Houke M. Klomp

Trimodality therapy for malignant pleural mesothelioma: results from an EORTC phase II multicentre trial

The European Organisation for Research and Treatment of Cancer (EORTC; protocol 08031) phase II trial investigated the feasibility of trimodality therapy consisting of induction chemotherapy followed by extrapleural pneumonectomy and post-operative radiotherapy in patients with malignant pleural mesothelioma (with a severity of cT3N1M0 or less). Induction chemotherapy consisted of three courses of cisplatin 75 mg·m−2 and pemetrexed 500 mg·m−2. Nonprogressing patients underwent extrapleural pneumonectomy followed by post-operative radiotherapy (54 Gy, 30 fractions). Our primary end-point was “success of treatment” and our secondary end-points were toxicity, and overall and progression-free survival. 59 patients were registered, one of whom was ineligible. Subjects’ median age was 57 yrs. The subjects’ TNM scores were as follows: cT1, T2 and T3, 36, 16 and six patients, respectively; cN0 and N1, 57 and one patient, respectively. 55 (93%) patients received three cycles of chemotherapy with only mild toxicity. 46 (79%) patients received surgery and 42 (74%) had extrapleural pneumonectomy with a 90-day mortality of 6.5%. Post-operative radiotherapy was completed in 37 (65%) patients. Grade 3–4 toxicity persisted after 90 days in three (5.3%) patients. Median overall survival time was 18.4 months (95% CI 15.6–32.9) and median progression-free survival was 13.9 months (95% CI 10.9–17.2). Only 24 (42%) patients met the definition of success (one-sided 90% CI 0.36–1.00). Although feasible, trimodality therapy in patients with mesothelioma was not completed within the strictly defined timelines of this protocol and adjustments are necessary.

Spinal-cord stimulation in critical limb ischaemia: a randomised trial

Summary Background For patients with critical limb ischaemia, spinal-cord stimulation has been advocated for the treatment of ischaemic pain and the prevention of amputation. We compared the efficacy of the addition of spinal-cord stimulation to best medical treatment in a randomised controlled trial. Methods 120 patients with critical limb ischaemia not suitable for vascular reconstruction were randomly assigned either spinal-cord stimulation in addition to best medical treatment or best medical treatment alone. Primary outcomes were mortality and amputation. The primary endpoint was limb survival at 2 years. Findings The mean (SD) age of the patients was 72·6 years (10·3). Median (IQR) follow-up was 605 days (244–1171). 40 (67%) of 60 patients in the spinal-cordstimulator group and 41 (68%) of 60 patients in the standard group were alive at the end of the study, (p=0·96). There were 25 major amputations in the spinalcord-stimulator group and 29 in the standard group, (p=0·47). The hazard ratio for survival at 2 years without major amputation in the spinal-cord stimulation group compared with the standard group was 0·96 (95% CI 0·61–1·51). Interpretation Spinal-cord-stimulation in addition to best medical care does not prevent amputation in patients with critical limb ischaemia.

Pulmonary squamous cell carcinoma following head and neck squamous cell carcinoma: metastasis or second primary?

Purpose: To distinguish a metastasis from a second primary tumor in patients with a history of head and neck squamous cell carcinoma and subsequent pulmonary squamous cell carcinoma. Experimental Design: For 44 patients with a primary squamous cell carcinoma of the head and neck followed by a squamous cell carcinoma of the lung, clinical data, histology, and analysis of loss of heterozygosity (LOH) were used to differentiate metastases from second primary tumors. Results: Clinical evaluation suggested 38 patients with metastases and 6 with second primaries. We developed a novel interpretation strategy based on biological insight and on our observation that multiple LOH on different chromosome arms are not independent. LOH analysis indicated metastatic disease in 19 cases and second primary squamous cell carcinoma in 24 cases. In one case, LOH analysis was inconclusive. For 25 patients, LOH supported the clinical scoring, and in 18 cases, it did not. These 18 discordant cases were all considered to be second primary tumors by LOH analysis. Conclusions: A considerable number of squamous cell lung lesions (50% in this study), clinically interpreted as metastases, are suggested to be second primaries by LOH analysis. For these patients, a surgical approach with curative intent may be justified.

