A few weeks ago was the 2012 Chicago Multidisciplinary Symposium in Thoracic Oncology, where there doesn’t tend to be many breakthrough results presented, but often a few nuggets of exciting new work are presented. The main story was the relatively disappointing results of the PointBreak trial, one positive trial became a quick darling of the media. Dr. David Gerber from the University of Texas-Southwestern in Dallas presented results from a randomized phase II trial in previously treated advanced NSCLC, in which patients received either Taxotere (docetaxel) alone or in combination with one of two doses of the novel immunotherapy bavituximab. The excitement came from the fact that a doubling of overall survival (OS) was reported, alongside a less striking but still provocative improvement in response rate (RR) and progression-free survival (PFS) for the bavituximab-containing arms vs. chemo alone. Unfortunately, there’s more to the story.
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Celebration of Science and Keeping the Party Going
September 19th, 2012 - by Susan C. Mantel
I recently spent a remarkable weekend seeing the results of two decades of investment in scientific research across many different areas of healthcare. This amazing event, called “A Celebration of Science” was organized by Faster Cures, and included 1,200 attendees from 200 organizations. Participants represented the NIH, NCI and other public and private research institutions; the FDA; leading advocacy groups; patients who shared the impact of scientific advances on their lives; philanthropists; the pharmaceutical, biotech, and device industries, and many of our elected representatives.
The week-end was designed to “honor individuals whose work saves, improves and extends lives, and those who make that work possible,” including patients who participate in clinical trials and those who share their stories. Above all, it was designed to really make the case for why investing in research is a smart decision in any economy. Research creates jobs in the lab and through new types of science-related businesses. Even more importantly, by saving lives and improving quality of life for those affected by various diseases, it results in a more productive workforce and society.
Like all of us in the lung cancer trenches, I want progress in lung cancer to be much further and faster than it has been, and I remember thinking the first afternoon–when I saw the statistic that the overall five-year cancer survival rate is now 66%–“lung cancer is still so far below that.” But being with all of these brilliant people dedicated to making life better through science, hearing how thoughtful and determined they were to continue innovating along all the aspects of the scientific continuum, and seeing some honest-to-goodness breakthroughs gave me so much hope! I was also reminded of how all these advances build off each other.
For example, the cost of sequencing the human genome the first time was about $3 billion and took over a decade. Now it’s less than $10,000 and takes a couple of weeks, with $1,000 sequencing in days in sight. This is turning the conversation to “precision medicine,” which was brought vividly to life by a set of twins who were successfully treated for a genetic defect—going from minimal muscle control and other grave challenges as children to competitive teenage athletes today. Then a couple of days after the meeting, the squamous cell lung cancer findings from the Cancer Genome Atlas were published.
Until this year, most of the advances in lung cancer treatment through targeted therapies were happening in adenocarcinomas. With about 400,000 people dying of squamous cell lung cancer worldwide each year, this is another area of urgent need. And more than 60% of the tumors had mutations that are potentially “druggable” with medicines in development for other cancers. So, we have new information with which we can potentially DO something. The “what” has a “so what”. Furthermore, this form of lung cancer is only the second common cancer type for which a genetic analysis was performed as part of the Cancer Genome Atlas. Attention is being paid!
The Celebration showcased so many other tremendous advances, including in fields like HIV (did you know about “the Berlin patient”—the first known case of someone cured of HIV?), brain imaging, and research and rehabilitation of our wounded soldiers. Yes, these areas all still have unmet needs, and we have miles to go in areas like Alzheimer’s, traumatic brain injury and PTSD, and, of course, lung cancer. Ultimately, though, we are living in exciting times of progress and collaboration, where continued investment in research is yielding progress of which generations before us could only dream. I can’t wait for the “Amazing Advances in Lung Cancer” session at the “Celebration of Science” event of the future!
