Corneal abrasion in hysterectomy and prostatectomy: role of laparoscopic and robotic assistance.

BACKGROUND: Radical prostatectomy (RP) is most commonly performed laparoscopically with a robot (robotic-assisted laparoscopic radical prostatectomy, R/PROST). Hysterectomy, which may be open hysterectomy (O/HYST) or laparoscopic hysterectomy (L/HYST), has been increasingly frequently done via robot (R/HYST). Small case series suggest increased corneal abrasions (CAs) with less invasive techniques. METHODS: The authors identified RP (166,942), O/HYST (583,298), or L/HYST (216,890) discharges with CA in the Nationwide Inpatient Sample (2000-2011). For 2009-2011, they determined odds ratios (ORs) and 95% confidence intervals (CIs) for CA, in R/PROST, non-R/PROST, L/HYST, O/HYST, and R/HYST. Uni- and multivariate models studied CA risk depending on surgical procedure, age, race, year, chronic illness, and malignancy. RESULTS: In 2000-2011, 0.18% RP, 0.13% L/HYST, and 0.03% O/HYST sustained CA. Compared with 17,554 non-R/PROSTs (34 abrasions, 0.19%) in 2009-2011, OR was not significantly higher in 28,521 R/PROSTs (99, 0.35%; OR 1.508; CI 0.987 to 2.302; P < 0.057). CA significantly increased in L/HYST (70/51,323; 0.136%) versus O/HYST (70/191,199; 0.037%; OR 3.821; CI 2.594 to 5.630; P < 0.0001), further increasing in R/HYST (63/21, 213; 0.297%; OR 6.505; CI 4.323 to 9.788; P < 0.0001). For hysterectomy, risk of CA increased with age (OR 1.020; CI 1.007 to 1.034; P < 0.003) and number of chronic conditions (OR 1.139; CI 1.065 to 1.219; P < 0.0001). CA risk was likewise elevated in R/HYST with number of chronic conditions. Being African American significantly decreased CA risk in R/PROST and in R/HYST or L/HYST. CONCLUSIONS: L/HYST increased CA nearly four-fold, and R/HYST approximately 6.5-fold versus O/HYST. Identifiable preoperative factors are associated with either increased risk (age, chronic conditions) or decreased risk (race).

Empiric antibiotics for an elevated prostate-specific antigen (PSA) level: a randomised, prospective, controlled multi-institutional trial.

OBJECTIVE: To determine the impact of empiric antibiotics on men with an elevated prostate-specific antigen (PSA) level. SUBJECTS/PATIENTS AND METHODS: Men of any age with a PSA level of >2.5 ng/mL and normal digital rectal examination undergoing their first prostate biopsy were recruited from five medical centres. Patients with previous biopsy, prostate cancer, urinary tract infection (UTI) or prostatitis within the prior year, antibiotic use within 1 month, 5α-reductase inhibitor use, allergy to fluoroquinolones or clinical suspicion of UTI were excluded. Men were randomised to 2 weeks of ciprofloxacin or no antibiotic. A PSA measurement was obtained 21-45 days after randomisation immediately before prostate biopsy. The primary endpoint was the change in PSA level between baseline and immediately before biopsy. RESULTS: Complete data were available for 77 men with a mean (interquartile range) age of 60.6 (53-66) years. In the control group of men not receiving antibiotic (39 men), the mean baseline and pre-biopsy PSA levels were 6.5 and 6.9 ng/mL, respectively (P = 0.8). In men receiving ciprofloxacin (38 men), the mean baseline PSA level was 7.6 ng/mL and after 2 weeks of ciprofloxacin was 8.5 ng/mL (P = 0.7). Compared with controls not receiving antibiotic, use of ciprofloxacin was not associated with a statistically significant change in PSA level (P = 0.33). Prostate cancer was detected in 36 (47%) men, 23 (59%) in the control group and 13 (34%) in the antibiotic group (P = 0.04). Detection rates were not significantly associated with the change in PSA level between baseline and biopsy. The primary limitation of the study is early stoppage due to an interim futility analysis and poor accrual. CONCLUSION: Despite not meeting the target accrual goal, empiric use of antibiotics for asymptomatic men with an elevated PSA level does not appear to be of clinical benefit.