The Relationship Between Volume or Surgeon Specialty and Outcome in the Surgical Treatment of Lung Cancer A Systematic Review and Meta-Analysis

Background: Whether improvement of quality of surgical cancer care can be achieved by centralizing care in high-volume specialized centers is a subject of ongoing debate. We have conducted a meta-analysis of the literature on the effect of procedural volume or surgeon specialty on outcome of lung resections for cancer. Methods: A systematic search of articles published between January 1, 1990 and January 20, 2011 on the effects of surgeon specialty and hospital or surgeon volume of lung resections on mortality and survival was conducted. After strict inclusion, meta-analysis assuming a random-effects model was performed. Meta-regression was used to identify volume cutoff values. Heterogeneity and the risk of publication bias were evaluated. Results: Nineteen relevant studies were found. Studies were heterogeneous, especially in defining volume categories. The pooled estimated effect size was significant in favor of high-volume hospitals regarding postoperative mortality (odds ratio [OR] 0.71; confidence interval 0.62–0.81), but not for survival (OR 0.93; confidence interval 0.84–1.03). Surgeon volume showed no significant effect on outcome. General surgeons had significantly higher mortality risks than general thoracic (OR 0.78; 0.70–0.88) or cardiothoracic surgeons (OR 0.82; 0.69–0.96). A minimal annual volume of resections for lung cancer could not be identified. Conclusions: Hospital volume and surgeon specialty are important determinants of outcome in lung cancer resections, but evidence-based minimal-volume standards are lacking. Evaluation of individual institutions in a national audit program might help elucidate the influence of individual quality-of-care parameters, including hospital volume, on outcome.

Is 18F-FDG PET/CT Useful for the Early Prediction of Histopathologic Response to Neoadjuvant Erlotinib in Patients with Non–Small Cell Lung Cancer?

Early prediction of treatment response is of value in avoiding the unnecessary toxicity of ineffective treatment. The objective of this study was to prospectively evaluate the role of integrated 18F-FDG PET/CT for the early identification of response to neoadjuvant erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. Methods: From October 2006 to March 2009, 23 patients with non–small cell lung cancer eligible for surgical resection were evaluated for this study. Patients received preoperative erlotinib (150 mg) once daily for 3 wk. 18F-FDG PET/CT was performed before and at 1 wk after the administration of erlotinib. Changes in tumor 18F-FDG uptake during treatment were measured by standardized uptake values and assessed prospectively according to the criteria of the European Organization for Research and Treatment of Cancer. Patients with a decrease in standardized uptake values of 25% or more after 1 wk were classified as “metabolic responders.” The metabolic response was compared with the pathologic response, obtained by histopathologic examination of the resected specimen. Results: Following the 18F-FDG PET/CT criteria of the European Organization for Research and Treatment of Cancer, 6 patients (26%) had a partial response within 1 wk, 16 patients (70%) had stable disease, and 1 patient (4%) had progressive disease. The median percentage of necrosis in the early metabolic responder group was 70% (interquartile range, 30%–91%), and the median percentage of necrosis in the nonresponder group was 40% (interquartile range, 20%–50%; P = 0.09). The κ-agreement between the metabolic and pathologic responders was 0.55 (P = 0.008). Conclusion: The results of this study suggest that early during the course of epidermal growth factor receptor tyrosine kinase inhibitor therapy, 18F-FDG PET/CT can predict response to erlotinib treatment in patients with non–small cell lung cancer.

Technical Data and Complications of Spinal Cord Stimulation: Data from a Randomized Trial on Critical Limb Ischemia

This study was done to evaluate the effect of spinal cord stimulation (SCS) on critical limb ischemia and to report technical problems and complications. One hundred and twenty patients with critical limb ischemia were eligible for randomization between medical treatment and medical treatment plus SCS. Sixty received a spinal cord stimulator (Itrel II; Medtronic, Minneapolis, Minn., USA). Primary outcome measures were limb salvage and pain relief. The mean pain reduction in both treatment groups was 50% (from 5 to 2.5 on the visual analog scale). The 2-year limb survival was 52% (SCS) versus 46% (standard treatment; p = 0.47). The number of patients undergoing major amputations in the SCS group with intermediate TcpO2 values was half of that in the standard group (14 vs. 28; 24 vs. 48%; p = 0.17). Implantation was successful in 51 patients. Technical problems such as loss of stimulation due to lead displacement occurred in 13 patients (22%), local infection at the site of implantation occurred in 3 patients (5%), resulting in a total complication rate of 27%. Prematue depletion of the battery occurred within 2 years in 3 patients (5%). There were no lead fractures, epidural infections, hematoma or cerebrospinal fluid leakage. Training of physicians and better reliability of the hardware should reduce the frequency of technical problems. Lead displacement remains the major technical problem. The search for prognostic factors of limb salvage is important. One microcirculatory measurement (TcpO2) seems to have a prognostic value, which remains to be described more precisely.