Lung Conference Day 1, 7/4/2011
July 5th, 2011 - by Dr. Jared Weiss
Ah, I must be in Europe. After seeing a few old friends last night, including our very own Jack West and a few hours of sleep, I got some much-needed sleep. On the way to the tram, my roommate, Tom Stinchcombe, and I stopped by a coffee shop for a cup, only to learn that they didn’t serve coffee—it’s the other kind of coffee shop! Welcome, lung-cancer docs, to Amsterdam!
The Lung Cancer Epidemic
The conference room is now full with thoracic oncologists from all over the world waiting for the first session to start. Appropriately, it started with Dr. Jan Willem Coebergh speaking about the epidemic in the Netherlands. Apparently, the Dutch considered lung cancer to be endemic since 1949, and had a case-control study to demonstrate the causative effects of cigarettes in 1957. To this day, the Netherlands is a major cigarette exporter to the rest of Europe. Statistics on incidence in the Netherlands look remarkably like the stats I know better from the US—male lung cancer is declining, while female lung cancer is increasing. Small cell and squamous cell carcinoma are declining, while other histologies are roughly stable; this likely reflects the effects of filters.
Next up was Dr. Richard Peto discussing patterns of mortality across the world. He started by noting that prolonged smoking is the greatest risk factor. With great dry British humor, he encouraged us that if we want to kill ourselves, we should start before 20, and keep going, because quitting smoking works. He showed a graph of lung cancer incidence by time of quitting–stopping smoking at age 30 was closer to being a never smoker than it was to stopping at age 50 or never stopping (reproduced below from Petro, BMJ, 2000). It’s never too late to quit, and the earlier the better!
He also showed us data from the UK Million Women Study, which showed that the lung cancer risk in women was directly linear to number of cigarettes smoked per day. The risk of lung cancer by age of stopping smoking was parabolic—there was a huge benefit to stopping early, with a rapid increase in the rise in risk between 30 and 40 years. Overall, about ½ of smokers in this study died from their smoking; ¼ were killed in middle age (35-69), losing many years of life.
In comparing French data to US data, he commented that Lung Cancer is a political disease. In France between 1990 and 2009, cigarette price triples, consumption halved and as a consequence, smoking fell off. He advocated doing the same in China, where domestic cigarette consumption is on the rise. He argued that everyone wins with a higher cigarette tax—the government gets more money and citizens suffer less from lung cancer.
Dr. Thorgeir Throgeirsson next spoke about lung cancer susceptibility genes. He classified them into three types: genes that influence lung cancer independent of smoking status, others that influence the risk of smoking, and yet others that interact with smoking to cause lung cancer. His group found a susceptibility locus for lung cancer on 15q25. He showed data that supported the idea that this variant at 15q25 confers risk by causing smokers to smoke more aggressively, increasing exposure to harmful elements of cigarette smoke. The variant does not appear to confer risk of lung cancer in never smokers or influence susceptibility to lung cancer from smoking.
Dr. Coehberg then took the stage again to discuss survival from lung cancer. He pointed out significant differences in outcomes across Europe. The major driver seems to be process and awareness more than talent of the physicians.
Dr. Flieder commented on the changing histopathologic picture of lung cancer. We have noted many times here how important histology is in optimizing therapy, and so changes in histologic trends have the potential to change the face of lung cancer. Squamous cell cancer seems to be falling while adenocarcinoma is on the rise. He explained that a lot has changed at the same time to explain this change—changes in cigarettes, changes in society, and changes in medicine. The dominant change in cigarettes was the introduction of filters. The filters stop large particles that cause cancer in large airway, yet they also allow deeper inhalation. Tar and nicotine levels have declined, which has lead to increased puffing per minute with deeper puffs, leaving total nicotine exposure unchanged. Blended reconstituted cigarettes have become more popular, increasing levels of other harmful chemicals. Society too has changed; leading to increased smoking in women relative to men, increased tolerance of pollutants, and increased smoking cessation. Medical classification of cancers has changed, leading to increased subtyping of lung cancer. Much large cell carcinoma has been reclassified as adenocarcinoma while others have been reclassified as SqCC.
