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Background: Several strategies have been investigated to improve the 4% survival advantage of adjuvant chemotherapy in early-stage non-small-cell lung cancer (NSCLC). In this investigator-initiated study we aimed to evaluate the predictive utility of the messenger RNA (mRNA) expression levels of excision repair cross complementation group 1 (ERCC1) and thymidylate synthase (TS) as assessed in resected tumor., Patients and Methods: Seven hundred and seventy-three completely resected stage II-III NSCLC patients were enrolled and randomly assigned in each of the four genomic subgroups to investigator's choice of platinum-based chemotherapy (C, n = 389) or tailored chemotherapy (T, n = 384). All anticancer drugs were administered according to standard doses and schedules. Stratification factors included stage and smoking status. The primary endpoint of the study was overall survival (OS)., Results: Six hundred and ninety patients were included in the primary analysis. At a median follow-up of 45.9 months, 85 (24.6%) and 70 (20.3%) patients died in arms C and T, respectively. Five-year survival for patients in arms C and T was of 65.4% (95% CI (confidence interval): 58.5% to 71.4%) and 72.9% (95% CI: 66.5% to 78.3%), respectively. The estimated hazard ratio (HR) was 0.77 (95% CI: 0.56-1.06, P value: 0.109) for arm T versus arm C. HR for recurrence-free survival was 0.89 (95% CI: 0.69-1.14, P value: 0.341) for arm T versus arm C. Grade 3-5 toxicities were more frequently reported in arm C than in arm T., Conclusion: In completely resected stage II-III NSCLC tailoring adjuvant chemotherapy conferred a non-statistically significant trend for OS favoring the T arm. In terms of safety, the T arm was associated with better efficacy/toxicity ratio related to the different therapeutic choices in the experimental arm., Competing Interests: Disclosure GVS received honoraria from AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, Johnson & Johnson, Takeda; consulting or advisory role for Eli Lilly, BeiGene and AstraZeneca, received institutional research funding from Eli Lilly and MSD and received travel, accommodations from Bayer. SN received honoraria or consulted for Eli Lilly, Amgen, BeiGene, AstraZeneca, Bristol Myers Squibb, Abbvie, Boehringer Ingelheim, MSD, Roche, Pfizer and Takeda. All other authors have declared no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Immune checkpoint inhibitors (ICIs) induce durable clinical responses only in a subset of advanced non-small cell lung cancer (NSCLC) patients. There is a need to identify mechanisms of ICI resistance and immunotherapy biomarkers to improve clinical benefit. In this study, we evaluated the prognostic and predictive value of circulating endothelial and leukocyte-derived extracellular vesicles (EV) in patients with advanced NSCLC treated with anti-PD-1/PD-L1 agents. In addition, the relationship between total blood circulating EV proteome and response to ICIs was investigated. An optimized flow cytometry method was employed for the identification and subtyping of blood circulating EVs in 59 patients with advanced NSCLC. Blood samples were collected from patients receiving anti-PD-1/PD-L1 inhibitors ( n = 31) or chemotherapy ( n = 28). An exploratory proteomic analysis of sorted blood EVs was conducted in a subset of patients. Our results show that a low blood concentration of circulating endothelial-derived EVs before treatment was strongly associated to longer overall survival ( p = 0.0004) and higher disease control rate ( p = 0.045) in patients treated with ICIs. Interestingly, shotgun proteomics revealed that EVs of responders to anti-PD-1 therapy had a specific protein cargo before treatment. In addition, EV protein cargo was specifically modulated during immunotherapy. We identified a previously unknown association between circulating endothelial-derived extracellular vesicle concentration and immunotherapy-related clinical outcomes. We also observed differences in circulating extracellular vesicle proteome according to anti-PD-1-based treatment response in NSCLC patients. Overall, these results may contribute to the identification of novel circulating biomarkers for rational immunotherapy approaches in patients affected by NSCLC.

