Impact of Smoking Cessation on Mortality From Kidney Cancer
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Dr. Mahdi Sheikh and Dr. David Zaridze join Dr. Shannon Westin to discuss how quitting smoking after diagnosis may impact survival in kidney cancer.

TRANSCRIPT  The guest on this podcast episode has no disclosures to declare.* Dr. Shannon Westin: Hello everyone, and welcome to another episode of JCO After Hours*. This is the podcast where we get in-depth on manuscripts that have been published in the Journal of Clinical Oncology*. As always, I'm your host, Shannon Westin, Gynecologic Oncologist and Social Media Editor for the JCO*. And I am so excited to be here today. We are going to be discussing the paper, “Smoking Cessation After Diagnosis of Kidney Cancer Is Associated With Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study),” which was published in the JCO* on March 29, 2023. And this very intriguing paper, I have two of the major authors from this paper. First is Mahdi Sheikh, who is a scientist and epidemiologist at the International Agency for Research on Cancer, the World Health Organization in Lyon, France. Welcome, Dr. Sheikh. Dr. Mahdi Sheikh: Thank you very much, Dr. Westin, and thanks for having us. Dr. Shannon Westin: And then with Dr. Sheikh is Dr. David Zaridze. He is the Director of the Department of Clinical Epidemiology at the N.N. Blokhin Russian Cancer Research Center in Moscow and also the President of the Russian Cancer Society. We are with greatness today. Dr. David Zaridze: Thank you. Thank you very much. Nice to be with you. Dr. Shannon Westin: Very nice to be with the two of you. So, let's get started. I first wanted to just level set. Could one of you review just the overall incidence of kidney cancer and what proportion of patients with kidney cancer are known to be smokers at diagnosis? Dr. David Zaridze: The figures I'm going to present are rates. They are adjusted to standard world population. Why am I saying that? Because in America you sometimes use adjustment to the US population. These figures will be different from what you are accustomed to see. Okay, incidence of kidney cancer in Russia, in men, 14.1 per 100,000. I compare this with the United States of America, men, 16.5. Very small difference. Women in Russia, 8 per 100,000. In the United States of America, 8.8 per 100,000 of population. Exactly the same. Very close. These rates are sort of high-ish, but there are very high rates, for example, in the Czech Republic, where rates are more than 20 and other Central European countries. In Russia, kidney cancer mortality in men is 6 per 100,000. In USA, 3 per 100,000. In women in Russia, 1.9. In the United States, 1.3. I would say that there is a difference in mortality in men, not much in women. The incidence of kidney cancer is increasing in Russia sharply, sharply. Since 1990 it has increased - it’s tripled. It increased from 5 per 100,000 in 1990 to 14 per 100,000 in 2019. Mortality is stable or declining. This is suggesting that kidney cancer is overdiagnosed in Russia and probably elsewhere. But this is not a problem of our discussion now. The frequency of the prevalence of smoking in kidney cancer patients. It is estimated that 15% to 20% of patients with kidney cancer smoke. In Russia, we have results only from our study. 18% of patients smoked at admission to our cancer center. Dr. Shannon Westin: Got it. Okay, good. Well, that's really helpful, especially to those of us that don't take care of patients with kidney cancer every day. It helps us just understand. And I guess the next question is what do we know about the impact of tobacco cessation on the risk of kidney cancer? So you were talking about that increasing incidence. How does tobacco cessation impact that? Dr. Mahdi Sheikh: Tobacco smoking is a known risk factor for kidney cancer and an estimated 17% of the kidney cancer burden worldwide can be attributed to tobacco smoking. There is a recent meta-analysis of 56 studies that was published a few years ago that clearly showed a dose-response relationship between smoking and kidney cancer, meaning that the more cigarettes a day you smoke, the risk of kidney cancer will go up. For example, the risk that was shown for five cigarettes per day was 20%. It goes up until 70% for 30 cigarettes per day. And also with a duration, the more years you smoke, the risk for kidney cancer will go higher. However, the good news is that when you quit smoking, there is strong evidence that the risk for developing kidney cancer will be lower compared to if you continue smoking. And there is some evidence that shows again dose-response relationship, meaning that the more years you spend in quitting smoking, the lower your risk would be for developing kidney cancer compared to if you continue smoking. So this is not only about renal cancer or kidney cancer but also true about many other cancer sites as well. Dr. Shannon Westin: Okay, that's super helpful. And then I guess prior to your study that we're about to talk about, did we have any information on what happens when patients quit smoking after their diagnosis? Any limitations to those data that were available? Dr. David Zaridze: You mean the data which was prior our study? You know, the negative effect of smoking after diagnosis has