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Introduction: Anaplastic lymphoma kinase (ALK) fusions identify a limited subset of non-small cell lung cancer (NSCLC) patients, whose therapeutic approach have been radically changed in recent years. However, diagnostic procedures and clinical-radiological responses to specific targeted therapies remain heterogeneous and intrinsically resistant or poor responder patients exist., Methods: A total of 290 patients with advanced NSCLC defined as ALK+ by immunohistochemistry (IHC) and/or fluorescent in situ hybridisation (FISH) test and treated with single or sequential multiple ALK inhibitors (ALKi) from 2011 to 2017 have been retrospectively retrieved from a multicentre Italian cancer network database. In 55 patients with enough leftover tumour tissue, specimens were analysed with both targeted and customised next generation sequencing panels. Identified fusion variants have been correlated with clinical outcomes., Results: Of the 55 patients, 24 received crizotinib as first-line therapy, 1 received ceritinib, while 30 received chemotherapy. Most of the patients (64%) received ALKi in sequence. An ALK fusion variant was identified in 73% of the cases, being V3 variant (E6A20) the most frequent, followed by V1 (E13A20) and more rare ones (e.g. E6A19). In three specimens, four new EML4-ALK fusion breakpoints have been reported. Neither fusion variants nor brain metastases were significantly associated with overall survival (OS), while it was predictably longer in patients receiving a sequence of ALKi. The presence of V1 variant was associated with progression-free survival (PFS) improvement when crizotinib was used (p = 0.0073), while it did not affect cumulative PFS to multiple ALKi., Conclusion: Outcomes to sequential ALKi administration were not influenced by fusion variants. Nevertheless, in V1+ patients a prolonged clinical benefit was observed. Fusion variant identification by NGS technology may add relevant information about rare chromosomal events that could be potentially correlated to worse outcomes., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The non-inferiority of dexamethasone (DEX) on day 1, with or without low-dose DEX on days 2 and 3, combined with oral NEPA (netupitant/palonosetron), compared with the guideline-consistent use of DEX was demonstrated in cisplatin. Here, we complete the analysis by assessing the impact of emesis on daily lives of patients receiving DEX-sparing regimens using the Functional Living Index-Emesis (FLIE)., Methods: Chemotherapy-naïve patients undergoing cisplatin (≥70 mg/m 2 ), were given NEPA and DEX (12 mg) on day 1 and randomized to receive either 1) no further DEX (DEX1), 2) oral DEX (4 mg daily) on days 2-3 (DEX3), or 3) DEX (4 mg twice daily) on days 2-4 (DEX4; control). Patients completed the FLIE questionnaire on day 6 of cycle 1. Endpoints included the FLIE nausea domain, vomiting domain, and overall combined domain scores, as well as the proportion of patients with no impact on daily life (NIDL; overall score > 108). This was a protocol-planned analysis., Results: In the DEX1 group, no significant differences were observed in the FLIE nausea score (48.9 [±1.8; SE] vs. 53.7 [±1.5]), vomiting score (56.6 [±1.4] vs. 58.7 [±0.8]) and overall score (105.6 [±2.8] vs.112.4 [±1.9]) versus DEX4 control; similar results were observed in the DEX3 group for nausea score (49.6 [±1.7]), vomiting score (58.2 [±1]) and overall score (107.8 [±2.4]) versus control. There were no significant between-group differences in the proportion of patients reporting NIDL., Conclusion: Reducing DEX, when administered with NEPA, does not seem to adversely impact the daily functioning in patients undergoing cisplatin., Trial Registration: ClinicalTrials.gov NCT04201769 . Registration date: 17/12/2019 - Retrospectively registered., (© 2022. The Author(s).)

Background: To reduce the overall exposure to dexamethasone (DEX) in patients receiving cisplatin-based chemotherapy, we evaluated the noninferiority of DEX on day 1, with or without low-dose DEX on days 2 and 3, combined with an oral fixed-dose combination of netupitant and palonosetron (NEPA), compared with the guideline-consistent use of 4-day DEX., Patients and Methods: In this open-label, multicenter study, chemotherapy-naïve patients undergoing high-dose cisplatin (≥70 mg/m 2 ), were given NEPA and DEX (12 mg) on day 1 and randomized (1:1:1 ratio) to receive either (a) no further DEX (DEX1), (b) oral DEX (4 mg daily) on days 2-3 (DEX3), or (c) DEX (4 mg twice daily) on days 2-4 (DEX4). The primary efficacy endpoint was complete response (CR: no emesis and no rescue medication) during the 5-day overall phase. The noninferiority margin was set at -15% difference (DEX1 or DEX3 minus DEX4). Secondary efficacy endpoints included complete protection (CP: CR and none or mild nausea)., Results: Two-hundred twenty-eight patients, 76 in each arm, were assessable. Noninferiority was met for both DEX-sparing regimens and the reference arm, with overall phase CR rates of 76.3% in each of the DEX1 and DEX3 arms and 75.0% in the DEX4 arm (95% confidence interval, -12.3% to 15% for each comparison). During the overall phase, CP rates were similar between groups., Conclusion: A simplified regimen of NEPA plus single-dose DEX offers comparable chemotherapy-induced nausea and vomiting prevention throughout 5 days post-chemotherapy with the advantage of sparing patients additional doses of DEX in the high-emetic-risk setting of cisplatin-based chemotherapy., Implications for Practice: Dexamethasone (DEX) has traditionally played an integral role in the management of chemotherapy-induced emesis. Although generally considered safe, even short-term DEX use is associated with various side effects, and some evidence suggests that concurrent steroids may reduce the efficacy of immunotherapies. This study demonstrates comparable antiemetic control during the 5 days post-chemotherapy with a simplified regimen of netupitant/palonosetron plus single-dose DEX versus the standard 4-day DEX reference treatment in high-dose cisplatin. This represents a clinically relevant achievement as it not only simplifies antiemetic prophylaxis but also offers an opportunity to appropriately use in patients where caution with corticosteroid use is advised., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Small cell lung cancer (SCLC) is an aggressive disease, difficult to treat. There have been no significant therapeutic advances over platinum and etoposide chemotherapy in the last 20 years until the introduction of immunotherapy. In 2020 atezolizumab, an immune checkpoint inhibitor against PD-L1 was approved in Italy in combination with carboplatin and etoposide for the first-line treatment of patients with extensive stage disease (ES-SCLC), becoming the new standard treatment. On May 20, 2021, a virtual meeting, directed by profs. Federico Cappuzzo and Emilio Bria, was held in which 14 clinicians from different oncology centers in Lazio, Umbria and Sardinia discussed the issues of ES-SCLC patients treatment, after the advent of immunotherapy. The aim of the meeting was to share their clinical experience and to provide a series of practical indications that can support clinicians in the management of ES-SCLC patients in first-line with chemo-immunotherapy.

