatter material above the IOBT applicator, leading to a lower dose than predicted by conventional TG-43 dose calculations. To estimate the uncertainty in the MOSFET measurements, the dosimetric characteristics, including reproducibility, stability, linearity, and angular and energy response were measured using a HDR Ir-192 source, kilovoltage treatment unit and a high energy linac. Measurements were compared with previously published Monte Carlo data. Variability of the response of the MOSFETs due to angular variation contributed the largest uncertainty in dose measurements. Using the IOBT applicator without adequate scatter material resulted in a reduction of delivered dose of on average 10%, but was dependent on the location on the applicator and the treatment field size. Theoretical calculations based on previously published study indicated an expected reduced dose of on average 4%. MOSFET devices provide an ideal measurement tool in the presence of high dose gradients, however, the dosimetric characteristics of the detector must be accounted for when estimating the uncertainty.

Purpose: Sorafenib, an oral multikinase inhibitor, has shown preliminary activity in non-small-cell lung cancer (NSCLC). Patients with advanced NSCLC were treated with erlotinib with or without sorafenib in this multicenter phase II trial., Patients and Methods: Key eligibility criteria included the following: stage IIIB or IV NSCLC; one to two prior regimens; Eastern Cooperative Oncology Group performance status of 0 to 2; and measurable disease. Patients were randomly assigned 2:1 to sorafenib (400 mg orally twice a day) plus erlotinib (150 mg orally daily) or placebo plus erlotinib and stratified by squamous/nonsquamous histology and prior bevacizumab. Treatment efficacy, measured by progression-free survival (PFS) and overall response rate (ORR), was compared. Treatment of 168 patients allowed detection of 40% improvement in the historical PFS of 2.2 months with single-agent erlotinib., Results: One hundred sixty-eight patients enrolled from February 2008 to February 2009. Clinical characteristics of the two groups were similar. ORRs for sorafenib/erlotinib and placebo/erlotinib were 8% and 11%, respectively (P = .56); disease control rates were 54% and 38%, respectively (P = .056). Median PFS was 3.38 months for sorafenib/erlotinib versus 1.94 months for placebo/erlotinib (hazard ratio, 0.86; 95% CI, 0.60 to 1.22; P = .196). Seventy-two patients consented to analyses of tumor epidermal growth factor receptor (EGFR). In 67 patients with EGFR wild-type (WT) tumors, median PFS was 3.38 months for sorafenib/erlotinib versus 1.77 months for placebo/erlotinib (P = .018); median overall survival (OS) was 8 months for sorafenib/erlotinib versus 4.5 months for placebo/erlotinib (P = .019). An OS advantage for sorafenib/erlotinib was suggested among 43 patients with fluorescent in situ hybridization (FISH) EGFR-negative tumors (P = .064). Both regimens were tolerable, with modest toxicity increase with sorafenib., Conclusion: Although there was little difference in ORR or PFS, subset analyses in EGFR WT and EGFR FISH-negative patients suggest a benefit for the combination of erlotinib/sorafenib compared with single-agent erlotinib with respect to PFS and OS.

Purpose: To compare the efficacy and safety of docetaxel plus high-dose calcitriol (DN-101) to docetaxel plus prednisone in an open-label phase III trial., Patients and Methods: Nine hundred fifty-three men with metastatic castration-resistant prostate cancer (CRPC) were randomly assigned to Androgen-Independent Prostate Cancer Study of Calcitriol Enhancing Taxotere (ASCENT; 45 μg DN-101, 36 mg/m(2) docetaxel, and 24 mg dexamethasone weekly for 3 of every 4 weeks) or control (5 mg prednisone twice daily with 75 mg/m(2) docetaxel and 24 mg dexamethasone every 3 weeks) arms. The primary end point was overall survival (OS), assessed by the Kaplan-Meier method., Results: At an interim analysis, more deaths were noted in the ASCENT arm, and the trial was halted. The median-follow-up for patients alive at last assessment was 11.7 months. Median OS was 17.8 months (95% CI, 16.0 to 19.5) in the ASCENT arm and 20.2 months (95% CI, 18.8 to 23.0) in the control arm (log-rank P = .002). Survival remained inferior after adjusting for baseline variables (hazard ratio, 1.33; P = .019). The two arms were similar in rates of total and serious adverse events. The most frequent adverse events were GI (reported in 75% of patients), and blood and lymphatic disorders (48%). Docetaxel toxicity leading to dose modification was more frequent in the ASCENT (31%) than in the control arm (15%)., Conclusion: ASCENT treatment was associated with shorter survival than the control. This difference might be due to either weekly docetaxel dosing, which, in a prior study, showed a trend toward inferior survival compared with an every-3-weeks regimen, or DN-101 therapy.

