A randomised phase II study of extended pleurectomy/decortication preceded or followed by chemotherapy in patients with early-stage pleural mesothelioma: EORTC 1205.

BACKGROUND: The role of surgery in pleural mesothelioma remains controversial. It may be appropriate in highly selected patients as part of a multimodality treatment including chemotherapy. Recent years have seen a shift from extrapleural pleuropneumonectomy toward extended pleurectomy/decortication. The most optimal sequence of surgery and chemotherapy remains unknown. METHODS: EORTC-1205-LCG was a multicentric, noncomparative phase 2 trial, 1:1 randomising between immediate (arm A) and deferred surgery (arm B), followed or preceded by chemotherapy. Eligible patients (Eastern Cooperative Oncology Group 0-1) had treatment-naïve, borderline resectable T1-3 N0-1 M0 mesothelioma of any histology. Primary outcome was rate of success at 20 weeks, a composite end-point including 1) successfully completing both treatments within 20 weeks; 2) being alive with no signs of progressive disease; and 3) no residual grade 3-4 toxicity. Secondary end-points were toxicity, overall survival, progression-free survival and process indicators of surgical quality. FINDINGS: 69 patients were included in this trial. 56 (81%) patients completed three cycles of chemotherapy and 58 (84%) patients underwent surgery. Of the 64 patients in the primary analysis, 21 out of 30 patients in arm A (70.0%; 80% CI 56.8-81.0%) and 17 out of 34 patients (50.0%; 80% CI 37.8-62.2%) in arm B reached the statistical end-point for rate of success. Median progression-free survival and overall survival were 10.8 (95% CI 8.5-17.2) months and 27.1 (95% CI 22.6-64.3) months in arm A, and 8.0 (95% CI 7.2-21.9) months and 33.8 (95% CI 23.8-44.6) months in arm B. Macroscopic complete resection was obtained in 82.8% of patients. 30- and 90-day mortality were both 1.7%. No new safety signals were found, but treatment-related morbidity was high. INTERPRETATION: EORTC 1205 did not succeed in selecting a preferred sequence of pre- or post-operative chemotherapy. Either procedure is feasible with a low mortality, albeit consistent morbidity. A shared informed decision between surgeon and patient remains essential.

Comparing modeling strategies combining changes in multiple serum tumor biomarkers for early prediction of immunotherapy non-response in non-small cell lung cancer.

BACKGROUND: Patients treated with immune checkpoint inhibitors (ICI) are at risk of adverse events (AEs) even though not all patients will benefit. Serum tumor markers (STMs) are known to reflect tumor activity and might therefore be useful to predict response, guide treatment decisions and thereby prevent AEs. OBJECTIVE: This study aims to compare a range of prediction methods to predict non-response using multiple sequentially measured STMs. METHODS: Nine prediction models were compared to predict treatment non-response at 6-months (n = 412) using bi-weekly CYFRA, CEA, CA-125, NSE, and SCC measurements determined in the first 6-weeks of therapy. All methods were applied to six different biomarker combinations including two to five STMs. Model performance was assessed based on sensitivity, while model training aimed at 95% specificity to ensure a low false-positive rate. RESULTS: In the validation cohort, boosting provided the highest sensitivity at a fixed specificity across most STM combinations (12.9% -59.4%). Boosting applied to CYFRA and CEA achieved the highest sensitivity on the validation data while maintaining a specificity >95%. CONCLUSIONS: Non-response in NSCLC patients treated with ICIs can be predicted with a specificity >95% by combining multiple sequentially measured STMs in a prediction model. Clinical use is subject to further external validation.

Identification of protein biomarkers for prediction of response to platinum-based treatment regimens in patients with non-small cell lung cancer.

The majority of patients with resected stage II-IIIA non-small cell lung cancer (NSCLC) are treated with platinum-based adjuvant chemotherapy (ACT) in a one-size-fits-all approach. However, a significant number of patients do not derive clinical benefit, and no predictive patient selection biomarker is currently available. Using mass spectrometry-based proteomics, we have profiled tumour resection material of 2 independent, multi-centre cohorts of in total 67 patients with NSCLC who underwent ACT. Unsupervised cluster analysis of both cohorts revealed a poor response/survival sub-cluster composed of ~ 25% of the patients, that displayed a strong epithelial-mesenchymal transition signature and stromal phenotype. Beyond this stromal sub-population, we identified and validated platinum response prediction biomarker candidates involved in pathways relevant to the mechanism of action of platinum drugs, such as DNA damage repair, as well as less anticipated processes such as those related to the regulation of actin cytoskeleton. Integration with pre-clinical proteomics data supported a role for several of these candidate proteins in platinum response prediction. Validation of one of the candidates (HMGB1) in a third independent patient cohort using immunohistochemistry highlights the potential of translating these proteomics results to clinical practice.

