Werner Spengler

Pulmonary Lesion Assessment: Comparison of Whole-Body Hybrid MR/PET and PET/CT Imaging—Pilot Study

PURPOSE To compare the performance of magnetic resonance (MR)/positron emission tomography (PET) imaging in the staging of lung cancer with that of PET/computed tomography (CT) as the reference standard and to compare the quantification accuracy of a new whole-body MR/PET system with corresponding PET/CT data sets. MATERIALS AND METHODS Institutional review board approval and informed consent were obtained. Ten patients in whom bronchial carcinoma was proven or clinically suspected underwent clinically indicated fluorine 18 fluorodeoxyglucose (FDG) PET/CT and, immediately thereafter, whole-body MR/PET imaging with a new hybrid whole-body system (3.0-T MR imager with integrated PET system). Attenuation correction of MR/PET images was segmentation based with fat-water separation. Tumor-to-liver ratios were calculated and compared between PET/CT and MR/PET imaging. Tumor staging on the basis of the PET/CT and MR/PET studies was performed by two readers. Spearman rank correlation was used for comparison of data. RESULTS MR/PET imaging provided diagnostic image quality in all patients, with good tumor delineation. Most lesions (nine of 10) showed pronounced FDG uptake. One lesion was morphologically suspicious for malignancy at CT and MR imaging but showed no FDG uptake. MR/PET imaging had higher mean tumor-to-liver ratios than did PET/CT (4.4 ± 2.0 [standard deviation] for PET/CT vs 8.0 ± 3.9 for MR/PET imaging). Significant correlation regarding the tumor-to-liver ratio was found between both imaging units (ρ = 0.93; P < .001). Identical TNM scores based on MR/PET and PET/CT data were found in seven of 10 patients. Differences in T and/or N staging occurred mainly owing to modality-inherent differences in lesion size measurement. CONCLUSION MR/PET imaging of the lung is feasible and provides diagnostic image quality in the assessment of pulmonary masses. Similar lesion characterization and tumor stage were found in comparing PET/CT and MR/PET images in most patients.

Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE)

PURPOSE Concurrent chemoradiotherapy with or without surgery are options for stage IIIA(N2) non-small-cell lung cancer. Our previous phase II study had shown the efficacy of induction chemotherapy followed by chemoradiotherapy and surgery in patients with IIIA(N2) disease and with selected IIIB disease. Here, we compared surgery with definitive chemoradiotherapy in resectable stage III disease after induction. PATIENTS AND METHODS Patients with pathologically proven IIIA(N2) and selected patients with IIIB disease that had medical/functional operability received induction chemotherapy, which consisted of three cycles of cisplatin 50 mg/m(2) on days 1 and 8 and paclitaxel 175 mg/m(2) on day 1 every 21 days, as well as concurrent chemoradiotherapy to 45 Gy given as 1.5 Gy twice daily, concurrent cisplatin 50 mg/m(2) on days 2 and 9, and concurrent vinorelbine 20 mg/m(2) on days 2 and 9. Those patients whose tumors were reevaluated and deemed resectable in the last week of radiotherapy were randomly assigned to receive a chemoradiotherapy boost that was risk adapted to between 65 and 71 Gy in arm A or to undergo surgery (arm B). The primary end point was overall survival (OS). RESULTS After 246 of 500 planned patients were enrolled, the trial was closed after the second scheduled interim analysis because of slow accrual and the end of funding, which left the study underpowered relative to its primary study end point. Seventy-five patients had stage IIIA disease and 171 had stage IIIB disease according to the Union for International Cancer Control TNM classification, sixth edition. The median age was 59 years (range, 33 to 74 years). After induction, 161 (65.4%) of 246 patients with resectable tumors were randomly assigned; strata were tumor-node group, prophylactic cranial irradiation policy, and region. Patient characteristics were balanced between arms, in which 81 were assigned to surgery and 80 were assigned to a chemoradiotherapy boost. In arm B, 81% underwent R0 resection. With a median follow-up after random assignment of 78 months, 5-year OS and progression-free survival (PFS) did not differ between arms. Results were OS rates of 44% for arm B and 40% for arm A (log-rank P = .34) and PFS rates of 32% for arm B and 35% for arm A (log-rank P = .75). OS at 5 years was 34.1% (95% CI, 27.6% to 40.8%) in all 246 patients, and 216 patients (87.8%) received definitive local treatment. CONCLUSION The 5-year OS and PFS rates in randomly assigned patients with resectable stage III non-small-cell lung cancer were excellent with both treatments. Both are acceptable strategies for this good-prognosis group.