Purpose: Because of promising efficacy signals in single-arm studies, a placebo-controlled, double-blind, randomized phase II trial was designed to assess the efficacy and safety of adding bevacizumab to first-line standard chemotherapy for treatment of extensive-stage small-cell lung cancer (SCLC)., Patients and Methods: Patients with SCLC were randomly assigned to receive bevacizumab or placebo, with cisplatin or carboplatin plus etoposide, for four cycles followed by single-agent bevacizumab or placebo until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS)., Results: Fifty-two patients were randomly assigned to the bevacizumab group and 50 to the placebo group; 69% versus 66%, respectively, completed four cycles of therapy. Median PFS was higher in the bevacizumab group (5.5 months) than in the placebo group (4.4 months; hazard ratio [HR], 0.53; 95% CI, 0.32 to 0.86). Median overall survival (OS) was similar for both groups (9.4 v 10.9 months for bevacizumab and placebo groups, respectively), with an HR of 1.16 (95% CI, 0.66 to 2.04). Overall response rates were 58% (95% CI, 43% to 71%) for the bevacizumab group and 48% (95% CI, 34% to 62%) for the placebo group. Median duration of response was 4.7 months for the bevacizumab group and 3.2 months for the placebo group. In the bevacizumab and placebo groups, 75% versus 60% of patients, respectively, experienced one or more grade 3 or higher adverse events. No new or unexpected safety signals for bevacizumab were observed., Conclusion: The addition of bevacizumab to cisplatin or carboplatin plus etoposide for treatment of extensive-stage SCLC improved PFS, with an acceptable toxicity profile. However, no improvement in OS was observed.

Purpose: Novel approaches are needed for patients with metastatic urothelial cancer (UC). This trial assessed the efficacy and toxicity of bevacizumab in combination with cisplatin and gemcitabine (CGB) as first-line treatment for patients with metastatic UC., Patients and Methods: Chemotherapy-naive patients with metastatic or unresectable UC received cisplatin 70 mg/m(2) on day 1, gemcitabine 1,000 to 1,250 mg/m(2) on days 1 and 8, and bevacizumab 15 mg/kg on day 1, every 21 days., Results: Forty-three patients with performance status of 0 (n = 26) or 1 (n = 17) and median age of 66 years were evaluable for toxicity and response. Grade 3 to 4 hematologic toxicity included neutropenia (35%), thrombocytopenia (12%), anemia (12%), and neutropenic fever (2%). Grade 3 to 5 nonhematologic toxicity included deep vein thrombosis/pulmonary embolism (21%), hemorrhage (7%), cardiac (7%), hypertension (5%), and proteinuria (2%). Three treatment-related deaths (CNS hemorrhage, sudden cardiac death, and aortic dissection) were observed. Best response by Response Evaluation Criteria in Solid Tumors was complete response in eight patients (19%) and partial response in 23 patients (53%), for an overall response rate of 72%. Stable disease lasting ≥ 12 weeks occurred in four patients (9%), and progressive disease occurred in six patients (14%). With a median follow-up of 27.2 months (range, 3.5 to 40.9 months), median progression-free survival (PFS) was 8.2 months (95% CI, 6.8 to 10.3 months) with a median overall survival (OS) time of 19.1 months (95% CI, 12.4 to 22.7 months). The study-defined goal of 50% improvement in PFS was not met., Conclusion: CGB demonstrates promising OS and antiangiogenic treatment-related toxicities in the phase II setting of metastatic UC. The full risk/benefit profile of CGB in patients with metastatic UC will be determined by an ongoing phase III intergroup trial.

