Anne-Marie C. Dingemans

Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials

BACKGROUND The standard of care for operable, stage I, non-small-cell lung cancer (NSCLC) is lobectomy with mediastinal lymph node dissection or sampling. Stereotactic ablative radiotherapy (SABR) for inoperable stage I NSCLC has shown promising results, but two independent, randomised, phase 3 trials of SABR in patients with operable stage I NSCLC (STARS and ROSEL) closed early due to slow accrual. We aimed to assess overall survival for SABR versus surgery by pooling data from these trials. METHODS Eligible patients in the STARS and ROSEL studies were those with clinical T1-2a (<4 cm), N0M0, operable NSCLC. Patients were randomly assigned in a 1:1 ratio to SABR or lobectomy with mediastinal lymph node dissection or sampling. We did a pooled analysis in the intention-to-treat population using overall survival as the primary endpoint. Both trials are registered with ClinicalTrials.gov (STARS: NCT00840749; ROSEL: NCT00687986). FINDINGS 58 patients were enrolled and randomly assigned (31 to SABR and 27 to surgery). Median follow-up was 40·2 months (IQR 23·0-47·3) for the SABR group and 35·4 months (18·9-40·7) for the surgery group. Six patients in the surgery group died compared with one patient in the SABR group. Estimated overall survival at 3 years was 95% (95% CI 85-100) in the SABR group compared with 79% (64-97) in the surgery group (hazard ratio [HR] 0·14 [95% CI 0·017-1·190], log-rank p=0·037). Recurrence-free survival at 3 years was 86% (95% CI 74-100) in the SABR group and 80% (65-97) in the surgery group (HR 0·69 [95% CI 0·21-2·29], log-rank p=0·54). In the surgery group, one patient had regional nodal recurrence and two had distant metastases; in the SABR group, one patient had local recurrence, four had regional nodal recurrence, and one had distant metastases. Three (10%) patients in the SABR group had grade 3 treatment-related adverse events (three [10%] chest wall pain, two [6%] dyspnoea or cough, and one [3%] fatigue and rib fracture). No patients given SABR had grade 4 events or treatment-related death. In the surgery group, one (4%) patient died of surgical complications and 12 (44%) patients had grade 3-4 treatment-related adverse events. Grade 3 events occurring in more than one patient in the surgery group were dyspnoea (four [15%] patients), chest pain (four [15%] patients), and lung infections (two [7%]). INTERPRETATION SABR could be an option for treating operable stage I NSCLC. Because of the small patient sample size and short follow-up, additional randomised studies comparing SABR with surgery in operable patients are warranted. FUNDING Accuray Inc, Netherlands Organisation for Health Research and Development, NCI Cancer Center Support, NCI Clinical and Translational Science Award.

Crizotinib Therapy for Advanced Lung Adenocarcinoma and a ROS1 Rearrangement: Results From the EUROS1 Cohort

PURPOSE Approximately 1% of lung adenocarcinomas are driven by oncogenic ROS1 rearrangement. Crizotinib is a potent inhibitor of both ROS1 and ALK kinase domains. PATIENTS AND METHODS In the absence of a prospective clinical trial in Europe, we conducted a retrospective study in centers that tested for ROS1 rearrangement. Eligible patients had stage IV lung adenocarcinoma, had ROS1 rearrangement according to fluorescent in situ hybridization, and had received crizotinib therapy through an individual off-label use. Best response was assessed locally using RECIST (version 1.1). All other data were analyzed centrally. RESULTS We identified 32 eligible patients. One patient was excluded because next-generation sequencing was negative for ROS1 fusion. Median age was 50.5 years, 64.5% of patients were women, and 67.7% were never-smokers. Thirty patients were evaluable for progression-free survival (PFS), and 29 patients were evaluable for best response. We observed four patients with disease progression, two patients with stable disease, and objective response in 24 patients, including five complete responses (overall response rate, 80%; disease control rate, 86.7%). Median PFS was 9.1 months, and the PFS rate at 12 months was 44%. No unexpected adverse effects were observed. Twenty-six patients received pemetrexed (either alone or in combination with platinum and either before or after crizotinib) and had a response rate of 57.7% and a median PFS of 7.2 months. CONCLUSION Crizotinib was highly active at treating lung cancer in patients with a ROS1 rearrangement, suggesting that patients with lung adenocarcinomas should be tested for ROS1. Prospective clinical trials with crizotinib and other ROS1 inhibitors are ongoing or planned.