Background: Lung neuroendocrine carcinoma (NEC) is characterized by aggressive clinical behavior and lack of treatment advances. We evaluate the prognostic and the predictive roles of systemic inflammatory biomarkers in patient circulating blood: neutrophil-lymphocyte ratio (NLR), lactate dehydrogenase (LDH), advanced lung cancer inflammation index (ALI), and the Lung Immune Prognostic Index (LIPI) score., Methods: A total of 120 patients with small-cell lung cancer (SCLC) ( n  = 110) and large cell neuroendocrine carcinoma (LCNEC) ( n  = 10) were enrolled. Overall survival (OS) was evaluated by Kaplan-Meier estimator and univariate and multivariate Cox proportional hazard analyses were performed to determine prognostic factors associated with OS while χ 2 test was used for categorical data., Results: NLR cutoff value was 1.93. NLR was measured before and after first-line chemotherapy; 25 (21%) patients had higher NLR (delta NLR >1), whereas NLR was lower in 37 (31%). At the univariate analysis, median OS was 12 months: OS for SCLC and LCNEC were 11 months and 14 months, respectively. OS had a prognostic positive value in patients with pre-treatment NLR <1.93 ( p  = 0.0002), LDH <600 U/L ( p  = 0,03) and ALI ⩾34 ( p  = 0,0065). At the multivariate analysis, Eastern Cooperative Oncology Group performance status, LDH levels and response after first-line chemotherapy were independently associated with OS. Median OS for good, intermediate, and poor LIPI was 15 months, 11 months, and 9 months, respectively( p  = 0.091). Patients with higher NLR (>1.93) had an increased probability of tumor progression ( p  = 0.045, χ 2 test)., Conclusion: This study demonstrated that systemic inflammatory biomarkers could facilitate the understanding of survival differences in the clinical management of lung NEC patients, underlying the need for prospective biomarker-driven studies in the immune checkpoint inhibitors setting., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

In Non-Small-Cell Lung Cancer (NSCLC) patients treated with Tyrosine Kinase-Inhibitors (TKIs) therapy, the emergence of acquired resistance can be investigated by plasma monitoring of circulating tumor DNA (ctDNA). A series of 116 patients with EGFR -positive lung adenocarcinomas were treated with first/second generation EGFR TKIs. At clinical progression, 64 (55%) EGFR T790M plasma positive patients were subjected to second line-treatment with osimertinib and strictly monitored during the first month of therapy. Plasma analysis by the EGFR Cobas test showed in 57 (89%) cases a substantial decrease in the levels of the sensitizing EGFR mutant allele (s EGFR ma), down to a not detectable value. These patients were defined as plasmatic good responders (PGR). In 7 (11%) patients, the s EGFR ma did not drop to zero (plasmatic poor responders, PPR). In these latter cases, Massive Parallel Sequencing (MPS) analysis at the end of the first month and at clinical progression showed the presence of resistant-inducing mutations, including MET and HER2 gene amplification, KRAS and PIK3CA gene mutations. PPR showed disease progression in 5 (71%) cases, stable disease in 2 (29%) cases, and a shorter median Progression-free survival (PFS) (4.3 ± 1.1 months) than that observed in PGR (13.3 ± 1.2 months) ( P < 0.0001). Our data indicate that plasma monitoring by a simple RT-PCR-based EGFR mutation test in the first month of treatment may be useful for a rapid identification of patients to be subjected to further characterization by MPS. A diagnostic algorithm for an early detection of resistance-inducing mutations and patient management is reported., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest.