Prognostic Value of Nivolumab Clearance in Non-Small Cell Lung Cancer Patients for Survival Early in Treatment.

INTRODUCTION: Immune checkpoint inhibitors improved survival of advanced stage non-small cell lung cancer patients, but the overall response rate remains low. A biomarker that identifies non-responders would be helpful to allow treatment decisions. Clearance of immune checkpoint inhibitors is related to treatment response, but its prognostic potential early in treatment remains unknown. Our primary aim was to investigate the prognostic potential of nivolumab clearance for overall survival early in treatment. Our secondary aim was to evaluate the performance of nivolumab clearance as prognostic biomarker. PATIENTS AND METHODS: Individual estimates of nivolumab clearances at first dose, 6 and 12 weeks after treatment initiation were obtained via nonlinear mixed-effects modelling. Prognostic value of nivolumab clearance was estimated using univariate Cox regression at first dose and for the ratios between 6 and 12 weeks to first dose. The performance of nivolumab clearance as biomarker was assessed by calculating sensitivity and specificity. RESULTS: During follow-up of 75 months, 69 patients were included and 865 died. Patients with a nivolumab clearance ≥ 7.3 mL/h at first dose were more likely to die compared to patients with a nivolumab clearance < 7.3 mL/h at first dose (hazard ratio [HR] = 3.55, 955 CI 1.75-7.20). The HRs of dose nivolumab clearance ratios showed similar results with a HR of 3.93 (955 CI 1.66-9.32) for 6 weeks to first-dose clearance ratio at a 0.953 cut-point and a HR of 2.96 (955 CI 1.32-6.64) for 12 weeks to first-dose clearance ratio at a cut-point of 0.814. For nivolumab clearance at all early time points, sensitivity was high (≥ 0.95) but specificity was low (0.11-0.29). CONCLUSION: Nivolumab clearance is indicative of survival early in treatment. Our results encourage to further assess the prognostic potential of immunotherapy clearance.

Prevalence and Predictors of Physician-Patient Discordance in Prognostic Perceptions in Advanced Cancer.

BACKGROUND: Discordance between physicians' and patients' prognostic perceptions in advanced cancer care threatens informed medical decision-making and end-of-life preparation, yet this phenomenon is poorly understood. We sought to: (1) describe the extent and direction of prognostic discordance, patients' prognostic information preferences in cases of prognostic discordance, and physicians' awareness of prognostic discordance; and (2) examine which patient, physician, and caregiver factors predict prognostic discordance. MATERIALS AND METHODS: Oncologists and advanced cancer patients (median survival ≤12 months; n = 515) from 7 Dutch hospitals completed structured surveys in a cross-sectional study. Prognostic discordance was operationalized by comparing physicians' and patients' perceptions of the likelihood of cure, 2-year mortality risk, and 1-year mortality risk. RESULTS: Prognostic discordance occurred in 20% (likelihood of cure), 24%, and 35% (2-year and 1-year mortality risk) of physician-patient dyads, most often involving patients with more optimistic perceptions than their physician. Among patients demonstrating prognostic discordance, the proportion who preferred not knowing prognosis varied from 7% (likelihood of cure) to 37% (1-year mortality risk), and 45% (2-year mortality risk). Agreement between physician-perceived and observed prognostic discordance or concordance was poor (kappa = 0.186). Prognostic discordance was associated with several patient factors (stronger fighting spirit, self-reported absence of prognostic discussions, an information source other than the healthcare provider), and greater physician-reported uncertainty about prognosis. CONCLUSION: Up to one-third of the patients perceive prognosis discordantly from their physician, among whom a substantial proportion prefers not knowing prognosis. Most physicians lack awareness of prognostic discordance, raising the need to explore patients' prognostic information preferences and perceptions, and to tailor prognostic communication.