Phase II Trial of a Trimodality Regimen for Stage III Non-Small-Cell Lung Cancer Using Chemotherapy As Induction Treatment With Concurrent Hyperfractionated Chemoradiation With Carboplatin and Paclitaxel Followed by Subsequent Resection: A Single-Center Study

PURPOSE We started a phase II trial of induction chemotherapy and concurrent hyperfractionated chemoradiotherapy followed by either surgery or boost chemoradiotherapy in patients with advanced, stage III disease. The purpose is to achieve better survival in the surgery group with minimum morbidity and mortality. PATIENTS AND METHODS Patients treated from 1998 to 2002 with neoadjuvant chemoradiotherapy and surgical resection for stage III NSCLC were analyzed. The treatment consisted of four cycles of induction chemotherapy with carboplatin/paclitaxel followed by chemoradiotherapy with a reduced dose of carboplatin/paclitaxel and accelerated hyperfractionated radiotherapy with 1.5 Gy twice daily up to 45 Gy. After restaging, operable patients underwent thoracotomy. Inoperable patients received chemoradiotherapy up to 63 Gy. Study end points included resectability, pathologic response, and survival. Results One hundred twenty patients were enrolled; 25% patients had stage IIIA, 73% had stage IIIB, and 2% stage IV. After treatment, 47.5% had downstaging, 29.2% had stable disease, and 23.3% had progressive disease. Thirty patients (25%) were not eligible for operation because of progressive disease, stable disease, and/or functional deterioration with one treatment-related death. The 30-day mortality was 5% in patients who underwent operation. The 5-year survival rate for 120 patients was 21.7%, and it was 43.1% in patients with complete resection. In postoperative patients with stage N0 disease, 5-year survival was 53.3%; if stage N2 or N3 disease was still present, 5-year survival was 33.3%. CONCLUSION Staging and treatment with chemoradiotherapy and complete resection performed in experienced centers achieve acceptable morbidity and mortality.

Assessment of tumor vascularity in lung cancer using volume perfusion CT (VPCT) with histopathologic comparison: a further step toward an individualized tumor characterization.

Objective To measure perfusion in different lung cancer subtypes and compare results with histopathological/immunohistochemical results. Methods Seventy-two consecutive untreated patients with lung cancer (40 adenocarcinomas, 20 squamous cell, and 12 small cell lung cancers) were enrolled. A 40-second volume perfusion computed tomography of the tumor bulk was obtained. Blood flow (BF), blood volume (BV), and transit constant were determined. Tumor volume and tumor necrosis were determined on contrast-enhanced computed tomography. Pathologic specimens were assessed for microvessel density (MVD), hypoxia-induced transcription (hif-1/-2), and proliferation (Ki-67). Results Higher MVD is associated with higher BF and BV. Higher tumor grade leads to lower BF but increased necrosis and tumor volume. Markers of hypoxia were independent from perfusion parameters, extent of necrosis or MVD. Blood flow, BV, and MVD were not significantly different among lung cancer subtypes. Transit constant was significantly reduced in small cell lung cancer versus adenocarcinoma. Conclusions Perfusion values are related to MVD and tumor grade but vary considerably among lung cancer subtypes.

EGFR-tyrosine kinase inhibitor treatment beyond progression in long-term Caucasian responders to erlotinib in advanced non-small cell lung cancer: A case-control study of overall survival

