Abstract
The Second European Lung Cancer Conference was held in Geneva, Switzerland from 28 April to 1 May 2010, under the cosponsorship of the International Association for the Study of Lung Cancer and the European Society for Medical Oncology. The main topics included: tobacco control, which represents a crucial challenge for thoracic oncologists; personalized medicine, consisting of the identification of driver genetic alterations in patients’ tumors before tailoring targeted treatment against these molecular alterations; and current developments of radiotherapy, including improvement of techniques, combination with third- or fourth-generation cytotoxic agents, and increased quality control. Overall, the conference provided lung cancer specialists with an up-to-date comprehensive overview of the most significant advances in research and treatment and enhanced multidisciplinary interactions between physicians and researchers worldwide.
The second European Lung Cancer Conference was held in Geneva, Switzerland from 28th April to 1st May 2010, under the cosponsorship of the International Association for the Study of Lung Cancer (IASLC) and the European Society for Medical Oncology (ESMO). Co-chairs of the Scientific Committee were Françoise Mornex for IASLC and Rafael Rosell for ESMO. The main objective of the conference was to provide lung cancer specialists with an up-to-date, comprehensive, educational overview of the most significant advances in research and treatment, as well as to enhance multidisciplinary interactions between physicians and researchers worldwide. As an extensive coverage of the conference is out of the scope of this report, we decided to focus on the most significant presentations. A complete podcast of the sessions is available on the ESMO and IASLC websites.
Tobacco control: a crucial challenge for lung cancer
The opening lecture of the conference was given by Ala Alwan, Assistant Director-General of the Noncommunicable Diseases and Mental Health Cluster at the WHO (Geneva, Switzerland). Tobacco smoking represents the most preventable risk factor for cancer, and physicians may play a major role in implementing tobacco control policies. Carolyn Dresler, Associate Professor of Health Policy and Management at the University of Arkansas for Medical Sciences (AR, USA), further developed the role of oncologists in tobacco cessation programs. A recent meta-analysis reported an estimated 5-year survival for patients with early stage non-small-cell lung cancer (NSCLC) who pursue smoking after diagnosis of 33% compared with 70% for those who quit smoking at time of diagnosis; similar estimates were made for limited-stage disease Citation[1]. Tobacco cessation therefore represents a priority for thoracic oncologists in routine practice.
Translational research
Treatment decisions for patients with lung cancer have historically been based upon tumor histology. However, with the emergence of new targeted agents, information regarding the molecular composition of tumors has become increasingly important Citation[2]. EGF receptor (EGFR) mutations are the best illustration of the therapeutic relevance of identifying molecular clusters of lung cancer based on driver genetic alterations. Daniel Costa from the Beth Israel Deaconess Medical Center at Harvard Medical School (MA, USA), and Robert Pirker from the Medical University of Vienna (Austria), both extensively reviewed the clinical and biological data regarding EGFR mutations. Briefly, EGFR mutations strongly predict the efficacy of EGFR inhibitors, with response rates of more than 70% observed in multiple studies Citation[3]. Two prospective randomized Phase III studies (Iressa Pan-Asia Study [IPASS] and WJTOG3405) for patients with untreated metastatic adenocarcinoma have found that, compared with standard platinum-based doublet chemotherapy, first-line gefitinib leads to a longer progression-free survival for those with EGFR mutant tumors Citation[3,4].
Targeted treatment tailored according to the genetic makeup of individual tumors – a concept called ‘personalized medicine’ – therefore involves a paradigm shift. From a clinician standpoint, ‘tissue is the issue’ and the collection of sufficient and suitable tumor samples for molecular profiling remains a major challenge, especially in metastatic patients who are not operated on and for whom lung cancer diagnosis relies on small-size biopsy.
For those patients, serum biomarkers represent a promising approach to predicting the response to EGFR inhibitors. David Carbone of the Vanderbilt–Ingram Comprehensive Cancer Center (TN, USA), analyzed baseline plasma samples available from 441 patients included in the BR.21 study comparing erlotinib with placebo as second- or third-line treatment of metastatic NSCLC Citation[5]. Interestingly, 99% of patients had a successful determination of proteomic status, and proteomic profiles were significantly different in responders than in nonresponders to erlotinib.
Beyond EGFR, the identification of additional driver mutations is now a major challenge for researchers Citation[2]. Anthony Iafrate, Director of the Diagnostic Molecular Pathology Laboratory at Massachusetts General Hospital (MA, USA), gave a comprehensive lecture regarding one of the most promising targets, namely the fusion of the anaplastic lymphoma kinase (ALK) and the echinoderm microtubule-associated protein-like 4 (EML4) genes. This translocation has been identified in 3–7% of NSCLC tumors Citation[6]. Tumors that harbor EML4–ALK fusions appear responsive to pharmacologic ALK inhibition. PF02341066 (Pfizer, NY, USA) is a small molecule tyrosine kinase inhibitor with submicromolar activity against ALK, and is currently being investigated in a randomized trial versus standard chemotherapy in ALK-mutant tumors (clinicaltrials.gov ID: NCT00932893), following promising results in Phase I–II trials, which reported disease control rates of 65–70% Citation[7].
