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Ruchika Talwar: Hi everyone, and welcome back to UroToday's Health Policy Center of Excellence. My name is Ruchika Talwar, and today I'm joined by Dr. Hannah Kay, a PGY-3 resident from UNC Chapel Hill, as well as Dr. Marc Bjurlin, an Associate Professor of Urologic Oncology, also from UNC Chapel Hill. They'll be discussing some of their recent work on the reporting of smoking status in bladder cancer trials. Thanks so much to both of you for being here with us today.

Marc Bjurlin: Thanks for the opportunity.

Hannah Kay: Thank you so much. Once again, this is an honor to be here. We really appreciate it. This is an area that Dr. Bjurlin and myself are quite passionate about within the bladder cancer sphere. So the title of our study and review is "Clearing the Smoke: The Underreporting of Smoking Status in Food and Drug Administration Approved Bladder Cancer Therapeutic Trials." So, as a little bit of background, anyone practicing urology understands that cigarette smoking is the most common modifiable risk factor for the development of bladder cancer, accounting for up to 50% of diagnosed cases of cancer. Continued smoking after the diagnosis of bladder cancer can have negative impacts on multiple components of bladder cancer recovery. This includes but is not limited to worse surgical outcomes due to higher anesthetic risk and poor tissue recovery. There's a greater risk of chemotherapy adverse effects, and we do see less benefit from neoadjuvant chemotherapy in smokers, which we'll discuss briefly in future slides. There's also a known greater risk of radiation adverse effects.

So, every aspect of bladder cancer therapy can be impacted by smoking. In addition, there are known impacts on quality of life in all cancer patients, but especially in our bladder cancer patients if they continue to smoke after diagnosis. So despite the known negative associations between smoking and bladder cancer or BC outcomes, the details of clinical trial participants' smoking status remain largely understudied in the bladder cancer sphere. So, how does this relate on a more genomic and molecular level? Smoking history in and of itself is associated with distinct changes to a patient's tumor molecular biology. Bladder cancer patients who smoke are actually correlated with a higher PD-L1 expression, up to greater than 50% compared to non-smokers. This has been shown to modulate the efficacy of multiple immunotherapy drugs. In addition, patients who smoke have higher proportions of TP53, PIK3CA, and ERBB2 or HER2, which can impact the efficacy of drugs as well.

The oncogenic differences seen in smokers can be a pathway for more precise selection of therapeutics for bladder cancer patients. Within cigarette smoking itself, there are tobacco-related carcinogens that can impact the pharmacokinetics of bladder cancer therapeutics, such as polycyclic aromatic hydrocarbons, which are known to be CYP450 inducers. This is relevant in particular to the drug erlotinib, which is a CYP-dependent drug that's rapidly cleared by smokers due to the induction of CYP450. Smoking also induces the overexpression of cytidine deaminase, which can increase the catabolism of gemcitabine, a very commonly utilized drug in the bladder cancer sphere. And finally, studies have shown that smoking may reduce the efficacy of one of our most powerful treatments, intravesical BCG.

So, we took that information and our understanding on that level and thought, how is smoking evaluated within clinical trials relevant to bladder cancer therapeutics? For the purpose of our investigation, we looked at all bladder cancer drugs that have been FDA-approved from 2013 to 2023. So, 10 years of drugs. We then evaluated the major PubMed-indexed studies, which led to their approval, and we assessed their clinical trial designs for whether they reported smoking status among trial participants. In order to have a good understanding of how this related to other smoking-related malignancies, we performed the same analysis for non-small cell lung cancer and small cell lung cancer drugs that have also been approved within the past 10 years. And again, we chose to do that because these are cancers known to be associated with smoking.

In terms of our results, they are brief, but I do believe they're powerful. There were nine bladder cancer drugs approved within the last 10 years, and across that, we evaluated 17 trials. Only 41.2% of these reported smoking status in their trial design. Conversely, we evaluated 22 non-small cell lung cancer trials, and of those, 86.3% reported smoking status in their trial design. And 100% of the nine small cell lung cancer trials we evaluated reported smoking status. I think perhaps the most interesting part of our study was that four of the drugs that were studied, pembrolizumab, nivolumab, atezolizumab, and durvalumab, were approved for both bladder cancer and either non-small cell or small cell lung carcinoma. Smoking status in those particular drugs was reported in only 44% of the bladder cancer trials but 100% of the relevant lung cancer trials. So, there's clearly a difference in how these trials are designed even for the same drug across malignancies.

So, in conclusion, as I just said, there are different rates of reported smoking status across bladder cancer versus other smoking-related malignancies. We feel this may be related to different public and scientific perceptions of how smoking relates to these two different malignancies. Furthermore, there's no current standardized method or requirement for reporting of smoking status in clinical trials, which is highlighted by that last data point I raised, which is the difference in design for the same drug. And I think it's worth noting, this figure on the right is from JAMA Health Forum, and it goes over the last 10 or so years of smoking prevalence data, which fortunately we are seeing a downward trend in adult smoking rates. Which is great, but there's still work to be done and there's still understanding to be done, especially for this population of adults, 65 and older, where we're not really seeing that downward trend. And that's generally the population we're treating when it comes to bladder cancer.

So in terms of next steps, past, present, and future. There's a lot of acronyms here that I unfortunately don't have memorized, but it's worth noting that the relationship between cancer treatment and smoking status is not a new connection that we're making. There's a clear understanding of the relationship between the two. Multiple task forces have been introduced. Even 10 years ago, we were already talking about this. But I think the most powerful part of this slide is the future direction in terms of clinical trials uniformly assessing tobacco use and how it impacts these therapeutic outcomes. And our hope is that this discussion today can promote that across urologists, and we can start making those policy changes and putting them into practice.