Identification of residual metabolic-active areas within individual NSCLC tumours using a pre-radiotherapy 18Fluorodeoxyglucose-PET-CT scan

BACKGROUND AND PURPOSE Non-small cell lung cancer (NSCLC) tumours are mostly heterogeneous. We hypothesized that areas within the tumour with a high pre-radiation (18)F-deoxyglucose (FDG) uptake, could identify residual metabolic-active areas, ultimately enabling selective-boosting of tumour sub-volumes. MATERIAL AND METHODS Fifty-five patients with inoperable stage I-III NSCLC treated with chemo-radiation or with radiotherapy alone were included. For each patient one pre-radiotherapy and one post-radiotherapy FDG-PET-CT scans were available. Twenty-two patients showing persistent FDG uptake in the primary tumour after radiotherapy were analyzed. Overlap fractions (OFs) were calculated between standardized uptake value (SUV) threshold-based auto-delineations on the pre- and post-radiotherapy scan. RESULTS Patients with residual metabolic-active areas within the tumour had a significantly worse survival compared to individuals with a complete metabolic response (p=0.002). The residual metabolic-active areas within the tumour largely corresponded (OF>70%) with the 50%SUV high FDG uptake area of the pre-radiotherapy scan. The hotspot within the residual area (90%SUV) was completely within the GTV (OF=100%), and had a high overlap with the pre-radiotherapy 50%SUV threshold (OF>84%). CONCLUSIONS The location of residual metabolic-active areas within the primary tumour after therapy corresponded with the original high FDG uptake areas pre-radiotherapy. Therefore, a single pre-treatment FDG-PET-CT scan allows for the identification of residual metabolic-active areas.

Randomized Phase II and Pharmacogenetic Study of Pemetrexed Compared With Pemetrexed Plus Carboplatin in Pretreated Patients With Advanced Non–Small-Cell Lung Cancer

PURPOSE We performed a randomized phase II trial comparing pemetrexed with pemetrexed plus carboplatin (PC) in patients experiencing relapse after platinum-based chemotherapy. PATIENTS AND METHODS Main eligibility criteria were histologic or cytologic proof of advanced non-small-cell lung cancer (NSCLC), relapse more than 3 months after platinum-based chemotherapy, normal organ function, and Eastern Cooperative Oncology Group performance status 0 to 2. Patients were randomly assigned to pemetrexed 500 mg/m(2) (arm A) or carboplatin area under the curve 5 and pemetrexed 500 mg/m(2) (arm B), both administered intravenously every 3 weeks. Response assessment was performed every 6 weeks; toxicity assessment was performed every 3 weeks. Primary end point was time to progression (TTP); secondary end points were objective response rate (ORR), overall survival (OS), and toxicity. The study was designed to detect a 33% decrease in the hazard of disease progression in the combination arm (alpha = 0.05, two-sided log-rank test). Polymorphisms of thymidylate synthase, the reduced folate carrier, gamma-glutamyl hydrolase, and methylenetetrahydrofolate reductase (MTHF) were investigated in peripheral WBCs of consenting patients. RESULTS Two hundred forty patients were enrolled. Median TTP was 2.8 months for arm A versus 4.2 months for arm B (hazard ratio, 0.67; 95% CI, 0.51 to 0.89; P = .005). Median OS was 7.6 months and 8.0 months and ORR was 4% and 9% for arms A and B, respectively. Subgroup analyses found adenocarcinoma to be associated with favorable outcome. Toxicities in both arms was negligible, with one potential toxic death in arm A. Patients with MTHFR C677T homozygous mutation had increased progression-free survival compared with patients with wild-type or heterozygous mutations (P = .03). CONCLUSION PC as second-line treatment for relapsed NSCLC resulted in a significant 33% reduction of the hazard of disease progression as compared with pemetrexed alone.

Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non-Small-Cell Lung Cancer

PURPOSE We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach. PATIENTS AND METHODS In total, 166 patients with stage III or medically inoperable stage I to II non-small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide >or= 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0. RESULTS The median prescribed TTD was 64.8 Gy (standard deviation, +/- 11.4 Gy) delivered in 25 +/- 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable. CONCLUSION Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

Radical Treatment of Non-Small-Cell Lung Cancer Patients with Synchronous Oligometastases Long-Term Results of a Prospective Phase II Trial (Nct01282450)

Background: Stage IV non–small-cell lung cancer (NSCLC) patients with oligometastases (< 5 metastatic lesions) may experience long-term survival when all macroscopic tumor sites are treated radically, but no prospective data on NSCLCs with synchronous oligometastases are available. Methods: A prospective single-arm phase II trial was conducted. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov, number NCT01282450. Results: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44–81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval 7.6–19.4); 1-, 2-, and 3-year OS was 56.4%, 23.3%, and 17.5%, respectively. Median progression-free survival (PFS) was 12.1 months (95% confidence interval 9.6–14.3); 1-year PFS was 51.3%, and both 2- and 3-year PFS was 13.6%. Only two patients (5%) had a local recurrence. No patient or tumor parameter, including volume and 18F-deoxyglucose uptake was significantly correlated with OS or PFS. The treatment was well tolerated. Conclusion: In this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favorable subgroup before therapy is needed.

Selective Nodal Irradiation on Basis of 18FDG-PET Scans in Limited-Disease Small-Cell Lung Cancer: A Prospective Study

PURPOSE To evaluate the results of selective nodal irradiation on basis of (18)F-deoxyglucose positron emission tomography (PET) scans in patients with limited-disease small-cell lung cancer (LD-SCLC) on isolated nodal failure. METHODS AND MATERIALS A prospective study was performed of 60 patients with LD-SCLC. Radiotherapy was given to a dose of 45 Gy in twice-daily fractions of 1.5 Gy, concurrent with carboplatin and etoposide chemotherapy. Only the primary tumor and the mediastinal lymph nodes involved on the pretreatment PET scan were irradiated. A chest computed tomography (CT) scan was performed 3 months after radiotherapy completion and every 6 months thereafter. RESULTS A difference was seen in the involved nodal stations between the pretreatment (18)F-deoxyglucose PET scans and computed tomography scans in 30% of patients (95% confidence interval, 20-43%). Of the 60 patients, 39 (65%; 95% confidence interval [CI], 52-76%) developed a recurrence; 2 patients (3%, 95% CI, 1-11%) experienced isolated regional failure. The median actuarial overall survival was 19 months (95% CI, 17-21). The median actuarial progression-free survival was 14 months (95% CI, 12-16). 12% (95% CI, 6-22%) of patients experienced acute Grade 3 (Common Terminology Criteria for Adverse Events, version 3.0) esophagitis. CONCLUSION PET-based selective nodal irradiation for LD-SCLC resulted in a low rate of isolated nodal failures (3%), with a low percentage of acute esophagitis. These findings are in contrast to those from our prospective study of CT-based selective nodal irradiation, which resulted in an unexpectedly high percentage of isolated nodal failures (11%). Because of the low rate of isolated nodal failures and toxicity, we believe that our data support the use of PET-based SNI for LD-SCLC.

Response Assessment Using 18F-FDG PET Early in the Course of Radiotherapy Correlates with Survival in Advanced-Stage Non–Small Cell Lung Cancer

This study investigated the possibility of early response assessment based on 18F-FDG uptake during radiotherapy with respect to overall survival in patients with non–small cell lung cancer. Methods: 18F-FDG PET/CT was performed before radiotherapy and was repeated in the second week of radiotherapy for 34 consecutive lung cancer patients. The CT volume and standardized uptake value (SUV) parameters of the primary tumor were quantified at both time points. Changes in volume and SUV parameters correlated with 2-y overall survival. Results: The average change in mean SUV in the primary tumor of patients with a 2-y survival was a decrease by 20% ± 21%—significantly different (P < 0.007) from nonsurvivors, who had an increase by 2% ± 22%. A sensitivity and specificity of 63% and 93%, respectively, to separate the 2 groups was reached for a decrease in mean SUV of 15%. Survival curves were significantly different using this cutoff (P = 0.001). The hazard ratio for a 1% decrease in mean SUV was 1.032 (95% confidence interval, 1.010–1.055). Changes in tumor volume defined on CT did not correlate with overall survival. Conclusion: The use of repeated 18F-FDG PET to assess treatment response early during radiotherapy is possible in patients undergoing radiotherapy or sequential or concurrent chemoradiotherapy. A decrease in 18F-FDG uptake by the primary tumor correlates with higher long-term overall survival.

