Faculty Bibliography

A posteriori evidence suggests that radiotherapy to a targeted tumor can elicit an immune-mediated abscopal (ab-scopus, away from the target) effect in non-targeted tumors, when combined with an anti-cytotoxic T-lymphocyte antigen-4 monoclonal (CTLA-4) antibody. Concurrent radiotherapy and ipilimumab (a human monoclonal anti-CTLA-4 antibody) induced immune-mediated abscopal effects in poorly immunogenic pre-clinical tumor models and metastatic melanoma patients. However, no such reports exist for patients with metastatic lung adenocarcinoma. We report the first abscopal response in a treatment-refractory lung cancer patient treated with radiotherapy and ipilimumab. A post-treatment increase in tumor-infiltrating cytotoxic lymphocytes, tumor regression, and normalization of tumor markers was observed. One year after treatment with concurrent radiotherapy and ipilimumab the patient is without evidence of disease.

PURPOSE: Advanced non-small cell lung cancer (NSCLC) is a common and lethal malignancy that has rarely benefited from chemotherapy. Erlotinib is highly effective in NSCLC patients selected by clinical characteristics and/or the presence of epidermal growth factor receptor-sensitizing mutations. However, the way to delay or bypass erlotinib resistance is not systematically addressed. Different erlotinib-failure modes have been reported in NSCLC, and strategies to prolong erlotinib efficacy are perhaps adaptable to them. We report the feasibility and efficacy of continued erlotinib maintenance and local salvage radiation to overcome erlotinib resistances in selected NSCLC patients. PATIENTS AND METHODS: Thirty of 52 consecutive erlotinib-treated advanced NSCLC from the NYU Langone Medical Center and the Arnau de Vilanova Hospital of Lleida responded initially to erlotinib. Twenty-six patients eventually showed a generalized-progression to erlotinib, and four progressed in solitary tumor sites. These four patients were treated with continued erlotinib maintenance and local salvage radiation. RESULTS: The progression-free survival (PFS) was statistically similar in patients with oligo or generalized-progression to erlotinib. However, all four cases with solitary-progression did benefit from continued erlotinib maintenance and salvage radiation with 41-140 % prolongation of PFS. It was reflected in an improved overall survival when they were compared with patients with generalized-progression (76.4 vs. 19.9 months; p = 0.018). CONCLUSION: Continued erlotinib maintenance and local salvage radiation is feasible and could contribute to a better outcome in selected NSCLC patients with solitary-progression to erlotinib. Prospective randomized trials of this strategy are warranted.

This phase 2 study assessed PF-3512676 plus erlotinib in patients with epidermal growth factor receptor-positive advanced non-small cell lung cancer after prior chemotherapy failure. Patients were randomized 1:1 to PF-3512676 (0.20 mg/kg injected subcutaneously once weekly) plus erlotinib (150 mg daily) or erlotinib alone. The primary objective was to estimate progression-free survival (PFS). Patients received PF-3512676 plus erlotinib (n = 18) or erlotinib alone (n = 21). The study was halted because an unplanned interim analysis indicated that large improvement in PFS with addition of PF-3512676 would be unlikely. In the PF-3512676-plus-erlotinib and erlotinib-alone arms, median PFS was 1.6 and 1.7 mo (hazard ratio, 1.00; 95% confidence interval, 0.5-2.0; P = 0.9335), respectively. Salient grade >/= 3 adverse events in PF-3512676-plus-erlotinib and erlotinib-alone arms were diarrhea (5/0), dyspnea (5/6), fatigue (4/1), other flu-like symptoms (2/0), anemia (2/1), and lymphocytopenia (based on laboratory values, 1/4). Adding PF-3512676 to erlotinib did not show potential for increased progression-free survival over erlotinib alone in patients with advanced recurrent epidermal growth factor receptor-positive non-small cell lung cancer.

Background: Cytoreductive surgery for malignant pleural mesothelioma (MPM) should be reserved for patients with favorable tumor biology. Osteopontin (OPN) and the ratio of absolute neutrophil to absolute lymphocyte counts (NLR) have been reported as possible prognostic biomarkers. These were studied with other clinical/ laboratory variables in a mixed surgical/non-surgical MPM population to define independent predictors of survival (OS) and progression (TTP). Methods: Forty-four MPM patients (12 F, 32M; 26 cytoreduction, 18 no cytoreduction; 31 epithelial, 13 non-epithelial; 15 Stage I/II, 29 Stage III/IV) were examined with regard to pretreatment plasma OPN (ELISA, R&D, Minneapolis, MN), NLR age, gender, therapy, histology, stage, platelet count and WBC count. Cut points for age, OPN, NLR, platelets, and WBC were determined by X-tile Software (Yale, New Haven, CT) and univariate/multivariate Cox analyses performed. Results: Median OS were 11 m, 21m, and 8m for all 44 MPMs, cytoreduced and non-cytoreduced MPMs, respectively. Of platelet count, WBC, NLR, and OPN, only OPN was statistically significant between Stage I/II and Stage III/IV (80.3 ng/ml vs 148 ng/ml, p<0.018). The only independent covariate predictive of OS was plasma OPN. For TTP in cytoreduced patients, only age, stage, platelet count, and OPN were significant in univariate analysis, and multivariate modeling retained stage (p=0.04, HR=2.75, 95% CI=1.0517 to 7.1879) and OPN (p=0.0008, HR=17.471, 95% CI=3.3054 to 92.3461). Conclusions: Plasma OPN is promising for the stratification of tumors into good or bad risk categories and to help select potential candidates for cytoreduction and further postoperative therapy. (Table Presented)

Background Epidermal growth factor receptor (EGFR) inhibitors are widely used medications in the treatment of cancers. Objective To review the cutaneous adverse events related to EGFR inhibitors. Methods A retrospective chart review of all cases referred for the management of cutaneous adverse events after the initiation of EGFR inhibitor therapy between the years of 2006 and 2009 was performed. The study was approved by the institutional review board. Results Four men and 11 women had cutaneous adverse events while receiving erlotinib (mean dose: 112.5 mg) for lung and pancreatic cancer. The most common cutaneous adverse reaction observed was a papulopustular rash in 12 cases (80%). Eczema and xerosis were the only findings in three patients, alopecia in one case, and nail changes in three cases. The treatment modalities prescribed were doxycycline and topical antibiotics for the papulopustular rash; topical high potency steroids, tacrolimus, pimecrolimus, and moisturizers for xerosis and eczema; and cetirizine for the pruritus. The paronychia was treated with warm soaks, topical steroids, and podiatry referral. The majority of patients improved with symptomatic therapy, with the exception of one patient who experienced herpes zoster super infection and Stevens-Johnson syndrome. The patient was hospitalized and required discontinuation of the erlotinib therapy. Conclusion The most common cutaneous adverse event in our cohort was papulopustular rash, followed by eczema and xerosis. Patients were managed with symptom target therapy, and suspension of the EGFR inhibitor was rarely required. As the use of EGFR inhibitors increases, it is important to promptly identify and treat adverse events. Further studies are necessary to develop targeted therapeutic and preventative measures