Lung-sparing surgery for patients with advanced mesothelioma results in prolonged survival, new study shows

Patients with advanced malignant pleural mesothelioma (MPM) treated with a combination of surgery to remove the cancer but save their lung, plus photodynamic therapy and chemotherapy, had a median survival of nearly three years, with a subset of patients living longer than seven years, according to new research published in the Annals of Thoracic Surgery.

The disease, which is most commonly caused by exposure to asbestos, is an incurable cancer that affects the lining of the chest cavity. Patients treated with chemotherapy alone, the standard of care, typically live only 12 to 18 months. In the United States, 2,000 to 3,000 patients are diagnosed with MPM each year.

"These are among the best results ever published for patients with an epithelial subtype of pleural mesothelioma, which accounts for about two thirds of all cases," says the lead author, Joseph S. Friedberg, MD, the Charles Reid Edwards Professor of Surgery and Head of the Division of Thoracic Surgery at the University of Maryland School of Medicine and Thoracic Surgeon-in-Chief of the University of Maryland Medical System.

"This is among the most virulent cancers known to man, and we have a long way to go, but it's encouraging to have achieved results we can report in years not months even for these patients with such advanced disease," Dr. Friedberg says. "Although, from a technical perspective, it is more challenging to save the lung than to sacrifice it, it does appear that this technique helps to not only extend life but to also preserve quality of life."

The study followed 73 patients with MPM who had surgery to remove the cancer, followed by a therapy using a photosensitizing agent and light to kill microscopic cancer cells. Ninety-two percent of the patients also received chemotherapy. Overall median survival for all the patients in the study was nearly three years (35 months), the researchers report, but that figure more than doubled, to 7.3 years, for 19 of these patients whose cancer had not spread to their lymph nodes. Median survival is the length of time at which 50 percent of patients are alive after treatment. In addition, researchers also found that overall survival was three times higher than disease-free survival, which is the length of time until the cancer recurs.

For the 73 patients in the study, median disease-free survival was 1.2 years, a third of the overall survival of three years. In the group of 19 patients with overall survival of 7.3 years, disease-free survival was 2.3 years. The majority of the patients had Stage III or Stage IV disease.

"It's unusual to find such a difference in between overall and disease-free survival rates. When this cancer recurs, which it almost always does, patients usually live only a few months," says Dr. Friedberg of the study results, which were published online in November.

While the researchers caution against drawing definitive conclusions based on this non-randomized study, they are intrigued by the findings. Dr. Friedberg and his colleagues are now looking for mechanisms behind the difference, in order to work on improving survival even more.

Dr. Friedberg performed the lung-sparing surgery on the patients in the study while he was at the University of Pennsylvania, where the research was conducted. He has pioneered lung-sparing surgery for mesothelioma and now serves as Director of the Mesothelioma and Thoracic Oncology Treatment and Research Center at the University of Maryland School of Medicine. The center is part of the University of Maryland Greenebaum Comprehensive Cancer Center.

The lung-sparing surgery is a 6- to 14-hour operation to remove detectable cancer from the lining of the chest and spares the lung and as many other normal structures as possible. Dr. Friedberg developed his lung-sparing technique as an alternative to removing the entire lung, diaphragm and sac around the heart.

Dr. Friedberg and his colleagues say that this study shows that the lung-sparing technique can be safely used to achieve a "macroscopic complete resection" -- the removal of all detectable cancer -- while preserving the lung. "The role for lung-sparing surgery for mesothelioma has not been completely defined, but this series demonstrates that it is an option, even in advanced stage cases," they conclude in the journal article.

"The results showing extended overall survival for some patients are very promising and warrant further study," says E. Albert Reece, MD, PhD, MBA, vice president for medical affairs at the University of Maryland and the John Z. and Akiko K. Bowers Distinguished Professor and dean of the University of Maryland School of Medicine. "Under Dr. Friedberg's leadership, our new Mesothelioma and Thoracic Oncology Treatment and Research Center is fast becoming an major center for important scientific discovery as well as highly specialized, multidisciplinary care for patients with mesothelioma and other thoracic cancers."