Integrin expression profiling identifies integrin alpha5 and beta1 as prognostic factors in early stage non-small cell lung cancer

BackgroundSelection of early stage non-small cell lung cancer patients with a high risk of recurrence is warranted in order to select patients who will benefit from adjuvant treatment strategies. We evaluated the prognostic value of integrin expression profiles in a retrospective study on frozen primary tumors of 68 patients with early stage non-small cell lung cancer.MethodsA retrospective study was performed on frozen primary tumors of 68 early stage non-small cell lung cancer patients with a follow up of at least 10 years. From all tumor tissues, RNA was isolated and reverse transcribed into cDNA. qPCR was used to generate mRNA expression profiles including integrins alpha1, 2, 3, 4, 5, 6, 7, 11, and V as well as integrins beta1, 3, 4, 5, 6, and 8.ResultsThe expression levels of integrins alpha5, beta1 and beta3 predicted overall survival and disease free survival in early stage NSCLC patients. There was no association between integrin expression and lymph node metastases. Comparison between the histological subtypes revealed a distinct integrin signature for squamous cell carcinoma while the profiles of adenocarcinoma and large cell carcinoma were largely the same.ConclusionIntegrin expression in NSCLC is important for the development and behavior of the tumor and influences the survival of the patient. Determining the integrin expression profile might serve as a tool in predicting the prognosis of individual patients.

Monitoring Response to Antiangiogenic Therapy in Non–Small Cell Lung Cancer Using Imaging Markers Derived from PET and Dynamic Contrast-Enhanced MRI

With antiangiogenic agents, tumor shrinkage may be absent, despite survival benefit. The present study assessed the predictive value of molecular imaging for the identification of survival benefit during antiangiogenic treatment with bevacizumab and erlotinib in patients with advanced non–small cell lung cancer. Methods: Patients were evaluated using an imaging protocol including CT, 18F-FDG PET, H215O PET, and dynamic contrast-enhanced MRI to derive measurements on tumor size, glucose metabolism, perfusion, and microvascular permeability. The percentage change in imaging parameters after 3 wk of treatment as compared with baseline was calculated and correlated with progression-free survival (PFS). Results: Forty-four patients were included, and 40 underwent CT and 18F-FDG PET at both time points. Complete datasets, containing all imaging modalities, were available for 14 patients. Bevacizumab and erlotinib treatment resulted in decreased metabolism, perfusion, and tumor size. A decrease in standardized uptake value or tumor perfusion of more than 20% at week 3 was associated with longer PFS (9.7 vs. 2.8 mo, P = 0.01, and 12.5 vs. 2.9 mo, P = 0.009, respectively). Whole-tumor Ktrans (the endothelial transfer constant) was not associated with PFS, but patients with an increase of more than 15% in the SD of tumor Ktrans values—that is, an increase in regions with low or high Ktrans values—after 3 wk had shorter PFS (2.3 vs. 7.0 mo, P = 0.008). A partial response, according to the response evaluation criteria in solid tumors (RECIST), at week 3 was also associated with prolonged PFS (4.6 vs. 2.9 mo, P = 0.017). However, 40% of patients with a partial response as their best RECIST response still had stable disease at week 3. In these cases tumor perfusion was already decreased and Ktrans heterogeneity showed no increase, indicating that the latter parameters seem to be more discriminative than RECIST at the 3-wk time point. Conclusion: PET and dynamic contrast-enhanced MRI were able to identify patients who benefit from bevacizumab and erlotinib treatment. Molecular imaging seems to allow earlier response evaluation than CT.