Olga Martelli

Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomised controlled trial

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.

Carboplatin- or Cisplatin-Based Chemotherapy in First-Line Treatment of Small-Cell Lung Cancer: The COCIS Meta-Analysis of Individual Patient Data

PURPOSE Since treatment efficacy of cisplatin- or carboplatin-based chemotherapy in the first-line treatment of small-cell lung cancer (SCLC) remains contentious, a meta-analysis of individual patient data was performed to compare the two treatments. PATIENTS AND METHODS A systematic review identified randomized trials comparing cisplatin with carboplatin in the first-line treatment of SCLC. Individual patient data were obtained from coordinating centers of all eligible trials. The primary end point was overall survival (OS). All statistical analyses were stratified by trial. Secondary end points were progression-free survival (PFS), objective response rate (ORR), and treatment toxicity. OS and PFS curves were compared by using the log-rank test. ORR was compared by using the Mantel-Haenszel test. RESULTS Four eligible trials with 663 patients (328 assigned to cisplatin and 335 to carboplatin) were included in the analysis. Median OS was 9.6 months for cisplatin and 9.4 months for carboplatin (hazard ratio [HR], 1.08; 95% CI, 0.92 to 1.27; P = .37). There was no evidence of treatment difference between the cisplatin and carboplatin arms according to sex, stage, performance status, or age. Median PFS was 5.5 and 5.3 months for cisplatin and carboplatin, respectively (HR, 1.10; 95% CI, 0.94 to 1.29; P = .25). ORR was 67.1% and 66.0%, respectively (relative risk, 0.98; 95% CI, 0.84 to 1.16; P = .83). Toxicity profile was significantly different for each of the arms: hematologic toxicity was higher with carboplatin, and nonhematologic toxicity was higher with cisplatin. CONCLUSION Our meta-analysis of individual patient data suggests no differences in efficacy between cisplatin and carboplatin in the first-line treatment of SCLC, but there are differences in the toxicity profile.

TAILOR: A phase III trial comparing erlotinib with docetaxel as the second-line treatment of NSCLC patients with wild-type (wt) EGFR.

LBA7501 Background: While the benefit of EGFR tyrosine kinase inhibitors in the treatment of patients with NSCLC harboring EGFR mutations has been widely established, their value in treating patients with wt EGFR is still debated. To assess the role of erlotinib in these patients, we performed an independent multicenter phase III trial (Tarceva Italian Lung Optimization Trial [TAILOR] NCT00637910), comparing erlotinib to docetaxel in second line treatment, having overall (OS) and progression free survival (PFS) as principal and secondary endpoints, respectively. METHODS EGFR and KRAS mutational status were assessed by direct sequencing in all eligible patients; only patients with wt EGFR NSCLC (exons 19 and 21) at progression, and previously treated with a first line platinum-based regimen, were randomized to receive either erlotinib 150 mg daily or docetaxel 75 mg/m2 (3-weekly) or 35 mg/m2 (weekly) until disease progression or unacceptable toxicity occurred. To detect an hazard ratio of 0.67 (2-sided 5% significance level for the log-rank test and a power of 80%), 199 events were required for both OS and PFS evaluation. RESULTS On the planned analysis date (March 30, 2012), 221 patients had been randomized and 218 were evaluable (docetaxel 110, erlotinib 108; three major violations excluded). At a median follow-up of 20 months, 199 relapses and 157 deaths were recorded. The Kaplan-Meier PFS curves showed a highly significant increase favoring docetaxel (HR 0.70 with 95% CI 0.53-0.94; p = 0.016) over erlotinib regimen. The HR translated into an estimated absolute difference in 6-months PFS of 12% (16% vs 28%). Data concerning toxicity were consistent with the literature. CONCLUSIONS In terms of PFS, our results indicate a clear superiority of docetaxel over erlotinib as second line treatment for patients without EGFR mutations in exons 19 or 21. Analysis of OS will be conducted as far as the planned number of 199 deaths is reached.

SHORT HYDRATION REGIMEN AND NEPHROTOXICITY OF INTERMEDIATE TO HIGH-DOSE CISPLATIN-BASED CHEMOTHERAPY FOR OUTPATIENT TREATMENT IN LUNG CANCER AND MESOTHELIOMA

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 (≥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.

Outcomes of small-cell lung cancer patients treated with second-line chemotherapy: A multi-institutional retrospective analysis

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.

Treatment of patients with small-cell lung cancer: From meta-analyses to clinical practice

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.

A 3-week schedule of gemcitabine plus cisplatin as induction chemotherapy for Stage III non-small cell lung cancer

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.

Effects of granulocyte-colony-stimulating factor and granulocyte/macrophage-colony-stimulating factor administration on T cell proliferation and phagocyte cell-surface molecules during hematopoietic reconstitution after autologous peripheral blood progenitor cell transplantation

Abstract 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 factor (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 Fcγ receptor I density and monocytes from GM-CSF-treated patients had a more elevated Fcγ receptor II and MHC class II molecules density. The up-modulation of Fcγ 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.

Value of KRAS as prognostic or predictive marker in NSCLC: results from the TAILOR trial

BACKGROUND The prognostic and predictive role of KRAS mutations in advanced nonsmall-cell lung cancer (NSCLC) is still unclear. TAILOR prospectively assessed the prognostic and predictive value of KRAS mutations in NSCLC patients treated with erlotinib or docetaxel in second line. PATIENTS AND METHODS NSCLC patients from 52 Italian hospitals were genotyped for KRAS and EGFR mutational status in two independent laboratories. Wild-type EGFR patients (N = 218) received first-line platinum-based chemotherapy and were randomly allocated at progression to erlotinib or docetaxel. Overall survival (OS) according to KRAS mutational status was the primary end point. RESULTS KRAS mutations were present in 23% of TAILOR randomized cases. The presence of a KRAS mutation did not adversely affect progression-free (PFS) or overall (OS) survival [hazard ratio (HR) PFS = 1.01, 95% confidence interval (CI) 0.71-1.41, P = 0.977; OS = 1.24, 95% CI 0.87-1.77, P = 0.233], nor influenced treatment outcome (test for interaction: OS P = 0.965; PFS P = 0.417). Patients randomized to docetaxel treatment experienced longer survival independently from the KRAS mutational status of their tumors (HR: mutated KRAS 0.81, 95% CI 0.45-1.47; wild-type KRAS 0.79, 95% CI 0.57-1.10). CONCLUSION In TAILOR, KRAS was neither prognostic nor predictive of benefit for either docetaxel or erlotinib. Docetaxel remains superior independently from KRAS status for second-line treatment in EGFR wild-type advanced NSCLC patients. CLINICAL TRIAL REGISTRATION NCT00637910.

Maintenance therapy in NSCLC: why? To whom? Which agent?

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.