Modeling strategies to analyse longitudinal biomarker data: An illustration on predicting immunotherapy non-response in non-small cell lung cancer.

Serum tumor markers acquired through a blood draw are known to reflect tumor activity. Their non-invasive nature allows for more frequent testing compared to traditional imaging methods used for response evaluations. Our study aims to compare nine prediction methods to accurately, and with a low false positive rate, predict progressive disease despite treatment (i.e. non-response) using longitudinal tumor biomarker data. Bi-weekly measurements of CYFRA, CA-125, CEA, NSE, and SCC were available from a cohort of 412 advanced stage non-small cell lung cancer (NSCLC) patients treated up to two years with immune checkpoint inhibitors. Serum tumor marker measurements from the first six weeks after treatment initiation were used to predict treatment response at 6 months. Nine models with varying complexity were evaluated in this study, showing how longitudinal biomarker data can be used to predict non-response to immunotherapy in NSCLC patients.

Characteristics of patients with advanced cancer preferring not to know prognosis: a multicenter survey study.

BACKGROUND: For some patients with advanced cancer not knowing prognosis is essential. Yet, in an era of informed decision-making, the potential protective function of unawareness is easily overlooked. We aimed to investigate 1) the proportion of advanced cancer patients preferring not to know prognosis; 2) the reasons underlying patients' prognostic information preference; 3) the characteristics associated with patients' prognostic information preference; and 4) the concordance between physicians' perceived and patients' actual prognostic information preference. METHODS: This is a cross-sectional study with structured surveys (PROSPECT). Medical and thoracic oncologists included patients (n = 524), from seven Dutch hospitals, with metastatic/inoperable cancer and an expected median overall survival of ≤ 12 months. For analysis, descriptive statistics and logistic regression models were used. RESULTS: Twenty-five to 31% of patients preferred not to know a general life expectancy estimate or the 5/2/1-year mortality risk. Compared to patients preferring to know prognosis, patients preferring unawareness more often reported optimism, avoidance and inability to comprehend information as reasons for wanting limited information; and less often reported expectations of others, anxiety, autonomy and a sense of control as reasons for wanting complete information. Females (p < .05), patients receiving a further line of systemic treatment (p < .01) and patients with strong fighting spirit (p < .001) were more likely to prefer not to know prognosis. Concordance between physicians' perceived and patients' actual prognostic information preference was poor (kappa = 0.07). CONCLUSIONS: We encourage physicians to explore patients' prognostic information preferences and the underlying reasons explicitly, enabling individually tailored communication. Future studies may investigate changes in patients' prognostic information preferences over time and examine the impact of prognostic disclosure on patients who prefer unawareness.

Crizotinib-induced fatal fulminant liver failure.

Herein we describe a case of a 62-year-old female in good clinical condition with non-small-cell lung cancer who was treated with crizotinib. After 24 days of crizotinib therapy she presented with acute liver failure. Serum aspartate aminotransferase and alanine aminotransferase levels had increased from normal prior to crizotinib start to 2053 IU/L and 6194 IU/L, respectively. Total bilirubin and prothrombin time (PT-INR) increased up to 443 IU/L and 5.33, respectively, and symptoms of hepatic encephalopathy and hepatorenal syndrome emerged. Despite crizotinib discontinuation and intensive supportive therapy, the patient died 40 days after treatment with crizotinib was initiated due to acute liver failure with massive liver cell necrosis.

Concentrations of Erlotinib in Tumor Tissue and Plasma in Non-Small-Cell Lung Cancer Patients After Neoadjuvant Therapy.

