Consensus on the use of immune-related response criteria to evaluate the efficacy of immunotherapy in non-small cell lung cancer.

INTRODUCTION: Many methods used to assess the effectiveness of immune checkpoint (programmed death-ligand 1 or cytotoxic T-lymphocyte-associated protein 4) inhibitors for non-small cell lung cancer (NSCLC) are insufficient, as the therapeutic benefit of these agents is often underestimated. Consequently, immune-related evaluation criteria have been developed to better reflect their efficacy. The aim of this consensus was to obtain the opinion of lung cancer experts on the adequacy of immune-response criteria for evaluating the efficacy of these treatments. METHODS: Through two rounds of a modified Delphi consensus, 18 Spanish lung cancer experts participated in a 15-item questionnaire regarding the use of immunotherapies for NSCLC and the assessment criteria used to evaluate their effectiveness. RESULTS: Consensus was achieved on 80% of the items in the questionnaire. The panelists agreed that although the Response Evaluation Criteria in Solid Tumors (RECIST) are standard for the evaluation of solid tumors, immune-related response criteria would be useful for measuring the efficacy of immunotherapy. In addition, they considered that an overall survival (OS) rate at 2-5 years is the most useful end point for assessing the benefit of immunotherapy, as clinical benefit may extend beyond the RECIST criteria-defined progression of disease. CONCLUSIONS: Although immune-related response criteria have been developed to better evaluate the efficacy of immunotherapy, their use has not been validated and is restricted to investigational applications. However, they may prove to be a useful tool for measuring the efficacy of immunotherapy agents in NSCLC, especially the OS rate at 2-5 years.

Acute airway obstruction in a patient with forestier disease. Case report. / Obstrucción aguda de vía aérea en paciente con enfermedad de Forestier. Caso clínico.

Ossification of the anterior longitudinal ligament of the spine, known as Forestier disease or diffuse idiopathic skeletal hyperostosis, is usually an asymptomatic disorder. The area most frequently affected is the thoracic spine, followed by lumbar and cervical regions. In the case of cervical involvement with clinical manifestations, the most common symptoms include dysphagia, dyspnoea, dysphonia, and can exceptionally cause an acute airway obstruction. The airway management of these patients represents a great anaesthetic challenge. The case is reported of an eighty-five-year-old patient who had an acute airway obstruction associated with Forestier disease. A fibre-optic-assisted intubation was accomplished under sevoflurane inhaled anaesthesia, maintaining spontaneous ventilation, with subsequent tracheostomy performed by ENT surgeons.

Efficacy of tyrosine kinase inhibitors in EGFR-mutant lung cancer women in a real-world setting: the WORLD07 database.

BACKGROUND: The WORLD07 project is a female specific database to assess the characteristics of women with lung cancer. METHODS: WORLD07 database sets up in 2007, and prospectively stores clinical characteristics, treatment, outcome, and follow-up of lung cancer women. All women with epidermal growth factor receptor (EGFR) mutation non-small cell lung cancer (NSCLC) were selected for this analysis. RESULTS: From October 2007 to December 2012, a total of 1775 NSCLC women were recruited. EGFR mutation was identified in 34.4% of patients. Upfront EGFR tyrosine kinase inhibitor (TKI) reported a response rate of 60%, a median progression-free survival of 11.7 months, and median overall survival of 23.0 months. EGFR TKI, EGFR-mutation type, and smoking status did not impact in the outcome of treated women. CONCLUSION: Prevalence of EGFR mutation in women with NSCLC is higher than overall population with NSCLC. Efficacy of EGFR TKI in this real-world setting is similar to that previously reported.

Long-term survival in advanced non-squamous NSCLC patients treated with first-line bevacizumab-based therapy.

BACKGROUND/AIM: First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. PATIENTS AND METHODS: This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9 months. RESULTS: Median overall survival and PFS were 30.7 and 15.1 months, respectively. The overall response rate was 83 %. Weight loss ≤5 %, ECOG PS = 0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. CONCLUSION: Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.

A consensus statement on the gender perspective in lung cancer.

Lung cancer is the most common cancer globally and has the highest mortality. Although this disease is not associated with a particular gender, its incidence is rising among women, who are diagnosed at an increasingly younger age compared with men. One of the main reasons for this rise is women taking up smoking. However, many non-smoking women also develop this disease. Other risk factors implicated in the differential development of lung cancer in women are genetic predisposition, tumour histology and molecular profile. Proportionally more women than men with lung cancer have a mutation in the EGFR gene. This consensus statement reviews the available evidence about the epidemiological, biological, diagnostic, therapeutic, social and psychological aspects of lung cancer in women.