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News Source:
University of Maryland Medical Center/School of Medicine.

New genetic insights into mesothelioma

Mesothelioma is a rare but deadly form of cancer: the five-year survival rate for patients diagnosed with the disease is between five and ten percent. Although aggressive surgery can help some patients with early-stage mesothelioma, current treatments for patients with more advanced mesothelioma are not effective. Physician-researchers from the International Mesothelioma Program at Brigham and Women's Hospital (BWH) have been caring for patients with mesothelioma for the past 25 years and, in parallel, studying the disease in the laboratory to better understand its biology and develop treatment strategies to target its vulnerabilities. In a comprehensive genomic analysis using more than 200 tumors, investigators from Brigham and Women's Hospital and scientists from Genentech have found previously unknown genetic alterations, including some that may be clinically actionable, as well as others that may improve diagnostics, screening and predictions about outcomes for patients. The team's results are published this week in Nature Genetics.

"By studying so many samples, we've been able to describe a spectrum of mutations for this rare disease. A small number of these mutations have been found previously in other cancers, and drugs have been developed to target these mutations," said lead author Raphael Bueno, MD, chief of the Division of Thoracic Surgery at BWH and co-director of the BWH Lung Center. "No one knew before now that these mutations might also be found in mesothelioma tumors. This new work suggests that patients with such mutations may benefit from certain existing drugs."

In collaboration with colleagues at Genentech, researchers analyzed 216 malignant pleural mesothelioma (MPM) samples, comparing DNA and RNA from normal tissue to cancerous tissue. They uncovered more than 2,500 alterations, and identified 10 significantly mutated genes. They also captured information on the presence of immune cells at the site of the tumor. Some of the genetic alterations they found suggest that targeted therapies, such as a BCR-ABL-1 inhibitor, could be matched to a patient's tumor. Other alterations and the presence of particular immune targets could serve as better markers to help pathologists accurately diagnose mesothelioma and predict which patients will have poor or better outcomes. The study also analyzed tumors for expression of PD-L1, a cancer immunotherapy target, and found that sarcomatoid histology, a subtype of the mesothelioma, might be a good candidate for anti-PD-L1 therapy.

Each year, more than 3,200 people are diagnosed with mesothelioma, and an equal number of people die of the disease every year in the U.S. About 80 percent of mesothelioma cases are linked to exposure to asbestos, which continues to be mined and used in many countries, including China, India, Brazil, Russia and others. The International Mesothelioma Program, one of the largest mesothelioma treatment and research program in the world, provides consultation and care for hundreds of newly diagnosed patients each year. Based on their findings, Bueno and colleagues see genotyping their patients in the clinic -- a process of looking for genetic differences at precise locations in the genome -as an important next step.

"When you have a cancer that has a 80 to 90 percent mortality rate within five years of diagnosis, and you discover evidence that a small percentage of people may have actionable mutations, that means that you could reduce mortality," said Bueno. "Even for a mutation that happens one to two percent of the time, it could mean the difference between life and death for a patient. We plan to continue this important research through investigator-sponsored trials evaluating the potential use of cancer immunotherapies for the treatment of mesothelioma."

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News Source:
Brigham and Women's Hospital.

Active agent from the Caribbean sea cucumber could improve treatment for malignant pleural mesothelioma

Researchers at the Comprehensive Cancer Center of MedUni Vienna and Vienna General Hospital have discovered a new option for treating malignant pleural mesothelioma. For the first time in the world, they were able to show in a preclinical study, both in the cell culture and in the animal model, that trabectedin, a chemotherapy drug that is already successfully used for other types of cancer, is also effective against malignant pleural mesothelioma. The active agent originally occurs in the Caribbean sea cucumber, a marine-dwelling tunicate. The study results were recently published in "Molecular Cancer Therapeutics," the therapy-oriented journal of the American Association for Cancer Research (AACR). The initial interim results of a clinical study from Italy confirm these results and show that they are transferable to clinical practice.