INTRODUCTION: Tumors might not optimally respond to systemic therapy if minimal effective levels are not reached within the tumor. Erlotinib has mainly been studied in the adjuvant or palliative setting and, therefore, little is known about erlotinib tumor penetration. The purpose of this exploratory study was to investigate lung tumor tissue erlotinib concentrations after neoadjuvant therapy for non-small-cell lung cancer. PATIENTS AND METHODS: Patients were treated preoperatively with erlotinib (150 mg once daily for 3 weeks) up to 48 hours before surgery. Plasma samples were collected during treatment. Surgical resection involved radical resection of the lung tumor and tumor biopsies were frozen directly after surgery. Erlotinib and O-desmethyl erlotinib concentrations in lung tumor tissue and predose plasma were determined using high performance liquid chromatography coupled with tandem mass spectrometry. RESULTS: Thirteen evaluable patients were included. The mean plasma and lung tumor tissue erlotinib levels were 1222 ng/mL (SD, 678) and 149 ng/g (SD, 153), respectively. In 2 individual patients, erlotinib and O-desmethyl erlotinib concentrations in lung tumor tissue were detectable up to 13 days and 7 days after erlotinib intake, respectively. Mean erlotinib tissue concentrations extrapolated to a time point directly after intake of erlotinib were approximated at > 200 ng/g tissue, which is greater than the reported half maximal inhibitory concentration (IC50) of wild type epidermal growth factor receptor (EGFR) (183 ng/mL). CONCLUSION: No strong accumulation of erlotinib in lung tumor tissue was observed. Nevertheless, extrapolated intratumoral concentrations during erlotinib therapy were greater than the IC50 of wild type EGFR.

Phase I/II study with ruthenium compound NAMI-A and gemcitabine in patients with non-small cell lung cancer after first line therapy.

BACKGROUND: This phase I/II study determined the maximal tolerable dose, dose limiting toxicities, antitumor activity, the pharmacokinetics and pharmacodynamics of ruthenium compound NAMI-A in combination with gemcitabine in Non-Small Cell Lung Cancer patients after first line treatment. METHODS: Initial dose escalation of NAMI-A was performed in a 28 day cycle: NAMI-A as a 3 h infusion through a port-a-cath at a starting dose of 300 mg/m(2) at day 1, 8 and 15, in combination with gemcitabine 1,000 mg/m(2) at days 2, 9 and 16. Subsequently, dose escalation of NAMI-A in a 21 day schedule was explored. At the maximal tolerable dose level of this schedule an expansion group was enrolled of which 15 patients were evaluable for response. RESULTS: Due to frequent neutropenic dose interruptions in the third week, the 28 day schedule was amended into a 21 day schedule. The maximal tolerable dose was 300 and 450 mg/m(2) of NAMI-A (21 day schedule). Main adverse events consisted of neutropenia, anemia, elevated liver enzymes, transient creatinine elevation, nausea, vomiting, constipation, diarrhea, fatigue, and renal toxicity. CONCLUSION: NAMI-A administered in combination with gemcitabine is only moderately tolerated and less active in NSCLC patients after first line treatment than gemcitabine alone.

Tumor flare after start of RAF inhibition in KRAS mutated NSCLC: a case report.

Here we describe a case of striking tumor flare after start of treatment with sorafenib and metformin as part of a phase II clinical trial. Previous reports have described a paradoxal activation of the MAPK pathway after treatment with a weak RAF inhibitor. This mechanism is based on inhibition of a negative feedback loop to upstream effectors of RAF and subsequently increased stimulation of the RAS-RAF-MEK-ERK (MAPK) pathway. We suggest that sorafenib may contribute to tumor progression through this mechanism and clinicians should be aware of this phenomenon when treating NSCLC patients with sorafenib.

Timing of metabolic response monitoring during erlotinib treatment in non-small cell lung cancer.

UNLABELLED: The purpose of this study was to prospectively evaluate the timing of metabolic response monitoring with (18)F-FDG PET of (neoadjuvant) erlotinib treatment in patients with early-stage non-small cell lung cancer. METHODS: This study was designed as an open-label phase II trial performed in 4 hospitals in The Netherlands. Patients received preoperative erlotinib (150 mg) once daily for 3 wk. Response evaluation was performed after 4-7 d and at 3 wk with (18)F-FDG PET/CT scans. Tumor (18)F-FDG uptake and changes were measured as standardized uptake values (SUVs). The metabolic response was classified on the basis of European Organization for Research and Treatment of Cancer criteria (>25% decrease in the maximum SUV) and was compared with histopathologic regression as observed in the resection specimen. RESULTS: From December 2006 to November 2010, 60 patients with non-small cell lung cancer eligible for surgical resection were enrolled in this study. For 43 patients (18 men and 25 women), baseline (18)F-FDG PET/CT scans as well as both monitoring scans and histopathologic response monitoring were available. A partial metabolic response on (18)F-FDG PET/CT scans was observed for 10 patients (23%) after 1 wk and for 14 patients (33%) after 3 wk. Histopathologic examination revealed regression (necrosis of >50%) in 11 patients (26%). In these patients, the maximum SUV decreased by a mean of 17% within 1 wk and a mean of 31% at 3 wk. Seven patients were identified as responders within 1 wk. CONCLUSION: Response monitoring with (18)F-FDG PET/CT within 1 wk after the start of erlotinib treatment identified approximately 64% of histopathologic responders on the basis of European Organization for Research and Treatment of Cancer criteria.

