Neoadjuvant and Adjuvant Chemotherapy in Bladder Cancer

It was mentioned earlier that bladder cancer has been a terrible red-headed stepchild, and thanks to many of the folks in the room, and who have already presented before me, and I’m honored to be on this faculty, we’ve really gotten to a point right now where bladder cancer is the sizzle. It’s actually sexy, and it’s interesting now, and we can do so much better. But the only way we’re going to get there in terms of really doing what’s best for the patient, but it really does end up with better outcomes, and outcomes are very, very important right now because that’s what healthcare is all about. It’s all about creating value, which is outcome divided by cost.

We’ve heard already, the importance and the efficacy of radical cystectomy. What an incredibly, if it were a drug it would be rather remarkable, But when the right patient, despite the fact that this is a highly technical, very skilled procedure with a tremendous amount of associated morbidity and even more mortality one can get remarkable survival rates when timed correctly. And it took a while but sometimes we think of things as intuitive but the data has to be shown, and then of course the clinical perspective always doesn’t match pathologically. When we see pathologically organ confined versus extravesical versus nodal metastases is that’s where we start to have our issues, and that’s where we’re now catching up in the field whether it’s in chemotherapy or now what we’ll hear in terms of the immuno-oncologics. John Stein, great work, really demonstrating this before it was really shown. It was intuitive but he was one of the first to really show this in this paper in JCO 2001.

So, optimizing, I really talked about, even though it says neoadjuvant chemotherapy we’re really thinking more in terms of perioperative chemotherapy and perioperative systemic therapy now, now that we have the checkpoint inhibiters, and that’s really where we’re driving I suspect, and future IBCUs will say wow, it’s just we won’t even talk about this nomenclature, we’ll just think about combination therapy and better markers to help us get there. But we have limited level one evidence, and then that ultimately should really be our north star, and that’s a lot of the work that you heard already presented by Sam Chang today on the non-muscle invasive, and then we look forward to getting the muscle invasive guidelines at the AUA this year.

But just as a quick summary looking at patients who are T2 to T4, perioperative chemotherapy why give it? We want to improve and eradicate clinical disease, and we want to really improve overall survival because we still have patients who succumb to the disease for various reasons, aggressive pathology and other comorbidities.

What are our options? You see them all listed here. I’m a big fan, although my talk is not on it today, on bladder sparing strategies because despite the literature that we have it really is one thing to talk about evidence-based literature it’s another thing to sit knee to knee with a patient and tell them you are going to take their bladder out. You get really deer in the headlights look, more than most things that we get in uro-oncology, and it’s for all appropriate reasons. So, bladder sparing strategies and how we can get there and avoid the morbidity of removing the bladder that’s actually, that’s clearly one of our Holy Grails.

Neoadjuvant chemotherapy, what are the advantages? Patients are clearly at that time presumably more fit, there’s an opportunity to see what the original primary tumor is, and does it correlate with prognostic significance? Will there be predictive biomarkers to better help us and then ultimately is there even an opportunity for organ preservation if indeed the patient has a robust response? And these are all things that we have to further investigate.

The disadvantages are the often times marked discordance, as already been shown today, between pathological and clinical staging. It’s particularly true in what we think is clinical T2.

Selecting patients for neoadjuvant chemotherapy, platinum based, and that was really the brilliance of the MVAC regimen, it was really getting to that. Now we’re getting a better understanding. We saw the conundrum of the p53 trial, but now we’re seeing different variants that may be better able to inform us regarding platinum-based therapy versus immunologic therapies. I’m sure Dan will talk about that and whether it’s luminal or basal or the particular subtypes within those compartments. But there are certainly patients who don’t receive platinum-based therapy, and there is many of these patients who have renal impairment and other whether it’s cardiovascular, etcetera, and these are often times elderly patients, as Dr. Pinthus has pointed out today, and they have many other comorbidities in addition to the usual smoking/alcohol predilections. So, poor performance status makes it very, very difficult, and again one of the more interesting and appealing potential aspects of immuno-oncologics which have very for the most part very well tolerability profiles.

This has already been shown. You’ve seen this now, and it is where we stand on the shoulders of giants before us, and this is a great trial, and this is an international collaboration of trials that really did show the benefit of getting chemotherapy upfront versus no chemotherapy in a large number of patients who underwent cystectomy and showed a 16% reduction in the risk of death with neoadjuvant chemotherapy with a pretty good follow-up duration. And then later on as Dave was integrally involved at SWOG, and thanks to him and others, look at the 8710. You’ve seen this trial referenced so many times today, and Bart Grossman is first author here, again, showing the benefit of neoadjuvant chemotherapy as well as the downstaging of the tumor.

