Prophylactic Topical Treatment for EGFR Inhibitor-Induced Papulopustular Rash: A Randomized Clinical Trial.

BACKGROUND: The incidence of epidermal growth factor receptor inhibitor (EGFRI)-induced papulopustular rash is 60-85%. OBJECTIVE: To investigate prophylactic topical treatment for EGFRI-induced rash. METHODS: A single-center, randomized, double-blind, placebo-controlled trial. Adult cancer patients initiating treatment with EGFRIs were randomized to receive facial topical treatment with chloramphenicol 3% + prednisolone 0.5% (CHL-PRED) ointment, chloramphenicol 3% (CHL) ointment, or aqua cream (AQUA). The primary end points were the incidence of ≥grade 3 rash using the Common Terminology Criteria for Adverse Events (CTCAE), on days 14 and 30. A subanalysis was conducted for incidence of a protocol-specified significant rash, defined as ≥10 facial papulopustular lesions. RESULTS: The per-protocol analysis on day 14 included 69 patients, who received CHL-PRED (21), CHL (23), or AQUA (25). The incidence of CTCAE ≥grade 3 rash was not statistically significant between arms; however, the incidence of the protocol-specified significant rash was: CHL-PRED 14%, CHL 39%, and AQUA 48% (p = 0.03, CHL-PRED vs. AQUA). At 30 days, the CTCAE ≥grade 3 incidence was similar, but the incidences of protocol-specified significant rash were 6%, 16%, and 43% (p = 0.03, CHL-PRED vs. AQUA). No significant differences were found between CHL and CHL-PRED and between CHL and AQUA. CONCLUSIONS: Prophylactic topical CHL-PRED was efficacious when compared to AQUA, in the treatment of EGFRI-induced facial papulopustular rash.

Correction to: Trimodally treatment for stage IIIa NSCLC patients increases survival while not effecting surgical mortality or complexity.

The original article [1] contained an error whereby all authors' names were mistakenly inverted. This error has now been corrected.

Trimodally treatment for stage IIIa NSCLC patients increases survival while not effecting surgical mortality or complexity.

INTRODUCTION: Advanced non-small cell lung cancer (NSCLC) is still a therapeutic challenge as the 5-year survival is under 30%. The optimal treatment regimen is still under debate. HYPOTHESIS: Neo adjuvant (NA) treatment given pre-pneumonectomy does not increase surgical complexity or peri-OP mortality while it has a potential to increase long term survival. METHODS: We have conducted a retrospective study of 169 patients who underwent a pneumonectomy for NSCLC between January 2005 to December 2015 and focused on stage IIIa patients; a cohort of 51 patients, 30 which received neo adjuvant chemo-radiation (NA group) prior to pneumonectomy and 21 patients who had undergone pneumonectomy followed by adjuvant treatment (Adjuvant group). Surgical complexity and short- and long-term survival were evaluated. Surgical complexity was assessed by surrogates as surgery duration, hospitalization length and interdepartmental transfer. RESULTS: While no statistically significant differences were found in surgery duration, hospitalization length, morbidity in the 1st year post-OP and the peri-OP mortality; The long term beneficiary effect among the neo adjuvant patients was clear; while 30% of the NA patients were alive 8 years post-OP, there were no survivors in the adjuvant group 5.5 years post-OP. CONCLUSION: We conclude that while NA treatment has no effect on operation complexity, peri-OP mortality or post-OP morbidity; its impact on long term survival is protuberant, therefore, we believe that NA treatment should be considered as the treatment of choice in advanced NSCLC in need for pneumonectomy.

High-Dose Radiotherapy as Neoadjuvant Treatment in Non-Small-Cell Lung Cancer.