been shown nearly three decades ago. The information exists already for thirty years, but it was largely ignored not only in clinical practice but also in clinical trials. And I have to stress that in clinical trials this information is still ignored. I came across these studies and decided to review them some time ago. All they were case-control studies and to my knowledge, none of them assessed the effect of quitting smoking. I decided to review these studies and included this review in my book, Smoking: A Major Cause of Cancer*, which was published in 2012 and was dedicated to Professor Richard Doll's anniversary. In fact, this was a stimulus for the study we are discussing. And in fact, the component of this study we are discussing today was built in and baked into the existing cohort study to which we added the active follow-up component for assessing the changes in smoking habit and disease status. Dr. Mahdi Sheikh: If you review the evidence, before publishing this study just like a few years ago, we find that there are many studies published talking about the effects of smoking cessation on cancer survival. However, as David mentioned when you go deep into these studies, you’ll find a lot of limitations. First of all, most of these studies are retrospective studies, which means that either case-control or retrospective course that patients developed the outcome, and then some investigators came to see their records to assess or ask family members before they developed the outcomes. There are a lot of biases with these types of studies. And with the epidemiologic study, perspective study that we did, has less limitations compared to retrospective ones. Another one is that when we go into the study you see, they only assess a small number of patients, small sample size. Some studies just assess 10 smokers, some assess like 30. By this study we try to assess a large number of smokers who quit smoking after diagnosis. Another limitation is that– First, let's see what exposure and what setting we are talking about. We're talking about smoking which is a very dynamic behavior. People quit smoking and they relapse smoking and they quit smoking and so on. So if you access this exposure for only a limited time, for example, for one year, then you may miss what happens after that which results in misclassification of some of the participants. So repeated assessment was not done in other studies that we did here in this study. Another one, you are talking about special setting patients who are diagnosed with cancer. These patients have special circumstances, they have treatments, they have family support, they might go under the stress of cancer, and all these different stages at diagnosis. And most studies that are available, they didn’t account for this. They didn't adjust or they didn't try to understand the role of these compounding factors, as we call it in epidemiology, on that, the thing that we're trying to address. And a prospective study, as I said, long follow-up time. Even the very few prospective studies that were available for other cancer sites that have only one year or maximum two years of follow-up with this type of exposure, so it is important to follow them for a long time. Another thing I would say was exposure assessment. Not only did we repeatedly try to assess exposure among participants, but try to call the people– David and his team who did the study in the field, called the participants and tried to ask the family members and sometimes their physicians about their smoking behaviors. When you go to current evidence you see, mostly smoking behavior was assessed using the record that is available like treatment records or patient records, which again has some limitations if you do not assess exposure among qualified participants. Finally, we're talking about a dynamic behavior in the follow-ups. Some people might change smoking. But there is a very important thing, in this study, we also collect at the time of quitting smoking. There's a very important thing in statistics we call Survivorship Bias, meaning that, if you were assessing an exposure doing the follow-up and if you do not pay attention to this, you will assess an exposure that is a proxy of people who lived longer. Meaning that people have enough time, they have a long time, and those who have longer time, will have more time to quit smoking. And then you will be assessing this, actually, not the exposure, but you're only assessing people who quit smoking, and then whatever you assess, you would end up with a beneficial effect. But if you have the time of quitting smoking and follow up and all these statistical things and lower sample size, you are able to account for this very very important bias in epidemiology. Dr. Shannon Westin: Before we go further, I'd love for just a bit of a description of exactly how you laid out your study to really add to where this data are so limited around survival and tobacco cessation. So maybe review the primary/secondary objectives, basic design, just to make sure our listeners are all on the same page. Dr. David Zaridze: The study has classical prospective cohort design that the study, which was basically a basic study, in which the new component was built in. This study used a user’s questionnaire-based exposure assessment