With around 90 new cases per year in Austria, malignant pleural mesothelioma is one of the rarer forms of cancer. However, it is on the increase. Malignant pleural mesothelioma is a very aggressive form of cancer that is associated with asbestos and is routinely treated with a combination of chemotherapy, surgery and radiotherapy. Since this particular type of tumour often develops resistance to chemotherapy and radiotherapy, the prognosis is very poor.

In order to improve the treatment options for pleural mesothelioma, an interdisciplinary research cooperative was set up at the CCC in 2008 and this has been very successful in the preclinical discovery and development of therapeutics to treat malignant pleural mesothelioma. In its latest preclinical study, the platform scientists investigated the action of trabectedin in malignant pleural mesothelioma. Trabectedin is an active substance that occurs in the Caribbean sea cucumber, can be synthetically manufactured for therapeutic purposes and has already been successfully used clinically for malignant soft tissue tumours and ovarian cancer.

Combination enhances effectiveness
The researchers led by Walter Berger, Deputy Head of MedUni Vienna's Institute for Cancer Research, and Alireza Hoda, Division of Thoracic Surgery at the Department of Surgery of MedUni Vienna/Vienna General Hospital, had already shown in previous works that trabectedin is very effective against cancer cells, while having minimal impact on healthy pleural cells. Furthermore, the researchers were able to demonstrate clear synergies with cisplatin, a standard therapeutic drug. In order to develop further potential combination therapies with trabectedin, the genome signatures of cells that were sensitive to the administration of trabectedin were compared with those of cell lines that were less sensitive. Berger: "Using bioinformatics, we were able to show that the increased formation of the protein bcl-2, which prevents cell death, reduces the effectiveness of trabectedin." Consequently, the scientists treated the malignant cells with a combination of trabectedin and the bcl-2 inhibitors obatoclax and venetoclax. Hoda: "When trabectedin is combined with these bcl-2 inhibitors, there is a significant improvement in destruction of malignant pleural mesothelioma cells. Trabectedin therefore seems to be a new, effective and safe treatment option for this disease." These preclinical results have just been confirmed by initial positive interim results from a clinical study conducted in Italy.

Berger: "The study has even been met with great interest from people affected. This is evidenced by the fact that the Comprehensive Cancer Centre publication has already been posted online and discussed in several international fora for asbestos and mesothelioma.

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News Source:
Medical University of Vienna.

New drug hope for mesothelioma

A new drug is showing promise as a treatment for mesothelioma -- one of the most lethal cancers of all.

The drug, known as HRX9, works by preventing the cancer cells from avoiding apoptosis -- the natural process by which unhealthy and damaged cells close themselves down and die.

"Both the immune system and nearby healthy cells send signals instructing damaged and unhealthy cells to undergo apoptosis, which is like programmed 'cell suicide'. But cancer cells have developed a wide range of strategies to ignore these instructions," says Professor Richard Morgan, from the University of Bradford's Institute of Cancer Therapeutics, who developed the drug and who led the research.

"There's a range of drugs which try to force apoptosis in different cancers, but this is the first one to work in mesothelioma."

Mesothelioma is a cancer of the lining of the lung. It's almost invariably caused by exposure to asbestos and is resistant to all current chemotherapies. Its prognosis is dismal, with those diagnosed usually given a year to live at most.

A study by the universities of Bradford and Surrey found that after three weeks' treatment with HXR9, human mesothelioma tumours in mice stopped growing, with a complete loss of tumour blood vessels and widespread cancer cell death. The results are published in BMC Cancer journal.

HXR9 targets the HOX gene family, which includes 39 fairly similar genes that help enable the remarkably rapid cell division in growing embryos. Many of these genes are usually switched off in adults, but previous research has shown that in many cancers -- including prostate, ovarian, and brain cancer, melanoma, and leukemia -- HOX genes are switched back on, helping the cancer cells to proliferate and survive.

"We've effectively knocked out a key defence mechanism in this cancer through targeting the HOX genes," says Professor Morgan.

A further key finding reported in the study, funded by the British Lung Foundation, was that mesothelioma has a very strong association with one of the HOX genes in particular -- known as HOXB4.

"We examined the amount of HOXB4 protein in tumours of 21 mesothelioma patients and compared it with their length of survival. There was a clear link: the more HOXB4 we found, the shorter time the patient survived, so we may also have found a way to predict which patients have the most aggressive form of this cancer," says Professor Morgan.