Lung cancer in women: an overview with special focus on Spanish women.

Lung cancer incidence is decreasing worldwide among men but rising among women due to recent changes in smoking patterns in both sexes. In Europe, the smoking epidemic has evolved different rates and times, and policy responses to it, vary substantially between countries. Differences in smoking prevalence are much more evident among European women reflecting the heterogeneity in cancer incidence rates. Other factors rather than smoking and linked to sex may increase women's susceptibility to lung cancer, such as genetic predisposition, exposure to sex hormones and molecular features, all of them linked to epidemiologic and clinical characteristics of lung cancer in women. However, biological bases of sex-specific differences are controversial and need further evaluation. This review focuses on the epidemiology and outcome concerning non-small cell lung cancer in women, with emphasis given to the Spanish population.

Cisplatin plus oral vinorelbine as first-line treatment for advanced non-small-cell lung cancer: a prospective study confirming that the day-8 hemogram is unnecessary.

INTRODUCTION: Cisplatin plus oral vinorelbine, one of the standard treatments for metastatic non-small-cell lung cancer (NSCLC), is associated with a high rate of neutropenia, and a hemogram is performed on day 8. We analyzed the oncologists' opinions and the result of the hemogram on day 8 to address the question of whether this hemogram could be avoided. MATERIALS AND METHODS: Fifty-eight chemotherapy-naive, advanced NSCLC patients were included. Each received intravenous doses of 75 mg/m(2) cisplatin on day 1 plus oral vinorelbine [60 mg/m(2) in the first cycle (80 mg/m(2) in subsequent cycles) on days 1 and 8], every 3 weeks, for a maximum of six cycles. RESULTS: Out of 257 cycles analyzed, oral vinorelbine was administered on day 8 in 214 (83.2 %) and the dose was canceled in 6 cycles (2.3 %) due to hematological toxicity. On analyzing the patients to whom chemotherapy had been administered on day 8, based on medical opinion without the doctor knowing the hemogram result, we found that the cycle had been administered with a hemogram showing fewer than 1,500 × 10(6) neutrophils in only 3 of the 185 evaluable cycles [event rate of 1.6 %, with confidence interval 95 % = (0.34-4.67 %)]. CONCLUSION: The hemogram on day 8 can be avoided and oral vinorelbine administered in relative safety in patients with good performance status, when confirmed by the clinician's perception, thereby making this regimen more comfortable for the patient. This is the first prospective study to examine this issue.

Phase II trial of the novel taxane BMS-184476 as second-line in non-small-cell lung cancer.

BACKGROUND: The purpose of this study was to evaluate the tolerability and efficacy of BMS-184476, an analog of paclitaxel, in patients with advanced non-small-cell lung cancer (NSCLC) progressing or relapsing following at least one prior chemotherapy regimen. PATIENTS AND METHODS: Fifty-six previously treated advanced NSCLC patients received BMS-184476 at a dose of 60 mg/m(2) administered intravenously over 1 h every 21 days. RESULTS: The median number of cycles delivered per patient was five (range one to 17). Dose reduction was required in only 3.8% of cycles. Grade 4 neutropenia occurred in 19.6% of patients, but no grade 4 thrombocytopenia or anemia was reported. Febrile neutropenia was observed in only two (3.6%) patients and there were no life-threatening events. Grade 3/4 peripheral sensory-motor neuropathy was reported in 9% of patients. Other non-hematological toxicities, such as nausea and vomiting, myalgia and arthralgia, diarrhea, and mucositis, were uncommon. Partial responses were observed in eight (14.3%) patients and stable disease in 33 (58.9%). Median progression-free survival was 3.7 months [95% confidence interval (CI) 2.7-5.4] and median overall survival was 10 months (95% CI 6-13.4). CONCLUSIONS: BMS-184476 was well tolerated at the dose of 60 mg/m(2) and showed evidence of antitumor activity in previously treated NSCLC.

Single nucleotide polymorphisms and outcome in docetaxel-cisplatin-treated advanced non-small-cell lung cancer.

