Quantitative measurement of minimal residual disease predicting recurrence in individual cancer patients is available only in very few indications, such as acute lymphoblastic leukemia, but is still ...missing in most solid tumors, including non-small cell lung cancer (NSCLC).
MAGE-A expression levels in blood and bone marrow determined as calibrator-normalized relative ratios by quantitative multimarker real-time RT-PCR for transcript amplification of
-A1, -A2, -A3/6, -A4, -A10, and -A12 in 94 patients with completely resected NSCLC were correlated with survival in a clinical study.
Patients with MAGE-A expression levels ≥0.2 in at least one sample of bone marrow or blood at tumor surgery had a significantly reduced overall (
= 0.007), cancer-free (
= 0.002), and distant metastasis-free survival (
< 0.001) versus patients below 0.2 in all samples without significant difference in locoregional recurrence-free survival. The corresponding HRs (≥0.2 vs. <0.2) for death, cancer-related death, and development of distant metastasis were 2.56 95% confidence interval (CI), 1.42-4.63, 3.32 (95% CI, 1.66-6.61), and 4.03 (95% CI, 1.77-9.18), respectively. Five-year Kaplan-Meier estimates of distant metastasis-free survival were 43% (MAGE-A ≥ 0.2) versus 87% (MAGE-A < 0.2).
MAGE-A expression in blood or bone marrow at tumor surgery is an independent predictor of survival in resected NSCLC. The reliable prediction of distant metastasis in individual patients with a statistically proven impact on overall survival may help to refine patient selection for adjuvant therapy urgently needed, especially in the clinical management of elderly patients.
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The MAGE-A3 protein is expressed in approximately 35% of patients with resectable non-small-cell lung cancer (NSCLC). Several immunization approaches against the MAGE-A3 antigen have shown few, but ...often long-lasting, clinical responses in patients with metastatic melanoma.
A double-blind, randomized, placebo-controlled phase II study was performed assessing clinical activity, immunologic response, and safety following immunization with recombinant MAGE-A3 protein combined with an immunostimulant (13 doses over 27 months) in completely resected MAGE-A3-positive stage IB to II NSCLC. The primary end point was disease-free interval (DFI).
Patients were randomly assigned to either MAGE-A3 immunotherapeutic (n = 122) or placebo (n = 60). After a median postresection period of 44 months, recurrence was observed in 35% of patients in the MAGE-A3 arm and 43% in the placebo arm. No statistically significant improvement in DFI (hazard ratio HR, 0.75, 95% CI, 0.46 to 1.23; two-sided P = .254), disease-free survival (DFS; HR, 0.76; 95% CI, 0.48 to 1.21; P = .248), or overall survival (HR, 0.81; 95% CI, 0.47 to 1.40; P = .454) was observed. Corresponding analysis after a median of 70 months of follow-up revealed a similar trend for DFI and DFS. All patients receiving the active treatment showed a humoral immune response to the MAGE-A3 antigen, although no correlation was observed with outcome. No significant toxicity was observed.
In this early development study with a limited number of patients, postoperative MAGE-A3 immunization proved to be feasible with minimal toxicity. These results are being investigated further in a large phase III study.
Background: Pulmonary metastasectomy (PM) is an established treatment option for selected patients with stage IV solid tumors. The aim of this study was to investigate the feasibility of and survival ...rate in PM for elderly patients. Methods: We retrospectively analyzed all of the patients who underwent PM with curative intention at our institution. The patients were categorized into two groups: the elderly group (≥70 years old) and the non-elderly group (<70 years old). Results: The elderly group consisted of 222 patients versus 538 patients in the non-elderly group. The median number of resected metastases was 2 ± 3 in the elderly group and 4 ± 5 in the non-elderly group (p < 0.01). No difference in the rate of postoperative complications was observed between the two groups (p = 0.3). The median length of hospital stay in each group was comparable (10 ± 5 vs. 10 ± 4.3 days, p = 0.3). The 5-year survival rate was 67% in the elderly group and 78% in the non-elderly group (p = 0.117). In the univariate analysis, COPD was associated with poor survival in the elderly group (p = 0.002). Conclusion: The resection of pulmonary metastases in elderly patients is safe, is not associated with increased risks of postoperative complication, and the survival benefit is not reduced in selected patients.
The optimal perioperative analgesic strategy in video-assisted thoracic surgery (VATS) for anatomic lung resections remains an open issue. Regional analgesic concepts as thoracic paravertebral or ...epidural analgesia were used as systemic opioid application. We hypothesized that regional anesthesia would provide improved analgesia compared to systemic analgesia with parenteral opioids in VATS lobectomy and would be associated with a lower incidence of pulmonary complications.