Oral Session: President’s Selection
After a coffee break, world lung became massively parallel, with many sessions occurring at the same time. I chose to attend the President’s conference where several major trials were discussed.
Giorgio Scagliotti from Italy discussed phase III results from a trial comparing zoldendronic acid (zometa) to denosumab (xgeva). Both drugs work to strengthen bone at sites where cancer has metastasized there, with the goal of decreasing skeletal events, including fracture, skeletal instability/loss of skeletal integrity, spine cord compression, the need for surgery or radiation therapy for a symptomatic bone metastasis, and hypercalcemia. The original zometa study in solid malignancies reduced skeletal relate events from 35% with zometa to 44% with placebo, including in lung cancer. Dr. Scagliottti published data showing noninferiority and maybe even more decrease in skeletal related events with denosumab (HR .84). Survival in the overall population was similar. However, a post-hoc analysis in the lung cancer subgroup showed superiority for survival with a HR of 0.79 (confidence interval 0.65 to 0.95). In patients with lung cancer, median survival time was 8.9 months with denosumab vs 7.7m with zometa, with some further separation of the curves after the median was reached. Patients with both adenoCA and SqCC seemed to benefit—the HR was .8 for adenoCA and .68 for SqCC. There were very few patients with SCLC, but there was a hint of benefit there too—the median survival was 5.1 with zometa compared to 7.5 months with denosumab; the p was .36 and HR .81. Severe adverse events were similar between the two arms, although there was more hypocalcemia in the denosumab arm. Of note, osteonecrosis of the jaw was similar between the two arms at .8% and .7%. These was less renal toxicity with denosumab, but more flu-like symptoms. Laboratory studies are underway to try to understand this effect—does denosumab modify the microenvironment to which cancer may spread? Some lung cancer cells express RANK, some express RANKL, and some express both. Laboratory work is underway to try to better understand the mechanism of action of this possible effect. This work should be considered preliminary as it was a retrospective, subgroup analysis; nonetheless, it is intriguing and I look forward to hearing more about it.
Next, Dr. Joachim von Pawel of Germany talked about one of the major disappointments from ASCO 2011—the randomized phase III trial of amrubicin vs. topotecan as second-line therapy for NSCLC. Patients with SCLC who failed one prior regimen were randomized to amrubicin or topotecan. Median survival was the same with the two drugs in the overall cohort at 7.8m for topotecan and 7.5m for amrubicin, HR.88, p.17. In patients with refractory disease, survival was 5.7 months with topotecan and 6.2 months with amrubicin, indicating possible benefit in this subgroup. Symptom improvement and stability looked better with amrubicine including appetite, cough, dyspnea, fatigue, and pain but not hemoptysis. Anemia, neutropenia, thrombocytopenia were less with amrubicin but there were more infections.
As a card-carrying member of the cisplatin-hater club, I enjoyed Dr. David Ferry’s data from a British Thoracic Oncology Group Trial (BTOG2) comparing gemcitabine (1250mg/m2) combined with three different platinum regimens- cisplatin 80mg/m2, cisplatin 50mg/2m, and carboplatin AUC6. Contrary to a prior meta-analysis, using carboplatin did not seem inferior for overall survival:
| Cisplatin 80mg/m2 | Cisplatin 50mg/m2 | Carboplatin AUC 6 | |
| Median Overall Survival1 | 9.5months | 8.2 months | 10 months |
| Response Rate2 | 34% | 23% | 30% |
| 1 Year Survival | 39% | 31% | 39% |
| Nausea | 2.7% | .6% | 1.3% |
| Vomiting | 2.4% | .2% | .8% |
1. Log rank .09
2. Chi p.008
Dr. Ferry emphasized the importance of the method for estimating kidney function to get the carboplatin dose, advocating for superiority of the Wright method, which increased dose by an average of 10%.