Because of greater awareness of the danger of asbestos in the West, the future incidence of mesothelioma is expected to decline. However, in Africa and some parts of Asia, asbestos is still commonly used in industries such as construction and ship building, and few precautions are taken when demolishing buildings that contain asbestos.

"Mesothelioma may become much less of a problem in the West, but it's still going to be a significant public health problem in many parts of the world. We already know that it's resistant to available drugs, which is why we need entirely new treatments," says Professor Morgan.

Ian Jarrold, Head of Research at British Lung Foundation said: "Although still early days, this study is a significant step forward in that it is the first time a drug has been observed causing so-called 'cell suicide' in mesothelioma.

"People living with mesothelioma often tell us that among their first reactions to diagnosis is despair at the lack of treatment available. We hope that the progress being made in research we fund will soon provide new treatments and new hope for patients."

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News Source:
University of Bradford.

First immunotherapy for mesothelioma on the horizon, early research suggests

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Malignant pleural mesothelioma or MPM is a rare cancer, but its incidence has been rising. This cancer is usually associated with asbestos exposure, and patients have a median life expectancy of only 13-15 months. All patients relapse despite initial chemotherapy, more than 50% of them within six months after stopping treatment. There are currently no effective therapeutic options for patients with MPM.

Early findings from an ongoing phase II clinical trial in France, MAPS-2, show that immunotherapy may slow the growth of MPM after relapse. At 12 weeks, cancer had not worsened in 44% of patients who received nivolumab (Opdivo) and in 50% of those who received nivolumab with ipilimumab (Yervoy).

The study will be featured in a press briefing today and presented at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting.

"Our findings suggest that immunotherapy may provide new hope to patients with relapsed mesothelioma," said lead study author Arnaud Scherpereel, MD, PhD, head of the Pulmonary and Thoracic Oncology Department at the University Hospital (CHU) of Lille in Lille, France. "This randomized phase II trial may be enough to support the use of immune checkpoint inhibitors in this setting, but it is too early to conclude whether nivolumab alone or the combination of nivolumab and ipilimumab is better."

About the Study
This multi-center clinical trial enrolled 125 patients with advanced MPM who had received up to two prior treatments, including standard platinum-based chemotherapy. The majority of patients (80%) were male, and the median age was 72 years. The patients were randomly assigned to treatment with nivolumab alone or nivolumab with ipilimumab until the cancer worsened; 70% of patients received at least 3 cycles of either treatment.

Key Findings
The authors report results from the first 108 patients treated on the study. The disease control rate or DCR, defined as the percentage of patients in which cancer either shrank or did not grow, was 44% among the patients who received nivolumab only and 50% among those who received nivolumab with ipilimumab (the 12-week DCR for all treatments previously tested in relapsed MPM was less than 30%). Tumors shrank in 17% of patients treated with nivolumab and 26% of those treated with nivolumab and ipilimumab.

After a mean follow-up of 10.4 months of the 125 patients, the median time until the cancer worsened (progression-free survival) was 4 months with nivolumab alone and 5.6 months with nivolumab and ipilimumab. The median overall survival was 10.4 months in the nivolumab group and not reached in the nivolumab with ipilimumab group (meaning that more than 50% were still alive at analysis). Mature quality-of-life data are not yet available.

The side effects were rather mild overall with the most common being thyroid problems, colon inflammation, and skin rash. Severe side effects were more common in the nivolumab plus ipilimumab group (18% vs. 10%), in which three treatment-related deaths occurred.

Next Steps
With 125 patients, MAPS-2 is the largest clinical trial of immune checkpoint inhibitors in mesothelioma to date, according to the authors. Many ongoing clinical trials are exploring nivolumab and other immune checkpoint inhibitors as second- or third-line treatments for MPM. In addition, several larger clinical trials investigating immune checkpoint inhibitors as initial therapy for MPM are already under way.