Purpose: To examine FOLFOX/bevacizumab/cetuximab in the first-line treatment of metastatic colorectal cancer (mCRC)., Design: Randomized phase II trial aimed at achieving a 60% objective response rate (ORR). Due to frequent cetuximab-related hypersensitivity reactions the trial was amended to a single-arm design. Eligibility: Previously untreated mCRC, measurable disease, Eastern Cooperative Oncology Group performance status (ECOG-PS) 0-1., Treatment: Modified FOLFOX6 (oxaliplatin 85 mg/m², leucovorin 350 mg, and 5-fluorouracil 400 mg/m² bolus; 2.4 g/m² infusion, 46 h) day 1; bevacizumab 5 mg/kg on day 1; cetuximab 400 mg/m² on day 1, then 250 mg/m² on days 1 and 8, every 14 days (1 cycle) until progressive disease (PD); restaging occurred every 4 cycles., Results: With emerging negative progression-free survival (PFS) data from a similarly designed trial, this trial closed early. Enrollment (N=31) was from August 2005-June 2008., Patient Characteristics: Median age was 55 years (29-78); 58% were male; 71% were ECOG-PS 0. Ten cycles (median) were completed (range 2-62). The ORR was 55% (95% confidence interval [CI], 36-73%); 11 patients (35%) had stable disease; 1 patient (3%) had PD; 2 patients (6%) were unevaluable. Median PFS was 9 months (95% CI, 8.3-15.2 months); median overall survival was 25.7 months (95% CI, 15.4-27.6 months). Grade 3/4 toxicities (>1 patient) included neutropenia (25%), rash (23%; grade 2 events, 45%), diarrhea (19%), fatigue (16%), pain (16%), anemia (13%), sensory neuropathy (13%), deep-vein thrombosis (10%), nausea (10%), pulmonary embolism (7%), anorexia (6%), and vomiting (6%)., Conclusion: In this limited trial, it is unclear whether cetuximab contributed to FOLFOX/bevacizumab efficacy, although the response rate, PFS, and overall survival were high. The regimen was generally well-tolerated, with expected skin effects; thromboembolic rates should be assessed in larger analyses. Cetuximab's role in first-line mCRC treatment is likely best guided by K-RAS testing in future clinical trials.

Purpose: To evaluate the efficacy and toxicity of the combination of bevacizumab, an angiogenesis inhibitor, and everolimus, an mTOR inhibitor, in the treatment of patients with advanced clear cell renal carcinoma., Patients and Methods: Two groups of patients with metastatic renal cell carcinoma were eligible for this study: those with no previous treatment with targeted agents and those with previous treatment with sunitinib and/or sorafenib. All patients received bevacizumab 10 mg/kg intravenously every 2 weeks and everolimus 10 mg orally daily. Patients were evaluated for response after 8 weeks of treatment; patients with objective response or stable disease continued treatment until disease progression or unacceptable toxicity occurred., Results: Eighty patients (50 untreated, 30 previously treated) entered this clinical trial. The combination of bevacizumab/everolimus showed activity in both groups. Median progression-free survivals in previously untreated and previously treated patients were 9.1 and 7.1 months, respectively. Overall response rates (30% and 23%) were similar in both groups. The regimen was well tolerated by most patients, with a toxicity profile as expected based on the known toxicities of these two agents. Grade 3 to 4 proteinuria was more frequent than expected (25%) and led to treatment discontinuation in six patients., Conclusion: Bevacizumab/everolimus is active and well tolerated in the treatment of advanced clear cell renal cancer, either as first-line treatment or after treatment with sunitinib and/or sorafenib. The benefits of this combination regimen, versus sequential use of these two agents, requires further study.

Purpose: We examined catheter displacement in patients treated with fractionated high-dose rate (HDR) brachytherapy boost for prostate cancer and the impact this had on tumor control probability (TCP). These data were used to make conclusions on an acceptable amount of displacement., Methods and Materials: The last 20 patients treated with HDR brachytherapy boost for prostate cancer at our center in 2007 were replanned using simulated interstitial catheter displacements of 3, 6, 9, and 12 mm with originally planned dwell times. The computer-modeled dose-volume histograms for the clinical target volumes were exported and used to calculate the TCP of plans with displaced needles relative to the original plan. Actual catheter displacements were also measured before and after manual adjustment in all patients treated in 2007., Results: In the 20 patients who were replanned for caudal catheter displacements of 3, 6, 9, and 12 mm, the median relative TCP was 0.998, 0.964, 0.797, and 0.265, respectively (p < 0.01 when all medians were compared). All patients replanned with a 3-mm displacement, compared with only 75% with a 6-mm displacement, had a relative TCP greater than 0.950. In the 91 patients treated in 2007, before adjustment, 82.3% of fractions had a displacement greater than 3 mm compared with 12.2% of fractions after adjustment., Conclusions: Catheter displacement in HDR brachytherapy significantly compromises the TCP. The tolerance for these movements should be small (< or =3 mm). Correcting these displacements to within acceptable limits is feasible., (Crown Copyright 2010. Published by Elsevier Inc. All rights reserved.)