Influence of related donor age on outcomes after peripheral blood stem cell transplantation.

BACKGROUND AIMS: The rising use of allogeneic transplantation in older recipients necessitates considering older related donors. The effect of related donor age for peripheral blood stem cell allografts (PBSC) on graft maintenance and outcomes, independent of CD34(+)cell dose, has not been well-characterized. METHODS: HLA-related donors (98% siblings) underwent a uniform filgrastim-based mobilization regimen aiming to collect and infuse 5 × 10(6) CD34(+) cells/recipient kg. Donor and recipient age were modeled in multiple ways to account for the correlation, and outcomes reported by decade of donor age. RESULTS: The median donor and recipient ages were 52 years and 54 years, respectively. The mean CD34(+) cell dose infused was 5.6 × 10(6) CD34(+)/kg and 75% of patients received a narrow range between 4.4 and 6.6 × 10(6) CD34(+) cells/kg. Neither better PBSC mobilization nor higher CD34(+) content of allografts was significantly associated with engraftment or transplant outcomes. After adjusting for recipient age and other prognostic factors, older donor age by decade conferred a lower risk of non-relapse mortality (NRM) [hazard ratio (HR) = 0.64, 95% confidence interval (CI) 0.45-0.91, P = 0.013] and borderline improvement in overall survival (OS) (HR = 0.76, 95% CI 0.58-0.99, P = 0.045) without altering progression-free survival (PFS) (HR = 0.85, 95% CI 0.66-1.07, P = 0.18). CONCLUSIONS: Older donor age does not worsen outcome after matched related donor PBSC transplantation in patients receiving a narrow range CD34(+) cells. The relatively small sample size mandates that the finding of similar to improved outcomes for older related donor age must be confirmed in larger studies.

Measurements of Hepatic Metastasis on MR Imaging:: Assessment of Interobserver and Intersequence Variability.

RATIONALE AND OBJECTIVES: The purpose of the study was to investigate interobserver and intersequence variability in the measurement of hepatic metastasis on magnetic resonance imaging (MRI). MATERIALS AND METHODS: This retrospective study was conducted with an institutional review board-approved waiver of informed consent and was in compliance with the Health Insurance Portability and Accountability Act. We searched medical records at our institution for patients with histologically proven metastases to the liver who had undergone MRI from January 2008 to June 2010. We identified 20 patients with 30 measurable liver lesions. The liver lesions were measured on five different MRI sequences. A presenter radiologist selected and localized all metastatic lesions considered to be measurable according to the Response Evaluation Criteria in Solid Tumors, and these lesions were measured (Eisenhauer et al., 2009) by three radiologists independently. We calculated lesion-wise intraclass correlation coefficients (ICCs) to estimate interobserver and intersequence agreement in lesion diameter measurement. A Bland-Altman plot was used to estimate the limits of agreement between radiologists and MRI sequences. RESULTS: There were 30 metastases, and almost all of which had regular and well-defined margins. Interobserver ICCs were greater than 0.95 for different MRI sequences except for the measurements in apparent diffusion coefficient images. Intersequence ICCs were greater than 0.92. Bland-Altman plots between physicians confirmed that reader measurements were closely tied together, with small differences in means. CONCLUSIONS: MRI can reproducibly measure hepatic metastatic lesions without significant variability among interpreting radiologists or among MRI sequences, and is thus a reliable method for assessing the size of hepatic metastasis.

Northern Latitude but Not Season Is Associated with Increased Rates of Hospitalizations Related to Inflammatory Bowel Disease: Results of a Multi-Year Analysis of a National Cohort.

