Marcin Zieliński

Adjuvant MAGE-A3 Immunotherapy in Resected Non–Small-Cell Lung Cancer: Phase II Randomized Study Results

PURPOSE 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. PATIENTS AND METHODS 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). RESULTS 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. CONCLUSION 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.

Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer.

Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small-cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. In 2009, the International Association for the Study of Lung Cancer (IASLC) introduced a new lymph node map. Some changes in this map have an important impact on mediastinal staging. Moreover, more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of computed tomography (CT)-enlarged or positron emission tomography (PET)-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography [endobronchial ultrasonography (EBUS)/esophageal ultrasonography (EUS)] with fine-needle aspiration (FNA) is the first choice (when available), since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred to mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumours ≤ 3 cm located in the outer third of the lung. In central tumours or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and FNA or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumours >3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high standardized uptake value. For restaging, invasive techniques providing histological information are advisable. Both endoscopic techniques and surgical procedures are available, but their negative predictive value is lower compared with the results obtained in baseline staging. An integrated strategy using endoscopic staging techniques to prove mediastinal nodal disease and mediastinoscopy to assess nodal response after induction therapy needs further study.

The International Association for the Study of Lung Cancer Lung Cancer Staging Project: Proposals for the Revision of the N Descriptors in the Forthcoming 8th Edition of the TNM Classification for Lung Cancer

Introduction: Nodal status is considered to be one of the most reliable indicators of the prognosis in patients with lung cancer and thus is indispensable in determining the optimal therapeutic options. We sought to determine whether the current nodal (N) descriptors should be maintained or revised for the next edition (8th) of the International Lung Cancer Staging System. Methods: The new International Association for the Study of Lung Cancer lung cancer database was created from 94,708 patients diagnosed as having lung cancer between 1999 and 2010. Among these, 38,910 and 31,426 patients with non–small-cell lung carcinoma were available for an analysis of the clinical (c)N and pathological (p)N status, respectively. The anatomical location of lymph node involvement was defined by either the Naruke (for Japanese data) or American Thoracic Society (for non-Japanese data) nodal charts. Survival was calculated by the Kaplan–Meier method, and prognostic groups were assessed by a Cox regression analysis. Results: The current N0 to N3 descriptors for both the cN and pN status consistently separated prognostically distinct groups. The 5-year survival rates according to the cN and pN status were 60% and 75% (N0), 37% and 49% (N1), 23% and 36% (N2), and 9% and 20% (N3), respectively. The differences in survival between all neighboring nodal categories were highly significant for both the cN and pN status. With regard to pathological staging, additional analyses regarding the prognosis were performed by further dividing N1 into N1 at a single station (N1a) and N1 at multiple stations (N1b); N2 into N2 at a single station without N1 involvement (“skip” metastasis, N2a1), N2 at a single station with N1 involvement (N2a2), and N2 at multiple stations (N2b). The survival curves for N1b and N2a2 overlapped each other, and N2a1 had numerically a better prognosis than N1b, although the difference was not significant. Geographic difference in N-specific prognosis was observed for both c-settings and p-settings. This might have been because of the difference in the used nodal map, surgical technique, and pathologist’s handling of the resected specimen. Conclusions: Current N descriptors adequately predict the prognosis and therefore should be maintained in the forthcoming staging system. Furthermore, we recommend that physicians record the number of metastatic lymph nodes (or stations) and to further classify the N category using new descriptors, such as N1a, N1b, N2a, N2b, and N3, for further testing.

Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Fewer than half of the patients with completely resected non-small-cell lung cancer (NSCLC) are cured. Since the introduction of adjuvant chemotherapy in 2004, no substantial progress has been made in adjuvant treatment. We aimed to assess the efficacy of the MAGE-A3 cancer immunotherapeutic in surgically resected NSCLC. METHODS In this randomised, double-blind, placebo-controlled trial, we recruited patients aged at least 18 years with completely resected stage IB, II, and IIIA MAGE-A3-positive NSCLC who did or did not receive adjuvant chemotherapy from 443 centres in 34 countries (Europe, the Americas, and Asia Pacific). Patients were randomly assigned (2:1) to receive 13 intramuscular injections of recMAGE-A3 with AS15 immunostimulant (MAGE-A3 immunotherapeutic) or placebo during 27 months. Randomisation and treatment allocation at the investigator site was done centrally via internet with stratification for chemotherapy versus no chemotherapy. Participants, investigators, and those assessing outcomes were masked to group assignment. A minimisation algorithm accounted for the number of chemotherapy cycles received, disease stage, lymph node sampling procedure, performance status score, and lifetime smoking status. The primary endpoint was broken up into three co-primary objectives: disease-free survival in the overall population, the no-chemotherapy population, and patients with a potentially predictive gene signature. The final analyses included the total treated population (all patients who had received at least one treatment dose). This trial is registered with ClinicalTrials.gov, number NCT00480025. FINDINGS Between Oct 18, 2007, and July 17, 2012, we screened 13 849 patients for MAGE-A3 expression; 12 820 had a valid sample and of these, 4210 (33%) had a MAGE-A3-positive tumour. 2312 of these patients met all eligibility criteria and were randomly assigned to treatment: 1515 received MAGE-A3 and 757 received placebo and 40 were randomly assigned but never started treatment. 784 patients in the MAGE-A3 group also received chemotherapy, as did 392 in the placebo group. Median follow-up was 38·1 months (IQR 27·9-48·4) in the MAGE-A3 group and 39·5 months (27·9-50·4) in the placebo group. In the overall population, median disease-free survival was 60·5 months (95% CI 57·2-not reached) for the MAGE-A3 immunotherapeutic group and 57·9 months (55·7-not reached) for the placebo group (hazard ratio [HR] 1·02, 95% CI 0·89-1·18; p=0·74). Of the patients who did not receive chemotherapy, median disease-free survival was 58·0 months (95% CI 56·6-not reached) in those in the MAGE-A3 group and 56·9 months (44·4-not reached) in the placebo group (HR 0·97, 95% CI 0·80-1·18; p=0·76). Because of the absence of treatment effect, we could not identify a gene signature predictive of clinical benefit to MAGE-A3 immunotherapeutic. The frequency of grade 3 or worse adverse events was similar between treatment groups (246 [16%] of 1515 patients in the MAGE-A3 group and 122 [16%] of 757 in the placebo group). The most frequently reported grade 3 or higher adverse events were infections and infestations (37 [2%] in the MAGE-A3 group and 19 [3%] in the placebo group), vascular disorders (30 [2%] vs 17 [3%]), and neoplasm (benign, malignant, and unspecified (29 [2%] vs 16 [2%]). INTERPRETATION Adjuvant treatment with the MAGE-A3 immunotherapeutic did not increase disease-free survival compared with placebo in patients with MAGE-A3-positive surgically resected NSCLC. Based on our results, further development of the MAGE-A3 immunotherapeutic for use in NSCLC has been stopped. FUNDING GlaxoSmithKline Biologicals SA.

Transcervical Extended Mediastinal Lymphadenectomy: Results of Staging in Two Hundred Fifty-Six Patients with Non-Small Cell Lung Cancer

Transcervical extended mediastinal lymphadenectomy (TEMLA) is a new surgical procedure for staging of the mediastinal lymph nodes in patients with non-small cell lung cancer (NSCLC). The operation is performed through the 5- to 8-cm collar incision in the neck and enables complete removal of all mediastinal nodal stations except for the pulmonary ligament nodes (station 9) and the most distal left paratracheal nodes (station 4L). Generally, TEMLA is an open procedure performed partly with mediastinoscopy-assisted and videothoracoscopy-assisted techniques. Operative technique of TEMLA includes elevation of the sternal manubrium with a special retractor and bilateral visualization of the laryngeal recurrent and vagus nerves. From January 1, 2004 to November 15, 2005, TEMLA was performed in 256 patients. Length of operation was 80 to 330 minutes (mean, 161 minutes). Complication of TEMLA occurred in 11.3% of patients with temporary laryngeal nerve palsy in 6 of 256 patients (2.3%) and permanent nerve palsy in 2 of 256 patients (0.8%). The number of dissected nodes during TEMLA was 15 to 85 (mean, 38.9). N2-3 nodes were found in 80 patients (31.3%). During subsequent thoracotomy, omitted N2 nodes were found in 5 of 138 patients, and omitted normal mediastinal nodes were found in 13 of 138 patients (9.4%). Sensitivity of TEMLA in discovery of N2-3 nodes was 94.1%, specificity was 100%, accuracy was 98%, negative predictive value was 97.2%, and positive predictive value was 100%. Preliminary results may suggest some therapeutic impact for patients who underwent TEMLA and subsequent R0 resection, with a 77.2% survival rate after the mean 24-month follow-up period.

Standard terms, definitions, and policies for minimally invasive resection of thymoma.