INTRODUCTION Some patients with advanced NSCLC show prolonged disease stabilization on treatment with an EGFR-tyrosine kinase inhibitor (TKI) such as erlotinib. It is not clear how to treat patients who progress after prolonged response to erlotinib. We hypothesized that TKI therapy beyond progression with added chemotherapy, radiotherapy or best supportive care may improve survival. PATIENTS AND METHODS We retrospectively analyzed all NSCLC patients treated with erlotinib at our institutions since 2004who progressed after at least stable disease on erlotinib for at least 6 months. The first 16 patients did not receive further TKI treatment after progression (controls). The following 25 patients were treated with TKI beyond progression (TKI patients). Overall survival (OS) was analyzed for the whole population, a case-control analysis of pairs matched for gender, smoking status, and histology (n=28), and for patients with known EGFR mutation status (n=23). RESULTS Treatment with TKI and chemotherapy was well tolerated. TKI-patients had a significantly longer OS from progression on TKI (case-control: median 14.5 vs. 2.0 months, HR 0.154) and longer OS from diagnosis of lung cancer (case-control: median 54.5 vs. 28.3 months, HR 0.474). An activating EGFR mutation was detected in 13 of the 23 patient tested (57%). Both among patients with and without detection of an activating EGFR mutation, those treated with erlotinib beyond progression had a longer survival. CONCLUSIONS In our case-control analysis in long-term erlotinib responders, treatment with TKI beyond progression in addition to chemotherapy or radiotherapy was feasible and lead to prolonged overall survival.

Pneumonectomy: calculable or non-tolerable risk factor in trimodal therapy for Stage III non-small-cell lung cancer?

OBJECTIVES Lung cancer is the leading cause of death in cancer statistics throughout developed countries. While single surgical approach provides best results in early stages, multimodality approaches have been employed in advanced disease and demonstrated superior results in selected patients. With either full-dose chemotherapy and/or radiotherapy, patients usually have a poor general condition when entering surgical therapy and therefore neoadjuvant therapy can lead to a higher morbidity and mortality. Especially in the case of pneumonectomy as the completing procedure, mortality rate can exceed over 40%. Therefore, chest physicians often shy away from recommending pneumonectomy as final step in trimodal protocols. We analysed our experience with pneumonectomy after neoadjuvant chemoradiotherapy in advanced non-small-cell lung cancer (NSCLC) with a focus on feasibility, outcome and survival. METHODS Retrospective, single-centre study of 146 patients with trimodal neoadjuvant therapy for NSCLC Stage III over 17 years time span. Follow-up was taken from our own outpatient files and with survival check of central registry office in Baden-Württemberg, Germany. RESULTS A total of 118 men and 28 women received 62 lobectomies, 6 bi-lobectomies and 78 pneumonectomies after two different neoadjuvant protocols for Stage III NSCLC. Overall morbidity rate was 53 and 56% after pneumonectomy. Overall hospital mortality rate was 4.8 and 6.4% after pneumonectomy. Overall median survival rate was 31 months with a 5-year survival rate of 38% (Kaplan-Meier). Pneumonectomy, right-sited pneumonectomy and initial T- and N-stages were no risk factors for survival (log-rank test). Significant factors for survival were ypT-stage, ypN-stage, yUICC-stage in univariate testing (log-rank test) and ypUICC-stage in multivariate testing (Coxs regression). CONCLUSIONS Pneumonectomy in neoadjuvant trimodal approach for Stage III NSCLC can be done safe with acceptable mortality rate. Patients should not withhold from operation because of necessitating pneumonectomy. Not the procedure but the selection, response rate and R0-resection are crucial for survival after trimodal therapy in experienced centres.

Does volume perfusion computed tomography enable differentiation of metastatic and non-metastatic mediastinal lymph nodes in lung cancer patients? A feasibility study.

Abstract Objectives: To compare the perfusion characteristics of mediastinal lymph node metastases with those of non-metastatic nodes in patients with newly diagnosed lung cancer using volume perfusion computed tomography (VPCT). Materials and methods: Between January 2010 and October 2011, 101 patients with histologically confirmed, untreated lung cancer received a 40-s VPCT of the tumor bulk; 32/101 patients had evident hilar/mediastinal metastatic disease and 17/101 patients had proven non-metastasized lymph nodes within the VPCT scan range. Validation or exclusion of metastatic node involvement was proven by mediastinoscopy, biopsy, positron emission tomography imaging and/or unequivocal volume dynamics on follow-up computed tomography. A total of 45 metastases and 23 non-metastatic lymph nodes were found within the scan range and subsequently evaluated. Blood flow (BF), blood volume (BV) and Ktrans were determined. Tumor volume was recorded as whole tumor volume. Results: In a comparison between metastatic and non-metastatic lymph nodes, we controlled for age, lymph node volume, lung tumor volume, lung tumor location, and histologic type effects and found no significant differences with respect to BF, BV, Ktrans or heterogeneity in nodal perfusion (P > 0.05, respectively), even after adjusting lymph node perfusion values to the perfusion parameters of the primary tumor (P > 0.05, respectively). Metastatic lymph node volume had a significant increasing effect on perfusion heterogeneity (P < 0.05, respectively) and BV in the primary was a highly significant factor for BV in metastatic disease (P < 0.001). Conclusion: Perfusion characteristics of mediastinal metastatic and non-metastatic lymph nodes in untreated lung cancer show considerable overlap, so that a reliable differentiation via VPCT is not possible.