BACKGROUND AND AIMS: There is growing evidence that the incidence and severity of inflammatory bowel disease (IBD) may be geographically and seasonally related. Why these associations are observed remains unclear. We assessed the impact of geographic location, season, and exposure to ultraviolet light on disease severity by measuring national hospital IBD-related discharge rates. METHODS: Utilizing the Nationwide Inpatient Sample (NIS), we identified all patients with IBD-related discharges from 2001-2007. Patients were included if they were discharged from states above the 40th parallel (north) or at or below the 35th parallel (south); and their discharge fell within the winter (January, February, and March) or summer (July, August, and September). Groups of patients were assessed comparing north to south within each season, and summer to winter within each region. UV index was recorded from the National Weather Service data and compared to monthly discharge rates. RESULTS: There was a consistent pattern of increased IBD-related hospitalization rates in northern states compared to southern states for both ulcerative colitis and Crohn's disease. Differences in IBD-related hospitalization rates by season, however, were not uniform across the years studied. UV index was significantly inversely associated although not proportional to discharge rates for both Crohn's disease and ulcerative colitis. CONCLUSIONS: In the US, there is a significant increased rate of IBD-related hospitalizations in the northern compared to southern states, which not fully explained by differences in UV exposure.

The impact of hormonal therapy on sexual quality of life in men receiving intensity modulated radiation therapy for prostate cancer.

PURPOSE: Sexual function is an important concern in men receiving intensity modulated radiation therapy (IMRT) for prostate cancer. Our aim was to study the impact of IMRT and androgen deprivation therapy (ADT) on sexual function over time and to report the effectiveness of sexual medications or aids. METHODS AND MATERIALS: A total of 179 men, median age 69, received definitive IMRT for prostate cancer and completed 2 surveys (Expanded Prostate Cancer Index Composite-26 and a sexual medicines/devices survey) for at least 2 time points. Surveys were prospectively collected at baseline (before all therapy), and 2, 6, 12, 18, and 24 months after IMRT. Median dose was 76 Gy to the prostate. ADT was administered to 59% of patients (median duration 5 months, initiated 2 months before IMRT). Global scores were generated for the Expanded Prostate Cancer Index Composite-26 questions. Longitudinal analysis was performed by constructing a generalized estimation equations model, and clinical variables were tested for association with global scores. RESULTS: Overall, there was a significant decline in global sexual score through 2 years. Men receiving ADT had a lower sexual score at 2 and 6 months, but this difference disappeared at 24 months. Analysis of individual sexual symptoms showed no significant difference at 24 months except that men on ADT were less likely to be sexually active (P = .02); this difference was not observed for men receiving short-term ADT only. Longitudinal analysis revealed that duration of ADT was the only factor associated with global sexual score. Phosphodiesterase inhibitors were attempted by roughly half of all men, with 66% experiencing benefit, whereas other aids were attempted by roughly 5% of men. CONCLUSIONS: Although ADT adversely affected short-term sexual function, there was no significant difference in global score and most sexual symptoms by 24 months. These data are useful for anticipatory guidance regarding expectations after IMRT.

Effects of extended pleurectomy and decortication on quality of life and pulmonary function in patients with malignant pleural mesothelioma.

BACKGROUND: Maximal cytoreductive surgeries--extrapleural pneumonectomy and extended pleurectomy and decortication (EPD)--are effective surgical treatments in selected patients with malignant pleural mesothelioma. Extended pleurectomy and decortication results in equivalent survival yet better health-related quality of life (HRQoL). METHODS: Patients with malignant pleural mesothelioma were studied for the effects of EPD on HRQoL and pulmonary function. The European Organization for Research and Treatment of Cancer Core Quality of Life Questionaire-C30 was used to evaluate HRQoL before operation, and at 4 to 5 and 7 to 8 months postoperatively. Pulmonary function tests were measured immediately before and 5 to 7 months after the operation. Patients were compared according to World Health Organization baseline performance status (PS). RESULTS: Of the 36 patients enrolled, 17 were PS 0 and 19 were PS 1 or PS 2 at baseline. Patients in groups PS 1 and PS 2 had significantly worse global health, functional, and symptoms scores. After EPD, PS 0 patients had no change in global health or function and symptoms scores except for emotional function, whereas PS 1 or PS 2 patients showed improvements at 4 to 5 months with further improvements at 7 to 8 months. The PS 0 patients demonstrated a significant decrease in forced vital capacity (p = 0.001), forced expiratory volume in 1 second (p = 0.002), total lung capacity (p = 0.0006) and diffusing capacity of the lung for carbon monoxide (p = 0.003) after EPD, whereas no change was observed in PS 1 and PS 2 patients. CONCLUSIONS: Extended pleurectomy and decortication did not improve overall HRQoL and had a negative impact in pulmonary function in minimally symptomatic patients. In symptomatic patients, a significant improvement in HRQoL was observed after EPD, which continued at late follow-up, although the pulmonary function was not affected. As changes in HRQoL are multidimensional, the preservation of the pulmonary function may have contributed to the net benefit observed in PS 1 and PS 2 patients.