At the epigenetic level, microRNAs (miRs) are a new class of molecules involved in gene-expression regulation. The role of miRs in lung cancer was reviewed by Marcin Skrzypski from the Medical University of Gdansk (Poland) during the molecular biology workshop of the conference. These short RNA chains bind to target sequences on mRNA, either up- or down-regulating gene expression. miR expression has been evaluated in several settings in lung cancer: screening, as miRs may be detected in blood or serum; evaluation of prognosis; and predictive value of response to chemotherapy. In addition, miRs can represent potential targets for therapeutics. The main advantage is that miRs may be detected in serum and blood, as well as in formalin-fixed, paraffin-embedded tumor specimens. miR tests might become widely applicable in routine oncology practice.
Radiotherapy
Current modalities of radiotherapy for lung cancer include 3D conformal techniques, which allow dose escalation and combination with chemotherapy agents to occur Citation[8]. Recent developments include improvement of radiation delivery techniques, combination with third- or fourth-generation cytotoxic agents, and increased quality control through optimized dedicated software and devices.
Cécile le Péchoux from the Gustave Roussy Institute (Villejuif, France), presented original results from the updated meta-analysis of the Meta-Analysis of Radiotherapy in Lung Cancer Collaborative Group, evaluating hyperfractionated radiotherapy. Hyperfractionation consists of scheduling the administration of radiation more than once a day, and may be combined with acceleration to decrease the total duration of the treatment Citation[8]. These protocols have not yet been widely developed, mostly because of the technical and organizational constraints they require. Meta-analysis of individual data of patients was performed and included nine trials comparing modified accelerated and/or hyperfractionated radiotherapy with standard radiotherapy. In NSCLC (eight trials, 1594 patients), hyper-fractionated radiotherapy led to significantly lower risk of death (HR: 0.87; 95% CI: 0.79–0.97; p = 0.009), resulting in a significant survival benefit of 2.6% at 5 years. In small-cell lung cancer (two trials, 685 patients), a similar difference was observed although it was not significant owing to a lack of power of the trials (HR: 0.87; 95% CI: 0.74–1.02; p = 0.08). Hyperfractionation led to significantly higher esophageal toxicity. These results are of great importance and give a rationale to prospectively re-evaluate the role of hyperfractionated radiotherapy in NSCLC.
Françoise Mornex reported the initial results of a Phase I trial evaluating the feasibility of combining pemetrexed to optimized radiotherapy in locally advanced NSCLC. A total of ten patients were treated with the following strategy: two induction cycles of full dose cisplatin–pemetrexed combination, followed by two cycles of concurrent chemoradiation with cisplatin and escalating doses of pemetrexed (400–600 mg/m2) with standard radiation to a total dose of 66 Gy. Only one dose-limiting toxicity occurred in a patient receiving 600 mg/m2 of pemetrexed. These data suggest that pemetrexed may be the only drug that could be administered without dose reduction when combined with radiotherapy. This regimen is currently being further evaluated in a Phase II trial.
Stereotactic radiotherapy corresponds to the administration of high daily doses of radiation (theoretically higher than 3 Gy, but usually ranging from 12 to 26 Gy) in a low number of fractions (1–4 on average), for a total dose equivalent to 66–74 Gy using standard fractionation schemes Citation[8]. This technique may be less toxic as it uses a highly localized radiation beam, sparing normal tissues. Initially developed for brain tumors, the stereotactic procedure requires at the thoracic level: a whole-body immobilization device, usually using a vacuum pillow within a rigid individualized mattress; the use of respiratory gating or other 4D techniques; and a strict quality control with beam-eyed portal films controlled before each fraction. Experience in the field was reviewed by Michael Brada from the Royal Marsden NHS Foundation Trust (Sutton, UK). Two abstracts further explored the role of optimized devices and software to better control radiation delivery and reproducibility. The ExacTrac® snap verification uses x-ray real-time images acquired at any time during treatment delivery or between fields to instantly detect and visualize isocenter displacement (beam on or off). Corina Udrescu from our center (Lyon, France) presented data on patients irradiated for lung tumors with stereotactic radiotherapy, showing that 2–5 mm deviations may occur between and, most importantly, during fractions, which can be corrected using the device. Nicolas Peguret from the Geneva University Hospital (Switzerland) developed simple 4D software that helps to determine which time in the respiratory cycle is the best to decrease the volume and spare normal lung tissues surrounding the tumor. Preliminary data suggest that gross tumor volume may then be reduced by up to 33% compared with the reference phase (maximal inspiration). Through integration of 4D dosimetry and respiratory gating, a concept called ‘breathe-adapted radiotherapy’, such software may translate the theoretical benefits of these optimized techniques into a real therapeutic gain for patients.
To conclude, the second European Lung Cancer Conference was a great opportunity for the entire lung cancer community of healthcare providers and researchers to share a comprehensive and optimistic overview of current developments and future directions for lung cancer treatment.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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