There really is now level one evidence that patients who do receive it have a, and that ultimately go onto get radical cystectomy there’s an absolutely 5% difference in mortality, and there’s a very significant PT0, as well as a downstaging. The problem is that a good 60% of patients don’t really have benefit from it, and how do we better select these patients? This also just continues to show the advantage of the survival benefit, and most improvement especially in patients who were T3 or greater.

You saw this slide earlier, I believe Seth presented it and I think also Sam did as well. Quality of surgery influences bladder cancer outcomes. Well, it seems intuitive. We say that all now, but I can say in the arc of my career not everybody always thought that or would say that. now we see that really the best work is done in “high-volume centers.” And as Raj Pruthi’s work that was shown earlier does it need to be 25 to 30 cystectomies before you really get your groove? Do you need to do ten a year? Should you be doing more a year? Is it more than just the surgeon? Is it the entire set up? I would argue that it really is. In addition to the surgeon’s skill there really has to be the entire operative team and the post-operative care. And the thing that really strikes me is that we’re moving into this era that so many of our academic and tertiary center colleagues are being somewhat flooded with many of these patients, and so where the rubber will meet the road is the issue of economics, and we often times don’t like to address that, but that will rear itself very dramatically now that we’re in this era of the macro transition of volume to value-based care. So, going to centers that can do it really well, get great patient outcomes, and do it in a costly way.

Why aren’t eligible patients receiving neoadjuvant chemotherapy? That’s a little bit of the challenge here. And what we’re seeing is that typically urologists and still about 80 to 85% of cancer care goes on in the community, and I’ll show you some data later on in this presentation that we’ve made some strides but it really hasn’t been as high as you would think. So, what are some of the reasons? Well, there’s the risk/benefit of who will benefit. Some patients will clearly benefit and a significant percentage will not. How do we define better markers and better risk stratification? How do we do better precision medicine? As Dan Theodorescu addressed.

There is the concern about delaying cystectomy, and then of course the associated toxicities. And I think a big answer to that goes back to the importance of urologists making sure that they’re having good multidisciplinary conversation with their medical oncologists, as well as shared decision making with the patients. It sounds glib to say, but we really need to do better at doing that because there are clearly segments of patients who will have excellent responses regardless of age.

One of the problems too, and after radical cystectomy, is that there’s a potential significant risk for renal function deterioration through either the perioperative experience or obstructive changes, and therefore the post-operative reductions could render patients ineligible for therapy that could have been very beneficial in a neoadjuvant setting.

But with that said we have adjuvant chemotherapy. They can be administered based upon our pathological stage. If a patient is PTO, one might feel that it was clear that there could be an opportunity to hold back and avoid chemotherapy, and the other advantage is it delays the potential for a whole host of reasons, we’re all familiar with them, in delaying scheduling cystectomy. Surgeon’s schedule, hospital’s schedule, patient’s schedule, etcetera, untoward complications of infections and multiple other life issues. The disadvantage is it’s more difficult to deliver a moderately toxic chemotherapy in the post-operative setting and give it the doses that need to be given.

But what’s the rationale? Well, it is widely used outside of clinical trials, the PT3/4, and for node-positive disease, and there are many small studies and anecdotal reviews. And I’m going to show you some really nice work that was published recently by Matt Galsky in JCO just a few months ago showing some meta-analyses suggesting that it does have improvement in overall survival. And this could be very appealing as well to surgeons who want to get the bladder removed as quickly as possible.

The advantage is that it’s based on further now and pathological staging, you’re able to immediately move to cystectomy. The disadvantage is the potential unnecessary exposure to chemotherapy for those who might already be exposed, who are cured by cystectomy, if they still felt compelled to go with a course of chemotherapy.

There have been a whole bunch of randomized trials of adjuvant therapy, you can see them all listed here. They’re relatively, you know, most were single institution, small numbers. And one of the biggest challenges for all of us who are trialists in the audience this is an area that because of the patient population and because of all of the moving parts it’s often very hard to accrue patients to these trials, another reason to really love what the SWOG was able to accomplish, but most of these contemporary trials are closed due to poor patient accrual.

But this is the paper I was mentioning to you published this year by Galsky in JCO, and that looking at a forest plot meta-analysis of real-world patients who get adjuvant chemotherapy, and I apologize that the hazard ratio, the forest plot here it’s a meta-analysis, you probably have a hard time seeing it. But looking at age, sex, nodal status, patients overall did well in this real-world aggregation of all of those different trials that we looked at, but it’s not level one evidence.

Some of the conclusions for chemotherapy is combining a cisplatin-based adjuvant chemotherapy can improve overall survival. Benefit appears to be larger in node-positive patients, but this is a limited dataset that could be exaggerating the treatment effect. So, neoadjuvant chemotherapy decision making, you’ve seen slides on this before. It’s not completely exhausted but it really would be the type of patient who you would say this should be someone who I would strongly consider who had some of these, if not any one of these particular factors, as well as reasonable performance status and can tolerate upfront four cycles of gem-cis or MVAC.