Late toxicity and quality of life after definitive treatment of prostate cancer: redefining optimal rectal sparing constraints for intensity-modulated radiation therapy.

The objective of this study was to assess late toxicity and quality of life (QOL) for patients receiving definitive intensity-modulated radiotherapy (IMRT) and image-guided radiation therapy (IGRT) with regard to normal tissue sparing objectives. Three hundred and seventy-two consecutive men treated with definitive IMRT for prostate adenocarcinoma. Toxicity was graded by CTC v3.0 genitourinary (GU) and gastrointestinal (GI) toxicity at each follow-up visit. Patient-reported QOL (EPIC-26) was prospectively collected for a subset of men. Dosimetric data for bladder and rectum were compared to toxicity and QOL global domain scores, specifically analyzing outcomes for men who met ideal rectal constraints (V70 <10%, V65 <20%, V40 <40%). The median age and prescription dose was 69 years and 76 Gy, respectively. Median follow-up was 47 months. At 4 years, freedom from Grade 2 (FFG2) GI toxicity was 92% and FFG2 GU toxicity was 76%. On univariate analysis, current smoking, larger bladder volume, and higher RT dose were associated with decreased FFG2 GU toxicity, while use of anticoagulation, increasing age, and not meeting ideal rectal constraints were associated with decreased FFG2 GI toxicity (all P ≤ 0.05). Bowel QOL remained stable over the 2-year follow-up period and was higher for patients who met ideal rectal constraints (P = 0.05). IMRT with IGRT is associated with low rates of severe toxicity and a high GI and GU QOL. The use of strict rectal constraints can further improve GI QOL and reduce GI toxicity.

Phase II study of the oral MEK inhibitor selumetinib in advanced acute myelogenous leukemia: a University of Chicago phase II consortium trial.

PURPOSE: The clinical relevance of targeting the RAS/RAF/MEK/ERK pathway, activated in 70% to 80% of patients with acute myelogenous leukemia (AML), is unknown. EXPERIMENTAL DESIGN: Selumetinib is an oral small-molecule inhibitor of MAP-ERK kinase (MEK)-1/2. Forty-seven patients with relapsed/refractory AML or 60 years old or more with untreated AML were enrolled on a phase II study. Patients were stratified by FLT3 ITD mutation status. The primary endpoint was response rate (complete, partial, and minor). Leukemia cells were analyzed for extracellular signal-regulated kinase (ERK) and mTOR phosphorylation. RESULTS: Common drug-related toxicities were grade 1-2 diarrhea, fatigue, nausea, vomiting, and skin rash. In the FLT3 wild-type cohort, six of 36 (17%) patients had a response [one partial response, three minor responses, two unconfirmed minor responses (uMR)]. No patient with FLT3 ITD responded. NRAS and KRAS mutations were detected in 7% and 2% of patients, respectively. The sole patient with KRAS mutation had uMR with hematologic improvement in platelets. Baseline p-ERK activation was observed in 85% of patients analyzed but did not correlate with a response. A single-nucleotide polymorphism (SNP) rs3733542 in exon 18 of the KIT gene was detected in significantly higher number of patients with response/stable disease compared with nonresponders (60% vs. 23%; P = 0.027). CONCLUSIONS: Selumetinib is associated with modest single-agent antileukemic activity in advanced AML. However, given its favorable toxicity profile, combination with drugs that target other signaling pathways in AML should be considered. The potential association of SNP rs3733542 in exon 18 of the KIT gene with antileukemic activity of selumetinib is intriguing, but will require validation in larger trials.

Pediatricians' knowledge, attitudes, and practice patterns regarding special education and individualized education programs.

