Mesothelioma update Spring 2016
In this issue:
- updates in mesothelioma surgical trials
- new approach to drug and vaccination therapies
- summary of this new information.
The landscape of mesothelioma is changing fast. In the past 5 years, researchers have reported that mesothelioma is often linked to particular gene mutations -some inherited from parents- making patients more susceptible to asbestos-induced toxicity.
Many clinical trials have completed and their outcomes published in the past 5 years. This has brought considerable evidence-based information in the field of mesothelioma.
Several publications analysing the outcomes of mesothelioma patients treated with or without surgery have reported that cancer-directed surgery is independently associated with better survival, suggesting that multimodal surgery-based therapy can benefit mesothelioma patients.
Published clinical trials
The MARS feasibility trial compared the outcomes of patients treated with chemotherapy and best supportive care versus trimodality therapy including chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant radiotherapy. Although the study -initially designed to enrol 650 patients- did not reach its target enrolment, it suggested that the sequence of chemotherapy, EPP and radiotherapy did not prolong survival and could potentially harm patients. Professor Lang-Lazdunski took an active part in the trial and operated on more patients than any other surgeons participating in the trial.
Recently, a large randomised Swiss collaborative trial (SAKK 17/04) showed that radical radiotherapy (high dose radiotherapy) following EPP did not significantly improve outcomes and survival versus chemotherapy and EPP only.
Interestingly, Dr de Perrot and colleagues from the Toronto group have recently showed that using accelerated radiotherapy before EPP could result in an acceptable mortality and complications and could improve survival (SMART trial).
Two large meta-analyses of the medical literature and of a large American database have reported better outcomes in patients undergoing pleurectomy/decortication versus EPP. The analysis of the large number of studies comparing P/D to EPP suggested that P/D is associated with a 2 ½-fold lower short-term mortality than EPP.
Based on the available evidence, most surgeons performing mesothelioma surgery now use radical pleurectomy/decortication (rP/D) as the default procedure in multimodality therapy schemes. P/D results in better outcomes and better quality of life and provides longer survival.
When radical surgery is not possible due to advanced-stage disease or patients frailty, other options are available. The MesoVATS study compared VATS talc pleurodesis (a form of keyhole surgery aiming at preventing accumulation of fluid/blood in the pleural cavity) versus VATS pleurectomy (a keyhole surgery aiming at removing the pleural tumour and reexpanding the lung). Although none of these procedures can achieve complete removal of tumour, it is interesting to note that the VATS pleurectomy procedure did not result in longer survival. In addition, patients going through VATS pleurectomy experienced more complications and had a longer hospital stay. Professor Lang-Lazdunski took part in the MesoVATS study as well. He no longer performs VATS pleurectomy and offers talc pleurodesis and indwelling pleural catheter placement whenever necessary.
Last year, Dr Zalcman and the French Thoracic Oncology Group reported the results of the randomised MAPS study. This important phase 3 study showed that the addition of bevacizumab (Avastin) -a drug cutting blood supply to tumours- had a beneficial impact and could extend life in mesothelioma patients when used concomitantly with chemotherapy (pemetrexed and cisplatin). Patients receiving chemotherapy only had a median survival around 16 months. Those receiving bevacizumab on top of chemotherapy had a median survival of 18.8 months. Therefore, we believe that chemotherapy and bevacizumab should become the new standard of care in mesothelioma -in the absence of contra-indications-.
Several phase 1 or phase 2 studies have reported on the impact of new drugs named "immune checkpoint inhibitors" in mesothelioma patients. Those drugs aim at boosting the immune system by assisting in better tumour recognition by the patient's own immune system. Other drugs with a similar mechanism of action (PD-1 or PD-L1 inhibition) are being tested presently all around the world. Recently, doctors in Philadelphia reported impressive results with a drug named pembrolizumab in a small phase 1 trial including 25 mesothelioma patients. All patients had received chemotherapy before and tumour was progressing. The study showed that 76% of patients had their tumour stabilised by treatment (shrank in 28% and stopped growing in 48%). Although the study was small, the drug seemed to be well tolerated and several larger trials are ongoing to see if pembrolizumab could benefit other patients at different stage of their disease. Other similar drugs such as nivolumab - a drug with a similar mechanism of action already licensed for use in lung cancer patients- are undergoing trials in mesothelioma around the world.
New approach to vaccination therapies
Other research approaches have involved targeting proteins present in mesothelioma cells (tumour antigens) such as Mesothelin or WT-1. Several phase 1 and phase 2 studies have been completed with encouraging results. Some of the drugs are used as "vaccines" and may find a place in the treatment of mesothelioma patients together with surgery, chemotherapy or other agents targeting key proteins in tumour cells and disrupting the cancer machinery.
Professor Lang-Lazdunski's opinion is that the prognosis of many mesothelioma patients will be improved significantly in the next few years thanks to those new drugs. One of the potential downside is that those drugs come at very high cost (a year of treatment can cost more than £ 100,000!). Many of those drugs will not be available routinely to all patients due to extremely high cost. As many of those drugs are still offered as part of clinical trials, it is possible for patients to receive those drugs for free at approved trial centres.
Professor Lang-Lazdunski routinely refers patients for phase 1, 2 and 3 clinical trials at approved trials centres in central London. He collaborates with medical oncologists at Sarah Cannon Research Institute to offer mesothelioma patients rapid access to clinical trials and new therapies. Sarah Cannon Research UK is a unique standalone trial facility that collaborates and works closely with clinical investigators to develop new and innovative cancer therapies for patients. Sarah Cannon Research UK is part of the Hospital Corporation of America (HCA) network in London. Sarah Cannon Research Institute specialises in the development of novel cancer therapies and provide a clinical research option for cancer patients in London. Sarah Cannon Research UK is the first trials unit outside the NHS that has the ability to offer new anti-cancer drugs in clinical trials. As a dedicated trials unit it is focused on fast study set-up time lines to offer patients rapid access to new investigational drug therapies.
Thanks to his extensive network of expert colleagues, Professor Lang-Lazdunski can obtain specialist opinions on particularly difficult cases and refer patients abroad when a particular therapy is only available at one centre. He is in regular contact with colleagues in the US, Canada, Europe and Australasia, who can assist when patients wish to be treated closer from home.