I returned in the afternoon to the supportive care meeting to see quality of life data from this study. This data was very important to me as my distaste for cisplatin arises from the increased side effects it causes. Three different measures of quality of life were obtained, including EORTC QLQ-30, EORTC LC13, and EQ5D, which together gave 27 measures of quality of life. It is now the largest study of quality of life in lung cancer. Overall, the global measure of QoL curve was fairly flat for all three groups, indicating that the three regimens all stopped lung cancer from causing worsening of quality of life, yet none improved quality of life dramatically. After the first cycle of treatment, most quality of life measures had some mild improvement, with a smaller number getting slightly worse. More specifically, cough improved the most, with smaller improvements in pain and appetite. Sour mouth, hair loss, and GI effects all got worse with chemo. Overall, I was surprised by the relative similarity between the three arms. Cisplatin seemed better than carboplatin for relieving dyspnea (shortness of breath) and carboplatin caused less nausea and less neuropathy. Quality adjusted survival showed similar results for gem/carboplatin and gem/cisplatin 80, with worse results for gem/cisplatin 50. Of note, the carboplatin dosing was higher than typically used in the US, potentially explaining both the good survival results, and the failure to be much gentler than cisplatin. Further, supportive care with cisplatin has improved significantly—the use of IV fluid, mannitol and frequent lab monitoring have reduced kidney damage, new anti-nausea drugs such as Zofran (ondansetron) and emend (aprepitant) have decreased nausea, and we have better drugs (Neurontin, pregabalin) to treat neuropathy (nerve pain caused by chemotherapy).
We’ve discussed maintenance chemotherapy a lot here on GRACE. As a reminder, the JMEN study showed a survival advantage for maintenance pemetrexed after initial treatment with non-pemetrexed 1st line (induction) therapy. But what about patients who get pemetrexed based induction therapy? Will they still benefit from more pemetrexed in maintenance? Is the benefit of switch maintenance in getting more total chemo, or does guaranteed exposure to another active drug play a big role? The paramount study, presented by Dr. Paz-Arez from Spain, doesn’t fully address these questions, but it does give some helpful hints. All patients got 4 cycles of pemetrexed and cisplatin then were randomized to placebo vs. maintenance pemetrexed. PFS was improved from 2.8 months to 4.1months with a HR of .62, p.00006. Toxicity was low with pemetrexed; fatigue, anemia and neutropenia predominated, but for grade 3-4 effects, all were <5%. There were hints of increased benefit in the elderly, in women, in never smokers, and in patients who had a response to their induction therapy.
The FLEX trial showed a modest survival advantage with the addition of cetuximab to cisplatin plus vinorelbine chemotherapy. Given that cetuximab targets the epidermal growth factor receptor, it makes sense that tumors actually expressing the EGFR receptor might better respond to it. Dr. Robert Pirker presented data addressing this question and they were dramatic. In patients with high EGFR expression, survival was increased from 9.6 months to 12 months with cetuximab treatment. At one year, overall survival was 50% with cetuximab compared to 37% without cetuximab. At two years, overall survival was 24% with cetuximab and 15% without. In contrast, patients with low egfr expression derived no benefit from cetuximab, with HR .99. Patients with adenocarcinoma and squamous cell carcinoma both benefitted; patients with adenocarcinoma and high expression improved survival from 13.6 months to 20.2 months with the addition of cetuximab. Patients with squamous cell carcinoma and high expression improved survival from 8.9 months to 11.2 months.
As of now, the best way to predict who will benefit from adjuvant chemotherapy after good surgical resection is stage. Patients with node positive disease benefit, and there is reason to believe that patients with tumors >4cm also benefit. But is it really all about stage, or is stage, in part, a surrogate for the underlying aggressiveness of the cancer? We have seen before attempts to use microarrays to better prognosticate lung cancer. Dr. Johannes Kratz’s study is unique in that it was validated by two different cohorts and that it was done in paraffin-embedded tissue (how most tissue is kept after surgery). The training set from UCSF was nicely divided into low, intermediate, and high risk cohorts. The test was then applied to two other cohorts—a Kaiser cohort and a Chinese Lung Cancer Consortium cohort; again, the risk groups separated nicely. The authors proposed a new staging system encorparating molecular status and showed that their proposed new system prognosticates better than the traditional one based on tumor, node status, and metastases (TNM) alone.