OBJECTIVE: The medical community has called upon pediatricians to be knowledgeable about an individualized education program (IEP). We sought to: 1) evaluate pediatricians' knowledge and attitudes regarding special education; 2) examine the relationship between perceived responsibilities and practice patterns; and 3) identify barriers that impact pediatricians' ability to provide comprehensive care to children with educational difficulties. METHODS: Surveys were mailed to a national sample of 1000 randomly selected general pediatricians and pediatric residents from October 2010 to February 2011. RESULTS: The response rate was 47%. Of the knowledge items, respondents answered an average of 59% correctly. The majority of respondents thought pediatricians should be responsible for identifying children who may benefit from special education services and assist families in obtaining services, but less than 50% thought they should assist in the development of an IEP. The majority of pediatricians inquired whether a child is having difficulty at school, but far fewer conducted screening tests or asked parents if they needed assistance obtaining services. Overall, the prevalence of considering a practice a pediatrician's responsibility is significantly higher than examples of such a practice pattern being reported. Financial reimbursement and insufficient training were among the most significant barriers affecting a pediatrician's ability to provide care to children with educational difficulties. CONCLUSIONS: In order to provide a comprehensive medical home, pediatricians must be informed about the special education process. This study demonstrates that there are gaps in pediatricians' knowledge and practice patterns regarding special education that must be addressed.

Intensity modulated radiation therapy after radical prostatectomy: Early results show no decline in urinary continence, gastrointestinal, or sexual quality of life.

PURPOSE: Although postprostatectomy radiation therapy (PPRT) has been shown to improve cause-specific survival in select high-risk men, its use may be tempered by the concern for toxicity. Limited data exist regarding the nature of how it may adversely affect quality of life in the era of intensity modulated radiation therapy (IMRT). METHODS AND MATERIALS: Between 2007 and 2010, 78 consecutive men received PPRT. Salvage RT was administered to 61 (78%) men and adjuvant RT to 17 (22%). The median dose of IMRT was 66.6 Gy (range, 60-72). Quality of life (QOL) data were prospectively collected using the Expanded Prostate Cancer Index Composite-26 tool and International Prostate Symptom Score (IPSS) at 2-, 6-, 12-, 18-, and 24-month follow-up visits. Paired t tests and multivariate longitudinal analysis were used to assess the QOL measures at baseline and follow-up. RESULTS: No significant changes were observed for any individual QOL domain or IPSS score from baseline through 2-year follow-up. Global urinary irritation or obstruction scores were unchanged to improved over time (82, 81, 89, and 88 at baseline, 2, 12, and 24 months, respectively; baseline to 24 months P = .06). Global urinary continence improved from baseline to 24 months in the subset of patients receiving adjuvant RT, who had higher rates of baseline urinary incontinence more than once daily (64% vs 28%, P = .03) and any pad use (73% vs 32%, P = .01) compared with the salvage subset. Global bowel domain scores were lower at 2 months but improved with time. Sexual domain scores were also reduced at 2 months but otherwise unaffected over follow-up. CONCLUSIONS: Compared with baseline, PPRT does not appear to be associated with a significant decline in patient-reported urinary, bowel, or sexual QOL indices 2 years after completion.

A randomized pilot phase I study of modified carcinoembryonic antigen (CEA) peptide (CAP1-6D)/montanide/GM-CSF-vaccine in patients with pancreatic adenocarcinoma.

BACKGROUND: CEA is expressed in >90% of pancreatic cancers (PC) and may be an appropriate immunotherapy target. CEA is poorly immunogenic due to immune tolerance; CAP1-6D, an altered peptide ligand can help bypass tolerance. We conducted a pilot randomized phase I trial in PC patients to determine the peptide dose required to induce an optimal CD8(+) T cell response. METHODS: Patients with a PS 0-1, HLA-A2+ and CEA-expressing, previously-treated PC were randomized to receive 10 µg (arm A), 100 µg (arm B) or 1000 µg (arm C) of CEA peptide emulsified in Montanide and GM-CSF, given every 2 weeks until disease progression. RESULTS: Sixty-six patients were screened and 19 enrolled of whom 14 received at least 3 doses of the vaccine and thus evaluated for the primary immunologic endpoint. A median of 4 cycles (range 1-81) was delivered. Median and mean peak IFN-γ T cell response by ELISPOT (spots per 10(4) CD8(+) cells, Arm A/B/C) was 11/52/271 (A vs. C, p = 0.028) for medians and 37/148/248 (A vs. C, p = 0.032) for means. T cell responses developed or increased in 20%/60%/100% of pts in Arms A/B/C. Seven of the 19 patients remain alive at a minimum 32 months from trial initiation, including three with unresectable disease. CONCLUSIONS: The T cell response in this randomized phase I trial was dose-dependent with the 1 mg CEA peptide dose eliciting the most robust T cell responses. A signal of clinical benefit was observed and no significant toxicity was noted. Further evaluation of 1 mg CEA peptide with stronger adjuvants, and/or combined with agents to overcome immune inhibitory pathways, may be warranted in PC pts. TRIAL REGISTRATION: ClinicalTrials.gov NCT00203892.