(18)F-fluorodeoxyglucose positron emission tomography versus computed tomography in predicting histopathological response to epidermal growth factor receptor-tyrosine kinase inhibitor treatment in resectable non-small cell lung cancer.

PURPOSE: To prospectively evaluate diagnostic computed tomography (CT) and (18)F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) for identification of histopathologic response to neoadjuvant erlotinib, an epidermal growth factor receptor-tyrosine kinase inhibitor in patients with resectable non-small cell lung cancer (NSCLC). METHODS: This study was designed as an open-label phase 2 trial, performed in four hospitals in the Netherlands. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. CT and FDG-PET/CT were performed at baseline and after 3 weeks of treatment. CT was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. FDG-PET/CT, tumor FDG uptake, and changes were measured by standardized uptake values (SUV). Radiologic and metabolic responses were compared to the histopathological response. RESULTS: Sixty patients were enrolled onto this study. In 53 patients (22 men, 31 women), the combination of CT, FDG-PET/CT, and histopathological evaluation was available for analysis. Three patients (6 %) had radiologic response. According to European Organisation for Research and Treatment of Cancer (EORTC) criteria, 15 patients (28 %) showed metabolic response. In 11 patients, histopathologic response (≥50 % necrosis) was seen. In predicting histopathologic response, relative FDG change in SUVmax showed more SUVmax decrease in the histopathologic response group (-32 %) versus the group with no pathologic response (-4 %) (p = 0.0132). Relative change in tumor size on diagnostic CT was similar in these groups with means close to 0. CONCLUSIONS: FDG-PET/CT has an advantage over CT as a predictive tool to identify histopathologic response after 3 weeks of EGFR-TKI treatment in NSCLC patients.

A phase II study of sorafenib in patients with platinum-pretreated, advanced (Stage IIIb or IV) non-small cell lung cancer with a KRAS mutation.

PURPOSE: Sorafenib inhibits the Ras/Raf pathway, which is overactive in cancer patients with a KRAS mutation. We hypothesized that patients with non-small cell lung cancer (NSCLC) with KRAS mutation will benefit from treatment with sorafenib. EXPERIMENTAL DESIGN: In this phase II study, patients with KRAS-mutated, stage IIIb or IV NSCLC that progressed after at least one platinum-containing regimen were treated with sorafenib. Treatment consisted of sorafenib 400 mg twice daily until disease progression or unacceptable toxicity. Pretreatment serum from each patient was obtained to predict outcome using a proteomic assay (VeriStrat). Primary endpoint was disease control rate (DCR) at 6 weeks. RESULTS: Fifty-nine patients were entered between May 2010 and February 2011. Fifty-seven patients started sorafenib. Mean age was 58.5 (SD = ±8.1) years, 16 male/41 female, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0/1/2 24/30/3. At 6 weeks, 5 partial response, 25 stable disease, and 27 progressive disease were observed; DCR was 52.6%. Median duration of treatment was 9 weeks. The median progression-free survival (PFS) was 2.3 months and median overall survival (OS) was 5.3 months. Patients with a prediction of good prognosis according to VeriStrat serum proteomics assay showed a significantly superior PFS [HR, 1.4; 95% confidence interval (CI), 1.0-1.9] but not OS (HR, 1.3; 95% CI, 0.9-1.7). Sorafenib-related grade III/IV toxicity was reported in 10 patients (17.5%); all but one patient experienced grade III skin toxicity (14.0%) or grade III gastrointestinal toxicity (8.8%). CONCLUSION: Treatment with sorafenib has relevant clinical activity in patients with NSCLC harboring KRAS mutations. Further randomized study with this agent is warranted as single-agent or combination therapy.

Prolonged sampling of spontaneous sputum improves sensitivity of hypermethylation analysis for lung cancer.