Introduction : Only 20-40% of patients respond to therapy with immune checkpoint inhibitors (ICIs). Therefore, the early identification of subjects that can benefit from such therapeutic regimen is mandatory. Areas covered : The immunobiological mechanisms of ICIs are briefly illustrated. Furthermore, the limitations of traditional radiological approaches are covered. Then, the pros and cons of molecular imaging through positron emission computed tomography (PET/CT) are reviewed, with a particular focus on 18 f-fluorodeoxyglucose ( 18 F-FDG) and PET-derived metabolic parameters. Lastly, translational perspective of radiopharmaceuticals others than 18 F-FDG such as 89 zirconium ( 89 Zr) or fluorine-18 ( 18 F) labeled monoclonal antibodies (e.g. 89 Zr-atezolizumab, 89 Zr-nivolumab) binding to specific biomarkers are discussed. Expert opinion : Molecular imaging presents a prominent role for the management of oncological patients treated with ICIs. Preliminary clinical data indicate that PET/CT with 18 F-FDG is useful for assessing the response to treatment and for the imaging of immune-related adverse effects. Nevertheless, the methodological approach (iPERCIST, PERCIMT, or others) to be used for an optimal diagnostic accuracy and patients' evaluation is still a debated issue. PET/CT with radioligands directed toward ICIs biomarkers, although is still in a translational phase, holds the promise of accurately predicting the response to treatment and revealing the acquired resistance to immunotherapy.

Introduction: Pemetrexed maintenance significantly improved progression-free survival (PFS) and overall survival (OS) in advanced nonsquamous non-small-cell lung cancer (NSCLC) patients not progressing after induction chemotherapy., Objectives: This study is aimed at examine the association of various clinical factor and survival in a real-world cohort analysis., Materials and Methods: One hundred ninety-four patients were included and classified as "PM" cohort ("Pemetrexed Maintenance", including patients given with pemetrexed maintenance after induction chemotherapy, n=112), and "noPM" cohort ("no Pemetrexed Maintenance" including those discontinuing pemetrexed, n=82)., Results: The median PFS was 8.8 and 5.4 months in the PM and noPM cohorts, respectively (p=0.001). The median OS was 19.6 months in the "PM" cohort and 13.2 months in the "noPM" cohort (p<0.02). In the multivariate analysis, ECOG Performance Status (PS) 0 and maintenance therapy were independently associated with improved PFS and OS. A longer median PFS was reported in patients given ≥5 cycles of pemetrexed maintenance (p<0.01)., Discussion: These results further confirm the survival benefit of pemetrexed maintenance in a real-word population. All eligible advanced NSCLC patients should be strongly considered for at least 5 of pemetrexed maintenance.

Introduction: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab., Methods: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging., Results: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes., Conclusions: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.

Background : Immune-checkpoint inhibitors have radically changed the treatment landscape of Non-Small-Cell Lung Cancer (NSCLC). It is still unclear whether specific clinical characteristics might identify those patients benefiting from immunotherapy more than others. The aim of this study was to identify clinical characteristics associated with disease-specific survival (DSS), time-to-treatment failure (TTF), objective responses (OR) and progressive disease (PD) in NSCLC patients treated with Nivolumab. Methods : This was a multicenter retrospective study conducted on 294 patients treated with Nivolumab for advanced NSCLC. Results : Of the more than 50 variables analyzed, five showed a significant correlation with DSS: ECOG PS, size of the biggest brain metastasis, number of metastatic sites, toxicity, and malignant pleural effusion. Three variables significantly correlated with TTF: malignant pleural effusion, number of metastatic sites, number of liver metastases. Malignant pleural effusion was the only variable showing a significant correlation with OR, as well as the only one correlating with all the endpoints of the study. Conclusions : This study identified clinical characteristics associated with survival and response during treatment with Nivolumab in NSCLC patients. The unfavorable association between malignant pleural effusion and objective response is a novel finding with important translational implications.

Objectives: Molecular diagnostics and care of non-small cell lung cancer (NSCLC) are continuously evolving. Few data document the current strategies to manage advanced NSCLC patients beyond progression in clinical practice., Patients and Methods: Be-TeaM is an Italian multi-center observational study conducted on consecutive EGFR-mutated stage IV NSCLC patients, progressed during/after a first-line EGFR-TKI. It consists of a retrospective phase, from first-line EGFR-TKI therapy start until study entry (i.e. beginning of the diagnostic process), and a prospective phase, until treatment choice or for 3 months if no therapy was prescribed. Primary objective was to describe the diagnostic and therapeutic approaches adopted after progression in a real-world setting., Results: Of 308 patients enrolled in 63 centers from July 2017 to June 2018, 289 were included in the analysis. In first line, 53.3 % received gefitinib, 32.5 % afatinib and 14.2 % erlotinib. The testing rate (i.e. rate of all patients undergone any biopsy -liquid and/or tissue- for the T790 M detection) was 90.7 %, with liquid biopsy being the most frequently executed. Of 262 biopsied patients, 64.5 % underwent only 1 liquid biopsy, 10.7 % only 1 tissue biopsy and 18.3 % >1 biopsy, both liquid and solid in 85.4 %. The T790M positivity rate was 45.3 %; of 166 patients undergone only a liquid biopsy and tested for the mutation, 39.8 % were T790M+ and 60.2 % T790M-/undetermined. By the observation end, 87.9 % patients had a post-progression treatment chosen, osimertinib being the most frequent among the T790M+., Conclusion: Be-TeaM provides the first snapshot of current practices for the management of NSCLC patients beyond progression in Italy; in clinical practice, assessing the T790M status is not always feasible., (Copyright © 2019. Published by Elsevier B.V.)

