27 November:Temel, QoL outcomes

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 1/19 Image
Today’s trial is one of the most thought-provoking of the month, and it has been discussed widely since its publication in 2010. It is a trial looking at the timing of referral to palliative care for people with advanced, incurable lung cancer. 2/19
Many people hold the view that palliative care is care at the end of life. While this is a component of it, palliative care physicians are experts in controlling symptoms, which is valuable in a highly-symptomatic disease like metastatic lung cancer. 3/19
This trial enrolled 151 people at Massachusetts General Hospital between 2006-2009. They were randomized to be referred to a palliative care specialist either within 12 weeks of diagnosis, or at the discretion of the oncologist (standard care). 4/19
The primary outcome was a Quality of Life measure, taken 12 weeks after diagnosis. The FACT-L (Functional Assessment of Cancer Therapy-Lung) is a questionnaire where respondents rate 36 items from 0-4, which are then summed to a total score (TOI). Page 1 is reproduced below. 5/19 Image
There were numerous other outcomes, including additional questionnaires focused on mood and depression, type and place of end of life care, and survival. 6/19
The trial was positive, with TOI improving by 2.3 points in the palliative care group, and deteriorating by 2.3 points in the standard of care group (p=0.04). People in the palliative care group had better depression scores, but no difference in anxiety scores. 7/19 Image
Provocatively, patients in the early palliative care group were less likely to receive aggressive end of life care, defined as any of:
1. Chemotherapy within 14 days of death
2. Never admitted to hospice
3. Admitted to hospice within 3 days of death
8/19
Most provocative of all, despite having less aggressive therapy at the end of life, people in the early palliative care group lived longer (median OS 11.6 vs 8.9 months, p=0.02). 9/19 Image
I want to talk about QoL outcomes before discussing the issues raised by this trial. There is widespread agreement that Quality of Life is a crucial outcome for patients, as important (or more so) than duration of survival. But how to measure it? 10/19
Most studies use a measure like this trial did: a composite score of one or many questionnaires about symptoms and experiences. They are administered sequentially, and usually report changes over time, rather than scores at a single time point. 11/19
Many oncologists feel some unease about these endpoints:

1. There are several competing questionnaires
2. The outcomes are mathematically complex, subject to potential manipulation
3. QoL seems ineffable: to these questionnaires truly capture it?
12/19
This trial has inspired a lot of commentary: firstly, is the Overall Survival advantage real? Certainly, it was a surprising finding, and likely the reason the trial was so widely read. It was a secondary endpoint, so not included in the 5% false-positive tolerance of the study.
Subsequent studies have also hinted at a survival advantage with quality palliative care. There is probably a real advantage there, but I think that even if there was not, the other advantages of early palliative care are meaningful, and are what we should want for our patients.
Second: as an oncologist, how much of this care can I provide myself? Though we focus on provision of active treatments, asking about symptoms, coping, and mood ought not to be outside our scope of practice, even if we are supported by palliative care specialists. 15/19
Third, the combination of less intense cancer care at end of life and improved survival has made me reflect on whether later lines of therapy actually make things worse.
There are lots of motivations for both patients & doctors to continue treatment into 3rd, 4th, 5th etc lines.
For some people this makes sense. For many though, particularly as performance status starts to decline, there likely comes a time where more cancer treatments are not just futile, but actually harmful. 17/19
I think this is a common problem. A few years ago in my clinic a resident asked me how many lines of therapy patients got, on average.
My immediate and unthinking response: “One too many”.
18/19
To date these reviews have focused almost exclusively on phase III randomized controlled trials. The next two days will look at non-randomized trials, and at randomized phase II designs, to discuss their strengths and weaknesses. 19/19 Image

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29 Nov
29 Nov: Chemo/gefitinib, randomized phase II

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 1/11 Image
All of the randomized studies we’ve looked at to date have been phase III studies, meaning that they are randomized studies with sufficient statistical power to demonstrate a clinically meaningful difference. Today we’ll look at a randomized phase II study. 2/11
Traditionally, phase II studies were preliminary studies done to see if a treatment approach was promising enough to warrant a proper phase III trial. They were single arm, and considered “positive” if they met some pre-specified level of treatment activity. 3/11
Read 11 tweets
28 Nov
28 November: ROS1, single arm trials

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 1/15 Image
This month I have focused exclusively on randomized studies, because I believe strongly that they are our best tools for evaluating the benefits and harms of cancer therapies. Today will be my sole foray into non-randomized studies. I hope to illustrate some of their limitations. ImageImage
In a single-arm study, every patient receives the study treatment. A common method of describing drug activity is the waterfall plot, below. Each bar on the plot is an individual patient. The height and direction of the bar show how the size of the tumours changed with treatment. Image
Read 15 tweets
24 Nov
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
Read 16 tweets
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

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