BACKGROUND: Trimodality therapy (chemoradiation followed by surgery) provides a benefit in progression-free survival but not overall survival. We sought to determine if a high dose of radiation could be delivered safely and provide a clinical benefit. METHODS: Consecutive patients with stage IIIA or IIIB non-small-cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy followed by surgery were reviewed with IRB approval. RESULTS: A total of 48 patients were treated from November 2007 to May 2014. Of these, 64% had stage IIIA disease while 36% had stage IIIB; 46% had adenocarcinoma, 34% squamous, and 23% NSCLC not otherwise specified. The median dose of chemoradiotherapy was 72 Gy (60-72). Overall, 86% of patients received cisplatin (50 mg/m2) and etoposide (50 mg/m2) concurrently with radiotherapy; 72% of patients underwent lobectomy following chemoradiotherapy and 28% underwent pneumonectomy. The 30- and 90-day mortality rates were 0%. The nodal downstaging rate was 82% and there was a 64% rate of pathologic complete response. The overall survival was 29.9 months (95% CI, 19-86 months). The median time to locoregional progression was 35.1 months and the median time to distant progression was 39.3 months. Locoregional failure was 8% and distant failure was 44%. CONCLUSION: High-dose preoperative chemoradiotherapy was safe and effective. This combination should be further considered.

Effectiveness and safety of nivolumab in advanced non-small cell lung cancer: The real-life data.

OBJECTIVES: Nivolumab has recently received regulatory approval as a 2nd-line treatment of non-small cell lung cancer (NSCLC). The data regarding its effectiveness and safety in real life setting is lacking. MATERIALS AND METHODS: 260 consecutive patients with advanced NSCLC treated with nivolumab at five Israeli cancer centers between January 2015 and March 2016 were evaluated for overall survival (OS) and toxicity. OS was analyzed by the Cox proportional-hazards regression model. Overall response rate (ORR) and progression-free survival (PFS) were assessed in 49 patients using RECIST, v.1.1. RESULTS: Median age was 67y (41-99); males 68%; smokers 76%; ECOG PS ≥2 46%; non-squamous/squamous/other/NR 70%/23%/6%/1%; brain metastases 21%; liver metastases 21%; treatment line: 1st/2nd/3rd+-line/NR 6%/64%/26%/4%. With median survival follow-up of 18.5 months (range, 12.0-26.9), 155 (60%) patients died; median OS comprised 5.9 months (95% CI 4.7-7.4). In univariate and multivariate analysis, the only variable which significantly correlated with OS was ECOG PS. Median OS of patients with ECOG PS 0/1 and ECOG PS ≥2 comprised 9.5 months (95% CI, 6.7-NR) and 3.5 months (95% CI, 2.6-4.5), respectively. For 49 patients evaluable for response (median follow-up of 8.4 months (range, 2-16.8), ORR was 35%, median PFS was 2.8 months (95% CI, 1.8-7.7), incidence of pseudo-progression was 9%. The nivolumab safety profile was in accordance with the literature data, except for febrile neutropenia and pericarditis (observed in 1 case each). CONCLUSION: In real life setting, the effectiveness of nivolumab is reasonable yet less prominent than it has been demonstrated in clinical trials. ECOG PS ≥2 is associated with poor prognosis.

Intracranial response to nivolumab in NSCLC patients with untreated or progressing CNS metastases.

Central nervous system (CNS) metastases occur in 30% of patients with advanced non-small cell lung cancer (NSCLC). Localized treatments targeting CNS metastases result in delays in systemic therapy administration and are associated with neurocognitive impairment. Nivolumab is an immune check-point inhibitor that is approved as a second-line treatment of NSCLC. Data regarding the intracranial activity of nivolumab is lacking. We retrospectively reviewed the efficacy and safety of nivolumab in five patients with advanced NSCLC and new/progressing intracranial metastases. Intracranial response was assessed by magnetic resonance imaging (MRI) using mRECIST v. 1.1 criteria. All patients had parenchymal brain metastases; two patients had leptomeningeal carcinomatosis diagnosed according to radiological criteria. All patients were asymptomatic and did not require corticosteroids or immediate local therapy. We observed one complete and one partial response in the brain. Stabilization of leptomeningeal carcinomatosis for 10 weeks was achieved in one additional patient. Two patients progressed in the CNS. Time-to-response comprised 5 weeks and 9 weeks; both responses are still ongoing at the time of the report (24+ and 28+ weeks since start of treatment). Systemic responses and intracranial responses were largely concordant. No treatment-related or CNS metastases-related grade≥3 adverse events were observed. Nivolumab might have intracranial activity and favorable safety profile in patients with CNS metastases secondary to NSCLC. Nivolumab CNS activity warrants further evaluation.