Background: In the field of oncological assistance, nowadays we have to deal with a complex scenario where patients got used to obtain a huge amount of information through internet or social media and to apply them in performing their health-related decisions. This landscape requires that clinicians become able to handle therapeutical approaches and adequate skills in communication tools to satisfy the current needs. Our project aimed to build a communication model based on clinical oncologists' real experiences in order to find a simple way to share with patients all the innovative therapeutical opportunities today available in lung cancer. The final goal is to design a flexible and personalized model adaptable to clinician's personal characteristics and to the specific patient he is facing. We applied both traditional educational tools and innovative techniques in order to make the results effective and applicable to support peer learning., Methods: The first step consisted in a Board synthesized the definition of the diagnostic process, the identification of treatment strategies and any potential communication barrier clinicians may face dealing with patients. The second step consisted in teamwork including a theoretical part and a training part. In the third step we produce five training videos and video interviews regarding communication praxis and a "Small communication manual". The last step consisted in the publication of the produced material on website and its diffusion through the social media., Results: In medicine, the universal application of a single model of communication does not represent the optimal solution. By contrary, the availability of simple and practical suggestions to improve the communicative style could allow clinicians to abandon stereotyped formulas identically repurposed to all patients. The "from bottom to top" training, starting from real-life to take advantage of the clinician's experience, give the clinicians the possibility to meditate about their own communicative style and to train in the context of a protected environment. Applying these rules, we design an effective communication model, based on healthcare humanization, which could represent a fundamental support for the patient in order to be gently driven by the clinician to the most appropriate therapeutical choice, balancing efficacy and quality of life. The relational training may improve the quality of clinician-patient communication and could be widespread to other clinicians through the media., Conclusions: Considering the innovative therapeutical options available, particularly for lung cancer patients, and the increasing access of health-related information through internet or social media the clinician-patient communication has become crucial to support the achievement of the most appropriate therapeutical choice for the patient, facing the intricate illness experience. Building a shareable and easy-to-apply communication model represents a challenge aimed to help clinicians and including technology not as a threat, but as a positive tool., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2018.12.32). The series “Targeted Therapy and Non-Small Cell Lung Cancer: A New Era?” was commissioned by the editorial office without any funding or sponsorship. UM served as the unpaid Guest Editor of the series. The authors have no other conflicts of interest to declare., (2019 Translational Cancer Research. All rights reserved.)

Background: The present study investigated the efficacy and safety of nivolumab in pre-treated patients with advanced NSCLC harbouring KRAS mutations., Methods: Clinical data and KRAS mutational status were analysed in patients treated with nivolumab within the Italian Expanded Access Program. Objective response rate, progression-free survival and overall survival were evaluated. Patients were monitored for adverse events using the National Cancer Institute Common Terminology Criteria for Adverse Events., Results: Among 530 patients evaluated for KRAS mutations, 206 (39%) were positive while 324 (61%) were KRAS wild-type mutations. KRAS status did not influence nivolumab efficacy in terms of ORR (20% vs 17%, P = 0.39) and DCR (47% vs 41%, P = 0.23). The median PFS and OS were 4 vs 3 months (P = 0.5) and 11.2 vs 10 months (P = 0.8) in the KRAS-positive vs the KRAS-negative group. The 3-months PFS rate was significantly higher in the KRAS-positive group as compared to the KRAS-negative group (53% vs 42%, P = 0.01). The percentage of any grade and grade 3-4 AEs were 45% vs 33% (P = 0.003) and 11% vs 6% (P = 0.03) in KRAS-positive and KRAS-negative groups, respectively., Conclusions: Nivolumab is an effective and safe treatment option for patients with previously treated, advanced non-squamous NSCLC regardless of KRAS mutations.

Aim: Ceritinib was evaluated within a compassionate use program of Italian patients., Patients & Methods: 70 patients with anaplastic lymphoma kinase-positive crizotinib-refractory advanced non-small-cell lung cancer received ceritinib., Results: Overall response was 40.6%, median progression-free survival was 8.2 months and median survival was 15.5 months. Dose reduction due to treatment-related adverse events occurred in 50.8% of patients starting at 750 mg/day. No significantly different progression-free survival was observed between patients who underwent any time dose reduction (n = 38) versus those who remained on the recommended dose of 750 mg/day (n = 32; p = 0.07)., Conclusion: The efficacy of ceritinib compassionate use program resembled that of clinical trials. Dose reductions and adjustments did not appear to negatively affect clinical outcome.

Background: Beyond progression after tyrosine kinase inhibitor in EGFR-positive non-small-cell lung cancer patients (BE-POSITIVE) was the first Italian multicenter observational study that reported the outcomes of first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) in a "real-life" Caucasian EGFR-mutated non-small-cell lung cancer (NSCLC) population. The sharing of multi-institutional experiences represents a crucial strategy to enrich knowledge about uncommon EGFR mutations. Therefore, we performed a post hoc analysis of the BE-POSITIVE study., Patients and Methods: Data of advanced NSCLC patients with uncommon EGFR mutations who received first-line first-generation EGFR-TKIs in 24 Italian Hospitals were collected. In this analysis we aimed to evaluate overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) of EGFR-TKIs in NSCLC patients harboring uncommon EGFR mutations., Results: Thirty-five patients harboring uncommon EGFR mutations (any mutation other than deletion 19 or substitution of leucine by arginine at codon 858) were included of the original 312 EGFR-mutated cases. Most of them were female (n = 20, 57.1%), former smokers (n = 23, 65.7%), with adenocarcinoma (n = 31, 88.6%). The most frequent EGFR mutations were G719X (n = 6, 17.2%) and L861Q (n = 5, 14.2%). The population presented an ORR of 25.7%, a median PFS of 5.19 months, and a median OS of 14.49 months. When stratified according to type of EGFR mutation, median OS ranged from 3.65 months for unspecified mutations to 21.29 for double EGFR mutations. Median PFS ranged from 1.77 months for unspecified mutations to 20.83 months for concomitant EGFR-anaplastic lymphoma kinase alteration. ORR varied from 0% in exon 18, 20 and double gene alteration to 66.6% in exon 19., Conclusion: Our study supports the existence of a strong outcome heterogeneity within patients harboring uncommon EGFR mutations, which needs to be clarified to achieve a real personalized treatment strategy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Pemetrexed maintenance therapy (MT) after induction with platinum-based chemotherapy has recently become a common treatment strategy for advanced nonsquamous non-small-cell lung cancer (NSCLC). However, the benefits of MT should be weighed with consideration of the patients' perceptions and preferences. The aim of the present study was to evaluate patients' attitudes toward MT and to describe physicians' awareness of their patients' inclinations., Materials and Methods: We administered a 12-question anonymous survey and the Distress Thermometer Questionnaire to patients with advanced or recurrent nonsquamous NSCLC. The survey was also distributed to the referring physicians., Results: From December 2014 to July 2015, 92 patients and 37 physicians were enrolled. All 92 patients completed the questionnaire at T0 (before starting chemotherapy) and 56.5% also did so at T1 (after completion of induction). The physicians completed the survey only at T0. Most patients had a positive attitude toward MT at both T0 (78.9%) and T1 (86.5%), and 100% of the physicians thought their patients would be in favor of MT. The physicians believed that their patients' attitudes toward MT would decrease proportionally with the reduction in the magnitude of the overall survival increase and expected benefits. The decrease expected by the physicians was much greater than that reported by the patients. This was especially true for an overall survival increase as small as 1 month (51.9% of patients accepting MT vs. 13.5% supposed by physicians) or when the only treatment benefit was radiologic tumor stabilization (69.3% of patients accepting MT vs. 37.8% supposed by physicians)., Conclusion: NSCLC patients have a generally positive attitude toward MT, which is not directly proportional to the expected benefits and greater than the attitude expected by physicians., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Non-small-cell-lung-cancer (NSCLC) patients harbouring epidermal growth factor receptor (EGFR) mutations develop drug resistance after 9-12 months of EGFR tyrosine kinase inhibitors (TKIs) therapy pointing out the issue of the second-line treatment choice., Materials and Methods: From June 2009 until May 2013 patients affected by advanced NSCLC harbouring EGFR mutations receiving first-line TKI were collected mainly retrospectively in 24 Italian Centers. Primary objective was to describe the percentage of EGFR mutated patients receiving second-line therapy after progression to first-line EGFR-TKIs assessing the type, the activity in terms of objective response rate (ORR), efficacy in terms of progression free survival (PFS) and overall survival (OS), and safety of second-line treatment. Secondary objective was to describe the efficacy of first-line EGFR-TKIs., Results: 312 patients were included. Most of them were females (203, 65.1%), never smokers (200, 64.1%), with adenocarcinoma histology (290, 92.9%). The most common mutations were EGFR exon 19 deletion and L858R, detected in 186 and 97 cases (59.6% and 31.1%), respectively. At data cut-off, 274 patients (95.1%) received any second-line treatment (including best supportive care or local treatments only). A total of 163 patients received second-line systemic therapy with an ORR of 20.9% (95% CI:14.62-27.10), a median PFS and OS of 4.7 (95% CI:3.81-5.26) and 24.5 (95% CI:21.65-27.37) months, respectively. Grade 3-4 hematological and non-hematological toxicities were reported in 9% and 6.3% of 144 patients treated with chemotherapy while non-hematological toxicity was reported in 4 cases of the 17 patients receiving second-line target agents., Conclusions: BE-Positive is the first multicenter observational study reporting outcomes of therapies in a "real-life Caucasian EGFR-mutated population", highlighting the need of further researches about new treatment strategies in this setting., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

