Mira Wollner

Mistletoe as complementary treatment in patients with advanced non-small-cell lung cancer treated with carboplatin-based combinations: a randomised phase II study.

INTRODUCTION Mistletoe preparations, such as iscador, are common complementary medications. This randomised phase II study of iscador combined with carboplatin-containing regimens was conducted in chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC) patients to assess its influence on chemotherapy-related side-effects and QoL. METHODS Patients with advanced NSCLC were randomised to receive chemotherapy alone or chemotherapy plus iscador thrice weekly until tumour progression. Chemotherapy consisted of 21-day cycles of carboplatin combined with gemcitabine or pemetrexed. RESULTS Seventy-two patients (control: 39; iscador: 33) were enrolled in the study. Most (65%) were in stage IV, and 62% had squamous histology. Median overall survival in both groups was 11 months. Median TTP was 4.8 months for the controls and 6 months in the iscador arm (p=NS). Differences in grade 3-4 haematological toxicity were not significant but more control patients had chemotherapy dose reductions (44% versus 13%, p=0.005), grade 3-4 non-haematological toxicities (41% versus 16%, p=0.043) and hospitalisations (54% versus 24%, p=0.016). CONCLUSION No effect of iscador could be found on quality of life or total adverse events. Nevertheless, chemotherapy dose reductions, severe non-haematological side-effects and hospitalisations were less frequent in patients treated with iscador, warranting further investigation of iscador as a modifier of chemotherapy-related toxicity.

Salvage therapy for non-Hodgkin's lymphoma with a combination of dexamethasone, etoposide, ifosfamide, and cisplatin

SummaryA total of 30 consecutive patients with refractory or relapsing non-Hodgkins lymphoma (NHL) were treated with a combination of dexamethasone, etoposide (VP-16), ifosfamide, and cisplatin (DVIP). In all, 9 subjects (30%) showed a partial response and 10 (33%) achieved a complete response (CR) lasting from 2.5 to 24+ months. Aggressive histology, no prior therapy with VP-16, a CR to previous chemotherapy, and a treatment-free interval of >6 months prior to the present study were associated with the high CR rate. DVIP caused pronounced myelosuppression (median granulocyte nadir and median platelet nadir, 380/mm3 and 73.000/mm3, respectively), but no drug-related death occurred. We conclude that DVIP is an effective salvage combination, especially in aggressive NHL, that produces acceptable toxicity.

ALK-Rearranged Non–Small-Cell Lung Cancer Is Associated With a High Rate of Venous Thromboembolism

Background Patients with lung cancer are at increased risk for venous thromboembolism (VTE), particularly those receiving chemotherapy. It is estimated that 8% to 15% of patients with advanced non–small‐cell lung cancer (NSCLC) experience a VTE in the course of their disease. The incidence in patients with specific molecular subtypes of NSCLC is unknown. We undertook this review to determine the incidence of VTE in patients with ALK (anaplastic lymphoma kinase)‐rearranged NSCLC. Patients and Methods We identified all patients with ALK‐rearranged NSCLC diagnosed and/or treated at the Princess Margaret Cancer Centre (PM CC) in Canada between July 2012 and January 2015. Retrospective data were extracted from electronic medical records. We then included a validation cohort comprising all consecutive patients with ALK‐rearranged NSCLC treated in 2 tertiary centers in Israel. Results Within the PM CC cohort, of 55 patients with ALK‐rearranged NSCLC, at a median follow‐up of 22 months, 23 (42%) experienced VTE. Patients with VTE were more likely to be white (P = .006). The occurrence of VTE was associated with a trend toward worse prognosis (overall survival hazard ratio = 2.88, P = .059). Within the validation cohort (n = 43), the VTE rate was 28% at a median follow‐up of 13 months. Combining the cohorts (n = 98), the VTE rate was 36%. Patients with VTE were younger (age 52 vs. 58 years, P = .04) and had a worse Eastern Cooperative Oncology Group performance status (P = .04). VTE was associated with shorter overall survival (hazard ratio = 5.71, P = .01). Conclusion The rate of VTE in our ALK‐rearranged cohort was 3‐ to 5‐fold higher than previously reported for the general NSCLC population. This warrants confirmation in larger cohorts. Micro‐Abstract We examined the rate of venous thromboembolism in a cohort of consecutive patients with ALK‐rearranged non–small‐cell lung cancer (NSCLC) at a single center and found it to be 3‐ to 5‐fold higher than previously reported in the setting of advanced NSCLC. The results were comparable when we included a validation cohort of consecutive patients at 2 other centers, with an overall rate of 36%. Prospective confirmation is warranted.

BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite Instability Status, and Response to Immune Check-Point Inhibitors

Introduction: The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown. Methods: Multi‐institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (group A, n = 21) and non‐V600E (group B, n = 18). Programmed death ligand 1 (PD‐L1) expression, tumor mutational burden (TMB) and microsatellite instability status were assessed in 29 (74%), 11 (28%), and 12 (31%) patients, respectively. Objective response rate, progression‐free survival (PFS) with ICPi, and overall survival were analyzed. Results: High (≥50%), intermediate (1–49%), and no (<1%) PD‐L1 expression was observed in 8 of 19 (42%), 6 of 19 (32%), 5 of 19 (26%), and 5 of 10 (50%), 1 of 10 (10%), and 4 of 10 (40%) cases in groups A and B, respectively. Two tumors in group A showed high TMB (25%); none were microsatellite instability status–high. Twenty‐two patients (group A, n = 12; group B, n = 10) received ICPi. Objective response rate with ICPi was 25% and 33% in groups A and B, respectively (p = 1.0). Median PFS with ICPi was 3.7 months (95% confidence interval [CI]: 1.6–6.6), and 4.1 months (95% CI: 0.1–19.6) in groups A and B, respectively (log‐rank test = 0.81, p = 0.37). Neither BRAF mutation type nor PD‐L1 expression affected the response probability/PFS. Median overall survival was not reached (95% CI: 13–NR) and comprised 21.1 months (95% CI: 1.8–NR) for patients who were and were not exposed to ICPi, respectively (log‐rank test = 5.58, p = 0.018). Conclusions: BRAF mutant NSCLC is associated with high level of PD‐L1 expression, low/intermediate TMB and microsatellite‐stable status. ICPi have favorable activity both in BRAF V600E and BRAF non‐V600E mutant NSCLC.

Severe complicated neutropenia in two patients with metastatic non-small-cell lung cancer treated with nivolumab

Checkpoint inhibitors effectively enhance the natural immune response against cancer, but they are also known to induce a unique spectrum of immune-related adverse events. Here, we report the first case of isolated neutropenia subsequent to nivolumab therapy. Prominent activated T-cells were found in the patients serum and bone marrow alongside evidence of maturational defects in neutrophil precursors. Antineutrophil antibodies were not detected despite reliable testing techniques. A T-cell-mediated response is probable, consistent with the established mechanism for the development of other immune-related toxicities. Awareness of this rare and severe side effect reinforces the importance of early diagnosis and prompt initiation of proper treatment.

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.

Oxaliplatin-Induced Pulmonary Toxicity in Gastrointestinal Malignancies: Two Case Reports and Review of the Literature

Oxaliplatin is a common chemotherapy drug, used mainly for colon and gastric cancer. Most common side effects are peripheral sensory neuropathy, hematological toxicity, and allergic reactions. A less common side effect is pulmonary toxicity, characterized mainly by interstitial pneumonitis. The incidence of this side effect is unknown, but the toxicity can be fatal. Twenty-six cases of pulmonary toxicity have been described in the literature, seven in the setting of adjuvant treatment. We describe two fatal cases of pulmonary injury related to oxaliplatin and a review of the literature.

Lower lung cancer rates in Jewish smokers in Israel and the USA

Lung cancer rates in Israeli Jews have remained stable over the last five decades and are much lower than in most developed countries despite high historical smoking rates. We compared lung cancer risk in Jews and non‐Jews in Israel and in the United States. Data were derived from a population‐based, case–control study in Israel (638 cases, 496 controls) to estimate lung cancer risk associated with smoking. Data were also acquired from a case–control study in the United States with information on religious affiliation (5,093 cases, 4,735 controls). Smoking was associated with lung cancer risk in all religion/gender groups in both studies. However, major differences in risk magnitude were noted between Jews and non‐Jews; ever smoking was associated with a moderately elevated risk of lung cancer in Jewish men and women in Israel (OR = 4.61, 2.90–7.31 and OR = 2.10, 1.36–3.24, respectively), and in Jewish men and women in the United States (OR = 7.63, 5.34–10.90 and OR = 8.50, 5.94–12.17) but were significantly higher in Israeli non‐Jewish men (OR = 12.96, 4.83–34.76) and US non‐Jewish men and women (OR = 11.33, 9.09–14.12 and OR = 12.78, 10.45–15.63). A significant interaction between smoking and religion was evident in light, moderate and heavy male and female smokers. The differences in risk level between Israeli Jews and non‐Jews could not be explained by lung cancer genetic risk variants which were identified in GWAS (genes in the CHRNA5, TERT and CLPTM1L regions). Data from the two studies support the notion of a reduced risk of lung cancer in Jewish compared to non‐Jewish smokers in different areas of the world.

Getting out of a wheelchair: an uncommon insertion mutation in exon 19 of EGFR responsive to erlotinib

BackgroundMost patients with non-small cell lung cancer (NSCLC) present with advanced disease and have poor long-term prognosis. Advanced NSCLC that contains characteristic mutations in epidermal growth factor receptor (EGFR) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). EGFR exon 19 insertions mutations are rare, and response to TKIs is still unclear.Case descriptionA young Arab patient was diagnosed with metastatic disease of NSCLC harboring an exon 19 insertion of 18 nucleotides. The patient showed a very impressive clinical and radiological response within few weeks treatment with TKI agent.Discussion and evaluationTo our best knowledge, This case is the first case in Arab woman and one of few cases described in the literature with this rare mutation responding to TKIs.ConclusionsTreatment with TKIs should be the standard choice in patients with metastatic disease NSCLC.