Alfredo Addeo

PCR-Detectable Nonneoplastic Bcl-2/IgH Rearrangements Are Common in Normal Subjects and Cancer Patients at Diagnosis but Rare in Subjects Treated With Chemotherapy

PURPOSE To assess whether nonneoplastic Bcl-2/IgH rearrangements act as a confounding factor in the setting of minimal residual disease analysis by evaluating their incidence in a panel of lymphoma-free subjects, including cancer-free donors and chemotherapy-naive and chemotherapy-treated cancer patients. PATIENTS AND METHODS A total of 501 nonlymphoma subjects have been assessed: 258 cancer-free patients and 243 patients with malignancies other than lymphoma, 112 of whom were chemotherapy-naive. Patients were primarily assessed by nested polymerase chain reaction (PCR), followed by real-time quantitative PCR if they scored positive. In addition, six initially PCR-positive cancer-free donors were prospectively reassessed by qualitative and quantitative PCR after 30 and 60 days. RESULTS The overall incidence of Bcl-2/IgH positivity was 9.6%, with a median number of 11 rearrangements per 1,000,000 diploid genomes (range, 0 to 2,845 rearrangements), as assessed by real-time PCR. The incidence was similar in healthy subjects and cancer patients at diagnosis (12% and 12.5%; P = not significant). In contrast, the incidence of this translocation was only 2.3% in chemotherapy-treated patients (P <.001). In addition, three initially PCR-positive cancer-free donors showed persistence of their rearrangements when assessed after 30 and 60 days. CONCLUSION The low incidence of nonneoplastic Bcl-2/IgH rearrangements following chemotherapy provides further evidence of the prognostic role of persistent PCR-positivity in the posttreatment molecular follow-up of follicular lymphoma patients.

Gefitinib (ZD1839): therapy in selected patients with non-small cell lung cancer (NSCLC)?

PURPOSE To evaluate response rate, toxicity and epidermal growth factor (EGFR) mutations and gene copy number as outcome predictive factors in Italian patients with non-small cell lung cancer (NSCLC) treated with gefitinib (Iressa) in an expanded access program (EAP). PATIENTS AND METHODS A total of 137 patients with advanced NSCLC received gefitinib as first line treatment or after failure of chemotherapy. In 43 cases, tissue specimens were available for EGFR status evaluation: immunohistochemical (IHC) for EGFR, fluorescence in situ hybridisation (FISH) or Chromogenic in situ hybridisation (CISH)-(ISH) analysis for EGFR and HER2 gene copy number, and PCR-DNA sequencing for mutational analysis of EGFR were performed. RESULTS In the study population, response rate (PR) was 13%; disease stabilization (DS) 26%; overall disease control rate 39%; median survival 6.3 months and time to progression 2.7 months. Toxicity was mild (G3 skin toxicity in 3% and G3 liver toxicity in 4% of patients). An EGFR-mutation was detected in 9/43 patients: Eight deletions in exon 19 and 1 missense mutation in exon 21. Increased gene copy number for EGFR and/or HER2 was detected in 17/43 patients. Response rate was significantly higher in women, non-smokers, in mutation carriers than in wild type carriers, in EGFR-trisomy/polysomy carriers and HER2-trisomy/polysomy carriers. CONCLUSIONS In this study, response rate and toxicity to gefitinib treatment were consistent with previously reported data for whites. Female gender, absence of smoking history, EGFR-mutations, EGFR and HER2-polysomy were significantly associated with response to gefitinib therapy in NSCLC patients.

Human pancreatic carcinoma cells secrete bioactive interleukin-18 after treatment with 5-fluorouracil : Implications for anti-tumor immune response

Recently we observed that pancreatic carcinoma cell lines constitutively express Interleukin-18 (IL-18). Bioactive IL-18 induces Interferon (IFN)-g production, Fas Ligand (FasL) expression, and inhibits angiogenesis, raising the issue of anti-tumor effects of a tumor-derived cytokine and motivating a more detailed analysis of IL-18 production in pancreatic carcinoma cells. This analysis included the study of effects of chemotherapeutic drugs (5-fluorouracil [5-FU], gemcitabine, cisplatin) commonly used in the treatment of pancreatic cancer patients on IL-18 production and processing. IL-18 expression and posttranslational processing were determined using RT-PCR, immunoblot and ELISA in pancreatic carcinoma cell lines and in tumor tissue and serum samples from pancreatic carcinoma patients in the presence and absence of chemotherapeutic drugs. We describe expression of IL-18 in pancreatic carcinoma cells and tissues associated with significantly elevated IL-18 levels in patients sera. Specifically, Capan-2 pancreatic tumor cells produced and secreted precursor IL-18 with no apparent biological activity. However, the chemotherapeutic agent 5-FU, by inducing Caspase-1 and Caspase-3 activation, induced secretion of proteolytically processed mature and degraded IL-18 species, respectively, in Capan-2 cells. Conditioned medium from 5-FU-treated but not control Capan-2 cells induced IFN-g production by activated T cells in an IL-18-dependent manner. Furthermore, adjuvant polychemotherapy including 5-FU significantly increased serum levels of mature, bioactive IL-18 in pancreatic carcinoma patients. Treatment of pancreatic cancer cells with 5-FU induced Caspase-dependent processing of pro-IL18 leading to the secretion of biologically active IL-18. These findings delineate a novel mechanism by which chemotherapeutic agents may modulate local anti-tumor cell-mediated immune responses.