MicroRNAs were described to target mRNA and regulate the transcription of genes involved in processes de-regulated in tumorigenesis, such as proliferation, differentiation and survival. In particular, the miRNA let-7 has been suggested to regulate the expression of the KRAS gene, a common mutated gene in non-small cell lung cancer (NSCLC), through a let-7 complementary site (LCS) in 3'UTR of KRAS mRNA. We have reported the analysis performed on the role of the polymorphism located in the KRAS-LCS (rs61764370) which is involved in the disruption of the let-7 complementary site in NSCLC patients enrolled within the TAILOR trial, a randomised trial comparing erlotinib versus docetaxel in second line treatment. In our cohort of patients, KRAS-LCS6 polymorphism did not have any impact on both overall survival (OS) and progression free survival (PFS) and was not associated with any patient's baseline characteristics included in the study. Overall, patients had a better prognosis when treated with docetaxel instead of erlotinib for both OS and PFS. Considering KRAS-LCS6 status, the TG/GG patients had a benefit from docetaxel treatment (HR(docetaxel vs erlotinib) = 0.35, 95% CI 0.15-0.79, p = 0.011) compared with the TT patients (HR(docetaxel vs erlotinib) = 0.72, 95% CI 0.52-1.01, p = 0.056) in terms of PFS.