The study was approved by the local ethics committee (AZ 99/15) and registered (germanctr.de; DRKS00007529, 10th June 2015). A retrospective analysis of anesthetic and surgical records between July 2014 und February 2016 in a single university hospital with 103 who underwent VATS lobectomy. Comparison of regional anesthesia (i.e. thoracic paravertebral blockade (group TPVB) or thoracic epidural anesthesia (group TEA)) with a systemic opioid application (i.e. patient controlled analgesia (group PCA)). The primary endpoint was the postoperative pain level measured by Visual Analog Scale (VAS) at rest and during coughing during 120 h. Secondary endpoints were postoperative pulmonary complications (i.e. atelectasis, pneumonia), hemodynamic variables and postoperative nausea and vomiting (PONV).
Mean VAS values in rest or during coughing were measured below 3.5 in all groups showing effective analgesic therapy throughout the observation period. The VAS values at rest were comparable between all groups, VAS level during coughing in patients with PCA was higher but comparable except after 8-16 h postoperatively (PCA vs. TEA; p < 0.004). There were no significant differences on secondary endpoints. Intraoperative Sufentanil consumption was significantly higher for patients without regional anesthesia (p < 0.0001 vs. TPVB and vs. TEA). The morphine equivalence postoperatively applicated until POD 5 was comparable in all groups (mean ± SD in mg: 32 ± 29 (TPVB), 30 ± 27 (TEA), 36 ± 30 (PCA); p = 0.6046).
Analgesia with TEA, TPVB and PCA provided a comparable and effective pain relief after VATS anatomic resection without side effects. Our results indicate that PCA for VATS lobectomy may be a sufficient alternative compared to regional analgesia.
The study was registered (germanctr.de; DRKS00007529 ; 10th June, 2015).
Circulating tumor DNA (ctDNA) has demonstrated great potential as a noninvasive biomarker to assess minimal residual disease (MRD) and profile tumor genotypes in patients with non‐small‐cell lung ...cancer (NSCLC). However, little is known about its dynamics during and after tumor resection, or its potential for predicting clinical outcomes. Here, we applied a targeted‐capture high‐throughput sequencing approach to profile ctDNA at various disease milestones and assessed its predictive value in patients with early‐stage and locally advanced NSCLC. We prospectively enrolled 33 consecutive patients with stage IA to IIIB NSCLC undergoing curative‐intent tumor resection (median follow‐up: 26.2 months). From 21 patients, we serially collected 96 plasma samples before surgery, during surgery, 1–2 weeks postsurgery, and during follow‐up. Deep next‐generation sequencing using unique molecular identifiers was performed to identify and quantify tumor‐specific mutations in ctDNA. Twelve patients (57%) had detectable mutations in ctDNA before tumor resection. Both ctDNA detection rates and ctDNA concentrations were significantly higher in plasma obtained during surgery compared with presurgical specimens (57% versus 19% ctDNA detection rate, and 12.47 versus 6.64 ng·mL−1, respectively). Four patients (19%) remained ctDNA‐positive at 1–2 weeks after surgery, with all of them (100%) experiencing disease progression at later time points. In contrast, only 4 out of 12 ctDNA‐negative patients (33%) after surgery experienced relapse during follow‐up. Positive ctDNA in early postoperative plasma samples was associated with shorter progression‐free survival (P = 0.013) and overall survival (P = 0.004). Our findings suggest that, in early‐stage and locally advanced NSCLC, intraoperative plasma sampling results in high ctDNA detection rates and that ctDNA positivity early after resection identifies patients at risk for relapse.
ctDNA profiling in plasma revealed higher levels and detection rates of ctDNA during tumor resection as compared to pretreatment time points in patients with early‐stage or locally advanced NSCLC. Moreover, patients testing positive for ctDNA immediately after tumor resection had worse clinical outcomes than patients with undetectable ctDNA. Our research highlights the role of ctDNA assessment for guiding treatment in patients with respectable NSCLC.
Objective: Sublobar resections spare pulmonary function and offer a method of increasing resection rates in patients with lung cancer and limited functional operability. Previous studies demonstrated ...an increased local recurrence rate following wedge resections compared to segmentectomies in stage IA non-small cell lung cancer (NSCLC). However, a prognostic impact of this observation has never been shown and is still under debate. Therefore, this study has been performed to analyse the cancer-related survival of sublobar resections in stage IA patients. Methods: Over a 17-year period 87 patients underwent sublobar complete resection (R0) of stage IA NSCLC via thoracotomy. Sublobar resection was reserved for patients with cardiopulmonary impairment. Wedge resections with selective lymphadenectomy were performed in 31 patients (36%) and segmentectomies with systematic lymphadenectomy in 56 patients (64%). Patient characteristics, functional parameters, tumour specifics and follow-up duration were analysed concerning their distribution between the two groups. Kaplan–Meier curves were compared and possible joint effects between prognostic parameters were analysed by multivariate Cox regression analysis. Results: The median follow-up duration was 45 months. There was no significant difference between the two groups in gender (p = 0.11), age (p = 0.08), American Society of Anesthesiology physical performance status (ASA)-score (p = 0.32), forced expiratory volume in 1 s FEV1 (p = 0.08), tumour size (p = 0.30), histology (p = 0.17), grading (p = 0.12), complication rate (p = 0.15) and follow-up duration (p = 0.29). The mean number of dissected lymph nodes in segmentectomies (12 ± 6) was higher than in wedge resections (6 ± 3) (p = 0.0001). The 5-year survival rate was 63%. There were significantly less locoregional recurrences (p = 0.001), an equal distribution of distant metastases (p = 0.53) and a better cancer-related survival (p = 0.016) following segmentectomies compared to wedge resections. Cox regression analysis showed that the prognostic effect of the resection type was independent from gender, age, ASA-score, respiratory function, tumour size, tumour histology, grading and number of dissected lymph nodes (p = 0.04, relative risk 1.16). Conclusions: Studies investigating survival after sublobar resection of stage IA NSCLC should always distinguish between anatomical segmentectomies and wedge resections. If limited functional operability requires a sublobar resection of stage IA NSCLC, segmentectomy with systematic lymphadenectomy should be preferred.