Introduction: This phase II trial evaluated the efficacy and toxicity of the combination of paclitaxel, carboplatin, bevacizumab, and erlotinib in the first-line treatment of patients with carcinoma of unknown primary site (CUP)., Methods: Patients with previously untreated CUP (adenocarcinoma, poorly differentiated carcinoma, poorly differentiated squamous carcinoma) without clinical or pathologic characteristics of a well-defined treatable subset were eligible. All patients received paclitaxel, carboplatin, bevacizumab, and erlotinib. Treatment cycles were repeated at 21-day intervals. After four cycles, paclitaxel and carboplatin were discontinued; bevacizumab-erlotinib treatment was continued until tumor progression. Patients were initially evaluated for response after completion of two treatment cycles; re-evaluations occurred every 6 weeks thereafter., Results: Forty-nine of 60 patients (82%) completed four cycles of therapy, and 44 patients (73%) subsequently received maintenance bevacizumab and erlotinib. Thirty-two patients (53%) had major responses to treatment; an additional 18 patients had stable disease. After a median follow-up of 19 months, the median progression-free survival time was 8 months, with 38% of patients progression free at 1 year. The median survival time and 2-year overall survival rate were 12.6 months and 27%, respectively. Treatment was generally well tolerated, with a toxicity profile as predicted based on the known toxicities of each treatment component., Conclusions: Empiric treatment with paclitaxel, carboplatin, bevacizumab, and erlotinib is effective and well tolerated as first-line treatment for patients with CUP. Further development of this regimen is warranted.

Background: Inhibition of the platelet-derived growth factor receptor (PDGFR) might improve the efficacy of chemotherapy by lowering interstitial tumor pressure and allowing increased tumor penetration by cytotoxic agents. In this phase II trial, we added imatinib, a PDGFR inhibitor, to docetaxel in the first-line treatment of women with metastatic breast cancer (MBC)., Patients and Methods: Women with MBC who had received a maximum of 1 previous chemotherapy regimen were eligible for this trial. Initially, patients received oral imatinib 600 mg daily and docetaxel 30 mg/m2 on days 1, 8, and 15 of a 28-day cycle. The imatinib dose was lowered from 600 mg to 400 mg daily because of toxicity (primarily gastrointestinal) observed in the first 15 patients. Patients were evaluated for response (Response Evaluation Criteria in Solid Tumors) after 8 weeks of therapy; treatment continued in responding/stable patients until tumor progression or unacceptable toxicity. The primary endpoint was the overall response rate., Results: Thirty-seven patients entered this trial between May 2005 and March 2008. This regimen was relatively poorly tolerated, even after reduction of the imatinib dose, primarily because of gastrointestinal toxicity (nausea, vomiting, and diarrhea). Eight patients (22%) stopped therapy because of toxicity before the 8-week initial evaluation. Six of 37 enrolled patients (16%; 95% CI, 4.3%-28.1%) had partial responses; an additional 4 patients had stable disease for > 6 months. The median progression-free and overall survivals were 9.3 months and 15.4 months, respectively., Conclusion: When compared with previous results with single-agent docetaxel, the combination of weekly docetaxel plus imatinib was tolerated relatively poorly and produced a low objective response rate. The efficacy of weekly docetaxel is not improved by concurrent administration of imatinib as a PDGFR inhibitor.

Purpose: Pemetrexed is a standard treatment against recurrent non-small cell lung cancer (NSCLC), and cetuximab has single-agent activity against NSCLC. This study evaluates the safety and efficacy of the combination of these agents in patients with advanced NSCLC., Patients and Methods: Patients with recurrent NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1 were entered. Patients on the phase I portion of the study received cetuximab 400 mg/m2 intravenously (IV) on day -7 followed by weekly doses of cetuximab at 250 mg/m2 IV with escalating doses of pemetrexed every 3 weeks (dose levels: 500, 600, 750, 900 mg/m2) in a standard 3 + 3 design. Once the maximum tolerated dose (MTD) of the combination was determined, patients were enrolled on the phase II portion. The primary end point was to determine the median time to disease progression (TTP) (null hypothesis 12 weeks, alternative hypothesis 24 weeks)., Results: Thirty-six patients were enrolled (phase I: n = 13, phase II: n = 23). Patient characteristics included 60.6% men, median age 64 years (range, 37-80 years), 57.6% had performance status 0 and 54.6% had adenocarcinoma histology. The median number of previous regimens was 2 (range, 1-6). The maximum tolerated dose of pemetrexed in combination with cetuximab was determined to be 750 mg/m2. The median TTP was 14.6 weeks. The median survival time was 42 weeks and 1-year survival was 38.5%., Conclusion: The combination of pemetrexed at 750 mg/m2 every 21 days with weekly cetuximab at 250 mg/m2 was feasible; however, in this unselected patient population, the combination regimen does not seem to improve TTP compared with historical controls of either single agent.