Background: Oral vinorelbine administered at the maximum tolerated dose has already showed activity and a good safety profile in advanced non-small-cell lung cancer (NSCLC). The MA.NI.LA study was a phase II, multicenter, randomized, controlled trial that aimed to assess the effects of a 'switched maintenance' regimen with oral metronomic vinorelbine (OMV) in patients with NSCLC who had not progressed after first-line platinum-based chemotherapy., Patients and Methods: Patients were randomly assigned in a 1:1 ratio to either OMV (50 mg three-times weekly) as maintenance treatment or best supportive care (BSC). The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), objective disease control rate (DCR, CR + PR + SD), safety and quality of life., Results: In total, 61 and 59 patients were assigned to OMV and BSC, respectively. At a median follow-up of 23.9 (IQR 10.2-38.2) months, patients treated with OMV reported a significantly lower progression rate compared to patient in the BSC arm (89% [54/61] vs 96% [56/58]; HR 0.73; 90% CI 0.53-0.999, p = 0.049). Median PFS for patients treated with vinorelbine was 4.3 months (95% CI 2.8-5.6) vs 2.8 months (95% CI 1.9-4.5) for patients receiving BSC. This benefit was specifically evident in patients aged ≥70 years, in current smokers, and in those who reported disease stabilization as best response to induction chemotherapy. OS and response rate and quality of life were similar in the two arms. Drop-out rate for major toxicity with OMV was unexpectedly high (25%, 14/61) mainly due to grade 3-4 neutropenia (11%, 7/61). Conclusions In patients with unselected NSCLC achieving disease control after platinum-based chemotherapy switch maintenance therapy with OMV prolonged PFS compared to BSC; however, the optimal dose of OMV requires further investigation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

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 major challenge for treating non-squamous (non-Sq) non-small cell lung cancer (NSCLC) patients without actionable biomarkers is the actual selection of proper treatment, weighing expected clinical outcomes and safety profile., Methods: Consecutive non-Sq NSCLC patients were treated with platinum-pemetrexed (PP) doublets in clinical practice. Subgroup analyses were conducted in patients treated with standard (s)PP and modified (m)PP doublets (because of age, performance status, and/or comorbidities) and in patients treated with cisplatin-based and carboplatin-based PP doublets. Activity, efficacy, safety, and toxicities were evaluated., Results: From November 2009 to April 2017, 111 patients were treated: 87 (78.4%) with sPP and 24 (21.6%) with mPP; 76 (68.5%) with cisplatin-based and 35 (31.5%) with carboplatin-based regimens. The objective response rate (ORR), median progression-free survival (PFS), and median overall survival (OS) were 49.0%, 7, and 13 months in the entire patient population, respectively. We found no significant differences in ORR, median PFS, and median OS between sPP and mPP. Cisplatin-based PP showed higher ORR (53.7%) versus carboplatin-based PP (38.7%) and longer PFS (7 vs. 6 months; P = 0.028) and OS (18 vs. 11 months; P = 0.006). We confirm that carboplatin has a better toxicity profile than cisplatin. The received dose-intensities were ~80% of standard full doses., Conclusions: Accurate management allowed us to treat the majority of advanced non-Sq NSCLC patients with PP combination therapy without significant differences in ORR, median PFS, and median OS. Even considering the selection bias, our data seems to confirm the greater effectiveness of cisplatin-based over carboplatin-based regimens., (© 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Crizotinib, a mesenchymal-epithelial transition/anaplastic lymphoma kinase/c-ros oncogene 1 (ROS1) inhibitor, has recently been approved by the US Food and Drug Administration for the treatment of patients with advanced ROS1-positive non-small-cell lung cancer (NSCLC). Therefore, interest in ROS1 testing is growing. ROS1 gene fusions affect approximately 0.5% to 2% of unselected NSCLCs. Limited data are available on the prevalence and distribution of ROS1 fusions in patients with advanced-stage NSCLC., Material and Methods: A series of 727 lung adenocarcinomas from patients with stage IV disease, negative for epidermal growth factor receptor and anaplastic lymphoma kinase alterations, were tested for ROS1 fusions by fluorescent in situ hybridization analysis, with confirmation by immunohistochemistry. Results were correlated with clinicopathologic parameters and compared with data from the literature., Results: ROS1 fusions were detected in 29 patients (4%), including 27 of 266 females (10.2%) and two of 461 males (0.4%; P = 1.2 E-10 ). The mean age of patients with ROS1-positive disease was lower than that of patients with ROS1-negative disease (49.21 v 62.96 years, respectively; P = 1.1 E-10 ). Eleven of 583 smokers (1.9%) and 18 of 144 nonsmokers (12.5%) showed ROS1 rearrangement ( P = 4.05 E-7 ). By logistic regression analysis, ROS1 fusions were independently associated with female sex, younger age at diagnosis, and absence of smoking history, (odds ratios, 12.4, 7.9, and 3.6, respectively). These data, integrated with those reported in the literature, indicate that the prevalence of ROS1 fusions in females and in nonsmokers was higher in patients with advanced disease than in patients with operable disease (11.2% v 3.1%, P < .001; 11.6% v 2.8%, P < .001, respectively). The mean age at diagnosis was significantly lower in patients with advanced disease (49.8 years) than in patients with operable disease (55.6 years; P < .001)., Conclusion: Our data indicate that ROS1 fusions in patients with advanced-stage lung adenocarcinoma are more frequent in females, particularly if young and nonsmokers. A diagnostic algorithm for an accurate screening of ROS1 alterations was elaborated.