Background: Erlotinib is registered for treatment of all patients with advanced non-small-cell lung cancer (NSCLC). However, its efficacy for treatment of patients whose tumours are EGFR wild-type-which includes most patients-is still contentious. We assessed the efficacy of erlotinib compared with a standard second-line chemotherapy in such patients., Methods: We did this randomised controlled trial in 52 Italian hospitals. We enrolled patients who had metastatic NSCLC, had had platinum-based chemotherapy, and had wild-type EGFR as assessed by direct sequencing. Patients were randomly assigned centrally (1:1) to receive either erlotinib orally 150 mg/day or docetaxel intravenously 75 mg/m(2) every 21 days or 35 mg/m(2) on days 1, 8, and 15, every 28 days. Randomisation was stratified by centre, stage, type of first-line chemotherapy, and performance status. Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation, investigators who analysed results were. The primary endpoint was overall survival in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT00637910., Findings: We screened 702 patients, of whom we genotyped 540. 222 patients were enrolled (110 assigned to docetaxel vs 112 assigned to erlotinib). Median overall survival was 8·2 months (95% CI 5·8-10·9) with docetaxel versus 5·4 months (4·5-6·8) with erlotinib (adjusted hazard ratio [HR] 0·73, 95% CI 0·53-1·00; p=0·05). Progression-free survival was significantly better with docetaxel than with erlotinib: median progression-free survival was 2·9 months (95% CI 2·4-3·8) with docetaxel versus 2·4 months (2·1-2·6) with erlotinib (adjusted HR 0·71, 95% CI 0·53-0·95; p=0·02). The most common grade 3-4 toxic effects were: low absolute neutrophil count (21 [20%] of 104 in the docetaxel group vs none of 107 in the erlotinib group), skin toxic effects (none vs 15 [14%]), and asthenia (ten [10%] vs six [6%])., Interpretation: Our results show that chemotherapy is more effective than erlotinib for second-line treatment for previously treated patients with NSCLC who have wild-type EGFR tumours., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Despite decades of intensive biological and clinical research, there still remains a substantial lack of consensus regarding the appropriate therapeutic management of patients with small-cell lung cancer (SCLC). Many randomized studies have been performed to identify the most effective treatment strategy, the best agents or treatment duration, the most appropriate dose and timing of radiotherapy and thus providing more reliable evidence for clinical practice. Unfortunately most of these trials reported contrasting results, and in several meta-analyses have been performed, with the intent to clarify the strategic approach for each issue. This review focuses on the contribution of the main meta-analyses in defining the standard approaches in the treatment of SCLC, discussing their real value and influence on every-day decision making. According to the results of available meta-analyses, platinum-based chemotherapy should be considered the standard of care for the treatment of SCLC. Cisplatin and carboplatin have shown similar efficacy, and the choice of the platinum compound for the treatment of patients with extensive stage SCLC should consider the expected toxicity profile, organ function, performance status, and comorbidities. Thoracic radiotherapy, administered early and in combination with chemotherapy, improves long-term results, although with higher toxicity. Prophylactic cranial irradiation in patients with limited disease obtaining response after induction treatment is a standard of care. Maintenance treatment, intensified chemotherapy and use of growth factors have not proven significant efficacy. Topotecan is effective as second-line treatment, although evidence on clinical benefit for patients relapsed after first-line is limited., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: A recent pooled analysis of randomized trials indicated significant improvement in overall survival from cisplatin-based adjuvant chemotherapy for non-small cell lung cancer (NSCLC), depending on disease stage (only in stages II and III) and PS (≤ 1). Post-operative radiotherapy (RT) is optional for pN2 tumours., Patients and Methods: To evaluate opinions and daily clinical practice of Italian Oncologists about adjuvant treatment of NSCLC, a 46-item questionnaire was delivered via e-mail., Results: Seventy-eight physicians from 68 Centers (out of 98 contacted) returned their questionnaire. Seventy-four, 86, 94, and 78% of them give the indication for adjuvant chemotherapy for stage IIA, IIB, IIIA, and IIIB disease, respectively and 14% in stage IB disease. Stage, PS, and age are taken into consideration evaluating adjuvant approach by 97, 95 and 73%, respectively. Cisplatin-vinorelbine (64%) and cisplatin-gemcitabine (33%), for 4 cycles (81%), are the preferred regimens, while 32% use different regimens. Ninety-two percent indicate RT in pN2 disease and/or positive resection margins. Real Number of patients Needed to Treat (NNT) is probably not completely known/understood and/or used by physicians., Conclusions: A substantial adherence between clinical daily practice in Italy and scientific progresses is described in this paper, even with some discordances regarding the most appropriate adjuvant chemotherapy regimen., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: Patients with small-cell lung cancer (SCLC) that progress after first-line chemotherapy have a poor prognosis and the evidence of a benefit from second-line (SL) chemotherapy is limited. Patients relapsing or progressing more than 90 days after completion of first-line treatment are considered platinum sensitive and may be rechallenged with platinum-based chemotherapy. Topotecan is approved as SL treatment independent of time to progression. This retrospective analysis evaluates the clinical outcomes of SCLC patients who received SL chemotherapy after platinum-etoposide chemotherapy., Patients and Methods: We retrospectively reviewed 161 patients who received SL chemotherapy for SCLC. Patients were divided into four subgroups by type of SL treatment: (1) platinum-based rechallenge; (2) anthracycline-based regimens; (3) topotecan; (4) other single agents. The endpoints were overall survival (OS), progression-free survival (PFS) and response rate (RR). Survival curves were plotted using the Kaplan-Meier method. The Cox proportional hazard model was used for multivariate analysis to investigate factors influencing survival., Results: The median age was 63. There were 125 males and 36 females. Eastern Cooperative Oncology Group performance status (ECOG-PS) was 0, 1 and 2 in 12.5%, 62.5% and 25% of patients, respectively. Platinum sensitive/platinum resistant/platinum refractory/unknown=121/29/3/8 patients. Median time to SL chemotherapy was 6.9 months. The median PFS from starting second-line treatment was 4.3 months and median OS was 5.8 months. The overall RR was 22.9%. There was a trend toward higher RR (34.5% vs 17.5%, p for trend: 0.06) and OS (9.2 months vs 5.8 months, p=0.08) for patients with sensitive disease who were rechallenged with platinum-based chemotherapy. A multivariate analysis that adjusted for the time to SL treatment showed that a platinum-containing regimen achieves better RR, PFS and OS independently of the time to SL chemotherapy and that response to first-line treatment and PS at SL are the only independent prognostic factors., Conclusions: The outcome for second-line therapy for SCLC was poor and benefit appeared to be limited to those patients with good PS and rechallenged with platinum-based chemotherapy. Platinum-based rechallenge should be considered as a standard comparator in future randomized controlled trials of SL chemotherapy., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Maintenance therapy is emerging as a treatment strategy in the management of advanced non small cell lung cancer (NSCLC). Initial trials addressing the question of duration of combination chemotherapy failed to show any overall survival benefit for the prolonged administration over a fixed number of cycles with an increased risk for cumulative toxicity. Nowadays several agents with different ways of administration and a different pattern of toxicity have been formally investigated in the maintenance setting. Maintenance strategies include continuing with an agent already present in the induction regimen or switching to a different one. Taking into consideration that no comparative trials of maintenance with different chemotherapy drugs or targeted agents have been conducted, the choice and the duration of maintenance agents is largely empirical. Furthermore, it is still unknown and it remains an open question if this approach needs to be proposed to every patient in the case of partial/complete response or stable disease after the induction therapy. Here, we critically review available data on maintenance treatment, discussing the possibility to tailor the right treatment to the right patient, in an attempt to optimize costs and benefits of an ever-growing panel of different treatment options.

Background: Increased knowledge about the treatment of pancreatic cancer has influenced the management of locally advanced and metastatic disease. Nonetheless, prognosis remains dismal (24%, 1-year survival). The impact on overall survival (OS) of second-line therapy has not been clarified and the use of platinum salts and/or fluoropyrimidines is hotly debated. It is the hope that future treatment can be tailored to predict chemosensitivity in order to improve outcomes in patients with locally advanced and metastatic pancreatic cancer. Since DNA-damaging agents could be one therapeutic option, a retrospective multicenter study was performed to evaluate the efficacy of salvage treatment with the hypothesis that levels of the DNA repair gene excision repair cross complementing 1 (ERCC1) could influence OS., Patients and Methods: In a population of 160 patients treated with fluoropyrimidine-based second-line chemotherapy, expression levels of ERCC1 were determined by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR). In 108 patients with locally advanced and metastatic pancreatic cancer treated with either fluoropyrimidines and platinum salts (group A=58) or fluoropyrimidines alone (group B=50), ERCC1 levels were correlated with OS, time to progression and response to chemotherapy., Results: Median survival was significantly higher in group A with low ERCC1 levels [11.9 versus 9.9 months; p ≤ 0.05] (median follow-up 24 months). Moreover in the same group, a trend towards longer time to progression was observed. No differences in OS were observed when ERCC1 was studied (low versus high) in patients not treated with platinum salts. On multivariate analysis of pretreatment prognostic factors, ERCC1 emerged as an independent predictive factor for OS., Conclusion: The results of this study indicate that ERCC1 may predict survival in pancreatic cancer patients treated by platinum and fluoropyrimidine as second-line chemotherapy.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), developed for patients with advanced non-small cell lung cancer (NSCLC), give modest results similar to those with chemotherapy. There is evidence of a greater survival benefit from TKIs in patients with certain molecular and clinical features, but results are conflicting. To assess the role of these factors in predicting TKI efficacy, a pooled analysis was performed on data from randomized trials in NSCLC., Materials and Methods: An electronic search of all randomized trials comparing the efficacy or activity of TKIs and a pooled analysis were performed. The hazard ratio (HR) with 95% confidence interval (CI) was calculated for each level of the factors and an interaction test was used to detect differences in treatment effect related to the different levels., Results: Of ten randomized trials identified, five were considered for analysis. Smoking was shown to be the only clinical factor to have a predictive effect (non smokers: overall survival (OS) HR 0.53, 95% CI 0.42-0.67; smokers: HR 0.91, 95% CI 0.81-1.02; p-value for interaction <0.001). A negative predictive value was suggested for K-ras mutations (K-ras(+): HR 1.97 95% CI 1.16-3.33; K-ras(-): HR 0.79, 95% CI 0.59-1.05; p-value for interaction 0.003)., Conclusion: At the present time, none of the biological features which have been evaluated in patients who have undergone therapy using TKIs is proven to be of predictive value; only K-ras mutations and smoking habits can be considered as a possible criteria for selection. Results of prospective randomized trials on biological markers are awaited.