"Mesothelioma cells build a protective tumor microenvironment to shield themselves against the immune system's attacks and even act against anti-tumor immune response," said Dr. Scherpereel. "Therefore, therapies that shift the tumor microenvironment from a state of immune suppression to one of immune activation may hold promise in MPM."

About Mesothelioma
Malignant pleural mesothelioma is a cancer that begins in the lining of the lungs. This cancer is associated with occupational exposure to asbestos, which causes chronic inflammation. It typically takes 30 to 40 years from asbestos exposure to development of MPM.

The peak of asbestos use was between the 1960s and the 1980s. Although use of asbestos has been banned in the United States and many European countries, asbestos is still being used and extracted in many developing countries. "For these reasons, we expect to continue to see growing incidence of mesothelioma in the coming decades," said Dr. Scherpereel.

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News Source:
American Society of Clinical Oncology.

Pembrolizumab shows promise in treatment of mesothelioma

Pembrolizumab, an antibody drug already used to treat other forms of cancer, can be effective in the treatment of the most common form of mesothelioma, according to a new study led by investigators from the Perelman School of Medicine at the University of Pennsylvania. The study, published this month in The Lancet Oncology, is the first to show a positive impact from checkpoint inhibitor immunotherapy drugs on this disease.

Malignant pleural mesothelioma is a rare and aggressive cancer that represents about 90 percent of all malignant mesothelioma cases. It's primarily caused by the inhalation of asbestos, a fiber commonly found in some forms of insulation, vinyl floor tiles, and other material. Tumors form in the pleura, a thin membrane of cells that line the lungs and chest wall. Most patients survive less than a year. This poor prognosis is partially due to the fact that most patients are not diagnosed until they are already at a late stage of the disease. The standard first-line therapy treatment involves chemotherapy, and currently there is no approved second-line therapy.

"There have been a lot of studies looking at different drugs, but researchers have not seen positive results," said the study's lead author Evan Alley, MD, PhD, chief of Hematology and Medical Oncology at Penn Presbyterian Hospital. "But we've found this new class of drugs, checkpoint inhibitors, seems to be more effective than what's been available in the past."

Checkpoint inhibitors are a class of drugs designed to free the body's immune system to fight back against cancer. Pembrolizumab, in particular, has been used to treat melanoma, non-small cell lung cancer, and in some cases, head and neck cancers.

Alley and his team presented data from KEYNOTE-028, an ongoing trial involving 13 different research sites in six different countries all looking at the effect of pembrolizumab on patients with advanced malignancies, including malignant pleural mesothelioma. The study evaluated 25 patients with pleural mesothelioma, all of whom were over the age of 18 and had either already been treated with chemotherapy or were unable to receive it. Patients who had already received another checkpoint inhibitor were not included in the study.

Beginning with the first enrollees two years ago, doctors gave each patient a dose of pembrolizumab every two weeks. The tumor reduced in size in 14 of those patients. On average, patients went about six months without their disease progressing, and overall survival was about 18 months. Fourteen patients passed away during the study, while four were still undergoing treatment as of the study's writing.

"Most patients who receive a second-line therapy have a life expectancy of about six or seven months, so to have four patients still ongoing at two years is very encouraging," Alley said.

The most common side-effects reported were fatigue, nausea, loss of appetite, and dry mouth.

"One great sign in this study is that none of the patients had to stop treatment because of side-effects," Alley said. "Some had temporary stoppages, but they were able to continue. The drug appears to be well-tolerated."

There are multiple studies going on right now to confirm these findings, which the authors note is a necessary step before the drug can become a standard second-line therapy.

"This study provides evidence that some patients can have long-term disease control with this drug, which we haven't seen before," Alley said. "We need to better understand what we can do next to make immunotherapy more effective for more patients."

Alley said there are already plans for trials that will test combination therapies, which will utilize pembrolizumab in conjunction with other treatments. Those studies are expected to launch later this year, including two at Penn.

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News Source:
Perelman School of Medicine at the University of Pennsylvania.

Mesothelioma: New trial to fight cancer caused by asbestos

Patients with a hard-to-treat type of cancer are being given new hope in a ground-breaking clinical trial.

Researchers at the University of Southampton and the University of Leicester are trialling a drug that could boost the body's immune system to fight off mesothelioma, which can be caused by asbestos.