The National Lung Screening Trial
December 6th, 2010 - by Jerry Sorkin
I am very fortunate to be able to write this post. In 2007, I was diagnosed with Stage IV lung cancer. Most lung cancer patients die within the year following their diagnosis. At the time I was diagnosed, I was 42, a healthy father of two young girls, and I had never smoked. Since then, I have had more than forty rounds of chemotherapy and two gamma knife procedures. I am lucky because my disease has remained stable and I have enjoyed an excellent quality of life.
Few lung cancer patients share my good fortune. Lung cancer is our nation’s number one cancer killer – and we have made little progress in reducing mortality rates in the four decades since the war on cancer was first declared. We have made little progress because the funding and pace of lung cancer research is far too slow. If we are going to catch-up with this disease and help save the 160,000 Americans who die from it every year, our nation must support bold and aggressive lung cancer research.
The recently announced National Lung Screening Trial (NLST) found 20 percent fewer lung cancer deaths among participants screened with low-dose spiral CT than among those screened with a standard chest X-ray. The NLST is a fantastic example of the life-saving capability of scientific research and technological advances. But those of us fighting to slow and stop a disease that now kills more Americans than any other cancer find it hard to be patient and cheered by confirmation of what we already suspected was highly effective.
My personal experience is illustrative. I had a full physical with multiple chest x-rays, showing no evidence of disease, just a few months before a CT scan showed that I had metastatic lung cancer with nodules throughout my chest. I did not need the NLST trial to prove that CT scans were more effective than x-rays. Neither did most physicians. Chest X-rays can only detect tumors one to two centimeters in size, while CT scans can detect tumors far smaller. CT scans are obviously better diagnostic tools than x-rays – but they have downsides – additional radiation and more false positives.
Our government spent more than $250 million on the eight year NLST study. And while we waited for the results of NLST we lost 1.5 million Americans to lung cancer. How many lives could have been saved if we had embraced CT scans rather than studying them? How many more lives could be saved if we dedicated the $250 million to developing better diagnostics and treatments?
Our science needs to move beyond the obvious to take lung cancer detection and treatment to the next level. One area where those breakthroughs are most likely is in the area of biomarkers, which hold the key to better diagnostics and treatment. Research should focus on the next generation of detection tools like blood sampling or sputum tests that could replace invasive lung biopsies. Scientists could identify therapeutic agents that provide customized genetic intervention for lung cancer, in order to extend patients’ lives and improve quality-of-life post-diagnosis.
Scientific research is vital to making life-saving advancements, but funding pools are critically low and the pace of research is slow. Over 200,000 Americans are diagnosed with lung cancer every year, which means each of us, or someone we love, will likely be affected. Our nation must commit to supporting critical lung cancer research. Going forward, our government and scientific organizations must move more aggressively – not merely confirming what we already know.
We must move quickly because millions of lives are at stake.
National Lung Screening Trial
November 10th, 2010 - by Andrea Ferris
Those of us in the lung cancer community know the underlying grimness that accompanies the words “you have lung cancer.” We know that those words are delivered to nearly 200,000 Americans every year and that nearly 160,000 die each year of this dise
ase–more than the number of people who die of breast, colorectal, pancreatic and prostate cancers combined. While we are making incremental progress on many fronts in the battle against lung cancer, breakthroughs have been elusive. For that reason, the recent announcement by the National Cancer Institute that the National Lung Screening Trial (NLST) recorded twenty percent fewer lung cancer deaths among current and former smokers screened with a spiral CT scan rather than the commonly used chest X-ray is monumental. It proves that lives can and will be saved if lung cancer is diagnosed at earlier stages.