Clinical staging as I mentioned before is notoriously inaccurate. We’ve come to recognize that. I do think in listening to even Sam’s really great review of all of the non-muscle invasive guidelines even with that and all of that hard work that gets done is how often does that really translate and get inculcated into the community? And so much of our staging inaccuracy continues to occur, and we certainly need to do a better job. So, not only with predictive markers for figuring out therapeutics, but newer imaging modalities will hopefully make this staging inaccuracy less of an issue.

Neoadjuvant toxicity does not reduce the rates of actual radical cystectomy. Now, this is in trial settings, and this was nicely shown in the 8710 SWOG trial that virtually the same number, percentage of patients ended up getting cystectomies, but we know that that’s a little bit different in a real world sometimes. And that is also some of the taint of that changes, and I think that it affects community-based clinicians. And as I mentioned earlier, not all patients are eligible for neoadjuvant chemotherapy.

This is just a summary, it’s a little bit detailed. I’ll let you sort of read through it, comparing neoadjuvant versus adjuvant. You can get copies of these, which really summarizes it. I do think just a note on the issue for bladder preservation and bladder sparing strategies, I do think that that is something that despite that fact that we can get great results in cystectomy patients for the right patient, right time, no doubt that’s the standard of care, I would be somewhat provocative and suggest that if we can do a better job of finding the right patients for bladder preservation that that will be a rather remarkable feat whether it’s in the patients who fail BCG and go onto some sort of PARP and/or immunologic new treatment or is it in patients who might even have some aggressive resected radiation adjuvant combination. Some additional summaries of the disadvantages of neoadjuvant as well as the disadvantages of adjuvant, which I’ve already said.

Which is, this is NCCN, which is administered? And how is it administered? Well, first and foremost level one evidence neoadjuvant it gets a higher level of evidence. There are different dose-dense regimens for MVAC and as well as gemcitabine and cisplatin. Interestingly, the medical oncologists know this, you know, these therapies, despite the fact that they’re all in guidelines, have no actual formulary approval. And I continue to be amazed and fascinated by the fact how medical oncologists, most of their treatment selection is based in non-approved regimens from a registrational standpoint, and urologists we tend to be very doctrinaire about how we use therapies. And I think that that will probably change over time.

Optimizing perioperative chemotherapy; there is a disconnect between efficacy and effectiveness. The fellow on the bottom right is not a real patient, it’s a Hollywood actor. Just kidding. That was for the pharma people in the audience. And the actual patient up there, that’s actually Crawford. I photoshopped him in there. [Laughter] But we know that unfortunately efficacy, how an intervention performs in a clinical trial is one thing and then there is ultimately real-world, and we all get that.

This is just, I mentioned to you earlier, just so you see there’s about a two-fold increase in the amount or the percentage over the years in neoadjuvant chemotherapy from 10 to 20% while overall, you know, adjuvant chemotherapy has remained somewhat the same. Now, this is 2006/2010 data. With all of the advents of newer markers, with the immuno-oncologics I do think I would hope that these percentages will change with time.

Just to finish up, because this is an international conference this is the European Association of Urology guidelines on muscle invasive and metastatic bladder cancer. This is from 2013. Their summary, radical cystectomy as you can see don’t delay, really well-performed lymph node dissection. I thought Seth Lerner’s presentation was outstanding, and really I think the data really supports the templates that he’s addressed. There’s ongoing debate about robotics and open, but I think the writing is on the wall that our training will only have robotic surgeons in the future. And then neoadjuvant chemotherapy should be considered and clearly discussed as the patient shared decision-making nomenclature that we all have out there.

Here is some additionally on who to select for your neoadjuvant chemotherapy, not recommended for patients with poor performance status and impaired renal function. And in case of progression, and this is really important, is when and how and when will we be thinking about either other chemotherapeutic regimens but more importantly and more likely the checkpoint inhibitors. So, we have opportunities to improve the effectiveness of perioperative chemotherapy. It’s not my talk but we certainly hear more about these predictive biomarkers and how to better risk stratify, barriers to progress.

In conclusion, radical cystectomy, extended lymph node dissection is the standard currently now. If you’re going to be giving any form of chemotherapy-based treatment it needs to be platinum based. Surgery quality is an important predictor no doubt, and then ultimately it’s really the predictive biomarkers which will inform us on how to best do precision medicine, which is certainly extremely important.

It’s really important that we have a collaborative relationship that we have here, and I thank, and really appreciative of David’s efforts. So, we have the level one evidence for platinum-based neoadjuvant chemotherapy, but most importantly optimizing the integrative approach, which I think we all have mentors, or at least I was fortunate enough to work with Drs. Yagoda and Vaughan. It should inform many of us about, and especially any younger folks in the room. Thank you.