Long-lasting drop in perfusion of a non-small cell lung cancer induced by monotherapy with the epithelial growth factor receptor inhibitor erlotinib persisting despite tumor progression at remote sites.

A 56-year-old woman was diagnosed at our hospital with G2 adenocarcinoma of the lung (T3, N2, M1) metastatic to the brain. Subsequently, first-line therapy with gemcitabine and cisplatin and whole-brain radiation therapy were initiated. Because of therapy-related hardness of hearing, cisplatin had to be replaced by carboplatin after two therapy cycles. After 4 months, tumor progression was diagnosed by computed tomography (CT), and consequently, third-line therapy with EGFR tyrosine kinase inhibitor erlotinib was initiated. Contrast-enhanced CT performed at this time included additional volume perfusion measurement of the primary tumor (Figure 1, upper panel). Longest tumor diameter recorded was 73.6 mm, whereas automatically determined blood flow (BF), blood volume (BV), and vessel wall permeability (PMB) in the primary tumor yielded 56/18.5/9.5 ml/100 ml tissue/min, respectively. Eight weeks later, during ongoing therapy, repeated CT volume perfusion showed neither significant tumor size change (longest diameter, 70.5 mm) nor signs of tumor spread, but a marked drop in BF (28.4 ml/100 ml tissue/min), BV (10.5 ml/100 ml tissue/min), and PMB (10.5 ml/100 ml tissue/min) assumed to represent antiangiogenic switch induced by erlotinib therapy (Figure 1, middle panel). Another 12 weeks later, there was still no significant change in tumor size (current longest diameter, 70.7 mm) but further reduction of tumor perfusion parameters, BF (27 ml/100 ml tissue/min) and BV (4.5 ml/100 ml tissue/min), whereas PMB (18 ml/100 ml tissue/min) increased (Figure 1, lower panel). However, whole-body CT disclosed, at this time, new osseous metastases in the cervical spine indicating tumor progression (progressive disease), despite ongoing decrease of tumor perfusion parameters. Inhibitors of the EGFR tyrosine kinase have clinical efficacy when given as secondor third-line therapy for advanced NSCLC.1 Knowingly, tumor size measurements, irrespective of their accuracy (uni-bidimensional or computer-assisted volumetry), are not expected to objectively reflect response to treatment, at least early after treatment onset.2,3 However, because of erlotinib impact on tumor angiogenesis, perfusion measurements represent a reliable surrogate parameter capable of confirming early response to EGFR inhibitors.4 Thus, preliminary results of clinical-radiologic trials focusing on noninvasive quantification of blood flow parameters by using dynamic contrast-enhanced perfusion CT proved successful in demonstrating decreasing effects of different angiogenesis inhibitors on tumor blood flow parameters. Herein, we present serial measurements of tumor volume and tumor perfusion in a patient with NSCLC receiving monotherapy with erlotinib, using a new CT volume perfusion technique, which is able to noninvasively assess blood flow parameters (BF, BV, and PMB). This technique uses rapid table movement, robust motion correction, and low-dose energy parameters, thus overcoming classic sampling errors that were inherent in earlier tumor perfusion protocols addressing only limited tumor regions (slices) caused by technical CT limitations. Perfusion analysis of the primary tumor in our patient expectedly demonstrated marked decrease in tumor perfusion during erlotinib therapy persisting even after tumor progression was confirmed at other sites. Interestingly, tumor size did not change significantly at follow-up, which is going along with current data regarding the impact of targeted therapies on tumor volume. Therefore, acquisition of functional data is imperative in these cases. However, they only represent a useful adjunct to whole-body investigational protocols, which are still required for correct evaluation of the course of the disease.