The current classification of pulmonary neuroendocrine tumours includes four subtypes: low-grade typical carcinoid tumour (TC), intermediate-grade atypical carcinoid tumour (AC), and two high-grade malignancies: large cell neuroendocrine carcinoma and small cell lung cancer (SCLC). Unfortunately, with the exclusion of SCLC, no large phase II and III trials for pulmonary neuroendocrine tumours have been published. Thus, several treatment approaches are available for their treatment but none of them has been validated in appropriately designed and adequately sized clinical trials. The main problem of the published studies is that they include neuroendocrine tumours from various sites of origin with different clinical behaviour. It is important that future studies consider these tumours separately. In this regard, increased awareness and referral of these patients to tertiary centres, in which a multidisciplinary management is available, may be of value. The aim of this review is to evaluate the state of the art and discuss future developments in the management of pulmonary neuroendocrine tumours excluding SCLC which we consider should be addressed in a different issue., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Mutations inducing resistance to anti-epidermal growth factor receptor (EGFR) therapy may have a clinical impact even if present in minor cell clones which could expand during treatment. We tested this hypothesis in lung cancer patients treated with tyrosine kinase inhibitors (TKIs). Eighty-three patients with lung adenocarcinoma treated with erlotinib or gefitinib were included in this study. The mutational status of KRAS and EGFR was investigated by direct sequencing (DS). KRAS mutations were also assessed by mutant-enriched sequencing (ME-sequencing). DS detected KRAS mutations in 16 (19%) of 83 tumors; ME-sequencing identified all the mutations detected by DS but also mutations in minor clones of 14 additional tumors, for a total of 30 (36%) of 83. KRAS mutations assessed by DS and ME-sequencing significantly correlated with resistance to TKIs (P = .04 and P = .004, respectively) and significantly affected progression-free survival (PFS) and overall survival (OS). However, the predictive power of mutations assessed by ME-sequencing was higher than that obtained by DS (hazard ratio [HR] = 2.82, P = .0001 vs HR = 1.98, P = .04, respectively, for OS; HR = 2.52, P = .0005 vs HR = 2.21, P = .007, respectively, for PFS). Survival outcome of patients harboring KRAS mutations in minor clones, detected only by ME-sequencing, did not differ from that of patients with KRAS mutations detected by DS. Only KRAS mutations assessed by ME-sequencing remained an independent predictive factor at multivariate analysis. KRAS mutations in minor clones have an important impact on response and survival of patients with lung adenocarcinoma treated with EGFR-TKI. The use of sensitive detection methods could allow to more effectively identify treatment-resistant patients.