Durable brain response with pulse-dose crizotinib and ceritinib in ALK-positive non-small cell lung cancer compared with brain radiotherapy.

Crizotinib achieves excellent systemic control in anaplastic lymphoma kinase-rearranged (ALK+) non-small cell lung cancer (NSCLC); however, central nervous system (CNS) metastases frequently occur as an early event. Whole brain irradiation, the standard treatment, results in neurocognitive impairment. We present a case series of three ALK+ NSCLC patients with progressing CNS metastases who were treated with pulse-dose crizotinib followed by ceritinib. Three ALK+ NSCLC patients treated between 2011 and 2014 (two males, two never smokers, age range 20-54years, all echinoderm microtubule-associated protein-like 4/ALK rearrangement), were diagnosed with progressing cerebral disease while receiving crizotinib. Clinico-pathological characteristics, treatments, and outcomes were analyzed. In two patients the progression was limited to the CNS, and radiological evidence of leptomeningeal spread was present in one patient. Sequential use of crizotinib 500mg administered once daily (pulse-dose) followed by ceritinib on progression achieved control of the disease in the CNS for over 18 months and over 7 months in Patient 1 and Patient 2, respectively. This strategy provided durable CNS control after whole-brain radiotherapy failure in Patient 1, and allowed the whole-brain radiotherapy to be deferred in Patient 2. Limited CNS progression was documented in Patient 3 while he was on standard-dose/pulse-dose crizotinib for 15months; durable (over 7 months) complete remission was achieved with stereotactic radiotherapy and ceritinib. Manipulating the crizotinib schedule in ALK+ NSCLC patients with CNS metastases and using a novel ALK-inhibitor at the time of further progression may provide durable CNS control and allow brain radiotherapy to be deferred.

EGFR mutation testing practice in advanced non-small cell lung cancer.

PURPOSE: Testing tumor samples for the presence of a mutation in the epithelial growth factor receptor (EGFR) gene is recommended for advanced non-squamous non-small cell lung cancer (NSCLC) patients. We aimed to collect data about common practice among Medical Oncologists treating lung cancer patients, regarding EGFR mutation testing in advanced NSCLC patients. METHODS: An internet-based survey was conducted among members of the Israeli Society for Clinical Oncology and Radiotherapy involved in the treatment of lung cancer patients. RESULTS: 24 Oncologists participated in the survey. The participants encompass the Oncologists treating most of the lung cancer patients in Israel. 79% of them use EGFR testing routinely for all advanced NSCLC patients. Opinions were split regarding the preferable biopsy site for EGFR testing material. 60% of participants recommend waiting for EGFR test results prior to initiation of first-line therapy. CONCLUSIONS: EGFR testing is requested in Israel routinely by most treating Oncologists for all advanced NSCLC patients, regardless of histology. In most cases, systemic treatment is deferred until the results of this test are received.

The role of routine bronchoscopy for early detection of bronchial stump recurrence of lung cancer: 1 year post-surgery.

BACKGROUND: Local recurrence after complete resection (R(0)) occur in approximately 20% of patients with stage I disease and in up to 50% with stage III. This study focuses on early detection of stump recurrence by a routine bronchoscopy. METHODS: Prospective analysis 1 year after surgery between April 2006 and April 2008. RESULTS: 104 NSCLC patients (age 69.1+/-9.6 years) participated in the study; 97 underwent lobectomy and 7 pneumonectomy. 61% were stage I, 25% stage II, 10% IIIA, 5% IIIB and 1% stage IV. 66% had N0, 21% had N1 disease, 9% N2 disease and 4% had N3. Bronchoscopy was performed 12.9+/-3.8 months after surgery. Nine percents had stump polyp, 5 (5%) had a suspicious mucosa. Four of the nine polyps were malignant. Nine other patients had squamous metaplasia and two had squamous dysplasia. Malignant stump recurrence was observed in four cases, all had a stump polyp. All had R(0), but two had short (<1.0 cm) tumor-free bronchial margin, two had N1 disease and two N2 disease. Fisher exact analysis showed short bronchus (p=0.003), N2 vs. N0-1 (p=0.012), and N1 vs. N0 (p=0.011) as significant risk factor for stump recurrence. For stump recurrence, one patient underwent completion pneumonectomy and has no evidence for disease (32.2 months), two patients were treated by chemotherapy and one patient died from pneumonia before therapy. CONCLUSION: Routine bronchoscopy 1 year after thoracic resection for NSCLC is justified in patients who are at high risk for local recurrence, i.e. short free bronchial margins and N2/N1 disease.