Activity of weekly paclitaxel in advanced hormone-refractory prostate cancer.

Objective:We evaluated efficacy and toxicity of weekly paclitaxel in metastatic hormone-refractory prostate cancer (HRPC). Materials and Methods:Patients received weekly paclitaxel 80 mg/m2 by 1-hour intravenous infusion. A course of therapy consisted of 6 weekly treatments and 2 weeks rest. PSA response was defined as a PSA decrease not less than 50%, maintained for 4 weeks with stable or improved performance status. Results:The study enrolled 43 patients with metastatic HRPC diagnosed a median of 10.5 months before. Median age was 69 years (range, 58–86 years). Five had previous radioisotopes treatment for bone pain, 15 had previous treatment of metastatic hormone-refractory disease, mainly estramustine. The median number of weeks of therapy delivered each patient was 8 (range, 1–24 weeks; cumulative, 369 weeks). PSA response was registered in 13 patients of 36 evaluable for PSA response (36.1%; 95% confidence interval [CI], 20.8–53.8), with a median duration of 4.2 months. Among 16 patients evaluable for objective response, 5 partial responses (31.2%; 95% CI, 11.0–58.7) and 9 stable diseases were registered. Eleven (42.3%) of 26 patients presenting with cancer-related symptoms had improvement. Median survival time was 12.8 months (95% CI, 10.1–15.5) Therapy was associated with acceptable hematological toxicity (anemia grade 3, 16%; neutropenia grade 3–4, 12%) and moderate nonhematologic toxicities (thrombosis/embolism 10%; fatigue all grades, 60%). Conclusion:Docetaxel every 3 weeks is the standard of care for metastatic HRPC, but our results suggest some activity and an acceptable toxicity of weekly paclitaxel.

Oral Metronomic Vinorelbine in Advanced Non-small Cell Lung Cancer Patients Unfit for Chemotherapy

Aim: To explore the feasibility and activity of oral metronomic vinorelbine patients with advanced NSCLC not eligible to standard chemotherapy because of old age (≥70 years), and/or poor Eastern Cooperative Oncology Group performance status (≥2), and/or extensive brain or bone disease, and/or active comorbidities (≥2) requiring for pharmacological treatment. Patients and Methods: In a prospective phase II not randomized study, patients with stage IV NSCLC unfit to chemotherapy were treated with oral metronomic vinorelbine at 30 mg fixed dose three times a week until disease progression. Results: Fifty patients were treated, 19 (38%) in the first-line setting. Five patients (11%) experienced a grade 3 toxicity; no grade 4 toxicity occurred. Overall disease control rate was 32%, 44% and 26% in first and subsequent lines, respectively (p=0.39). Median OS and PFS were 7.3 months (95% confidence interval [CI]=4.7-10.0) and 2.7 months (95%CI=2.0-3.4), respectively. Conclusion: These data support the activity and safety of metronomic vinorelbine in a relevant proportion of patients usually excluded from any specific treatment.

Is There Room for Second-Line Treatment of Pleural Malignant Mesothelioma?