Having a common language including well-defined terms and adherence to certain policies and procedures in the management of patients with thymic malignancies is necessary to facilitate progress. This is especially true for minimally invasive resections. Different technical approaches have been used,1,2 and a careful examination of results is needed to understand the impact of the minimally invasive approach itself, as opposed to other factors. For example, during an open approach, most surgeons perform a complete en bloc resection of the tumor and a complete thymectomy with removal of the upper cervical poles and the surrounding mediastinal fat3; whether this is done during minimally invasive resections is hard to decipher at present. This article identifies key aspects that should be reported, common definitions that should be adopted and proposes certain standard policies that should be adhered to when performing a minimally invasive resection of a thymic malignancy. These definitions and policies do not apply to biopsies. These policies are not meant to stifle innovation; on the contrary, they should facilitate progress by providing a framework, so that experiences and outcomes can be compared and analyzed more clearly. These standards have been adopted by members of the International Thymic Malignancy Interest Group (ITMIG), which is a worldwide collaborative organization of individuals interested in mediastinal tumors. METHODS An initial work group of surgeons experienced in minimally invasive thymic resections was assembled to review definitions, terms, and procedures in the existing literature for minimally invasive thymoma resections (Alper Toker, Joshua Sonett, Marcin Zielinski, Federico Rea, Victor Tomulescu, and Frank C. Detterbeck). This work group formulated preliminary recommendations, which were refined by an extended work group (Harmik Soukiasian, Jens Ruckert, Mahmoud Ismail, Jeffrey Port, and Paul Van Schil). These were then debated among a large diverse group of specialists at an ITMIG workshop, which was supported by the International Association for the Study of Lung Cancer. After further comments by the entire ITMIG membership, the definitions and policies presented in this article were approved and adopted as a standard to follow in reporting data and discussing outcomes by the members of ITMIG.

Endobronchial ultrasound-guided needle aspiration in the non-small cell lung cancer staging.

OBJECTIVE The aim of the study was to assess the diagnostic yield of the endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-NA) in the mediastinal staging in non-small cell lung cancer (NSCLC) patients. METHODS Consecutive NSCLC patients with enlarged or normal mediastinal nodes on CT scans underwent EBUS-NA. All patients with negative EBUS-NA subsequently underwent the transcervical extended bilateral mediastinal lymphadenectomy (TEMLA) as a confirmatory test. RESULTS Two hundred and twenty-six patients underwent EBUS-NA between 1.02.07 and 30.04.08. There were 320 mediastinal lymph nodes biopsied (stations: 2R - 8, 4R - 83, 2L - 1, 4L - 61, 7 - 167). EBUS-NA revealed metastatic lymph node involvement in 129/226 patients (57.1%) and in 171/320 biopsies (53.4%). In 97 patients with negative EBUS-NA, who underwent subsequent TEMLA, metastatic nodes were diagnosed in 16 patients (7.1%) - in 12 (5.3%) in stations accessible for EBUS-NA (stations: 4R - 3, 4L - 2, 7 - 8) and in 4 (1.8%) in stations not accessible for EBUS-NA (stations: 5 - 4, 6 - 1). All positive N2 nodes diagnosed by the TEMLA contained only small metastatic deposits. A diagnostic sensitivity, specificity, accuracy, PPV and NPV of EBUS-NA were 89.0%, 100%, 92.9%, 100% and 83.5%, respectively. No complications of EBUS-NA were observed. CONCLUSIONS (1) EBUS-NA is an effective and safe technique for mediastinal staging in NSCLC patients. (2) In patients with negative results of EBUS-NA, surgical exploration of the mediastinum should be performed.

Preoperative mediastinal lymph node staging for non-small cell lung cancer: 2014 update of the 2007 ESTS guidelines

Accurate preoperative staging and restaging of mediastinal lymph nodes in patients with potentially resectable non-small cell lung cancer (NSCLC) is of paramount importance. In 2007, the European Society of Thoracic Surgeons (ESTS) published an algorithm on preoperative mediastinal staging integrating imaging, endoscopic and surgical techniques. Over the last years more evidence of the different mediastinal staging technique has become available. Therefore, a revision of the ESTS guidelines was needed. In case of CT-enlarged or PET-positive mediastinal lymph nodes, tissue confirmation is indicated. Endosonography (EBUS/EUS) with fine needle aspiration is the first choice (when available) since it is minimally invasive and has a high sensitivity to rule in mediastinal nodal disease. If negative, surgical staging with nodal dissection or biopsy is indicated. Video-assisted mediastinoscopy is preferred over mediastinoscopy. The combined use of endoscopic staging and surgical staging results in the highest accuracy. When there are no enlarged lymph nodes on CT and when there is no uptake in lymph nodes on PET or PET-CT, direct surgical resection with systematic nodal dissection is indicated for tumors ≤3 cm located in the outer third of the lung. In central tumors or N1 nodes, preoperative mediastinal staging is indicated. The choice between endoscopic staging with EBUS/EUS and fine needle aspiration or video-assisted mediastinoscopy depends on local expertise to adhere to minimal requirements for staging. For tumors larger than 3 cm, preoperative mediastinal staging is advised, mainly in adenocarcinoma with high SUV uptake.