Endobronchial stent for malignant airway obstructions.

BACKGROUND: Endobronchial stents are used to treat symptomatic patients with benign or malignant airway obstructions. OBJECTIVES: To evaluate the safety and outcome of airway stent insertion for the treatment of malignant tracheobronchial narrowing. METHODS: The files of all patients with malignant disease who underwent airway stent insertion in our outpatient clinic from June 1995 to August 2004 were reviewed for background data, type of disease, symptoms, treatment, complications and outcome. RESULTS: Airway stents were used in 34 patients, including 2 who required 2 stents at different locations, and one who required 2 adjacent stents (total, 37 stents). Ages ranged from 36 to 85 years (median 68). Primary lung cancer was noted in 35% of the patients and metastatic disease in 65%. Presenting signs and symptoms included dyspnea (82%), cough (11.7%), hemoptysis (9%), pneumonia (5.9%), and atelectasis (3%). The lesions were located in the left mainstem bronchus (31%), trachea (26%), right mainstem bronchus (26%), subglottis (14.3%), and bronchus intermedius (2.9%). Conscious sedation alone was utilized in 73% of the patients, allowing for early discharge. Eighteen patients (50%) received brachytherapy to the area of obstruction. Complications included stent migration (one patient) and severe or minimal bleeding (one patient each). Ninety-four percent of the patients reported significant relief of their dyspnea. Three of the four patients who had been mechanically ventilated before the procedure were weaned after stent insertion. Median survival from the time of stent placement was 6 months (range 0.25-105 months). CONCLUSION: Stent placement can be safely performed in an outpatient setting with conscious sedation. It significantly relieves the patient's symptoms and may prolong survival.

Hormone replacement therapy is more prevalent among Jewish BRCA1/2 mutation carriers.

The aim of this study was to compare reproductive factors, use of oral contraceptives (OC) and hormone replacement therapy (HRT) in consecutive Jewish Ashkenazi breast cancer patients, with and without BRCA1/BRCA2 mutations. Jewish Israeli women with breast cancer (n=385) were genotyped for the three predominant Jewish mutations in BRCA1 and BRCA2, and data on reproductive factors, OC and HRT use, were analyzed using logistic regression analyses. Overall, 28/385 (7.3%) of participants were mutation carriers, the majority of whom were Ashkenazi (n=22; 78.6%) and were diagnosed with breast cancer at or under age 49 years (n=18; 64.3%). Mutation carriers were more likely than non-carriers to ever use OC (39.3% vs. 20.2%; P=0.053), HRT (35.7% vs. 13.7%; P=0.007), and have first menarche at or below 12 years of age (71.4% vs. 40.6%; P=0.03). Multivariate analysis showed that Ashkenazi women diagnosed with breast cancer under 40 years of age, with a family history of breast/ovarian cancer, who ever used HRT were more likely to be mutation carriers. This study has shown that HRT use is more prevalent among Jewish Ashkenazi mutation carriers, but its role in modifying breast cancer risk in mutation carriers remains unknown.

Mutational analysis of hMsh6 in Israeli HNPCC and HNPCC-like families.

Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the present study, ethnically diverse individuals with HNPCC and HNPCC-like features were genotyped for hMsh6 germline mutations using exon-specific PCR, DGGE, and DNA sequencing. The study encompassed 92 individuals representing 88 unrelated families who were previously analyzed for Msh2 and Mlh1 mutations: Jewish Ashkenazim (n = 44), non-Ashkenazim (n = 27), Israeli Moslem-Arab (n = 15), Druze (n=3), and Cypriot non-Jews (n = 3). Of the study population, 71 had colon cancer (CRC), mean age at diagnosis was 50.9+/-13.2 years (range 16-73 years), 5 had endometrial cancer (two with concurrent CRC), (mean 43.6+/-3.26 years, range 38-45 years), and unaffected individuals (n = 18) were first degree relatives within HNPCC families and were genotyped at a mean age of 48.3+/-11.7 years (range 30-69 years). Of the 92 individuals analyzed, none showed a truncating hMsh6 mutation, and 6 (6.6%) harbored one of three germline missense mutations: a previously reported one (V878A), and two novel mutations (V509A, S227I). The pathogenic significance of these three missense mutations is yet unclear. In addition, 5 polymorphisms were detected, 2 of which were novel. We conclude that the rate of pathogenic hMsh6 mutations in HNPCC families of Jewish and Mediterranean origin is low, and that mutations in other genes probably account for the phenotype in these families.

Genetic analyses in consecutive israeli jewish colorectal cancer patients.

OBJECTIVES: Two APC germline mutations, E1317Q and I1307K, have been linked to colorectal cancer (CRC) risk. Whereas the I1307K variant is almost exclusively encountered in (Ashkenazi) Jews, E1317Q is not restricted to certain ethnic populations. Data on its contribution to CRC risk in Jewish patients are sparse. AIMS: To assess the contribution of E1317Q to CRC development in the Jewish population. METHODS: A total of 538 consecutive Israeli Jewish CRC patients and 440 controls were genotyped for E1317Q. In addition, the rate of the I1307K APC missense mutation and the two predominant Jewish mutations in hMSH2, A636P, and 324delCA, associated with hereditary nonpolyposis colon cancer (HNPCC), were determined. RESULTS: The E13117Q missense mutation was detected in 6/538 (1%) of CRC patients and 5/440 (1%) of controls. The I1307K variant was found in 8% of all patients and in 11% (35/322) of patients of Ashkenazi Jewish descent. Carriers and noncarrier CRC patients did not differ in age of onset or associated colonic adenomatous polyps. The carrier rate among controls was 5% among Ashkenazim and 1.6% among non-Ashkenazi individuals. The 324delCA hMSH2 mutation was not observed in this cohort, and 4 of 322 Ashkenazi patients (1.2%) displayed the A636P mutation. CONCLUSION: In Jewish CRC patients the E1317Q variant plays little if any role in colorectal cancer susceptibility and genetic testing for this variant is not warranted. The I1307K mutation is associated with a moderate excess risk for CRC, but age of onset seems not to be earlier and this variant is not associated with a multiple colonic polyp phenotype. Founder mutations in hMSH2 are rare in consecutive CRC patients.

Cancer disease predictive diagnosis: BAT/CD3-positive lymphocytes in cancer patients.

BAT is an immune-activating monoclonal antibody produced against Daudi cell membranes and selected for stimulating lymphocyte proliferation. The anti-tumor activity of BAT is related to its immunostimulatory properties. Both T and NK cells mediate the anti-tumor activity of BAT. CD4-positive T cells respond to BAT activation by proliferation and INF-gamma production. The aim of the study was to assess the probability that the BAT monoclonal antibody binding capacity to T cells is a marker for different cancers. Human peripheral blood T cells from colon, breast and prostate cancer patients, as well as healthy volunteer donors, were tested for the percentage of binding to BAT mAb (BAT/CD3 cells) by FACS analysis. All patients were tested before undergoing surgery or treatment, and their diagnosis was confirmed by histology. The results showed that the percentage of BAT monoclonal antibody binding to CD3-positive T cells in the peripheral blood was different in cancer patients with diverse tumor types. We found that lymphocytes from the blood of healthy donors contained 25% BAT/CD3 cells. In colon and breast cancer patients, a significant decrease to 13 and 11% of BAT/CD3 cells was found. In contrast, these cells increased ><50% in patients with prostate cancer. These findings may have a potential diagnostic significance and also assist in the evaluation of strategies for the therapeutic use of BAT for different cancer patients.

Genotype phenotype correlations in Israeli colorectal cancer patients.

