24 November: And now a word from our sponsor

For Lung Cancer Awareness Month #LCAM I’m going to review 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/16
To date we have reviewed at a couple of trials looking at the role of surgery in multidisciplinary management (Nov 6 & 8). Today we’ll look at a proper randomized trial of two surgical procedures for staging the mediastinum (the middle of the chest, between the lungs). 2/16
Knowing whether cancer has spread to mediastinal nodes is essential for staging a tumour. As we have seen, staging is required for any treatment decisions. Mediastinal nodes have numbers corresponding to the locations in the diagram below. 3/16
Surgeons may biopsy select nodes before or during surgery (mediastinal node sampling MLNS) and may also completely remove all nodes on one side during surgery (mediastinal node dissection MLND). This trial looked at whether MLND was necessary if MLNS was negative. 4/16
People suspected of having early-stage tumours had MLNS, consisting of stations 2R, 4R, 7, and 10R for right-sided cancers, or 5, 6, 7, and 10L for left-sided cancers.
If all these nodes were negative, patients were randomized in the OR to no further nodal assessment, or to MLND.
The hypothesis was that MLND might improve survival by removing involved nodes, or by identifying higher-stage patients for adjuvant therapy. The trial was powered to detect an 8% improvement in 5-year survival with a 1-sided test. 6/16
This was a large trial, enrolling 1023 people at 63 hospitals between 1999 and 2006. MLNS was performed by mediastinoscopy or by VATS thoracotomy (today some might be performed by ultrasound-guided bronchoscopy biopsies, EBUS). 7/16
By the primary endpoint the trial was negative. There was no difference in survival whether people got MLND or not. Of note, 4% of people with negative MLNS were found to have central (N2) lymph nodes after undergoing MLND. This would be lower today with routine pre-op PET scans.
This is another study where we interpret a lack of superiority as non-inferiority, whether that is rigourously correct or not. Subsequent development of PET scans and EBUS have made us increasingly confident in omitting MLND for most. 9/16
The study-design aspect I’ll talk about today is the role of the sponsor. This trial was sponsored by a co-operative group of doctors and other research professionals, the American College of Surgeon’s Oncology Group (ACOSOG).
Take a look at the statement below from the paper.
In contrast, many trials are sponsored by pharma companies. The company does a lot of the study design, analysis, and often the writing of the final paper with input from the doctors listed as authors. Compare the statement below to the one above. 11/16
Intrinsically, pharma studies are performed for the purpose of obtaining approval to sell their drugs. Cooperative group studies (November 1, 2, 3, 4, 9, 10, 17) may look at questions where there is no obvious profit motive. 12/16
I'm not going to demonize pharma: the system works well when their profit motive leads them to develop improved therapies that are a societal good
But the system works poorly when the drugs are not as good, but are marketed as important advances. Trials are part of that marketing
So when reading a pharma study it’s important to remember that they may have literally billions of dollars riding on the outcome. Pharma are rational actors who are incentivized to produce trials that show their products in the best possible light. 14/16
Look back to the 14 November thread (ADAURA) for examples of trial design elements that favour the sponsor. Recall yesterday regarding unusually elaborate statistical analyses.
It’s important to keep these considerations in mind for any study, but particularly those from pharma.
Tomorrow we’ll take a look at our first paper that’s not a randomized study, to consider meta-analysis. 16/16

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23 Nov
23 November: ALEX and clarity

This year for Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. 1/11 #lcsm
Today we’re returning to ALK-positive lung cancer. Way back on 5 November we looked at the PROFILE study that established crizotinib rather than chemotherapy as the second-line standard of care.
Today’s study compares crizotinib to a newer generation of ALK drug, alectinib. 2/11
This trial enrolled 303 previously untreated people between 2014 and 2016. Primary outcome was progression-free survival, with an 80% power to detect an increase in median PFS form 10.9 to 16.8 months. Particular attention was paid to brain metastases. 3/11
Read 11 tweets
22 Nov
22 November: PACIFIC, intention to treat

For Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/13 Image
We previously looked at locally-advanced lung cancer on 4, 6, and 9 November. We have established standard treatment as ~60 Gy radiotherapy with concurrent chemotherapy for those that are not resectable by lobectomy. Today’s trial looked at adding immunotherapy. 2/13 Image
The antibody in this trial is durvalumab. Like the previously mentioned pembrolizumab (Nov 13, 16) and nivolumab (Nov 19), durvalumab inhibits the interaction of PD-1 and PD-L1. Unlike the other two, durvalumab binds to PD-L1. Clinically, the difference seems negligible. 3/13
Read 13 tweets
21 Nov
21 November: Screening part 2

This year for Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/17 Image
Yesterday we went over the major results of the NLST. We discussed screening in general and the concept of overdiagnosis in particular. Today we’ll look at the Dutch-Belgian NELSON study, the next largest randomized study in this field. 2/17
NELSON enrolled 13 195 people between 2000 and 2004. They were randomly assigned to no screening, or to CT scans at baseline, 1 year, 3 years, and 5.5 years later. The trial was powered to detect a 25% reduction in lung cancer mortality over the 10 years from enrollment. 3/17
Read 17 tweets
20 Nov
20 November: Screening part 1

This year for Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/17 Image
I’m going to spend the next two days on screening studies. Honestly, I have some trepidation in posting on this topic. There are advocates of screening and sceptics about screening, both vocal, and I’m probably going to disagree with most of them. Let’s look at some evidence.2/17
I’m going to review two large screening studies: NLST and NELSON.

Screening is the testing of asymptomatic individuals at risk for a disease. An underlying assumption is that earlier detection results in better outcomes. For many cancers this seems to be the case. 3/17
Read 17 tweets
19 Nov
19 Nov: Ipi-nivo-meso, stratified randomization

For Lung Cancer Awareness Month #LCAM I’m going to review 30 important lung cancer trials in 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial.#lcsm 1/18 Image
We previously discussed a mesothelioma trial on 8 November. On 15 November I also briefly alluded to a study that established platinum/pemetrexed as the standard chemotherapy, in 2004. Today’s study expands the use of immunotherapy into this disease. 2/18
All of our previous immunotherapy trials (13, 16 Nov) have been about pembrolizumab, an antibody to PD-1. This trial uses the similar antibody, nivolumab, along with a second antibody, ipilimumab, which targets a different part of the immune response, called CTLA-4. 3/18
Read 18 tweets
18 Nov
18 November: Pemetrexed & placebo

For Lung Cancer Awareness Month #LCAM I’m going to summarize 30 important lung cancer trials over 30 days. These posts are directed at non-medical professionals, with descriptions of the results and of what makes a good trial. #lcsm 1/13 Image
Today’s trial takes us back to 2005, when standard first-line platinum doublet was given for 4-6 cycles, followed by a treatment break. People would be followed, usually for a few months, and when their cancer worsened they would get second-line chemo, often pemetrexed. 2/13
This trial asked the question of whether people would live longer if the pemetrexed started immediately after first-line chemo (maintenance treatment), rather than waiting and using it in second line. At the time of this study, pemetrexed was not used in first-line. 3/13
Read 13 tweets

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