A quarter of patients with clinical N1 (cN1) non-small cell lung cancer (NSCLC) based on positron emission tomography-computed tomography (PET-CT) imaging have occult mediastinal nodal involvement ...(N2 disease). In a prospective study, endosonography alone had an unsatisfactory sensitivity (38%) in detecting N2 disease. The current prospective multicentre trial investigated the sensitivity of preoperative mediastinal staging by video-assisted mediastinoscopy (VAM) or VAM-lymphadenectomy (VAMLA).Consecutive patients with operable and resectable (suspected) NSCLC and cN1 after PET-CT imaging underwent VAM(LA). The primary study outcome was sensitivity to detect N2 disease. Secondary endpoints were the prevalence of N2 disease, negative predictive value (NPV) and accuracy of VAM(LA).Out of 105 patients with cN1 on imaging, 26% eventually developed N2 disease. Invasive mediastinal staging with VAM(LA) had a sensitivity of 73% to detect N2 disease. The NPV was 92% and accuracy 93%. Median number of assessed lymph node stations during VAM(LA) was 4 (IQR 3-5), and in 96%, at least three stations were assessed.VAM(LA) has a satisfactory sensitivity of 73% to detect mediastinal nodal disease in cN1 lung cancer, and could be the technique of choice for pre-resection mediastinal lymph node assessment in this patient group with a one in four chance of occult-positive mediastinal nodes after negative PET-CT.
This is a multicentre prospective randomised controlled trial for patients with 3 or more resectable pulmonary metastases from colorectal carcinoma. The study investigates the effects of pulmonary ...metastasectomy in addition to standard medical treatment in comparison to standard medical treatment plus possible local ablative measures such as SBRT. This trial is intended to demonstrate an overall survival difference in the group undergoing pulmonary metastasectomy. Further secondary and exploratory endpoints include quality of life (EORTC QLQ-C30, QLQ-CR29 and QLQ-LC29 questionnaires), progression-free survival and impact of mutational status. Due to the heterogeneity and complexity of the disease and treatment trajectories in metastasised colorectal cancer, well powered trials have been very challenging to design and execute. The goal of this study is to create a setting which allows treatment as close to the real life conditions as possible but under well standardised conditions. Based on previous trials, in which patient recruitment in the given setting hindered successful study completion, we decided to (1) restrict inclusion to patients with 3 or more metastases (since in case of lesser, surgery will probably be the preferred option) and (2) allow for real world standard of care (SOC) treatment options before and after randomisation including watchful waiting (as opposed to a predefined treatment protocol) and (3) possibility that patient can receive SOC externally (to reduce patient burden). Moreover, we chose to stipulate 12 weeks of systemic treatment prior to possible resection to further standardize treatment response and disease course over a certain period of time. Hence, included patients will be in the disease state of oligopersistence rather than primary oligometastatic. The trial was registered in the German Clinical Trials Register (DRKS-No.: DRKS00024727).
Lung cancer is one of the leading causes of cancer related death worldwide with more than a million deaths per year. The poor prognosis is due to its high aggressiveness and its early metastasis. ...Although the exact mechanisms are still unknown, the process of epithelial to mesenchymal transition (EMT) seems to be involved in these neoplastic processes. We already demonstrated that serum levels of CCL18, a primate specific chemokine, are highly elevated in patients with lung cancer and correlate with their survival time of patients with adenocarcinoma of the lung. Therefore, we hypothesized that CCL18 may be directly involved in pathological processes of lung cancer, e.g. EMT. We investigated the effect of CCL18 on A549, an adenocarcinoma cell line of the lung, on EMT and other cell functions like proliferation, chemotaxis, invasion, chemoresistance and proliferation. Exposure of A549 lung cancer cells to CCL18 in various concentrations decreases the epithelial marker E-cadherin, whereas FSP-1, a marker of the mesenchymal phenotype increases. Accordingly, CCL18 induced the transcriptional EMT regulator SNAIL1 in a dose dependent fashion. In contrast, an increasing CCL18 concentration was associated with a decline of cell proliferation rate. In addition, CCL18 induced chemotaxis of these cells and increased their chemoresistance. Therefore, CCL18 may be an interesting therapeutic target for NSCLC.
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