While genetic factors clearly play a key role in colorectal cancer (CRC) pathogenesis and in determining its phenotypic features, the precise genes that involved are largely unknown. To gain insight into these genes, consecutive Israeli CRC patients were genotyped using SNPs from within candidate genes: APC, beta-Catenin, K-RAS, DCC, P16, PTEN, RB1, P15, APOE, ERCC2, P53, MTHFR and hMSH2. Genotyping of consecutive, unselected colorectal cancer patients was done mostly by utilizing the MassARRAY technology (Sequenom) and to a lesser extent DGGE, ARMS and direct DNA sequencing. Correlation of genotypes with specific phenotypic features was carried out for all patients and separately for the Ashkenazim. Overall, 456 patients were analyzed, the majority (64.25%) being of Ashkenazi origin; mean age at diagnosis was 65.6 +/- 14 (range 25-90 years), and the mean follow-up was 4.7 +/- 0.28 (range 0-30 years). Statistically significant associations were noted between SNPs in beta-catenin and APOE and a positive family history of cancer (beta-catenin: p=0.034, APOE: p=0.033); tumor location and a DCC SNP (p=0.038) and the P53 R72P mutation and survival (p=0.0336). In Ashkenazi patients, ERCC2 and MTHFR genes' SNPs were associated with age at diagnosis (ERCC2: p=0.025, MTHFR: p=0.0005); a P53 polymorphism, APOE and Rb SNPs with a family history of cancer (P53 p=0.034;APOE p=0.04, Rb p= 0.022); DCC SNP with tumor location (p=0.014); and p15 SNP with tumor grade (p=0.032). This preliminary study shows that genetic factors play a role in determining CRC phenotypic features and that a larger cohort with longer follow-up is clearly needed.

Analysis of polymorphic patterns in candidate genes in Israeli patients with prostate cancer.

BACKGROUND: The precise genes involved in conferring prostate cancer risk in sporadic and familial cases are not fully known. OBJECTIVES: To evaluate the genetic profile within several candidate genes of unselected prostate cancer cases and to correlate this profile with disease parameters. METHODS: Jewish Israeli prostate cancer patients (n = 224) were genotyped for polymorphisms within candidate genes: p53, ER, VDR, GSTT1, CYP1A1, GSTP1, GSTM1, EPHX and HPC2/ELAC2, followed by analysis of the genotype with relevant clinical and pathologic parameters. RESULTS: The EPHX gene His113 allele was detected in 21.4% (33/154) of patients in whom disease was diagnosed above 61 years, compared with 5.7% (4/70) in earlier onset disease (P < 0.001). Within the group of late-onset disease, the same allele was noted in 5.5% (2/36) with grade I tumors compared with 18% (34/188) with grade II and up (P = 0.004). All other tested polymorphisms were not associated with a distinct clinical or pathologic feature in a statistically significant manner. CONCLUSIONS: In Israeli prostate cancer patients, the EPHX His113 allele is seemingly associated with a more advanced, late-onset disease. These preliminary data need to be confirmed by a larger and more ethnically diverse study.

Mutational analysis of the hMSH6 gene in familial and early-onset colorectal and endometrial cancer in Israeli patients.

Familial colorectal cancer (CRC) is noted in about 15% of incident CRC cases, and at times is hallmarked by an age at diagnosis less than 50 years. Familial adenomatous polyposis (FAP) and hereditary non-polyposis colon cancer (HNPCC) account for about 40% of familial cases. Thus, the majority of familial and early-onset CRC remain genetically elusive. Similarly, the majority of familial and early onset endometrial cancer (EC), the most prevalent extracolonic tumor in HNPCC, are genetically undefined. An attractive candidate is the hMSH6 gene. Israeli patients with early onset (age under 50 years) (n = 44) and familial nonsyndromic (n = 23) CRC, and women with familial clustering of EC or CRC (n = 12), and those diagnosed with EC at, or under, the age of 50 years (n = 5) were genotyped for germ-line mutations within the hMSH6 gene. Exon-specific PCR was followed by denaturing gradient gel electrophoresis (DGGE) analysis, complemented by DNA sequencing of abnormally migrating fragments. No patients displayed a truncating mutation, and 1 CRC patient harbored a novel missense mutation (V878A). In addition, 6 previously described polymorphisms were detected. In conclusion, mutations in the hMSH6 gene occur uncommonly in Israeli patients with familial and early-onset CRC and EC.