Background: The chronomodulated infusion of 5-FU, FA and oxaliplatin allows a significant increase in dose intensity and antitumor efficacy in patients with metastatic colorectal cancer. Here we investigated if substitution of oxaliplatin with cisplatin produced a similar antitumor activity in previously untreated patients with advanced colorectal cancer., Methods: We enrolled 21 consecutively evaluated ambulatory patients with metastatic colorectal cancer. Each treatment cycle consisted of a 5-day course of continuous chronomodulated venous infusion of drugs. Daily doses were 600 mg/m2 5-FU, 150 mg/m2 FA (L-form), and 12 mg/m2 cisplatin. The cycles were repeated every 21 days., Results: All patients completed at least 3 cycles. Overall a total number of 105 cycles were administered. One partial response (lasting 3 months) and 13 stable disease (lasting from 3 to 12 months) were observed. The remaining 7 patients had progression of the disease. Hematologic and gastrointestinal toxicity was always < or = G2 in all cycles., Conclusions: The results of this study discourage the substitution of cisplatin for the more active compound, oxaliplatin, in a chronomodulated schedule of infusion with 5-FU and FA in patients with metastatic colorectal cancer.

Background: The survival rate for surgically resected stage III N2 non-small cell lung cancer (NSCLC) patients is less than 10%., Methods: A phase II study of cisplatin, epirubicin, and VP-16 (PEV) was undertaken in an attempt to improve the curative potential of surgery. Forty-one patients with stage III N2 NSCLC received 3 cycles of pEV. Patients with either complete response (CR) or partial response (PR) underwent surgery and 3 additional courses of PEV., Results: The response rate in the whole patient population was 58%. Eighteen patients were resected; twelve resections were complete and 6 were incomplete. Toxicity was mild and consisted mainly of myelosuppression. Twenty-six patients have died, and the median survival of all 41 patients was 18.1 months, with a 3-year survival of 23%. The median survival for those patients who were resected was 27 months with a 3-year survival of 42%., Conclusions: PEV is an effective low toxic drug combination for limited NSCLC.

Background: Aminoglutethimide was the first aromatase inhibitor to be used successfully in breast cancer patients. However, this drug also inhibits mineralcorticoid and glucocorticoid synthesis, making co-medication with corticosteroids necessary, and it is often poorly tolerated. The primary objective of this trial was to evaluate the clinical efficacy and tolerability of vorozole, a new non-steroidal oral aromatase inhibitor, in postmenopausal breast cancer patients. The secondary objective was to evaluate the pharmacodynamic activity of the drug., Subjects and Methods: Thirty-four postmenopausal patients previously treated with tamoxifen in the adjuvant setting and/ or for advanced disease were treated with vorozole, 2.5 mg once daily. Patients were monitored with respect to treatment efficacy and safety. Hormonal evaluations were performed at baseline and during the course of treatment in order to evaluate the pharmacodynamic efficacy and safety of vorozole., Results: According to UICC criteria, there were seven responders, one complete and six partial, for an overall response rate of 21% (95% confidence interval (CI) 9%-38%). The median duration of response was 9.6 months (95% CI 4.6-0), the median time to progression for the entire group was 4.7 months (95% CI 2.9-6.6) and the median survival time was 29.7 months (95% CI 19.1-0). Tolerability was excellent to good in 97% of the patients. Oestradiol and oestrone levels were suppressed to the limit of detection of the assays used. No effect was observed on the other endocrine parameters., Conclusions: Our results suggest that vorozole is an effective and safe drug for the treatment of advanced postmenopausal breast cancer following tamoxifen failure.