Immune reconstitution after combined haploidentical and umbilical cord blood transplant.

Umbilical cord blood (UCB) stem cells are frequently employed for allogeneic stem cell transplant, but delayed myeloid and lymphoid immune reconstitution leads to increased risk of infections. We recently reported the clinical results of 45 patients enrolled on a pilot study combining UCB with a human leukocyte antigen (HLA)-haploidentical donor with reduced-intensity conditioning who showed rapid neutrophil and platelet recovery. We report here preliminary immune reconstitution data of these patients. Patients were assessed for lymphocyte subsets, T-cell diversity, Cylex ImmuKnow assay and serological response to pneumococcal vaccination. Natural killer (NK)-cell and B-cell reconstitution were rapid at 1 month and 3 months, respectively. T-cell recovery was delayed, with a gradual increase in the number of T-cells starting around 6 months post-transplant, and was characterized by a diverse polyclonal T-cell repertoire. Overall, immune reconstitution after haplo-cord transplant is similar to that seen after cord blood transplant, despite infusion of much lower cord blood cell dose.

Chemoradiation for patients with large-volume laryngeal cancers.

BACKGROUND: Patients with T4 laryngeal cancers, including those with large-volume (cartilage or tongue-base invasion) lesions, are often excluded from organ-preservation trials due to expectations of inferior outcome in terms of survival and function. We hypothesize that such patients indeed have acceptable survival and function when treated with organ-preservation strategies. METHODS: Retrospective analysis of prospectively collected data of a cohort of patients with T4 laryngeal cancer was carried out. Follow-up ranged from 0.18 to 15.6 years. All T4 laryngeal cancer patients who were enrolled in the University of Chicago concomitant chemoradiotherapy protocols from 1994 to the present were reviewed. This study was composed of 80 newly diagnosed T4 laryngeal cancer patients. Efficacy of treatment was determined through evaluations of survival and function. Survival was evaluated via Kaplan-Meier methods. Swallowing function was evaluated by an oropharyngeal motility (OPM) study and swallowing scores were assigned. Higher scores reflected increasing swallowing dysfunction. RESULTS: Fifty-five of 80 patients (~69%) had documented large-volume tumor. Two- and 5-year overall survivals were 60.0% and 48.7%, respectively. Disease-specific 2- and 5-year survivals for the group were 80.1% and 71.3%, and 79.4 and 74.3%, respectively, for the 55 patients with large volume status. Progression-free survival rates were 52.6% and 47.6%. Forty-four of 65 patients (~68%) with OPM data had a Swallowing Performance Status Scale (SPSS) score of ≤5, indicating various degrees of swallowing abnormalities not requiring a gastrostomy tube. This is a functional-preservation rate of 67.7%. CONCLUSIONS: Chemoradiation for patients with T4 laryngeal cancer appears to be an effective and reasonable option, particularly in light of the satisfactory survival and function-preservation rates.

Cediranib in patients with malignant mesothelioma: a phase II trial of the University of Chicago Phase II Consortium.

