Rangesh Kunnavakkam

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).

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.

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.

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. Clin Cancer Res; 18(8); 2336–43. ©2012 AACR.

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. Clin Cancer Res; 20(2); 490–8. ©2013 AACR.

Chemoradiation for Patients With Advanced Oral Cavity Cancer

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).

A Randomized Phase 1 Study of Testosterone Replacement for Patients with Low-Risk Castration-Resistant Prostate Cancer

BACKGROUND Even in castration-resistant prostate cancer (CRPC), the androgen pathway remains biologically relevant. In preclinical models, androgen therapy for CRPC leads to growth arrest, apoptosis, and tumor shrinkage. OBJECTIVE This study sought to determine the toxicity and feasibility of a testosterone therapy in early CRPC. DESIGN, SETTING, AND PARTICIPANTS Prostate cancer patients with progressive disease following androgen ablation, antiandrogen therapy, and withdrawal and no to minimal metastatic disease who were followed at the University of Chicago were randomized to treatment with three doses of transdermal testosterone. INTERVENTION Patients were treated with transdermal testosterone at 2.5, 5.0, or 7.5 mg/day. MEASUREMENTS Toxicity, prostate-specific antigen (PSA), imaging, quality of life (QoL), and strength were monitored. Treatment was discontinued for significant toxicity, clinical progression, or a 3-fold increase in PSA. RESULTS AND LIMITATIONS Fifteen men with a median age of 73 yr (range: 62-92) and a median PSA of 11.1 ng/ml (range: 5.2-63.6) were treated. Testosterone increased from castrate to median concentrations of 305 ng/dl, 308 ng/dl, and 297 ng/dl for dosages of 2.5 mg/day (n=4), 5.0 mg/day (n=5), and 7.5 mg/day (n=5), respectively. One patient was taken off of the study at 53 wk due to grade 4 cardiac toxicity. There were no other grade 3 or 4 toxicities related to the study medication, and the grade 2 toxicities were minimal. Only one patient experienced symptomatic progression, and three (20%) patients demonstrated a decrease in PSA (largest was 43%). Median time to progression was 9 wk (range: 2-96), with no detectable difference in the three dose cohorts. There was no significant improvement in QoL, and there was a borderline statistically significant improvement in hand-grip strength with treatment. The study was limited by sample size, single arm, and variability of baseline patient characteristics. CONCLUSIONS Testosterone is a feasible and reasonably well-tolerated therapy for men with early CRPC. A larger, randomized trial is under way to further characterize efficacy and impact on QoL measures.

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.

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.

Chemoradiation for patients with large-volume laryngeal cancers.

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.