Purpose: Gemcitabine plus carboplatin (GC) is active as front-line treatment for advanced non-small-cell lung cancer (NSCLC). For patients without progression, timing of second-line chemotherapy for optimum clinical benefit remains uncertain. This phase III, randomized trial assessed the efficacy and safety of docetaxel administered either immediately after GC or at disease progression., Patients and Methods: The chemotherapy-naïve patients enrolled had either stage IIIB NSCLC with pleural effusion or stage IV NSCLC. Gemcitabine (1,000 mg/m(2)) was administered on days 1 and 8 followed by carboplatin (area under the curve = 5) on day 1. After four 21-day cycles, patients who did not have progression were randomly assigned either to an immediate docetaxel group (docetaxel 75 mg/m(2) on day 1 every 21 days, with maximum of six cycles) or to a delayed docetaxel group. The primary end point was overall survival (OS) measured from random assignment. Additional analyses included tumor response, toxicity, progression-free survival (PFS), and quality of life (QOL)., Results: Enrollment totaled 566 patients; 398 patients completed GC; 309 patients were randomly assigned equally to the two docetaxel treatment groups. Toxicity profiles were generally comparable for the docetaxel groups. Median PFS for immediate docetaxel (5.7 months) was significantly greater (P = .0001) than for delayed docetaxel (2.7 months). Median OS for immediate docetaxel (12.3 months) was greater than for delayed docetaxel (9.7 months), but the difference was not statistically significant (P = .0853). QOL results were not statistically different (P = .76) between docetaxel groups., Conclusion: We observed a statistically significant improvement in PFS and a nonstatistically significant increase in OS when docetaxel was administered immediately after front-line GC, without increasing toxicity or decreasing QOL.

Purpose: The aim of this study was to evaluate the efficacy and toxicity of imatinib, a platelet-derived growth factor-beta receptor antagonist, when added to the combination bevacizumab/erlotinib in the treatment of patients with advanced clear cell renal carcinoma., Patients and Methods: Ninety-four patients with metastatic clear cell renal carcinoma were treated with bevacizumab 10 mg/kg intravenously every 2 weeks, erlotinib 150 mg orally daily, and imatinib 400 mg orally daily. Patients were reevaluated after 8 weeks of treatment; patients with objective response or stable disease (SD) continued to receive treatment until they experienced tumor progression., Results: Fifteen of 88 evaluable patients (17%; 95% confidence interval, 10%-26%) had partial responses, whereas an additional 54 patients (61%) had SD. The median progression-free and overall survival for all patients was 8.9 months and 17.2 months, respectively. The addition of imatinib markedly increased toxicity compared with the bevacizumab/erlotinib regimen; the most common grade 3/4 toxicities were diarrhea, rash, and fatigue., Conclusion: Bevacizumab/erlotinib/imatinib was unacceptably toxic in this group of patients. Inhibition of the PDGF receptor (PDGFR) with imatinib did not appear to improve efficacy compared retrospectively with the results of treatment with bevacizumab/erlotinib. The importance of PDGFR inhibition in the treatment of advanced clear cell renal carcinoma remains unclear. Further development of this particular combination is not planned or recommended.

Purpose: To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel., Patients and Methods: Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later., Results: Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%)., Conclusion: This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.