AIMS: The adequacy of lung cancer diagnosis with sputum cytology depends on duration of sputum sampling. The aim of this methodological study was to determine whether the hypermethylation detection rate of RASSF1A, adenomatous polyposis coli (APC) and cytoglobin (CYGB) is influenced by the duration of sputum collection. METHODS: Prospective sputum samples were collected from 53 lung cancer patients and 47 chronic obstructive pulmonary disease patients as controls. Subjects collected spontaneous sputum at home during nine consecutive days in three canisters I, II and III (ie, days 1-3, days 4-6, days 7-9, respectively). Quantitative methylation-specific PCR was performed to assess gene promoter methylation status of RASSF1A, APC and CYGB. RESULTS: Analysis of each canister separately showed hypermethylation of RASSF1A, APC and/or CYGB in samples I, II and III, in 43%, 40% and 47% of cases, respectively. In control samples, these numbers were 4%, 2% and 4%, respectively. Cumulative analysis for days 1-6 and days 1-9 revealed an increase in sensitivity to 53% and 64%, and specificity of 94% and 91%, respectively. CONCLUSION: Sputum collected over multiple successive days results in a gain in sensitivity for the detection of lung cancer, at the expense of a small loss in specificity. Condensed abstract Assessment of hypermethylation sensitivity of biomarkers in sputum collected over a prolonged period for the detection of lung cancer resulted in a promising gain in sensitivity, at the expense of a small loss in specificity.

Local treatment of pulmonary metastases: from open resection to minimally invasive approach? Less morbidity, comparable local control.

BACKGROUND: The level of evidence for efficacy of local treatment of pulmonary metastases is low; therefore, complication rates should be minimized. Minimally invasive techniques may have the potential to reduce morbidity but potentially lead to more local and/or ipsilateral recurrences. The objective of this study was to evaluate the introduction of a new treatment strategy incorporating the increased use of video-assisted thoracic surgery (VATS) and radiofrequency ablation (RFA), weighing complications against recurrence rates. METHODS: We retrospectively reviewed results of all local treatment of pulmonary metastases in the Netherlands Cancer Institute from 2002 to 2007. Each of 158 identified interventions was analyzed separately to retrieve procedure-related data. Overall survival data were analyzed per patient. To evaluate the introduction of a strategy incorporating minimally invasive techniques, the study period was split in two (before and after the introduction of this strategy in July 2004). RESULTS: In Strategy I, 47 interventions (2 VATS, no RFA) were performed in 37 patients; in Strategy II 111 interventions (51 VATS and RFA) in 86 patients. Metastases of a variety of primary tumors were treated. Median hospital stay was shorter (5 vs. 7 days) and procedure-related morbidity was less with Strategy II (p < 0.01). Time-to-recurrence rates were comparable (p = 0.18), as were local and ipsilateral recurrence rates within 3 years (p = 0.72). Estimated overall 3-year survival was 59% for patients treated with Strategy I and 54% with Strategy II. CONCLUSIONS: Increased use of minimally invasive techniques for local treatment of pulmonary metastatic disease is associated with low morbidity, without apparent reduction in (local) disease control.

Germline polymorphisms in patients with advanced nonsmall cell lung cancer receiving first-line platinum-gemcitabine chemotherapy: a prospective clinical study.

BACKGROUND: The authors assessed the impact of germline polymorphisms on clinical outcome in patients with advanced nonsmall cell lung cancer (NSCLC) who received platinum-gemcitabine (PG) chemotherapy. METHODS: In total, 137 patients with stage IIIB/IV NSCLC were included who received first-line PG chemotherapy (74% of patients received cisplatin, and 26% received carboplatin). Twenty-three germline polymorphisms that were identified in peripheral blood samples were analyzed for progression-free survival (PFS), treatment response, overall survival (OS), and toxicity. RESULTS: The median PFS was 5.8 months, the median OS was 10.2 months, and 44 patients (32%) had a partial treatment response. Carriers of the excision repair cross-complementation group 1 (ERCC1) mutant thymine (T) allele had a lower treatment response rate (29% vs 52%; P = .02), shorter PFS (adjusted hazard ratio [HR], 1.60; P = .04), and shorter OS (adjusted HR, 1.54; P = .05) compared with carriers of the wild-type cytosine/cytosine (CC) genotype. The xeroderma pigmentosum group A member 10 (XPD10) mutant adenine (A) allele (adjusted HR, 0.64; P = .04) and the x-ray cross-complementing group 1 (XRCC1) mutant guanine (G) allele (adjusted HR, 0.51; P = .02) also were independent predictors of OS. Carriers of the mutant adenosine triphosphate-dependent DNA helicase Q1 (RECQ1) C allele or the mutant cytidine deaminase (CDA) C allele were more likely to experience severe leukocytopenia (26% vs 10% [P = .03] and 28% vs 11% [P = .02], respectively) compared with wild-type genotype carriers. Patients who carried the homozygous mutant glutathione S-transferase π 1(GSTP1) GG genotype were at considerable risk for severe platinum-associated polyneuropathy (18% vs 3% in wild-type vs heterozygous mutant patients, respectively; P = .01). CONCLUSIONS: To the authors' knowledge, this is the first prospective study to date in patients with advanced NSCLC describing predictive germline polymorphisms not only for the clinical activity of PG chemotherapy (ERCC1, XPD10) but also for its toxicity (GSTP1, RECQ1, CDA). Nonplatinum-containing chemotherapy in carriers of the ERCC1 T allele or the XPD10 G allele should be studied prospectively.