Tumor Response and Toxicity of Neoadjuvant Erlotinib in Patients With Early-Stage Non–Small-Cell Lung Cancer

PURPOSE The development of targeted therapy has introduced new options to improve treatment outcome in selected patients. The objective of this prospective study was to investigate the safety of preoperative erlotinib treatment and the (in vivo) response in patients with early-stage resectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This study was designed as an open-label phase II trial, performed in four hospitals in the Netherlands, according to a Simons minimax two-stage procedure. Initially, operable patients with early-stage NSCLC (n = 15) were entered from an enriched population (never-smoker, female sex, nonsquamous histology, or Asian ethnicity); thereafter, unselected patients were included to a total of N = 60. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. Response to treatment was evaluated using [18F] fluorodeoxyglucose positron emission tomography (PET) and computed tomography (CT) scans during treatment and histologic examination of the resection specimen. Primary end points were toxicity and pathologic response. RESULTS Sixty patients were included. Seven patients stopped treatment prematurely (12%). Skin toxicity was present in 37 patients (62%), and diarrhea was present in 21 patients (35%). PET evaluation revealed metabolic response (> 25% standardized uptake value decrease) in 16 patients (27%); CT evaluation using Response Evaluation Criteria in Solid Tumors (RECIST) showed response in three patients (5%). At surgery, no unexpected complications occurred. Pathologic examination showed more than 50% necrosis in 14 patients (23%), of whom three (5%) had more than 95% tumor necrosis. The response rate in the enriched population was 34% (10 of 29 patients). CONCLUSION According to predefined criteria, neoadjuvant erlotinib has low toxicity and sufficient activity to deserve further testing in future studies in an enriched population.

Microscopic disease extension in three dimensions for non-small-cell lung cancer: development of a prediction model using pathology-validated positron emission tomography and computed tomography features.

PURPOSE One major uncertainty in radiotherapy planning of non-small-cell lung cancer concerns the definition of the clinical target volume (CTV), meant to cover potential microscopic disease extension (MDE) around the macroscopically visible tumor. The primary aim of this study was to establish pretreatment risk factors for the presence of MDE. The secondary aim was to establish the impact of these factors on the accuracy of positron emission tomography (PET) and computed tomography (CT) to assess the total tumor-bearing region at pathologic examination (CTV(path)). METHODS AND MATERIALS 34 patients with non-small-cell lung cancer who underwent CT and PET before lobectomy were included. Specimens were examined microscopically for MDE. The gross tumor volume (GTV) on CT and PET (GTV(CT) and GTV(PET), respectively) was compared with the GTV and the CTV at pathologic examination, tissue deformations being taken into account. Using multivariate logistic regression, image-based risk factors for the presence of MDE were identified, and a prediction model was developed based on these factors. RESULTS MDE was found in 17 of 34 patients (50%). The MDE did not exceed 26 mm in 90% of patients. In multivariate analysis, two parameters (mean CT tumor density and GTV(CT)) were significantly associated with MDE. The area under the curve of the two-parameter prediction model was 0.86. Thirteen tumors (38%, 95% CI: 24-55%) were identified as low risk for MDE, being potential candidates for reduced-intensity therapy around the GTV. In the low-risk group, the effective diameter of the GTV(CT/PET) accurately represented the CTV(path). In the high-risk group, GTV(CT/PET) underestimated the CTV(path) with, on average, 19.2 and 26.7 mm, respectively. CONCLUSIONS CT features have potential to predict the presence of MDE. Tumors identified as low risk of MDE show lower rates of disease around the GTV than do high-risk tumors. Both CT and PET accurately visualize the CTV(path) in low-risk tumors but underestimate it in high-risk tumors.

Pain and quality of life in patients with critical limb ischaemia: results of a randomized controlled multicentre study on the effect of spinal cord stimulation

We carried out an assessment of pain and quality of life of patients with critical limb ischaemia during the follow‐up of a multicentre randomized trial in more detail than previously reported.

Improved identification of peripheral lung tumors by using diffuse reflectance and fluorescence spectroscopy

INTRODUCTION A significant number of transthoracic diagnostic biopsy procedures for lung lesions show indeterminate results. Such failures are potentially due to inadequate recognition of vital tumor tissue. The objective of this study was to evaluate whether optical spectroscopy at the tip of a biopsy needle device can improve the accuracy of transthoracic lung biopsies. METHODS Ex vivo optical measurements were performed on lung tissue from 13 patients who underwent either lobectomy or segmental resection for primary non-small cell lung cancer or pulmonary metastases from various origins. From Diffuse Reflectance Spectroscopy (DRS) and Fluorescence Spectroscopy (FS) measurements, different parameters were derived such as tissue composition as well as physiological and metabolic characteristics. Subsequently, a classification and regression trees (CART) algorithm was used to classify the type of tissue based on the derived parameters. Histology analysis was used as gold standard to report sensitivity and specificity of the tissue classification based on the present optical method. RESULTS Collective analysis of all DRS measurements showed an overall discrimination between lung parenchyma and tumor tissue with a sensitivity and specificity of 98 and 86%, respectively. When the data were analyzed per individual patient, eliminating inter-patient variation, 100% sensitivity and specificity was achieved. Furthermore, based on FS parameters, necrotic and non-necrotic tumor tissue could be distinguished with 91% sensitivity and specificity. CONCLUSION This study demonstrates that DRS provides accurate diagnosis of malignant lung lesions, whereas FS enables identification of necrotic tissue. When both optical techniques are combined within a biopsy device, the diagnostic performance and the quality of transthoracic biopsies could significantly be enhanced.