Malignant pleural mesothelioma (MPM) is characterized by a bad prognosis and modest activity of systemic treatment. Currently, there is no clear agreement on the clinical role of second-line chemotherapy in patients with MPM; nevertheless, early case study reports including some pretreated patients had provided evidence that additional responses are possible with the use of further chemotherapy1 after the failure of firstline treatment. Unfortunately, the evidence supporting the efficacy of second-line treatment in this setting is globally weak. A randomized phase 3 trial, enrolling 243 patients, compared pemetrexed plus best supportive care vs best supportive care alone in patients previously treated with a first-line regimen not including pemetrexed. When this study was published, however, the use of pemetrexed in combination with cisplatin had been already accepted as standard first-line treatment. The study showed a statistically significant increase in objective response rate, disease control rate, and time to progression for pemetrexed, but without significant benefit in overall survival.2 Whether the benefit in other end points, in the absence of difference in survival, could be considered sufficient to recommend second-line pemetrexed for clinical practice is debatable. In any case, the trial recruited patients who were pemetrexed naive, which greatly reduces the current applicability of these results, with pemetrexed being part of first-line treatment in the majority of patients now. Can we consider the external validity of these results useful for clinical practice? Probably not. Even when we consider the shift from pemetrexed to other chemotherapy drugs, like vinorelbine, their use as second-line treatment is based on small, nonrandomized series. Following previous experience in the firstline setting,3 weekly vinorelbine was tested within a single-center phase 2 open-label study in 63 patients with previous exposure to chemotherapy. Like all the single-arm trials, the results obtained in this series of patients are at strong risk of being conditioned by selection bias: median interval between the end of the firstline chemotherapy and the start of the weekly secondline vinorelbine was 6 months, most patients had a good performance status, all were classified as low risk according to the European Organization for Research and Treatment of Cancer prognostic score, and median age of this highly selected population was 59 years. A total of 10 partial responses (16%) were observed, and a further 43 patients (68%) had stable disease defined as no evidence of progression for 6 months. Median overall survival was 9.6 months. However, can we trust in the reproducibility of these results in unselected patients, with a shorter treatment-free interval, older age, and worse performance status? Probably not. Similarly, rechallenge with platinum-pemetrexed chemotherapy is sometimes considered in patients who have obtained a long progression-free interval, but the evidence supporting this strategy is again weak. This strategy is probably more supported by the analogy with the rechallenge in other solid tumors where platinumbased therapy is used, rather than by data specifically produced in patients with MPM. In this specific setting, the rechallenge has been explored by Ceresoli et al,4 describing the outcome of patients who had obtained prolonged progression-free survival (PFS) (greater than 3 months) with the previous first-line treatment. Thirtyone patients were included in the study, but there was heterogeneity in the treatment adopted: 15 patients had a rechallenge with single-agent pemetrexed alone, while 16 had a real rechallenge with both drugs. One patient experienced a complete response, whereas a partial response was achieved in 5 patients, producing a modest overall objective response rate of 19%, and an overall disease control rate of 48%. Is this evidence sufficient to consider rechallenge with pemetrexed-based chemotherapy as a second-line treatment option in patients with MPM? Probably not. Considering this absence of robust evidence supporting the use of second-line treatment in clinical practice, what is the position of existing guidelines? National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines seem to support the use of secondline treatment. In fact, although specifying that limited data are available to guide the choice, NCCN guidelines state that “second-line chemotherapy options include pemetrexed (if not administered as first-line therapy), vinorelbine, or gemcitabine, and data suggest that rechallenging with pemetrexed is effective if patients had a good response to first-line pemetrexed.”5 Moving from the United States to Europe, current guidelines of the European Society of Medical Oncology, published in 2015, state that, given the absence of standard secondline or further-line therapy, it is recommended that patients who are in good clinical condition at disease progression after first-line treatment should be enrolled into clinical trials.6 There is no explicit recommendation for patients outside the opportunity of clinical trials, although the statement that “single agent vinorelbine has shown useful activity in phase II trials” implies that, although not standard, second-line treatment can be considered in clinical practice. Italian experts participating in the Third Italian Consensus Conference for MPM stated that, in patients progressing after a first-line pemetrexedbased regimen, there is no standard second-line therapy, and patients should be encouraged to participate in cliniVIEWPOINT

Adding an invasive procedure will not necessarily change treatment or outcome of NSCLC patients with preoperative clinical N1 disease

We have read with great interest and welcome the publication of a prospective multicentre study regarding the role of mediastinal staging by video-assisted mediastinoscopy (VAM) in patients with clinical N1 (cN1) nonsmall cell lung cancer (NSCLC) [1]. The objective of the study was to assess the sensitivity, negative predictive value and accuracy of VAM in a well-defined group of patients with cN1. Video-assisted mediastinoscopy or VAM-lymphadenectomy is not a standard procedure in cN1 disease http://ow.ly/dAZq30irs63

Immune-checkpoint inhibitors in non-small cell lung cancer: A tool to improve patients’ selection

The identification of reliable predictive biomarkers of efficacy or resistance to immune-oncology (I-O) agents is a major issue for translational research and clinical practice. However, along with PDL1 and molecular features other clinical, radiological and laboratory factors can be considered for the selection of those patients who would not be the best candidate for immune-checkpoint inhibitors (ICPIs). We examined these factors, emerging from the results of currently available studies in non-small cell lung cancer (NSCLC), aiming to provide a useful and manageable tool which can help Oncologists in their everyday clinical practice. A thorough patient evaluation and close clinical monitoring, due to limited, early or inconclusive currently available data, should be deserved for patients with a pre-existing symptomatic chronic obstructive pulmonary disease, age >75 years, Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥ 1, a time to progression (TTP) < three months and progressive disease (PD) as the best response to the previous treatment, hepatitis or HIV-infections, high neutrophil to lymphocyte ratio (NLR), or on treatment with high-dose steroids, when the use of ICPIs is considered. Limited data are available to consider that ICPIs are safe in patients with interstitial lung disease, bronchiolitis obliterans organizing pneumonia and autommune diseases. Early evidence on steroids, vaccinations and antibiotics suggest their possible interaction with ICPIs and need to be more investigated in clinical trials. Oncogene-addicted NSCLC harboring EGFR-mutations and low tumor-infiltrating T-lymphocytes (TILs) seems not to gain benefit from I-O.