Surgery after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer: why pneumonectomy should be avoided.

BACKGROUND: The role of surgery in the treatment of patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) is a hot topic. Since variable results of surgery versus radiotherapy after induction chemotherapy are being reported, this study aimed to analyze results of surgery after induction chemotherapy and to identify relevant factors influencing outcome in patients with stage IIIA NSCLC. METHODS: Patients with stage IIIA (N2) NSCLC, treated with platinum-based induction chemotherapy between 1994 and 2006, were identified. By a retrospective review of hospital records, response to induction treatment, short-term outcome, recurrence of disease and survival were evaluated. RESULTS: Ninety-nine patients, 66 men and 33 women, were identified. Median follow-up was 54 months (range 13-129). Median age at treatment was 62 (range 36-77). Mediastinal downstaging was seen in 32 patients. Forty-three patients received radical radiotherapy and 39 patients underwent surgery: 19 pneumonectomies, 19 lobectomies and one exploratory thoracotomy. Microscopic complete resection (R0) was reached in 30 patients. Pathological response to induction therapy was CR in 5%, PR in 59% and SD in 36%. Postoperative mortality was 3%. The 1-year mortality was 26% after pneumonectomy and 11% after lobectomy. Five-year survival after surgery was 28%, and was better after lobectomy than after pneumonectomy (43% versus 16%; p=0.03). Other factors as age, weight loss, clinical mediastinal downstaging, radicality, and histology did not substantially contribute to this difference. CONCLUSION: Type of surgical resection was the major factor influencing outcome in patients with stage IIIA (N2) NSCLC after induction chemotherapy. These results suggest that patients with stage IIIA (N2) NSCLC may benefit from surgical resection, as long as a lobectomy can be performed.

Evaluation of (18)F-FDG PET-CT for differentiation of pulmonary pathology in an approach of outpatient fast track assessment.

INTRODUCTION: The aim of our study was to evaluate the clinical performance/ implementation of integrated F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) for differentiation of pulmonary pathology in an approach of outpatient fast track assessment. METHODS: A prospective study was performed in 114 consecutive patients with pulmonary symptoms and/or abnormal chest x-ray were referred for fast track assessment to the Netherlands Cancer Institute from March 2005 to September 2007. The presence of malignancy was evaluated in a multidisciplinary setting, including F-fluorodeoxyglucose-PET, diagnostic CT, and bronchoscopy (including biopsy), with histopathological evaluation as the reference standard. RESULTS: In 105 patients (92%), a final diagnosis was achieved. A malignancy was diagnosed in 84% of the patients; non-small cell lung cancer in 67%, small cell lung cancer in 7%, and metastases or other malignancies in 10%. Nonmalignant lesions were found in 16% of the patients. Sensitivity, specificity, accuracy, positive predictive value and negative predictive value of positive PET/CT for the presence of malignancy were 97, 56, 90, 92, and 77%, respectively. PET/CT showed unexpected M1 disease (not detected on CT) in 10% of the patients. Almost half of the patients with a malignancy were scheduled for curative treatment, of whom 29 patients for surgery and 14 patients for chemoradiotherapy. CONCLUSION: In this outpatient fast track setting, PET/CT provides valuable information for diagnosing lung cancer, with a high positive predictive value, and is useful for clinical decision making.