INTRODUCTION: Malignant mesothelioma (MM) is an aggressive disease with limited therapeutic options. In preclinical models, vascular endothelial growth factor (VEGF) stimulates MM proliferation. In MM patients, higher plasma VEGF levels correlate inversely with survival. Cediranib is an orally administered tyrosine kinase inhibitor of VEGF receptors-1, -2, and -3. METHODS: We conducted a multi-center phase II trial of cediranib in patients with unresectable, histologically-confirmed MM who had received ≤1 prior regimen of chemotherapy. The primary endpoint was objective response rate. Initial cediranib dosing was 45 mg daily during a 28-day cycle. Due to substantial toxicity, the starting dose was subsequently lowered to 30 mg daily. RESULTS: Fifty-one patients enrolled at 9 centers; 50 were evaluable for response. Partial responses were observed in 10% of patients; stable disease was seen in 34%. Disease control (PR+SD) was higher at the 45 mg cediranib dose level (67% vs. 34%, p=0.04). Median progression-free survival was 1.8 months (95% CI 0.1, 14.2); median overall survival (OS) was 4.4 months (95% CI 0.9, 41.7). The 1-year survival rate was 15%. Grade 3/4 toxicities were more frequent in the 45 mg dose level group (87% vs. 43%, p=0.002). These included fatigue, hypertension, pulmonary embolism, angioedema, and reversible posterior leukoencephalopathy. Median OS was superior in patients who developed ≥grade 3 hypertension (8.5 vs. 4.1 months, p=0.024). CONCLUSION: This trial did not meet its pre-specified response endpoint. A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated.

A phase II study of lapatinib in recurrent/metastatic squamous cell carcinoma of the head and neck.

PURPOSE: This study sought to determine the efficacy and safety profile of lapatinib in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). EXPERIMENTAL DESIGN: This phase II multiinstitutional study enrolled patients with recurrent/metastatic SCCHN into two cohorts: those without (arm A) and those with (arm B) before exposure to an epidermal growth factor receptor (EGFR) inhibitor. All subjects were treated with lapatinib 1,500 mg daily. Primary endpoints were response rate (arm A) and progression-free survival (PFS; arm B). The biologic effects of lapatinib on tumor growth and survival pathways were assessed in paired tumor biopsies obtained before and after therapy. RESULTS: Forty-five patients were enrolled, 27 in arm A and 18 in arm B. Diarrhea was the most frequent toxicity occurring in 49% of patients. Seven patients experienced related grade 3 toxicity (3 fatigue, 2 hyponatremia, 1 vomiting, and 1 diarrhea). In an intent-to-treat analysis, no complete or partial responses were observed, and stable disease was the best response observed in 41% of arm A (median duration, 50 days, range, 34-159) and 17% of arm B subjects (median, 163 days, range, 135-195). Median PFS was 52 days in both arms. Median OS was 288 (95% CI, 62-374) and 155 (95% CI, 75-242) days for arms A and B, respectively. Correlative analyses revealed an absence of EGFR inhibition in tumor tissue. CONCLUSION: Lapatinib as a single agent in recurrent/metastatic SCCHN, although well tolerated, appears to be inactive in either EGFR inhibitor naive or refractory subjects.

Statin use and risk of prostate cancer recurrence in men treated with radiation therapy.

PURPOSE: There has been growing interest in the potential anticancer activity of statins based on preclinical evidence of their antiproliferative, proapoptotic, and radiosensitizing properties. The primary objective of this study was to determine whether statin use is associated with improved clinical outcomes in patients treated with radiotherapy (RT) for prostate cancer. PATIENTS AND METHODS: In total, 691 men with prostate adenocarcinoma treated with curative-intent RT between 1988 and 2006 were retrospectively analyzed. Of those, 189 patients (27%) were using statins, either during initial consultation or during follow-up. Lipid panels were collected (n = 298) a median of 5 months before RT start. Median follow-up was 50 months after RT. RESULTS: Statin use was associated with improved freedom from biochemical failure (FFBF; P < .001), freedom from salvage androgen deprivation therapy (FFADT; P = .0011), and relapse-free survival (RFS; P < .001). Improved FFBF for statin users was seen in low-, intermediate-, and high-risk groups (P = .0401, P = .0331, and P = .0034, respectively). The improvement in FFBF with statin use was independent of ADT use or radiation dose. On multivariable analysis, statin use was associated with improved FFBF (P < .001) along with pretreatment prostate-specific antigen < or = 8.4 (P < .001), stage less than T2b (P = .0111), and Gleason score < 7 (P = .0098). On univariate analysis, pretreatment total cholesterol < 187 (89% v 80%; P = .0494) and low-density lipoprotein (LDL) < 110 (96% v 85%; P = .0462) were associated with improved 4-year FFBF. CONCLUSION: Statin use was associated with a significant improvement in FFBF, FFADT, and RFS in this cohort of men treated with RT for prostate cancer. The favorable effect of statins may be mediated by direct effect or via the LDL-lowering effect of these medications.