Background: Darbepoetin alfa, has a longer halflife than epoetin alfa (rHuEPO) due to its increased sialylated carbohydrate content and can be administered less frequently. Its advantage in terms of response is not entirely clear., Patients and Methods: From August 2005 until October 2006, 64 anemic patients (hemoglobin < or =11.5 g/dl) with advanced metastatic cancer receiving chemotherapy (CT), median age 65 years (range 33-77), median Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (range 0-1), were treated with subcutaneous (s.c.) darbepoetin alfa 500 microg every 3 weeks (Q3W) and a single intravenous (i.v.) dose of 125 mg of elemental iron at the beginning of the treatment period followed by an oral daily iron supplement (200 mg of elementary iron). The treatment effect was evaluated as a response (Hb increase > or =1 g/dl) or a major response (Hb increase > or =2 g/dl) after 2, 4, 6 and 8 weeks. The patients were questioned about fatigue., Results: After 8 weeks of treatment, a treatment response was observed in 11 out of the 29 evaluable patients (38%) with a major response in 10%. The mean Hb change was 0 g/dl, +0.9 g/dl, +0.75 g/dl and +0.7 g/dl respectively at 2, 4, 6 and 8 weeks. Blood transfusions were required in 9 patients (31%). At baseline, 39 out of the 64 patients (61%) reported grade 1 or 2 fatigue. At 8 weeks the patients with a major response did not show any evidence of fatigue., Conclusion: Darbepoetin alfa Q3W is moderately effective in reducing anemia in heavily pretreated and advanced stage chemotherapy treated patients.

The purpose of this study is to establish if mucoid differentiation is associated with responsiveness to preoperative radiochemotherapy (RCT) in rectal adenocarcinomas. Thirty-two patients with rectal adenocarcinomas were preoperatively treated with 44 to 46 Gy in 22 to 23 fractions and with 5-fluorouracil (200 to 225 mg/m) before surgery. Mucoid differentiation was searched for both in pre-RCT biopsies with anti-MUC2 antiserum and in postoperative specimens. To evaluate the responsiveness to preoperative RCT, a regression grading was used (grades 0 to 4). Statistical analysis showed a significant negative correlation between immunohistochemical expression of MUC2 in pre-RCT biopsies and regression grade in postoperative specimens (r=-0.529; P=0.002). A significant cutoff value of 60% of MUC2 positive neoplastic cells in pre-RCT biopsies was observed (P=0.018): 13 cases with more than 60% exhibited a poor response to RCT (grade 0 in 5/13, grade 1 in 4/13, grade 2 in 4/13), whereas 19 cases with less than 60% showed a better response to RCT (grade 1 in 6/19, grade 2 in 9/19, grade 3 in 3/19, grade 4 in 1/19).

Aims and Background: Cisplatin, a standard component of combination chemotherapy for several tumors, presents important anti-tumor properties but also several toxic effects. In particular, the major dose-limiting effect appears to be renal toxicity. In several countries, to reduce nephrotoxicity after cisplatin administration, a 24-h hydration is recommended following a chemotherapy treatment in a hospital regimen. In our Institutions, cisplatin chemotherapy is an outpatient treatment that provides adequate hydration with an NaCl solution plus furosemide and diuresis monitoring during treatment., Methods and Study Design: To assess incidence of cisplatin nephrotoxicity using a short hydration regimen, which included 2000 ml of fluids with control of diuresis, individual outpatient data was pooled retrospectively from patients enrolled in large randomized studies regarding cisplatin-based chemotherapy in lung cancer and mesothelioma. From February 1999 to November 2002, 107 patients treated with cisplatin (> or = 75 mg/m2/cycle) were examined, monitoring serum creatinine and creatinine clearance levels., Results: Five patients out of 107 (4.6%) were withdrawn from chemotherapy because of renal toxicity. For the other 102 patients, serum creatinine and creatinine clearance measurements were stable around the normal values during treatment. No time trends relating to serum creatinine levels or creatinine clearance and cycle numbers or cisplatin-cumulative doses were detected (P = 0.36 and P = 0.64, for the relationship with cycle number, and P = 0.39 and P = 0.65 for the relationship with cumulative dose, respectively, random effect model) after adjusting for the total number of cycles administered., Conclusions: These observations indicate that intermediate to high-dose cisplatin administration is feasible in outpatient management with a short hydration regimen without high risk of nephrotoxicity.

Background: The aim of this phase II study was to evaluate efficacy and toxicity of single-agent docetaxel, administered every two weeks as second-line treatment for patients with recurrent non-small cell lung cancer (NSCLC)., Patients and Methods: Forty-eight patients with confirmed NSCLC were enrolled in this trial The median age was 56.5 years (range 43-76), median PS was 1, and the main histology type was adenocarcinoma (54%). Only 8% of patients had previously received paclitaxel. Patients received docetaxel i.v., 50 mg/m2 over 1 hour, on day 1 every 2 weeks., Results: The overall response rate was 8.3% (95% Confidence Interval 0.5-161%). The median time to disease progression, median survival time and 1-year survival rate were 3 months, 6 months and 21%, respectively. Grade 3-4 neutropenia was registered in 47% of patients, with only 1 patient (2%) experiencing febrile neutropenia. Nonhematological toxicity was mild (grade 1-2) and consisted mainly of asthenia (19%o) and diarrhea (10%)., Conclusion: The bi-weekly schedule of docetaxel showed an activity comparable to the standard tri-weekly 75 mg/m2 schedule as second-line treatment for recurrent NSCLC. Though non-hematological toxicity is significantly reduced, myelosuppression is still a matter of concern.

Purpose: To study the prognostic value for overall survival of baseline assessment of functional status, comorbidity, and quality of life (QoL) in elderly patients with advanced non-small-cell lung cancer treated with chemotherapy., Patients and Methods: Data from 566 patients enrolled onto the phase III randomized Multicenter Italian Lung Cancer in the Elderly Study (MILES) study were analyzed. Functional status was measured as activities of daily living (ADL) and instrumental ADL (IADL). The presence of comorbidity was assessed with a checklist of 33 items; items 29 and 30 of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30 (EORTC QLQ-C30) were used to estimate QoL. ADL was dichotomized as none versus one or more dependency. For IADL and QoL, three categories were defined using first and third quartiles as cut points. Comorbidity was summarized using the Charlson scale. Analysis was performed by Cox model, and stratified by treatment arm., Results: Better values of baseline QoL (P = .0003) and IADL (P = .04) were significantly associated with better prognosis, whereas ADL (P = .44) and Charlson score (P = .66) had no prognostic value. Performance status 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted shorter overall survival., Conclusions: Pretreatment global QoL and IADL scores, but not ADL and comorbidity, have significant prognostic value for survival of elderly patients with advanced non-small-cell lung cancer who were treated with chemotherapy. Using these scores in clinical practice might improve prognostic prediction for treatment planning.