BACKGROUND: Platinum-based doublets are the standard chemotherapy for advanced non-small-cell lung cancer (NSCLC). Excision-repair cross-complementing 1 (ERCC1), xeroderma pigmentosum group D (XPD) and ribonucleotide reductase subunit M1 (RRM1) are essential to the repair of cisplatin DNA adducts. Multidrug resistance 1 (MDR1) has been related to antimicrotubule resistance. We assessed whether single nucleotide polymorphisms (SNPs) in ERCC1, XPD, RRM1 and MDR1, and ERCC1 mRNA expression, predicted survival in docetaxel-cisplatin-treated stage IV NSCLC patients. PATIENTS AND METHODS: Using the TaqMan 5' nuclease assay, we examined ERCC1 118, XPD 751 and 312, RRM1 -37C/A, and MDR1 C3435T SNPs in peripheral blood lymphocytes (PBLs) obtained from 62 docetaxel-cisplatin-treated advanced NSCLC patients. ERCC1 expression was measured in RNA isolated from PBLs using real-time reverse transcriptase PCR. RESULTS: Overall median survival was 10.26 months. Median survival was 9.67 months for 34 patients with ERCC1 118 C/T, 9.74 months for 17 patients with T/T, and not reached for 11 patients with C/C (P=0.04). Similar significant differences in time to progression were observed according to ERCC1 118 genotype (P=0.03). No other significant differences were observed. CONCLUSIONS: Patients homozygous for the ERCC1 118 C allele demonstrated a significantly better survival. ERCC1 SNP assessment could be an important component of tailored chemotherapy trials.

Cisplatin plus gemcitabine versus a cisplatin-based triplet versus nonplatinum sequential doublets in advanced non-small-cell lung cancer: a Spanish Lung Cancer Group phase III randomized trial.

PURPOSE: To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV-VI). RESULTS: Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV-VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV-VI, 27%; CG v GV-VI, P =.003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV-VI, 27%; P <.05); neutropenic fever (CG, 4%; CGV, 19%; GV-VI, 5%; P <.0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV-VI, 3%; P =.0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV-VI, 6%; P <.0001). CONCLUSION: On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.

Three-week schedule of irinotecan and cisplatin in advanced non-small cell lung cancer: a multicentre phase II study.

A phase II multicentre study of a 3-week schedule of irinotecan (CPT-11) and cisplatin providing the highest recommended dose intensity of both agents in combination, was conducted in patients with advanced non-small cell lung cancer (NSCLC). Seventy-four stage IIIB (not suitable for radiotherapy) or stage IV NSCLC patients were enrolled to receive CPT-11 200 mg/m(2) i.v. and cisplatin 80 mg/m(2) i.v. on day 1 every 3 weeks. Relative dose-intensities for CPT-11 and cisplatin were 92 and 95%, respectively. No complete responses were observed. Twenty-five patients out of 73 obtained a partial response (34.2%). Partial responses were confirmed in 18 patients (24.7%: 95% CI, 15.3-36.1%). Median survival overall was 8.2 months, 9.7 months for patients with baseline performance status (PS) 0 and 1, and 4 months for patients with PS 2. The 1-year survival rate was 31%. Major clinical toxicities were grade 3 and 4 delayed diarrhoea (29% of patients) and febrile neutropenia (14% of patients). In conclusion, the present once-every-3-week schedule of CPT-11 and cisplatin is feasible and active in PS 0-1 advanced NSCLC patients, but results do not seem superior to those reported with other schedules.

[Evaluation of the UpsherScope laryngoscope in routine intubation with no expected difficulties]. / Evaluación del laringoscopio UpsherScope en intubación rutinaria sin dificultad prevista.

OBJECTIVES: To evaluate the new rigid, fiberoptic laryngoscope (UpsherScope) in cases with no expectation of intubation difficulty. MATERIAL AND METHODS: We studied 130 ASA I-II patients for whom no difficulty with tracheal intubation was predicted. Intubation attempts were undertaken by three staff anesthesiologists, with up to three tries permitted per patient. Causes of difficulty were recorded. A regression study of the number of tries per patient over the course of the study was used to identify a possible learning effect. Causes related to inexperience were identified by comparing their frequency of appearance between the first and second halves of the study using a chi-squared test. RESULTS: Ninety-nine patients (76%) were intubated, 70 of them (54%) on the first try. A total of 223 attempts at laryngoscopy (1.71 +/- 0.85) per patient) were made. The best relation in the regression analysis was linear, with a significant slope (-0.0193, p < 0.05) and R2 = 0.103 demonstrating a learning effect. The reasons for difficulty were hitting the endotracheal tube (ETT) against the right arytenoids (18), esophageal progression of the ETT (12), blood or secretions (8), vision obstructed by the epiglottis (7), clouding (7), lateral sliding of the stylet (6), hitting the ETT against the epiglottis (4). Only ETT impingement of the right arytenoids was related to inexperience (p < 0.001). We discuss the relation of these factors to the design of the laryngoscope. CONCLUSIONS: Our experience suggests that the UpsheScope does not offer advantages in routine intubations. The low success rate and the need for repeated attempts at intubation may be related to suboptimal design of the laryngoscope.

Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavily pretreated advanced solid tumors.

Gemcitabine (2',2'-difluorodeoxycytidine) is a nucleoside analog with antitumor activity against a variety of malignancies. The critical enzyme cytidine kinase is saturated at plasma concentrations achieved after a 30-min infusion at conventional doses. Prolonged infusion time may yield higher intracellular dFdCTP concentrations. A phase I study was designed to determine the maximum tolerated dose (MTD) of gemcitabine, given by infusion for 3 h, in heavily pretreated patients. Twenty-seven patients (13 head and neck cancer, seven sarcoma, three esophageal cancer, three non-small-cell lung cancer and one ovarian cancer) were enrolled. Twenty patients were defined as refractory at first- or second-line chemotherapy. Four different entry dose levels (300, 400, 450 and 500 mg/m(2)) were evaluated for gemcitabine administered on days 1, 8 and 15 of a 28-day cycle. The MTD was defined as 450 mg/m(2), with granulocytopenia, thrombocytopenia and asthenia being dose limiting. The maximum grade III/IV patient toxicities for hemoglobin, leukocytes, neutrophils and platelets for all doses were 7, 19, 19 and 11%, respectively. Non-hematological toxicities included asthenia, nausea/vomiting and diarrhea. Thus, gemcitabine administered at a fixed 3-h infusion was well tolerated up to 450 mg/m(2) in heavily pretreated patients. Myelosupression and asthenia were dose-limiting toxicities.

[Impact of meta-analysis in clinical practice: the example of psychiatry]. / Impacto del metaanálisis en la práctica clínica: el ejemplo de la psiquiatría.

BACKGROUND: To analyze the features of the studies on meta-analysis in psychiatry and assess the effect of these papers on the psychiatric reference textbooks. METHODS: Two researchers reviewed electronic databases Medline and Embase during the period 1977-98, using the key words: clinical trial, randomized observational trial, metaanalysis, systematic review. To confirm the validity of the searching strategy inter and intra-raters reliability was studied with satisfactory kappa figures. RESULTS: Psychiatry is the medical specialty in which more studies on meta-analysis have been carried out (N= 179, 11,79% out of the total), followed by cardiology and oncology. The increase in this kind of research during 1977-98 has been very high in all medical fields and, specifically, in psychiatry. There is no correlation between impact factor of a scientifical journal and number of meta-analysis published in it. Only 0.002% of the references of one of the most important textbook in psychiatry (Kaplan) are related to meta-analysis. There is no studies on meta-analysis developed by Spanish researchers. CONCLUSIONS: Studies on meta-analysis are not referred by psychiatric reference textbooks. As a consequence, their impact on clinical practice is scarce.

Phase II trial of paclitaxel plus gemcitabine in patients with locally advanced or metastatic non-small-cell lung cancer.

PURPOSE: Given the cisplatin-related myelotoxicity and nonhematologic toxicities, we were prompted to undertake a study of the noncisplatin combination of paclitaxel plus gemcitabine to evaluate the efficacy, tolerance, and survival of this combination in patients with locally advanced and metastatic non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received gemcitabine 2,000 mg/m(2) and paclitaxel 150 mg/m(2) on days 1 and 15 of a 28-day cycle, for a maximum of eight cycles. RESULTS: Between December 1997 and June 1998, 89 untreated NSCLC patients were enrolled; 30 (34%) had stage IIIB disease (23 with malignant pleural effusion and seven without), and 59 (66%) had stage IV disease. Eighty-six percent of patients had a performance status of 0 or 1. The median number of cycles administered was four (range, one to eight cycles). The mean dose-intensity for both paclitaxel and gemcitabine was nearly 100%. Hematologic and nonhematologic toxicities were mild. Thirty-eight patients received second-line chemotherapy after completion of the study. The overall intent-to-treat response rate was 32.2%, with a higher response rate for stage IIIB patients (43.3%) than for stage IV patients (26.3%). Overall median survival was 9.9 months, and 1-year survival was 38.8% (14.2 months for stage IIIB and 7.7 months for stage IV; P =.007). Median survival was 10.2 months for patients with a performance status of 0 or 1 and 4.8 months for patients with a performance status of 2 (P =.007). CONCLUSION: A biweekly paclitaxel/gemcitabine regimen was well tolerated, with an acceptable response rate and a reasonable median survival time, especially in patients with good performance status. It merits further exploration in future studies.