PABA/NO is a diazeniumdiolate of structure Me(2)NN(O)=NOAr (where Ar is a 5-substituted-2,4-dinitrophenyl ring whose 5-substituent is N-methyl-p-aminobenzoic acid). It has shown activity against human ovarian cancer xenografts in mice rivaling that of cisplatin, but it is poorly soluble and relatively unstable in water. Here we report structure-based optimization efforts resulting in three analogues with improved solubility and stability in aqueous solution. We sought to explain PABA/NO's physicochemical uniqueness among these four compounds, whose aminobenzoic acid precursors differ structurally only in the presence or absence of the N-methyl group and/or the position of the carboxyl moiety (meta or para). Studies revealed that PABA/NO's N-methyl-p-aminobenzoic acid substituent is bound to the dinitrobenzene ring via its carboxyl oxygen while the other three are linked through the aniline nitrogen. This constitutes a revision of the previously published PABA/NO structure. All four analogues reacted with GSH to produce bioactive nitric oxide (NO), but PABA/NO was the most reactive. Consistent with PABA/NO's potent suppression of A2780 human ovarian cancer xenograft growth in mice, it was the most potent of the four in the OVCAR-3 cell line.

PROLI/NO is an agent of structure XN(O)==NONa (X = L-prolyl) whose 2-s half-life for nitric oxide (NO) release at physiological pH makes it an excellent prodrug for localizing NO's therapeutic effects at the site of application, but a difficult one to formulate and certify as pure. Despite its extraordinary thermal and hydrolytic instability, however, PROLI/NO could be formulated as an injectable drug by dissolving it in cold 0.1 M sodium hydroxide containing 5% D-mannitol, then quickly ultrafiltering and lyophilizing it in evacuated septum vials. No evidence for decomposition was seen in the contents of these evacuated vials when stored at -20 degrees C over a 140-day observation period, as judged by quantifying NO release in simulated infusate solutions (10 mM carbonate/bicarbonate, pH 10.5). The only hydrolysis products detected were NO, nitrite ion, proline, and N-nitrosoproline, all products of normal human physiological processes.

Here, we explore the chemistry of the previously undocumented E form of diazeniumdiolates having the structure R(1)R(2)NN(O)=NOR(3). Reported crystallographic studies have uniformly revealed the Z configuration, and our attempts to observe a Z --> E conversion through thermal equilibration or photochemical means have, until now, consistently failed to reveal a significant amount of a second conformer. As a typical example, the NMR spectrum of trimethyl derivative Me(2)NN(O)=NOMe revealed no evidence for a second configuration. Electronic structure calculations attribute this finding to a prohibitively high interconversion barrier of approximately 40 kcal/mol. A similar result was obtained when we considered the case of R(1) = Me = R(3) and R(2) = H at the same levels of theory. However, when MeHNN(O)=NOMe was ionized by dissociating the N-H bond, the barrier was calculated to be lower by approximately 20 kcal/mol, with the E form of the anion being favored over Z. This circumstance suggested that an E isomer might be isolable if a Z anion were formed and given sufficient time to assume the E configuration, then quenched by reaction with an electrophile to trap and neutralize the E form and restore the putatively high interconversion barrier. Consistent with this prediction, basifying iPrHNN(O)=NOCH(2)CH(2)Br rapidly led to a six-membered heterocycle that was crystallographically characterized as containing the -N(O)=NO- functional group in the E configuration. The results suggest an approach for generating pairs of Z and E diazeniumdiolates for systematic comparison of the rates at which the individual isomers release bioactive NO and of other physicochemical determinants of their biomedical utility.

Purpose: This multicenter, open-label, phase II study was undertaken to assess the antitumor activity and safety of the oral mitogen-activated extracellular signal regulated kinase kinase (MEK) inhibitor, CI-1040, in breast cancer, colon cancer, non-small-cell lung cancer (NSCLC), and pancreatic cancer., Patients and Methods: Patients with advanced colorectal, NSCLC, breast, or pancreatic cancer received oral CI-1040 continuously at 800 mg bid. All patients had measurable disease at baseline, a performance status of 2 or less, and adequate bone marrow, liver, and renal function. Expression of pERK, pAkt, and Ki-67 was assessed in archived tumor specimens by quantitative immunohistochemistry., Results: Sixty-seven patients with breast (n = 14), colon (n = 20), NSCLC (n = 18), and pancreatic (n = 15) cancer received a total of 194 courses of treatment (median, 2.0 courses; range, one to 14 courses). No complete or partial responses were observed. Stable disease (SD) lasting a median of 4.4 months (range, 4 to 18 months) was confirmed in eight patients (one breast, two colon, two pancreas, and three NSCLC patients). Treatment was well tolerated, with 81% of patients experiencing toxicities of grade 2 or less severity. Most common toxicities included diarrhea, nausea, asthenia, and rash. A mild association (P < .055) between baseline pERK expression in archived tumor specimens and SD was observed., Conclusion: CI-1040 was generally well tolerated but demonstrated insufficient antitumor activity to warrant further development in the four tumors tested. PD 0325901, a second generation MEK inhibitor, has recently entered clinical development and, with significantly improved pharmacologic and pharmaceutical properties compared with CI-1040, it may better test the therapeutic potential of MEK inhibition in cancer.