Chemoradiation for patients with advanced oral cavity cancer.

OBJECTIVES/HYPOTHESIS: Patients with advanced oral cavity cancer (OCC) typically have not been enrolled in clinical trials utilizing contemporary multimodality strategies. There exist dogmatic expectations of inferior outcome in OCC patients secondary to ineffectiveness of treatment and unacceptable toxicity. The purpose of this study was to analyze survival, swallowing function, and incidence of osteoradionecrosis (ORN) of patients with stage III/IV OCC who have undergone primary concomitant chemoradiotherapy (CRT). METHODS: All advanced OCC patients who were enrolled in University of Chicago concomitant CRT protocols from 1994 to 2008 were reviewed. One hundred eleven newly diagnosed advanced OCC patients were evaluated. We performed a subset analysis of 27 additional advanced OCC patients who underwent surgery followed by postoperative CRT. Swallowing function was assessed via oropharyngeal motility study, and a Swallowing Performance Status Scale score was assigned. Presence of clinically significant ORN was documented. RESULTS: Median follow-up was 3.25 years. Five-year overall and progression-free survival was 66.9% and 65.9%, respectively. There was no difference in overall or progression-free survival when the surgery-first group was compared with the primary CRT group (P = .88 and P = .86 respectively). Function, without gastric tube requirement, was excellent, with 92.2% of patients able to maintain weight via oral route. Incidence of ORN was 18.4%, occurring in nine of 49 patients evaluated. CONCLUSIONS: Our data support the use of primary CRT as a viable treatment option for patients with advanced OCC. Survival is high, and overall function for the majority of patients is satisfactory. Patients with T4 oral tongue cancer may be spared total glossectomy. The incidence of ORN may be considered acceptable, in light of the benefits of enduring life and function.

Epidermal growth factor receptor inhibitor gefitinib added to chemoradiotherapy in locally advanced head and neck cancer.

PURPOSE: Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations. PATIENTS AND METHODS: Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization. RESULTS: Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02). CONCLUSION: Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.

Amifostine induces antioxidant enzymatic activities in normal tissues and a transplantable tumor that can affect radiation response.

PURPOSE: To determine whether amifostine can induce elevated manganese superoxide dismutase (SOD2) in murine tissues and a transplantable SA-NH tumor, resulting in a delayed tumor cell radioprotective effect. METHODS AND MATERIALS: SA-NH tumor-bearing C3H mice were treated with a single 400 mg/kg or three daily 50 mg/kg doses of amifostine administered intraperitoneally. At selected time intervals after the last injection, the heart, liver, lung, pancreas, small intestine, spleen, and SA-NH tumor were removed and analyzed for SOD2, catalase, and glutathione peroxidase (GPx) enzymatic activity. The effect of elevated SOD2 enzymatic activity on the radiation response of SA-NH cells was determined. RESULTS: SOD2 activity was significantly elevated in selected tissues and a tumor 24 h after amifostine treatment. Catalase and GPx activities remained unchanged except for significant elevations in the spleen. GPx was also elevated in the pancreas. SA-NH tumor cells exhibited a twofold elevation in SOD2 activity and a 27% elevation in radiation resistance. Amifostine administered in three daily fractions of 50 mg/kg each also resulted in significant elevations of these antioxidant enzymes. CONCLUSIONS: Amifostine can induce a delayed radioprotective effect that correlates with elevated levels of SOD2 activity in SA-NH tumor. If limited to normal tissues, this delayed radioprotective effect offers an additional potential for overall radiation protection. However, amifostine-induced elevation of SOD2 activity in tumors could have an unanticipated deleterious effect on tumor responses to fractionated radiation therapy, given that the radioprotector is administered daily just before each 2-Gy fractionated dose.