Purpose: Our objective was to determine the activity in terms of response rate, surgical resectability, and the tolerability of the new three-drug combination gemcitabine-cisplatin-paclitaxel (GCP) in unresectable stage IIIA(N2) and IIIB non-small cell lung cancer (NSCLC)., Patient and Methods: Forty-two chemo-naive patients with stage IIIA(N2)-IIIB NSCLC, median age of 59 years, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and the ability to tolerate pneumectomy, received gemcitabine (Gem) 1000 mg/m(2) IV days 1 and 8, cisplatin (CDDP) 50 mg/m(2) IV days 1 and 8, paclitaxel 125 mg/m(2) 1h infusion IV days 1 and 8, every 21 days for 3 cycles. After induction chemotherapy, patients were evaluated for surgery or definitive radiotherapy., Results: Grade 3-4 neutropenia was the main hematologic toxicity, occurring in 28% of patients. Grade 3-4 thrombocytopenia was observed in only 11% of cases. No neutropenic fever or bleeding episodes were recorded. Severe non-hematologic toxicity was uncommon. Thirty (71%, 95% CI: 57.2-84.7%) of the 42 eligible patients had objective responses (1 complete and 29 partial responses). After induction chemotherapy, 21 patients (50%) went to surgery. Complete resection was obtained in 16 patients (38%). Viable tumor was present in 18 of 21 resection specimens. In three cases only necrotic tumor cells were identified, for a pathological complete response of 7%. With a median follow-up of 13.9 months, median time to progression was 17.4 months, median survival 21.7 months and estimated 1-year survival 92%., Conclusions: GCP combination is active and well tolerated in locally-advanced, non-resectable NSCLC. The activity profile, in terms of response and surgical resection rate, is comparable to that obtained with standard doublets.

Background: The objective of the current study was to define the activity and tolerability, as well as the influence on resectability, of the combination of gemcitabine, paclitaxel, and cisplatin (GTP) as induction chemotherapy for patients with Stage IIIA(N2) nonsmall cell lung carcinoma (NSCLC)., Methods: Forty-nine chemotherapy-naïve patients (median age, 61 years; World Health Organization performance status, 0-1) with biopsy-proven Stage IIIA(N2) disease received 1000 mg/m(2) gemcitabine, 125 mg/m(2) paclitaxel, and 50 mg/m(2) cisplatin on Days 1 and 8 of every 3 weeks until reevaluation for surgery or definitive radiotherapy., Results: Grade 3-4 neutropenia was the most common hematologic toxicity, occurring in 32.7% of patients; however, only 1 case of febrile neutropenia was reported. Grade 3-4 thrombocytopenia occurred in 12.2% of patients but was not associated with bleeding. Severe nonhematologic toxicities were uncommon; the only Grade 4 nonhematologic toxicity was diarrhea, which occurred in 4% of patients. One patient died after the first course of therapy, but this event was found to be unrelated to treatment. Thirty-six patients (73.5%) achieved an objective response, and an additional 4 patients had stable disease with clearance of mediastinal lymph nodes. Overall, 29 patients underwent thoracotomy and 27 (55%) underwent complete resection. Mediastinal nodes were free of tumor in 35% of all cases, and 8 pathologic complete responses (16%) were reported. Median survival was 23 months, with a 1-year survival rate of 85%., Conclusions: GTP is highly active as an induction chemotherapy regimen for Stage IIIA(N2) NSCLC and yields good toxicity results. The use of GTP in combination with radiotherapy and new biologic drugs should be explored., (Copyright 2003 American Cancer Society.)

The present study describes supportive care (SC) in patients with advanced non-small-cell lung cancer (NSCLC), evaluating whether it is affected by concomitant chemotherapy, patient's performance status (PS) and age. Data of patients enrolled in three randomised trials of first-line chemotherapy, conducted between 1996 and 2001, were pooled. The analysis was limited to the first three cycles of treatment. Supportive care data were available for 1185 out of 1312 (90%) enrolled patients. Gastrointestinal drugs (45.7%), corticosteroids (33.4%) and analgesics (23.8%) were the most frequently observed categories. The mean number of drugs per patient was 2.43; 538 patients (45.4%) assumed three or more supportive drugs. Vinorelbine does not produce substantial variations in the SC pattern, while cisplatin-based treatment requires an overall higher number of supportive drugs, with higher use of antiemetics (41 vs 27%) and antianaemics (10 vs 4%). Patients with worse PS are more exposed to corticosteroids (42 vs 30%). Elderly patients require drugs against concomitant diseases significantly more than adults (20 vs 7%) and are less frequently exposed to antiemetics (12 vs 27%). In conclusion, polypharmacotherapy is a relevant issue in patients with advanced NSCLC. Chemotherapy does not remarkably affect the pattern of SC, except for some drugs against side effects. Elderly patients assume more drugs for concomitant diseases and receive less antiemetics than adults.

Objective: The objectives of this phase I/II study were to define the maximum tolerated dose (MTD), safety, and activity of cisplatin, etoposide, and gemcitabine (PEG) in the treatment of previously untreated patients with small-cell lung cancer (SCLC)., Patients and Methods: Chemonaive patients received fixed doses of gemcitabine (1000 mg/m(2) on days 1 and 8) and cisplatin (70 mg/m(2) on day 2) and escalating doses of etoposide (starting dose of 50 mg/m(2) on days 3, 4, and 5) every 3 weeks. No prophylactic granulocyte colony-stimulating factors were used., Results: From September 1998 to April 2000, 56 patients with limited- or extensive-stage SCLC were enrolled and received a total of 235 cycles. Two different etoposide doses were tested in eight patients. At the second level (75 mg/m(2)), two out of two patients experienced dose-limiting toxicities (neutropenia and thrombocytopenia) and no further dose-escalation was attempted, thus an etoposide dose of 50 mg/m(2) was defined as the MTD. In the subsequent phase II evaluation, 48 additional patients were enrolled, for a total of 54 patients treated at the MTD. Grade 3/4 neutropenia and thrombocytopenia occurred in 66.7 and 53.7% of patients, respectively. Non-hematologic toxicity was mild, with grade 3 diarrhea and fatigue as the main side effects. Two patients died of neutropenic sepsis (one at 75 mg/m(2) and the other at 50 mg/m(2) etoposide). Ten complete and 29 partial responses were reported, for an overall response rate of 72.2% (95% confidence interval, 56.6-85.0%). The median duration of response and median survival were 8.0 and 10 months, respectively, with a 1-year survival probability of 37.5%., Conclusions: The combination of PEG is feasible and well tolerated as front-line chemotherapy in SCLC. A randomized comparison of this triplet is underway.