Comparison of Endobronchial Ultrasound and/or Endoesophageal Ultrasound with Transcervical Extended Mediastinal Lymphadenectomy for Staging and Restaging of Non–Small-Cell Lung Cancer

Background: To compare the diagnostic yield of endobronchial ultrasound (EBUS) and/or endoesophageal ultrasound (EUS) with transcervical extended mediastinal lymphadenectomy (TEMLA) for primary staging and repeated staging (restaging) of non–small-cell lung cancer (NSCLC). Methods: In this retrospective study, all consecutive patients undergoing primary staging and restaging after neodjuvant chemo- or chemo-radiotherapy for NSCLC with EBUS, EUS, or EBUS combined with EUS (CUS) with fine needle aspiration biopsy and cytological examination and subsequent TEMLA from January 1, 2007 to December 31 2010, were included. Results: Primary staging was performed in 623 patients: EBUS in 351, EUS in 72, and CUS in 200 patients. TEMLA was performed for primary staging in 276 patients. There was no mortality and morbidity after EBUS or EUS. One patient died after TEMLA and morbidity rate after TEMLA was 7.2%. There was a significant difference between EBUS or EUS and TEMLA for sensitivity (87.8% and 96.2%; p < 0.01) and negative predictive value (82.5% and 99.6%; p < 0.01) in favor of TEMLA. In the restaging group, endoscopic staging was performed in 88 patients and TEMLA in 78 patients. There was a significant difference between EBUS or EUS and TEMLA for sensitivity (64.3% and 100%; p < 0.01) and negative predictive value (82.1% and 100%; p < 0.01) in favor of TEMLA. Conclusions: The results of this largest reported series comparing the endoscopic and surgical primary staging and restaging of NSCLC showed a significantly higher diagnostic yield of TEMLA when compared with that of EBUS or EUS.

Non-small-cell lung cancer restaging with transcervical extended mediastinal lymphadenectomy

BACKGROUND To analyse a diagnostic yield of the transcervical extended mediastinal lymphadenectomy (TEMLA) in restaging of the mediastinal nodes after neoadjuvant chemo- or chemo-radiotherapy for non-small-cell lung cancer (NSCLC). METHODS From 1 January 2004 to 30 April 2009, 63 patients who underwent induction chemotherapy or chemo-radiotherapy for N2 and N2/3 metastatic nodes discovered preoperatively were restaged. There were 12 women and 51 men in the age group of 43-71 (mean 57.8) years. There were 45 squamous cell carcinomas, 13 adenocarcinomas, one pleomorphic carcinoma and four NSCLCs. A total of 54 patients underwent neoadjuvant chemotherapy and nine chemo-radiotherapy. Seven patients had mediastinoscopy before neoadjuvant therapy. As many as 34 patients underwent endobronchial ultrasound (EBUS), one patient underwent endo-oesophageal ultrasound (EUS) and 10 patients underwent combined EBUS/EUS. The diagnostic results of TEMLA were compared with the results of the largest published series of restaging patients. The results of subsequent thoracotomies after negative TEMLA were presented. RESULTS There were no serious complications or mortality after TEMLA. Metastatic nodes were discovered in 22 patients including three patients with N3 nodes and 19 patients with N2 nodes. Stations 7, 4R, 2R and 4L were the most prevalent. Of the 63 patients, 42 underwent subsequently thoracotomy. Resectability for negative TEMLA was 92.7%. There were 37 R0 resections and four R1 resections. There was no postoperative mortality, two bronchial fistulas were developed (after inferior bilobectomy and right pneumonectomy; the second one healed spontaneously) and there were no other serious complications. During thoracotomy with completion lymphadenectomy one false-negative result was found (single node in station 8). Sensitivity of TEMLA in the discovery of N2/3 nodes during restaging was 95.5%, specificity 100%, accuracy 98.3%, negative predictive value (NPV) 97.4% and positive predictive value (PPV) 100%. TEMLA was found to have significantly better sensitivity and NPV (p<0.05) than other series of restaging. During follow-up a local recurrence was noted in six of 37 (15.7%) patients after pulmonary resection. CONCLUSIONS (1) The results of TEMLA in restaging of NSCLC (N2/3) patients after induction chemotherapy or chemo-radiotherapy were significantly better than those achieved with remediastinoscopy, EBUS and positron emission tomography/computed tomography (PET/CT). (2) The results of future studies will show if TEMLA should be considered the gold standard of mediastinal nodal restaging after neoadjuvant therapy in patients with NSCLC.