and molecular epidemiologic approach. I mean that, in addition to the questionnaire approach, we collected blood and tumor tissues for molecular studies. All patients with kidney cancer admitted to the cancer center were interviewed at admission before receiving any treatment. A structured lifestyle questionnaire was used. Participants were asked about their lifetime smoking history which included questions about the duration and frequency of smoking cigarettes, the average number of cigarettes smoked every day. They were also asked about their lifetime history of alcohol drinking. The questions included questions about exposures to carcinogens other than smoking, and health conditions, including chronic kidney diseases, hypertension, diabetes and so on. Height and weight were measured. Today, this study generated and continues to generate plenty of results and papers published in most prestigious journals such as Nature Genetics,* for example. So, as you know, we started from 2012, we started the follow up of the cohort members, we were focusing on Moscow residents and the follow-up includes regular annual contacts with the patients personally or via telephone or with patients’ household members, etc. Again, we collected information about changes in smoking behavior and disease status. We also used information from the regional cancer registry to confirm the information obtained from patients. The average period of follow up was eight years. And this is quite a long follow-up. Repeated assessment of smoking status reduces the likelihood that exposure to smoking was misclassified. However, regrettably, the self-reported information on smoking was not supported by biochemical tests, for example, by blood cotinine testing. To my knowledge, this is the only prospective cohort study in patients with cancer, not only with kidney cancer that have collected data on participants' smoking status prospectively for quite a long time. The average follow-up time was eight years. Dr. Shannon Westin: That was incredible. That definitely caught my eye. And I was looking, I was like, “Oh, how many did they lose?” And you guys kept 80-100% of the patients. I just was so impressed by that. And now hearing the mechanisms in which you did that, it makes sense. You were very diligent, multiple ways to contact patients and confirm the data. So you really are to be congratulated for the work that you're able to achieve. Dr. Sheikh, I'd love to hear, you talked a little bit about how some of the studies didn't really think about confounding variables. Can you kind of highlight some of the confounding variables that you all controlled for in order to really assess the impact of the cessation on survival? Dr. Mahdi Sheikh: Thanks to the high-quality data and also the large sample size and the way the study was designed, we were able to adjust for a lot of confounding. So we tried to adjust for all these things. So we used three approaches. The first approach was adjustment. When you ran this in the analysis, we tried a statistical model, we tried to adjust for these confounders like age, sex, treatment, socioeconomic status, smoking intensity, alcohol, and other factors. This is one effect, one approach. The second approach was stratification, meaning that we come and see the effect within people who have been diagnosed with only earlier stage tumors to see if the effect among people with earlier stage tumors differs with the effect that we see among people with higher stage tumors. But again, if you read the paper, you see that we saw the protective effects of smoking cessation on both groups of people, those who were diagnosed at earlier stages and those who were diagnosed at later stages. And also heavy smokers or mild to moderate smokers, again, we tried stratified analysis excluding those heavy smokers and saw the effect, again, among those who were light smokers or moderate smokers and also with the heavy smokers. I want to say that we tried all these types of analytical approaches and we really saw the protective effects across all patient subgroups. Finally, I talked again about the survivorship bias. So we used really strict statistical approaches to address this confounding, and because we had the time of quitting, we had the follow up time and all these things. And, again, whatever we did in the study we still could see the effects of smoking and all this is due to the good design, the large sample size, and the good questionnaire data that we have. Dr. Shannon Westin: That's awesome. I think, of course, now let's get to the bottom line. 40% reported that they quit smoking after diagnosis with none relapsing during the time period. And what did you see was the impact on overall survival as well as cancer-specific survival? Dr. Mahdi Sheikh: So we tried several outcomes - overall survival, cancer-specific survival, but also progression-free survival. And then because we had the large sample size we could assess all this. Interestingly, we saw the effect on all the three outcomes that we assessed. So the overall survival was better among those during the quitting time and also the cancer-specific survival was also better and also progression-free survival was better among all these participants. Dr. Shannon Westin: I think most people that have read this paper - and if you haven't read this paper you should run to read it right now - I really was impressed with that kind of clear benefit across cancer-specific mentality across all subgroups regardless of how much they smoked. So I don't know why you get a sense of like, “Oh, if you smoke a little bit you wouldn't see as big of an impact,” but a very clear impact. And I would love to hear why you think smoking negatively impacts these outcomes. How does the cessation help? This is a perfect time for that. Dr. Mahdi Sheikh: When we review the evidence about how smoking cessation may be beneficial for patients, for the survivorship of patients with cancer, we come to five mechanisms that are suggested in the literature. So the first one can be, is suggested, that is altered cancer biology. Smoke and tobacco smoke contain numerous carcinogens and mutagens. So it has been shown that cancer cells that are exposed to tobacco smoke, they may become more aggressive and the risk of metastasis might go higher and also, angiogenesis and all other effects on the biology of cancer cells. So it may affect the cancer cell biology. Another suggested mechanism might be altered immune response. So tobacco smoking affects the immune system and then the immune response among those who are exposed to tobacco might be affected by tobacco smoking. So their response to the cancer cells but also other bacteria, viruses, and other things might be affected as well. The third possible mechanism suggested altered drug metabolism. It has been shown that tobacco smoke and smoking can affect some of the enzymes that have metabolic responsibilities and metabolism of the drugs. So that can affect the washout period for the drug. It might not stay enough in the blood or vice versa as well. It might affect the toxicity. There is some evidence about this. The fourth mechanism suggested is about increasing treating-related complications or treatment-related complications. People who smoke have delayed wound healing, they have more complications, the surgery, the time they spend at the hospital might be longer. And this is also part of which smoking may affect the outcomes that we saw here. And finally, that is we are talking about tobacco smoking and patients with cancer are human beings with all these systems. So we know that smoking causes damage to the cardiovascular system, to the pulmonary system and also to the lungs and other things. So this is why we see different outcomes are affected by cancer. Dr. David Zaridze: I was impressed by the data that exposure to tobacco smoke condensate induces changes in tumor microenvironment. For example, it inhibits formation of interferons, interferon alpha and gamma, inhibits the migration to tumor microenvironment of the immune cells. The number of CD8+ T lymphocytes, T killers, are significantly lower in the tumor microenvironment of current smokers compared to former smokers and never smokers. And even more interestingly, the number of PD-L1+ cells are also lower in the tumor microenvironment of current smokers than former or never smokers. This is probably very important in terms of effectiveness of impairment by smoking of the immunotherapeutic approaches in cancer treatment. Dr. Shannon Westin: That's very important and we know the microenvironment has a huge impact on just the way the cells respond to treatment and develop resistance and so that makes a lot of sense. Okay, well, this has been amazing and I think one thing that you just said just struck me, Dr. Sheikh, that you've obviously shown this in lung cancer and you're looking at this in other cancers. I guess the question is: What should we be doing? How should we be implementing tobacco cessation efforts across all cancer diagnoses to help all patients that have really any diagnosis of cancer? Dr. David Zaridze: Let me first underline the clinical importance of these results. The benefits from quitting smoking are comparable or even superior to those recorded in the clinical trials of modern kidney cancer treatments such as immune checkpoint inhibitors. I refer to the results of pivotal trials in advanced renal cell cancer in the frontline setting and these results were reported at ASCO Meeting 2023 recently in May. If you compare the results of our study with results of these pivotal trials, it is very impressive. It is clear that our findings strengthen the case for making tobacco cessation treatment a standard part of the routine health care for all people with cancer, however, smoking is still quite high in cancer patients. And I would like to quote Peter Shields who is saying that, in the United States,10% to 50% of cancer patients smoke. As far as Russia is concerned, in our study, 80% of kidney cancer patients smoke, and in our lung cancer study, 58% of cancer patients smoke.  