Background: Our aim was to explore the activity and feasibility of gemcitabine plus cisplatin as induction chemotherapy in patients with Stage IIIA N(2) and selected IIIB non-small cell lung cancer (NSCLC)., Patients and Methods: From September 1997 to July 2000, 70 chemonaive patients with Stage III NSCLC, median age of 64 years, World Health Organization performance status 0, 1, or 2, and the ability to tolerate a pneumonectomy entered the study and received gemcitabine 1250 mg/m(2) on days 1 and 8 and cisplatin 70 mg/m(2) on day 2 every 3 weeks. After three cycles of induction chemotherapy, patients underwent resection or radiotherapy., Results: Responses were seen in 40 of the 69 assessable patients, for an intent-to treat overall response rate of 57.1% (95% confidence interval, 45-62%), with 4.2% complete response. Response rates were 68 and 35% in patients with Stage IIIA and IIIB disease, respectively. The overall pathological CR rate after induction chemotherapy was 3%, with an overall pathological downstaging rate of 20%. Median survival for all patients was 14.5 months, with an estimated 1-year survival rate of 67% (95% CI, 54.3-79.5%). The estimated time to treatment failure was 12.6 months. Grade 3/4 thrombocytopenia was the main hematologic toxicity, occurring in 26% of patients, but was not associated with life-threatening bleeding. Febrile neutropenia was rare and other severe non-hematologic toxicities were uncommon., Conclusions: The 3-week schedule of gemcitabine plus cisplatin is highly active as induction chemotherapy in Stage IIIA N(2) unresectable NSCLC. This suggests a need for a multimodality approach upfront, such as concurrent chemoradiation therapy, particularly in patients with Stage IIIB disease.

Background: In order to combine an active regimen with a simultaneous efficient mobilization of peripheral blood precursor cells (PBPC), we explored the combination of Docetaxel 75 mg/m2 and Epirubicin 120 mg/m2 with G-CSF 5 mcg/Kg/day s.c. to mobilize PBPC in breast cancer patients to support high-dose chemotherapy (HDC)., Patients and Methods: Forty patients were enrolled: 27 high risk and 13 metastatic. The entire procedure, including chemotherapy and PBPC collection, was on an outpatient basis., Results: The median day of starting apheresis was day +10 (range 10-12) and the average value of circulating CD34+ cells at peak was 175/microliter (range 33-403). The median yield of CD34+ cells per apheresis was 8.76 x 10(6)/Kg (range 1.83-27.87). None of the patients developed side effects which required hospitalization. All patients enrolled successively received HDC as consolidation treatment. High risk patients received one and metastatic patients two HDC with PBPC reinfusion. All patients obtained a complete engraftment. No significant differences between high-risk and metastatic patients were observed., Conclusions: Our study suggests that the combination of Docetaxel, Epirubicin, and G-CSF is feasible, safe and efficient outpatient mobilizing treatment for patients with breast cancer receiving HDC.

Thirty-four ovarian and breast cancer patients received autologous peripheral blood progenitor cell transplantation after high-dose myeloablative chemotherapy and either granulocyte-colony-stimulating factor (G-CSF) or granulocyte/macrophage-colony-stimulating fictor (GM-CSF) in the immediate post-transplant period. The recovery of T cell functionality was monitored by a three-color flow-cytometric approach using carboxyfluorescein diacetate succinimidyl ester, a probe the fluorescence intensity of which halves at each round of cell replication, in conjunction with CD3 and CD25 monoclonal antibodies. There was no significant difference between the two treatments on days 12, 20, and 40, T cell proliferation always being considerably lower than that of control cultures from healthy donors. At day 80, a significantly higher proportion of mitogen-stimulated T cells from GM-CSF-treated patients expressed interleukin-2 receptor, and a higher proportion of these T cells were actively proliferating. This phenomenon did not reflect any difference in the relative proportion of various lymphocyte subsets (T cells, CD4 and CD8+ T cells, CD45RA+ and CD45RO- T cells, and natural killer cells). At the end of follow-up (1-1.5 years) T cell proliferation had returned to values typically observed in healthy individuals in both groups of patients. Soon after transplantation (day 12), neutrophils from G-CSF-treated patients had a more elevated Fcgamma receptor I density and monocytes from GM-CSF-treated patients had a more elevated Fcgamma receptor II and MHC class II molecules density. The up-modulation of Fcgamma receptor II was maintained until day 40. Thus, administering G-CSF and GM-CSF in the post-transplant period affects T lymphocyte proliferation and phagocyte membrane molecules differently.

A 53-year-old woman experienced rapidly progressing liver failure four years after a quadrantectomy for a breast carcinoma. She had received adjuvant chemotherapy and radiotherapy, and second-line chemotherapy for bone metastasis one year earlier. The hepatic failure manifested with ascites, jaundice, elevation of serum bilirubin and hepatic enzyme levels and hypoalbuminemia. Imaging studies showed an enlarged liver without metastatic lesions. The patient died of hepatic decompensation within two weeks. Liver examination at autopsy revealed massive neoplastic infiltration consistent with a primary breast carcinoma. It is important to realize that this unusual pattern of liver metastasis cannot be demonstrated even with the most advanced techniques of instrumental diagnosis (CT scan, ultrasonography and magnetic resonance imaging), and should be taken into account in the differential diagnosis of rapidly progressing liver failure.

In 1989 we started an accelerated hyperfractionated schedule of radiotherapy (two 1.6 Gy daily fractions) in standard risk localized Ewing's sarcoma of bone, with the aim at reducing late effects in young patients and at improving disease control through a better integration of treatment modalities. From 1991, the same schedule was used in preoperative radiotherapy of adult soft tissue sarcomas of the extremities: the main purpose was to reduce the time to surgery and to evaluate surgical complications in comparison with a previous experience of hypofractionated radiotherapy (one 3 Gy daily fraction). From 1991 to 1997, 76 patients with Ewing's sarcoma and 24 patients with soft tissue sarcoma were treated at our Institution. Results and complication rates are analyzed in comparison with historical data. In Ewing's sarcoma, a correct evaluation of improvement in local control was difficult because of changing treatment policy (bulky disease was not included in the present series). Late effects, as evaluated in patients with a minimum follow-up of 3 years, occurred with similar incidence, but at higher total dose levels in patients treated with accelerated hyperfractionation. In patients with soft tissue sarcomas, incidence of surgical complications is reduced as compared to historical experience. Major problems of wound healing were seen in association with intraoperative brachitherapy boost.