Ruchika Talwar: Thank you so much, Dr. Kay, for that really interesting presentation of your work. I think this is a really important area of investigation. Particularly, there's been a focus on both assessing smoking status in the setting of clinical trials and investigations, but also focusing on how urologists can assist patients with smoking cessation, both before and during malignancy treatment, whether it's bladder cancer, prostate cancer, renal cell, etc. One thing that really stood out to me was, like you said, the lung cancer literature has done such a better job of reporting smoking status in their trials. And I know that you did have an area where you hypothesized perhaps why that is. Maybe it has to do with the fact that there's a direct perception link between lung cancer and smoking status. But Dr. Kay, I'm wondering if you could just share a little more of your thoughts on that.

Hannah Kay: Yeah, I think this is also pretty obvious when it comes to counseling our own patients on smoking cessation. There seems to be maybe a cognitive disconnect between the idea of inhaling something and then it impacts your bladder. I think it's a lot easier to make the connection that inhaling something will impact your lungs. And for patients and for the public, it's very clear, "Oh, my grandfather smoked and got lung cancer." It doesn't seem that far-fetched. But, "Oh, my grandfather smoked and he also somehow got bladder cancer," is very common. And I just think it's harder to make that connection outside of a medical background. So as much as we can do to advocate for that and help patients understand that connection more directly is helpful. I don't know if you have other thoughts on that, Dr. Bjurlin.

Marc Bjurlin: So, yeah, as Dr. Kay mentioned, the understanding of the link between bladder cancer and smoking is not nearly as well known, not only in our patient population but also among some providers. And that's really a next step is to inform not only our patients who have bladder cancer, but also we have some scientific conferences really exploring the link between bladder cancer and smoking. And then all the benefits that come with smoking cessation as well as avenues that we can improve smoking cessation counseling among our urology colleagues.

Ruchika Talwar: Yeah, absolutely. And Dr. Bjurlin, speaking of next steps, I'm curious from a policy perspective, we've seen pushes from both the FDA and other organizations such as the NCI leading in the trial space, looking at quality improvement initiatives in our clinical trials, such as increasing diverse enrollment in clinical trials. For me, this seems like an area ripe for quality improvement too. So I'm wondering if you could share your thoughts on potential ways from a policy perspective that agencies could encourage the reporting of smoking status.

Marc Bjurlin: Absolutely. And I entirely agree, and I think that's really on the table right now with the FDA. Making some notes going forward that in order for drugs to get FDA approval, their clinical study design will have to account for smoking status. And then probably equally important is to track smoking status going forward. Because we do know that the time of a malignant diagnosis is really a teachable moment. So patients may smoke up to the time of diagnosis and then hopefully consider cessation at that time, which can impact how the drug works and then how it works going forward in both the smoker and the patient who has quit smoking.

Ruchika Talwar: Yeah. And a lot of these trials are also sponsored or supported by the industry. And so, where do you feel the industry's role fits in all of this?

Marc Bjurlin: So indeed, a number of these trials are going to be run by large pharmaceutical companies who manufacture the drug. And I think that the more we learn about how smoking impacts the efficacy of the treatment of these patients, the more that the actual company is going to want that included in their clinical design. If patients who are, for example, in the immunotherapy space, it actually shows that it appears that smokers probably have a better response in the immunotherapy space compared to non-smokers. And we can really tailor an individual's treatment to this type of precision medicine, knowing the outcomes they could have.

Ruchika Talwar: Dr. Kay, as we wrap up, what are your messages to the broader urologic community? What are the main takeaways from your work, and how should we adapt our practice moving forward?

Hannah Kay: Yeah, that's a great question. And Dr. Bjurlin and I have spent a lot of time working on a couple of other studies. For me, what I am most passionate about, and what I'm taking away for patients, is counseling them on how smoking not only impacts the scientific aspects of their potential treatments but also their quality of life as not only an individual, just a person existing, but as a cancer patient. And there is data that we have found, and that we will be publishing hopefully soon, that shows that quality of life is pretty significantly impacted across domains for these patients who either are smokers up to their point of diagnosis or continue smoking past their point of diagnosis.

And like Dr. Bjurlin has published previously, it only takes four minutes to counsel a patient on smoking cessation. And then that's really a powerful tool that we can have as providers who are specialized, but oftentimes serving as primary care physicians for urologic patients and often following them much more frequently than other providers they might see. So I think we have a lot of power in this space, and the more data we can show for that is just going to continue to help. And I'm still young in my career, so I have a chance to really make it a part of my daily practice.

Ruchika Talwar: Great. Dr. Bjurlin, any parting words?

Marc Bjurlin: Yeah. I think, as Hannah suggested, it's really useful for providers to understand what resources they have both at the hospital and institutional level, as well as statewide and nationwide. Because obviously, we'd like to get all urologists to feel comfortable counseling their patients on smoking cessation, prescribing pharmacotherapy, and nicotine replacement. But we also know that it may not be a realistic expectation that every urologist would do that. But urologists can refer their patients who smoke to their tobacco treatment programs. There's 1-800-QUIT-NOW lines. There's a number of smoking cessation resources outside the actual urologic community that can be utilized. So I think knowing those resources would be really helpful in order to help promote smoking cessation among our patient population.

Ruchika Talwar: Absolutely. I couldn't agree more with both of you and am really excited to see this future work that you've referenced. I think it's an area that is in dire need of further investigation and improvement. So, thank you both again for taking the time to chat with us today.

Hannah Kay: Thank you for having us. We really appreciate it.

Ruchika Talwar: And to our audience, thank you so much for joining us. We'll see you next time.