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:
||Carboplatin AUC 6
|Median Overall Survival1
|1 Year Survival
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.