乌鸦传媒

At this year's Genitourinary Cancers Symposium, Shilpa Gupta, MD, of the Cleveland Clinic Taussig Cancer Institute in Ohio, discussed the best approaches to treating muscle-invasive bladder cancer (MIBC). In this exclusive 乌鸦传媒 video, Gupta reviews some of the highlights of her talk.

Following is a transcript of her remarks:

The current state for muscle-invasive bladder cancer is that there's a high risk of recurrence despite chemotherapy and surgery, and more than 50% of patients recur. And there's a high mortality associated with this disease. And the desired state is to improve survival in MIBC and remove access barriers and disparity barriers.

And to fulfill this gap, we need innovation in trial designs, novel therapies, harmonizing eligibility imaging and biomarkers, patient advocacy and multidisciplinary care.

The current state of the art in muscle-invasive bladder cancer is that we need to use cisplatin-based neoadjuvant chemotherapy prior to cystectomy, as this has shown to improve survival in the and the trials. However, despite this, neoadjuvant cisplatin-based chemotherapies highly underutilized -- only 30 to 40% of patients get it. And this is also because a lot of our patients are deemed ineligible for cisplatin due to a variety of reasons. And 30% of patients even refuse any kind of chemotherapy.

In standard practice, both dose dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride (Adriamycin), cisplatin] and gemcitabine/cisplatin are reasonable options. Meta-analysis show a 5-year overall survival improvement of 8% with neoadjuvant cisplatin-based chemotherapy.

A lot of bladder cancer patients are elderly, median age being 71 years. They are not candidates for cisplatin-based chemotherapy. And there's currently no standard or effective neoadjuvant treatment for patients who are cisplatin ineligible and they are usually taken for upfront surgery.

We also know that a goal for adequate adjuvant therapies is to improve disease-free survival and overall survival. And while there's no randomized chemotherapy trials showing improvement of survival with a single randomized trial, the advanced bladder cancer positive meta-analysis showed 6% absolute improvement in overall survival with adjuvant cisplatin-based chemotherapy at 5 years.

A major study, , showed that immediate chemotherapy with investigator's choice of cisplatin-containing regimen after cystectomy in patients with pT3–pT4 or N+ disease improved overall survival. The overall survival was 6.74 years with patients who got immediate chemotherapy versus 4.60 years in those who deferred chemotherapy when they recurred or became metastatic. Notably, this study was closed to accrual because of problems with accruing, and therefore it was underpowered. But this difference was huge, even though not statistically significant.

And immunotherapy has been studied in an adjuvant setting in high-risk muscle invasive urothelial cancer. For patients who received neoadjuvant cisplatin-based chemotherapy, this was defined as ypT2-T4a or node-positive disease. And for patients who were not eligible or declined adjuvant chemotherapy, this was pT3-T4a or node-positive disease. IMvigor010 study randomized patients with high risk disease to atezolizumab [Tecentriq] or observation. CheckMate-274 study randomized them to nivolumab [Opdivo] versus placebo. And the third study, , randomized patients to pembrolizumab [Keytruda] or observation. Notably, these included upper tract urothelial cancer patients too, but they were capped.

In the study, there was no disease-free survival or overall survival improvement with atezolizumab compared to observation. However, in the CheckMate-274 study, the primary endpoint of disease-free survival improvement was met. The median disease-free survival with adjuvant nivolumab for a year was 22 months versus 10.9 months with placebo. Notably, the benefit was even more pronounced in patients whose tumors expressed PD-L1.

In this study, we also saw that patients who receive neoadjuvant chemotherapy derive more benefit than those who did not. However, we have still not seen any positive overall survival signal as the events have not occurred, and hopefully we will see it in the future. But that is a big question, because the goal of all adjuvant therapies is to ultimately improve overall survival. And if we don't see overall survival benefit, the big question is do we really need patients to go through adjuvant therapy if, when they recur, therapies can improve survival? But this is an area of controversy.

Upper tract urothelial cancer is a more rare disease with poorer outcomes. The study, the only randomized trial, which showed that benefit of cisplatin or carboplatin compared to surveillance in these patients in the adjuvant setting. The overall hazard ratio was 0.45. The benefit with gemcitabine/cisplatin was much more than was seen with gemcitabine/carboplatin. Notably, after upper tract urothelial cancer surgery, patients are often cisplatin-ineligible because they now have a solitary kidney, and their creatinine clearance is compromised.

When we put this into perspective with what we saw from the IMvigor010 and the CheckMate-274 study, the benefit with immunotherapy was not as pronounced as what we saw with chemotherapy in the POUT trial. Not to compare across trials, but also the other issue was that the IMvigor010 and the CheckMate-274 trials had very few patients with upper tract disease.

Now switching gears to trimodality therapy. Basically, it is a maximal TURBT [transurethral removal of bladder tumor] followed by concurrent chemoradiation. Four patients with muscle invasive bladder cancer were select candidates. Now, historically, this was offered to patients with poor performance status or those who can't undergo cystectomy or those who are declining this and are elderly. But more and more, we are seeing that younger patients are also interested in bladder preservation, as it is a big quality of life issue. The gold standard has been radical cystectomy, but this is a valid option for bladder preservation in select patients. There's an absence of randomized trials comparing trimodality therapy versus radical cystectomy; but in cohort analysis and a meta-analysis, long-term survival appears similar. And disease-free survival at 5 years can approach up to 85% for good candidates.

In this setting, neoadjuvant chemotherapy prior to trimodality therapies is also being explored, because it is felt that just the chemotherapy given concurrently with radiation may not be enough to target the micrometastatic disease.

At the end of the day, for a patient with muscle-invasive bladder cancer, we need to have multidisciplinary clinics where the patient sees a urologist, medical oncologist and a radiation oncologist, and then can make an informed decision. And risks and benefits of each approach are discussed with the patient.

So if a patient is a candidate for cystectomy and is willing for cystectomy, then they should be offered neoadjuvant chemotherapy with cisplatin-based regimens if they're eligible, offered clinical trials with immunotherapy and antibody drug conjugate-based options. If they're not eligible for cisplatin, either they undergo upfront cystectomy or enroll on trials which offer immunotherapy-based approaches. And after cystectomy, there's the option of adjuvant nivolumab if they meet the criteria or other trials.

If the patient is not willing or not a candidate for cystectomy, bladder preservation should be offered. Trimodality therapy should be offered. And there's several clinical trials exploring the role of immunotherapy.

And we also want to address here that we talk about all these novel therapies being available, but they're not really available across the globe. They're only available in select countries. And if there's a big push towards changing policies, making these novel drugs available to a lot of countries and not just a select few. And within countries like the U.S. too, there's a lot of disparities in access as well as barriers to care.

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