It is critical to see the conclusion of the NLST study as a new beginning. Many doctors have believed that CT scans would help diagnose lung cancer at an earlier stage, but we did not have proof that using CT scans would save lives. With the release of initial findings for the NLST study, we have conclusive evidence of the importance of early diagnosis for lung cancer. What previously was intuitive is now demonstrably the case, and that is the true significance of the study. There will be continuing discussion of important considerations that arise out of the study: Who should get a CT scan? How often? Will insurance companies now be willing to pay for CT scans? Will false positives from the scans prove hugely problematic? How do we find lung cancer early for more people?
All of these questions deserve answers, and answers will be forthcoming. For now, what is of most consequence is the fundamental linkage between early diagnosis and survival. It is vital that we build on this research to develop more effective diagnostic and treatment methods that are cost-effective, widely available and utilized. Government and corporate funding have long neglected lung cancer research. Financial support for lung cancer research is vastly disproportionate to the number of people affected and killed by this disease. We must use the momentum provided by the NLST findings to push for additional funding for vitally needed research that has the potential to dramatically change the way we diagnose and treat lung cancer.
We need everyone in the lung cancer community to raise their voices and move lung cancer up on the national health agenda. We need you to reach outside the community and recruit others to commit to our cause. We need strong words and determined action. We need the nation to commit to ending lung cancer now.Rich Text AreaToolbarBold (Ctrl + B)Italic (Ctrl + I)Strikethrough (Alt + Shift + D)Unordered list (Alt + Shift + U)Ordered list (Alt + Shift + O)Blockquote (Alt + Shift + Q)Align Left (Alt + Shift + L)Align Center (Alt + Shift + C)Align Right (Alt + Shift + R)Insert/edit link (Alt + Shift + A)Unlink (Alt + Shift + S)Insert More Tag (Alt + Shift + T)Toggle spellchecker (Alt + Shift + N)▼
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Those of us in the lung cancer community know the underlying grimness that accompanies the words “you have lung cancer.” We know that those words are delivered to nearly 200,000 Americans every year and that nearly 160,000 die each year of this disease–more than the number of people who die of breast, colorectal, pancreatic and prostate cancers combined. While we are making incremental progress on many fronts in the battle against lung cancer, breakthroughs have been elusive. For that reason, the recent announcement by the National Cancer Institute that the National Lung Screening Trial (NLST) recorded twenty percent fewer lung cancer deaths among current and former smokers screened with a spiral CT scan rather than the commonly used chest X-ray is monumental. It proves that lives can and will be saved if lung cancer is diagnosed at earlier stages.
It is critical to see the conclusion of the NLST study as a new beginning. Many doctors have believed that CT scans would help diagnose lung cancer at an earlier stage, but we did not have proof that using CT scans would save lives. With the release of initial findings for the NLST study, we have conclusive evidence of the importance of early diagnosis for lung cancer. What previously was intuitive is now demonstrably the case, and that is the true significance of the study. There will be continuing discussion of important considerations that arise out of the study: Who should get a CT scan? How often? Will insurance companies now be willing to pay for CT scans? Will false positives from the scans prove hugely problematic? How do we find lung cancer early for more people?
All of these questions deserve answers, and answers will be forthcoming. For now, what is of most consequence is the fundamental linkage between early diagnosis and survival. It is vital that we build on this
research to develop more effective diagnostic and treatment methods that are cost-effective, widely available and utilized. Government and corporate funding have long neglected lung cancer research. Financial support for lung cancer research is vastly disproportionate to the number of people affected and killed by this disease. We must use the momentum provided by the NLST findings to push for additional funding for vitally needed research that has the potential to dramatically change the way we diagnose and treat lung cancer.
We need everyone in the lung cancer community to raise their voices and move lung cancer up on the national health agenda. We need you to reach outside the community and recruit others to commit to our cause. We need strong words and determined action. We need the nation to commit to ending lung cancer now.
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