The trial will be one of many to be conducted at the University of Southampton's Centre for Cancer Immunology, which will be the UK's first and only centre dedicated to cancer immunology research.

Mesothelioma rates are rising. Since the late 1970s, mesothelioma incidence rates have increased almost six-fold (497 per cent increase) in Great Britain. There were around 2,700 new cases of mesothelioma in the UK in 2013 -- more than seven cases diagnosed every day.

Current treatment methods include chemotherapy, radiotherapy or surgery and are mainly aimed at keeping the cancer under control.

The phase III randomised controlled trial, which is funded by Cancer Research UK and supported by Bristol Myers Squibb, will test whether nivolumab, a drug already used to successfully treat advanced melanoma and advanced kidney cancer, can be used to target mesothelioma.

It works by finding and blocking a protein called PD-1 on the surface of certain immune cells called T-cells. Blocking PD-1 activates the T-cells to find and kill cancer cells.

The trial has been launched ahead of International Clinical Trials Day, which is marked on 20 May each year, but this year has events taking place today (Friday, 19 May).

Professor Gareth Griffiths, the study's co-Chief Investigator from the Southampton Clinical Trials Unit at the University of Southampton, said: "The UK has one of the world's highest incidences of mesothelioma and currently there aren't many ways to treat it. Boosting the immune system by releasing killer T-cells that have previously been blocked could offer us a new way to treat more patients with this devastating disease."

The trial, which is being run in collaboration with the clinical lead Professor Dean Fennell at the University of Leicester, plans to recruit 304 patients, who have relapsed mesothelioma, across 20 UK-wide sites including Southampton and Leicester.

Professor Fennell said: "Preliminary studies targeting PD-1 in mesothelioma have shown promising activity. CONFIRM aims to definitively assess the true benefit of nivolumab for patients with relapsed mesothelioma in a setting where there is an unmet need. Critically, we aim to understand why patients respond (or not) to this drug, and identify biomarkers to ensure that we can personalise therapy to maximize the benefit for patients."

One person who has already benefited from using the immune system to fight mesothelioma is Mavis Nye, who was diagnosed with the disease in 2009. After various courses of treatments which failed, she joined a phase 1 immunotherapy trial to test the drug (Keytruda) on how well it blocked the PD-1 protein and enabled the body to fight off a number of cancers, including mesothelioma. After the first two years, scans revealed the tumours had decreased by 81 per cent, with three disappearing completely. Mavis is now cancer-free and spends her time raising awareness about the importance of clinical trials.

She said: "I was just an ordinary woman whose husband worked at the dockyards in Chatham. We didn't know what the effects of the asbestos on his clothes might be. Cancer is a terrible and devastating disease that turns everything on its head. I am so thankful that the trial I took part in worked. But it didn't work for every participant. We need more trials to help improve treatments and survival rates for cancer, and this new trial is a big step in the right direction."

Dr Catherine Pickworth, Cancer Research UK's science information officer, said: "Immunotherapy treatments work by turning the power of our immune system against cancer. They are already being used routinely to treat advanced skin and kidney cancers, and are showing promise for other types of cancer too. This clinical trial will find out whether an immunotherapy drug could benefit people with mesothelioma, which is hard for doctors to treat successfully. We urgently need trials like this to help improve survival for patients with this aggressive type of cancer."

The construction of the Centre for Cancer Immunology is expected to be completed by September and aims to be in full operation in summer 2018. It will bring world-leading cancer scientists together under one roof and enable interdisciplinary teams to expand clinical trials and develop lifesaving drugs.

The Centre, which is based at Southampton General Hospital site, is being funded by a £25 million fundraising campaign by the University of Southampton.

Professor Tim Elliott, Director of the Centre for Cancer Immunology, said: "The University has made major advances in tumour immunology and immunotherapy over the past 40 years and we enjoy a strong reputation for our 'bench to bedside' approach. The new Centre will go a long way in helping many more people with cancer become free of the disease, and we hope this new trial to fight a particularly sinister type of cancer will be the first of many successful trials."

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News Source:
University of Southampton