The barrier is that the oncologists do not believe or are accepting with a great deal of skepticism the results of our study. They don't believe the idea that anything else besides surgical, radiological, or medical treatment could improve the outlook of cancer patients. It's difficult for them to apprehend. Many of them think that smoking cessation after diagnosis is simply a waste of time. Many patients simply don't know that smoking cessation after diagnosis may be beneficial for them. In addition, they are pessimistic and they feel discouraged to quit smoking, as they might think it is too late. I would like to quote my favorite quote: “Smoking cessation treatment has to become the fourth pillar of cancer treatment, one that could affect cancer treatment outcomes as powerfully as surgery, chemotherapy, or radiation therapy.” This is Dr. Fiore, 2019. Dr. Shannon Westin: Thank you so much. And Dr. Sheikh, anything to add there around cessation efforts? Dr. Mahdi Sheikh: As we saw the results of these studies that smoking cessation is feasible and it is accessible at a minimum cost for many patients, it should really be integrated in the  management of patients with cancer. It is feasible, it is cheap, it is accessible. But unfortunately, when we review the evidence we see that only less than half of the physicians, like around 40% of physicians, send the patients to tobacco smoking cessation services. And even some do not discuss this issue. And as David mentioned, they do not know the effect of smoking cessation. So when you go through these studies to find the major barriers, in addition to what David had mentioned, we find two important points. First one is lack of education or experience in providing tobacco cessation interventions among those who deal with patients with cancer. So they do not have the education. And second is lack of available resources for referrals. Now we’re not only talking about the United States but also many other countries even high-income countries, we do not see the resources for referrals on smoking cessation services in cancer care settings. The take home message probably from this study and also from these barriers, would be for three groups. First, for the policymakers, we would recommend sustainable funding should be dedicated to tobacco cessation services. As we saw, the effect is huge and seems to be a very big effect and it is cheap so why not implement this smoking cessation service within cancer care settings.  And the second one, tobacco treatment training programs for healthcare providers. This is also very, very important that we try to implement this training program in the curriculum of healthcare providers, especially those who deal with cancers and tobacco-related outcomes. And also for physicians, we recommend that physicians should assess and address tobacco use in all patients with cancer. They should talk about this topic and also show the benefits of quitting smoking. And patients with cancer who smoke should be supported to stop smoking at any time and each visit after diagnosis is not like some time pass, as we saw, all patient subgroups could benefit from smoking cessation. This is important.  But something also very, very important that we shouldn't forget that cancer itself causes a lot of fear and anxiety and stress. And smoking cessation sometimes may be associated with stress and more anxiety. So it is very, very important to think about this point and provide the psychosocial support to patients who quit smoking. Sometimes they may relapse just because of the fear and anxiety they have. So it's not only showing the evidence, but also supporting these patients, telling them how to do that and also supporting them emotionally and also psychosocially. And finally for the patients, I would like to give this message that we see and we know that it is never too late to quit smoking. As David said, patients may feel like, “It is too late now I've developed cancers,” but no, it's really not too late. And if you quit smoking at any time after diagnosis, you would benefit a lot from smoking cessation. Dr. David Zaridze: In the United States there are guidelines, several guidelines for smoking cessation, specifically for cancer patients because smoking cessation in cancer patients is very different from smoking cessation in general population. In the general population, we more or less succeeded, I would say, and we have to look now at this direction to the smoking cessation in cancer patients. And this is a message to WHO, that countries, members of WHO, based on the recommendation guidelines of WHO, develop their own specific guidelines for smoking cessation in cancer patients. And that should be used in all cancer clinics and that should be a must, absolutely important part of anti-cancer treatment. And as I already told, it should be the fourth pillar in cancer treatment, as treatment, as surgery, chemotherapy and radiation. Dr. Shannon Westin: Thank you both. That was such a great discussion, and I hope that we've convinced everyone that this is a critical effort that they need to be addressing every day.  I just want to thank everyone who listened. This has been "Smoking Cessation after Diagnosis of Kidney Cancers Associated with Reduced Risk of Mortality and Cancer Progression: A Prospective Cohort Study", again published in the JCO* on March 29, 2023. Thank you guys again for listening to JCO After Hours*. Please check out our other podcast offerings. You can check them out on the website or wherever you get your podcasts and let us know what you think about the podcast on Twitter. Dr. David Zaridze: Thank you. Dr. Mahdi Sheikh: Thank you very much.  The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions. * * Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.*