Brain metastases from colorectal carcinoma.

AIMS AND BACKGROUND: Brain metastases are an unusual finding in patients with colorectal carcinoma. We wished to determine the clinical presentation, the time interval between the diagnosis of colorectal carcinoma and the appearance of brain metastases, and the overall survival. PATIENT CHARACTERISTICS: The median age of our patients was 61 years. Brain metastases developed subsequently to the diagnosis of colorectal cancer in nine patients. All patients had neurologic symptoms. All patients had progressing systemic disease at the moment of intracranial presentation. Four patients received whole brain radiation therapy. The median survival was 11 weeks. DISCUSSION: The development of brain metastasis is a late event in the course of colorectal carcinoma and occurs most often in patients with extensive systemic disease that contraindicates surgical resection. Radiotherapy can improve the survival of this group of patients whereas the role of chemotherapy is still unclear due to the low frequency of such cases.

[Why evidence-based medicine? 20 years of meta-analysis]. / Por qué la medicina basada en la evidencia? 20 años de metaanálisis.

BACKGROUND: Meta-analysis, described within evidence-based medicine, has become a frequent issue in recent medical literature. An exhaustive search of reported meta-analysis from any medical specialty is described. MATERIAL AND METHODS: Search of papers included in Medline or Embase between 1973-1998. A study of intra and inter-reviewers liability about selection and classification have been performed. A descriptive analysis of the reported papers (frequency tables and graphics) is described, including differences of mean of reported meta-analysis papers by medical specialty and year. RESULTS: 1,518 papers were selected and classified. Most frequently found (45.91%) were: methodology (15.7%), psychiatry (11.79%), cardiology (10.01%) and oncology (8.36%). Inter personal agreement was 0.93 in selecting papers and 0.72 in classifying them. Between 1977-1987 overall mean of reported studies of meta-analysis (1.67 + 4.10) was significatively inferior to the 1988-1998 (49.54 + 56.55) (p < 0.001). Global number of meta-analysis was positively correlated (p < 0.05) with the number of studies about fundamentals and methodology during the study period. CONCLUSIONS: The method used to identify meta-analysis reports can be considered to be adequate; however, the agreement in classifying them in medical specialties was inferior. A progressive increase in the number of reported meta-analysis since 1977 can be demonstrated. Specialties with a greater number of meta-analysis published in the literature were: psychiatry, oncology and cardiology. Diffusion of knowledge about fundamentals and methodology of meta-analysis seems to have drawn and increase in performing and reporting this kind of analysis.

Prognostic impact of bulky mediastinal lymph nodes (N2>2.5 cm) in patients with locally advanced non-small-cell lung cancer (LA-NSCLC) treated with platinum-based induction chemotherapy.

A group of 70 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), treated in different phase II-III trials with platinum-based chemotherapy in two institutions, have been evaluated to identify potential baseline prognostic factors predicting their survival. The eligibility criteria were patients with stage IIIA (N2)-IIIB, Eastern Cooperative Oncology Group performance status 0.1 and less than 5% weight loss. All 37 patients with stage IIIA(N2) were treated with platinum-based induction chemotherapy followed by surgery plus radiotherapy if no progression was observed. The other 33 patients with stage IIIB were treated with platinum-based induction chemotherapy followed by conventional fractionation radiotherapy if no progression was observed. The overall response rate to induction chemotherapy was 40%. Median survival of the 70 patients was 13 months, with a 4-year survival of 15%. At univariate analysis, two prognostic factors correlated with survival: partial or complete response to induction chemotherapy (P<0.00001) and bulky mediastinal lymph nodes (N2>2.5 cm) (P=0.03). At multivariate analysis, only the response to induction chemotherapy retained statistical significance (P=0.00001). Randomized well-balanced prospective trials considering initially mediastinal N2 node size are needed to clearly establish the role of chemotherapy, surgery and radiotherapy in LA-NSCLC.