The circadian rhythm-modulated delivery of anticancer drugs has been shown to reduce toxicity and improve anticancer efficacy. The aim of this phase I trial was to compare the feasibility and tolerability of carboplatin (CBDCA) administered at circadian-modulated or flat infusion rate in 24 patients with advanced cancer. Each treatment cycle consisted of a 5-day continuous intravenous infusion of CBDCA, to be repeated at 28-day intervals. Three dose levels were determined, with a CBDCA dose 15%, 40% and 60% over that calculated using Calvert's formula. Two schedules were compared: schedule A (forty-four courses), with a at circadian rhythm-modulated rate (peak at 16.00 hr) and schedule B (fifty courses), at a constant rate. At the first and second dose level neither of the administered cycles were accompanied by hematologic toxicity higher than Grade 3. At the third dose level, two cycles out of 15 for schedule A and two out of 20 for schedule B were accompanied by Grade 4 thrombocytopenia. The repeat cycles were delayed from day 28 to 42 in some patients, with no differences between circadian-modulated and flat infusion. Three partial responses out of 9 evaluable patients were observed in schedule A and 2 out of 10 evaluable patients in schedule B. We showed no potential advantage of the chronomodulated 5-day CBDCA continuous infusion method over the flat rate method. Although antitumor effects were observed in this pilot study, this treatment cannot be assessed for efficacy relative to other schedules.

We investigated if chronomodulated infusion of fluorouracil, folinic acid in combination with carboplatin shows antitumor efficacy in patients advanced metastatic colorectal cancer. Thirteen patients entered into the study. Each treatment cycle consisted of a 5 day course of continuous venous infusion of 5-fluorouracil (5-FU; 500 mg/m2/die), folinic acid (FA; L-form, 150 mg/m2/die) and carboplatin (CBDCA; the dose being calculated according to the Calvert's formula). Patients received the drugs according to the circadian-modified infusion schedule with a sinusoidally modulated delivery with peak flow rate at 4.00 AM for 5-FU and FA and 4.00 PM for CBDCA. Overall a total number of 54 cycles were administered. Two partial responses and one minor response were observed among the 5 untreated patients. Five patients had progression of disease. Stabilization of previously progressive disease was obtained in the 5 remaining patients. These preliminary results show that the combination of 5-FU, FA and CBCDA infused at circadian-modulated rate has moderate activity in colorectal cancer, specially in previously untreated patients, with a mild and acceptable toxicity.

A Phase I trial of interferon-alpha (IFN-alpha) administered at circadian-rhythm modulated rate was carried out to evaluate maximum tolerated dose (MTD) and toxicity in patients with advanced malignancies. Recombinant IFN-alpha-2b was administered as a 7-day continuous venous infusion with maximum delivery between 6 p.m. and 3 a.m. Entry dose levels were 0.2, 2 and 4 MU/m2/day. The dose was escalated by an amount equal to the starting dose until a maximum of 6 entry dose levels was achieved, with a 1-week rest between each cycle. The maximal daily dose of IFN-alpha administered was 24 MU/m2/day. A programmable-in-time ambulatory pump was used, so that all patients could receive their treatment at home. Eighteen patients were entered in the study and 16 were evaluable for toxicity. Toxicity was mild to moderate except for two patients who developed WHO grade III toxicity. No significant decline in performance status was associated with treatment. Two objective responses were observed in patients with previously treated metastatic renal cell carcinoma. As compared to standard s.c./i.m. administration or continuous nonchronomodulated i.v. infusion of IFN-alpha, this circadian schedule has allowed to deliver high doses of drug with acceptable toxicity.

Twenty patients with stage IIIA-IIIB non-small-cell lung cancer were treated with cisplatin, epirubicin and VP-16 (PEV) neoadjuvant chemotherapy (CDDP, 70 mg/m2, i.v., d 1; EDX, 60 mg/m2, i.v., d 1; VP-16, 100 mg/m2, i.v., d 1-2-3; every 3 weeks). A partial response was obtained in 11 cases (55%), stable disease in 3 cases (15%), and progressive disease in 6 cases (30%). After chemotherapy, 8 (40%) patients, all achieving a partial response, were elegible for surgery: 5 (25%) had a complete resection (4 IIIA and 1 IIIB) and 3 (15%) an incomplete resection. The treatment was well tolerated. These data show that PEV is an active regimen for neoadjuvant chemotherapy in NSCLC and recommend this therapeutic approach for stage IIIA patients.