Adding Perioperative Chemo to Surgery Improves Survival in Sarcomatoid UC

Rohan Garje, MD

The use of perioperative chemotherapy with surgery led to improvement in survival outcomes vs surgery alone in patients with sarcomatoid urothelial cancer (UC), according to research presented by Rohan Garje, MD, at the 2023 ASCO Annual Meeting.

In a study, experts compared the survival outcomes of sarcomatoid UC, a rare bladder cancer variant that has epithelial and mesenchymal differentiation, along with frequent TERT C228T promoter mutations, with classic UC in patients with T2-T4, N0-N1 bladder cancer after definitive therapy.

Overall, the median survival for patients with sarcomatoid UC who underwent surgery was 29.5 months (95% CI, 20.0-50.6) vs 43.1 months (95% CI, 25.3-64.4) for those who underwent surgery plus chemotherapy, respectively. For patients with classical UC, the median survival was 56.1 (95% CI, 53.7-58.6) for those who had surgery vs 78.0 (95%CI 75.1-81.1) months for those who had surgery and chemotherapy, respectively.

These findings show that while patients with sarcomatoid UC have a poorer prognosis than patients with classical UC, the addition of perioperative chemotherapy to surgery improves survival.

“The key takeaway is that there is benefit of perioperative chemotherapy for this rare histological cancer. I think this is a common practice question. Whenever you see this patient with a sarcomatoid variant in the clinic, it is whether to offer them chemotherapy or not. With this study, we found that there is a survival benefit,” Garje, chief of genitourinary oncology at the Miami Cancer Institute, told Targeted Oncology^TM, in an interview.

Further studies are warranted to investigate how novel immunotherapy agents may continue to improve outcomes for these patients, according to the study.¹

In the interview, Garje discussed his research on comparing the outcomes of sarcomatoid and classic UC of bladder.

Targeted Oncology: Can you discuss the background on this research?

Garje: We worked on a cohort of patients with bladder cancer with sarcomatoid histology. As you know, bladder cancer is common and in the top 10 cancers in men and women. But the most common variant is called classic variant urothelial cancer, which makes up most of the cases and most of the research is in that. At the same time, there are a fraction of patients who have this variant histology called sarcomatoid, where the cancer looks different compared with what the traditional urothelial cancer looks like. The big issue with those kinds of variant histologies is that there is no standard of care. Any of the clinical trials which are being run right now tend to exclude patients who have predominant sarcomatoid histology.

What was the main objective of the study?

My big goal was to make sure to have guidance and in terms of treatment in what works best. What we did in the study was we utilized something called the National Cancer Database. We identified about 400 plus patients with this histology, and looked at how they present in terms of the diagnosis, and selected patients who had muscle invasive bladder cancer with regional lymph node involvement, and then compared them with patients who have classic urothelial carcinoma. Having said that, what we saw was that there was a striking decrease in survival for patients who had sarcomatoid histology compared to the ones who had the classic urothelial carcinoma histology. That is obviously a big, important finding, because it's a rare cancer, and has inferior survival.

Now, the second important finding in the study was in the patients who received very operative chemotherapy, predominantly neoadjuvant chemotherapy, and the fraction of patients who got adjuvant chemotherapy in addition to surgery had better survival than the patients who had surgery alone. As a comparison, in classic variant urothelial carcinoma, the standard right now is to offer cisplatin-based chemotherapy followed by surgery, but there is no such standard for pure sarcomatoid. In the study, we did notice that even in this variant, if they get neoadjuvant and sometimes adjuvant chemotherapy, they had better responses, and their overall survival was better. This information is critical, for practicing clinicians where there is not much research or clinical trial driven guidance that these rare histologies do benefit with chemotherapy and can have better survival.

Can you explain some of the differences between the sarcomatoid and classic carcinoma of the bladder?

The primary obvious difference is histology. The patients who have sarcomatoid, they have both combinations of mesenchymal and epithelial differentiation, they have mutations which drive the cancer are different, and another thing is because it's been rare, the big issue has been that their enrollment to clinical trials has been very limited. These patients are generally not part of the studies which include classic variants. So, histological differences, molecular differences, and because of the rare nature of the cancer, they have not been represented in clinical trials.

We also have noticed that it is a male predominant cancer, but relative to classic urothelial, females had a little bit higher incidence of this cancer. We also see that this cancer is predominantly associated with higher staging, and the other important aspect we noticed are the risk factors. The traditional risk factor for the classic variant in general has been smoking. Now, similar risk factors exist for sarcomatoid, but exposure to radiation therapy for prior pelvic organ radiation or cyclophosphamide-based chemotherapy for various other reasons tend to be high-risk factors for sarcomatoid cancers.

What are the key takeaways from this research?

The key takeaway is that there is benefit of perioperative chemotherapy for this rare histological cancer. I think this is a common practice question. Whenever you see this patient with a sarcomatoid variant in the clinic, it is whether to offer them chemotherapy or not. With this study, we found that there is a survival benefit. There may still be various nuances in who may be the right patient or not, but at least this particular study is giving us the guidance that yes, there is benefit of cisplatin-based perioperative chemotherapy. Obviously, there's a lot more to do. There are additional things that can be done to improve survival because not everyone benefits and has cancer-free survival.

So, is there any role for immunotherapy, which is making a lot of impact in this group, is there a role for novel therapies such as enfortumab vedotin [Padcev], which has shown significant survival benefit in a metastatic setting. Now, there are a lot of studies of these agents, both immunotherapy and this novel antibody drug chemotherapy conjugates in the perioperative setting. The big next step for us would be to see if there is any added value for these novel agents in this setting.

What unmet needs still exist in this space?

In terms of unmet needs, whenever we see a rare cancer, the data is limited. The next level question is, what are all the models in terms of molecular information? What kind of mutations are common? Are there any set patterns of mutations that can be identified? Eventually, are they targetable? Are there any medications which we can use to control and have better response in the scans? In bladder cancer, we already have FGFR-based targets where we have shown there is a good response rate and survival benefit, but it's a small fraction. Again, this is a group predominantly with classic urothelial variants. Now, we are learning about HER2 amplifications in bladder cancer, and there are so many other new mutations, like DDR-based mutations, which we can identify in the subgroups that would be a good segue to find targeted treatments for this rare variant.

What other ongoing research excites you?

There are so many new studies that are coming up, even beyond bladder cancer. There are updates in prostate cancer with PARP inhibitors, and lutetium-based agents have been evaluated in prostate cancer. We are eager to look at the new things that are coming up, and updates on many phase 3 studies that have been done in kidney cancer. There have been results now with some interim results, so those are of great interest.

Reference:

Garje R, Ozair A, Manoharan M, et al. Survival outcomes of sarcomatoid versus classic urothelial carcinoma of bladder. J Clin Oncol. 2023;41(suppl 16):4588. doi:10.1200/JCO.2023.41.16_suppl.4588