A rapid, sensitive, and specific high-performance liquid chromatography-electrospray ionization-multistage mass spectrometry (MS) method for measuring endogenous ketolic estrogen metabolites in human urine has been developed. The method requires a single hydrolysis/extraction/derivatization step and only 2.5 mL of urine, yet is able to simultaneously quantify estrone and its 2-methoxy and 2-, 4-, and 16alpha-hydroxy derivatives, 16-ketoestradiol, and 2-hydroxyestrone-3-methyl ether metabolites. The combination of a simple hydrazone derivatization step with multistage MS greatly enhances the sensitivity and specificity of the analysis of endogenous estrogen within human urine. Standard curves are linear over a 100-fold concentration range with linear regression correlation coefficients typically greater than 0.99. The lower limit of quantitation for each ketolic estrogen is 0.2 ng/2.5-mL urine sample (10 pg on column), with an accuracy of 93-103% and an overall precision, including the hydrolysis, extraction, and derivatization steps, of 1-13% relative standard derivation (RSD) for samples prepared concurrently and 8-16% RSD for samples prepared in separate batches. This method also allows for the identification of 2-hydroxyestrone-3-methyl ether in urine obtained from both pre- and postmenopausal women. This potentially protective estrogen metabolite has been previously reported only in the urine of pregnant women. Since individual patterns of estrogen metabolism may influence the risk of breast cancer, accurate and specific measurement of estrogen metabolites in biological matrixes will facilitate future research on breast cancer prevention, screening, and treatment.

In this paper, we examine the effect of treatment parameters in a model used to evaluate permanent prostate implants. The model considers the prostate to be composed of 12 sub-sections, each sub-section is assigned a cell density based on the probability of finding cancer foci in that sub-section. Wasted dose as a result of the dose rate from the implant falling below a level adequate to counteract repopulation was found to vary by 2-16% over the range of radiosensitivity and repopulation rates considered. Within the model, applied to five dose distributions, the uncertainty in the tumour control probability (TCP) values calculated for each sub-section as a result of differences in the model parameters, was found to be less than 12% in most cases for the good quality implants. The difference in TCP values was much larger for the poor quality implant. Substituting a heterogeneous distribution of alpha for a single mean value resulted in generally lower TCP values though introducing a cutoff value with a Gaussian distribution had a profound effect on the calculated values. Despite uncertainties in the parameters, the model was able to identify sub-sections at risk of local recurrence but as a result of these uncertainties, the TCP values can only be considered in the relative rather than absolute sense.

Purpose: A method of prostate implant dose distribution assessment using a bioeffect model that incorporates a distribution of tumor cell densities is demonstrated. This method provides both a quantitative method of describing implant quality and spatial information related to the location of underdosed regions of the prostate. This model, unlike any other, takes into account the likelihood of finding cancer cells in the underdosed region., Methods and Material: The prostate volumes of 5 patients were divided into multiple subsections and a unique cell density was assigned to each subsection. The assigned cell density was a function of probability of finding tumor foci in that subsection. The tumor control probability (TCP) for each subsection was then calculated to identify the location of any significantly underdosed part of the prostate. In addition, a single TCP value for the entire prostate was calculated to score the overall quality of the implant., Results: Adequately dosed subsections scored TCP values greater than 0.80. The TCP for underdosed regions fell dramatically particularly in subsections at higher risk of containing tumor cells., Conclusions: Despite uncertainties in radiobiological parameters used to calculate the TCP and the distribution of cancer foci through the prostate, the bioeffect model was found to be useful in identifying regions of underdosed prostate that may be at risk of local recurrence due to inadequate dose. Unlike the isodose distribution, the model has the potential to demonstrate that small volumes of tissue underdosed in regions most likely to contain higher numbers of tumor cells may be more significant than larger volumes irradiated to a lower dose but with a lower probability of containing cancer cells.