CorrespondenceLUX-Lung 7: is there enough data for a final conclusion?

e266 www.thelancet.com/oncology Vol 17 July 2016 On the basis of the results of the LUX-Lung 3 study, the fi rst version of the National Comprehensive Cancer Network non-small-cell lung cancer (NSCLC) guidelines published in 2014 recommended the use of the second-generation EGFR tyrosinekinase inhibitors afatinib, gefitinib, and erlotinib as first-line treatments for advanced EGFR mutation-positive NSCLC. However, which of the three drugs is the best choice of treatment remains unclear. The LUX-Lung 7 study suggested that for advanced NSCLC positive for the EGFR mutation, fi rst-line afatinib treatment signifi cantly increased progression-free survival compared with that achieved with gefitinib, and decreased the risk of lung cancer progression by 27%, with a longer median duration of response for patients treated with afatinib than gefi tinib (10·1 months vs 8·4 months). However, can afatinib really replace gefitinib as the first-line treatment? If osimertinib, a third-generation irreversible mutant-selective EGFR inhibitor had not been released on the market, the answer might be affi rmative. The approval for marketing osimertinib in November, 2015, has now complicated the matter; thus, whether afatinib can still be the preferred fi rst-line treatment for NSCLC remains unknown. Not only can osimertinib inhibit mutations in EGFR exons 18, 19, and 21, but it also specifically inhibits the drug-resistant T790M mutation. For patients with NSCLC with a T790M mutation who acquired resistance to fi rst-generation EGFR tyrosine-kinase inhibitors, the proportion of patients with a response was 61% and median progression-free survival was 9·6 months. The mechanism of acquired resistance to fi rst-generation EGFR tyrosine-kinase inhibitors is fairly clear, with the most common mutation being T790M (incidence of 50–60%). However, afatinib is an ErbB family blocker, which irreversibly blocks signalling from all relevant homodimers and heterodimers of LUX-Lung 7: is there enough data for a fi nal conclusion?

Patterns of metastasis, response to treatment and survival in young patients with advanced non small cell lung cancer (NSCLC)

7343 Background: We analysed our cancer registry to determine the clinicopathologic characteristics, response to treatment and survival rates of NSCLC patients under 50 years of age at diagnosis. METHODS From 1997 to 2003 in our oncological centre we treated 47 patients under 50 years of age at diagnosis. Pts characteristics: male/female, 29/18; 9 pts were <40 years old; stage IIIA, IIIB, IV in 7/5/35; histological type: adenocarcinoma 18 pts (38%), NSCLC not specified 19 (40%). Radical treatment were applied only to 7 patients: chemoradiotherapy in 4 and chemosurgery in 3 pts. In pts with stage IV disease 46% had brain mts at the diagnosis, 34% bone mts, 29% liver mts, 23% adrenal mts and 50% presented multiple mts sites at diagnosis. In three pts the diagnosis was an incidental finding, the symptoms-diagnosis delay was < 1 month in 17 patients, 1-3 months in 9 pts and > 4 months in 18 pts. All patients were treated with first line chemotherapy: at the beginning of treatment ECOG-PS was 0/1/2 in 8/35/4; platinum-based doublets were administered in 90% of the patients. RESULTS in 40 pts evaluable for response we obtained 1 RC and 15 RP with ORR 40%; SD and PD were observed in 23% and 37%, respectively; (ORR intention-to-treat analysis 34%). Five pts progressed with brain metastasis and 2 with leptomeningeal carcinomatosis (49% of pts presented brain involvement during the clinical course). Median time to progression and survival were 2.8 and 10 months, respectively. Second-line chemotherapy was administered to 23 pts (49%): 14 pts were treated with taxanes. Fifteen pts were evaluable for response after second-line CT: we observed 3 PR (20%), 1 SD and 11 PD. CONCLUSIONS Patients younger than 50 years with advanced/metastatic disease present data of response to chemotherapy, time to progression and survival comparable to older patients. In these patients brain and bone involvement was more frequent than expected. No significant financial relationships to disclose.