Evolving Neoadjuvant Treatment Strategies in Muscle-Invasive Bladder Cancer


Expert perspectives on the evolving role of neoadjuvant therapy in muscle-invasive bladder cancer (MIBC) with considerations for mainstay regimens.


Shilpa Gupta, MD: Petros, give us an overview of neoadjuvant therapy. What’s your go-to regimen? Do you use gemcitabine-cisplatin, dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin], or trials? How do you approach patients who aren’t eligible to receive cisplatin?

Petros Grivas, MD, PhD: That’s a great question. I agree with Mamta’s great points. This is an important and rapidly evolving theme. We’re seeing a trend, especially with our involvement hearing patients—all 4 of us—with Bladder Cancer Advocacy Network. We see a trend toward higher desire and willingness to go for bladder preservation. This has been evolving because our urologists are also strong advocates for that in well-selected patients. We navigate discussions in a busy multidisciplinary clinic by trying to think about the particular patient in front of us. What’s the best locoregional definitive therapy, assuming no metastases and curative intent? Is radical surgery the best approach, or is it trimodality therapy [TMT] for bladder preservation? This has to do with a number of patient-related but also cancer-related characteristics—the presence of hydronephrosis, carcinoma inside is diffused, and so on. We take into account all those factors.

If the patient is a great candidate for bladder preservation, we offer that to the patient along with radical surgery. We try to counsel them to make an informed decision. It’s a decision-making model about the pros and cons of both processes. With that approach, approximately 15% to 20% of patients may undergo bladder preservation with the modern anecdotal statistics that we have. It’s a method of selection based on the criteria we use for bladder preservation.

Very briefly, I’ll comment on hydronephrosis, a diffuse CIS [carcinoma in situ] with multifocal large tumors; poor bladder function; poor capacity; a tumor near the trigone, the ureteral orifice; and a lot of urinary tract symptoms. All those factors make us less enthusiastic about bladder preservation, though the absence of those makes us more enthusiastic. It’s a selection process, and we discuss the multidisciplinary approach. If a is a candidate for radical surgery, we discuss the neoadjuvant-based chemotherapy briefly because it’s a long topic.

An important take-home message is that we don’t use carboplatin for neoadjuvant or adjuvant chemotherapy for bladder cancer. We use cisplatin-based chemotherapy, and there are 2 options in the neoadjuvant or adjuvant setting: dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] or accelerated MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin]. There are nuances in the way we do either of them, but all drugs are given 1 after the other on day 1. Dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] is given on day 1 and day 2. In the other scenario, growth factor support is given every 2 weeks. That’s very different from the older conventional MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] that was given 20 years ago. The other option is the gemcitabine-cisplatin that we use on a 21-day cycle: day 1, day 8 is treatment, and day 15 is off. We don’t routinely do primary prophylaxis with G-CSF [granulocyte colony-stimulating factor] for gemcitabine-cisplatin.

In another scenario, we use 4 cycles for node-negative disease. If you ask me if I have a preference based on the totality of the literature, prospective studies VESPER and SWOG S1314, and retrospective data, I have a slight bias favoring dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] and in patients who are feeling comfortable with a little higher toxicity. But most well-selected patients do OK. We always think about clinical trials. Neoadjuvant is the ideal scenario with level 1 evidence.

Shilpa Gupta, MD: Andrea, what’s your preference for dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] vs gemcitabine-cisplatin? A lot of our patients are in their 70s and may not be the most robust candidates for dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin]. Do you have a preference?

Andrea B. Apolo, MD: I discuss both of these with my patients. I talk about the VESPER trial data. That study used 6 cycles of dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] vs 4 cycles of gemcitabine-cisplatin, and it showed that dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] was a little better in terms of overall pathologic response rate and the 3-year disease-free survival and OS [overall survival], but it was a lot more therapy. In the neoadjuvant setting, I have a hard time getting 6 cycles to patients. I often can get 4, and I’m lucky if I can get 5. Usually, 4 is my limit, and I don’t have a preference.

I do discuss adverse effects. Dose-dense MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] causes more adverse effects, and I have hesitation to give it to frail patients, but I discuss both of these with my patients. Both are good options. Maybe this is a little different from the others, but I use also neoadjuvant chemotherapy even if the patient is going to undergo bladder preservation trimodality therapy because the goal of neoadjuvant chemotherapy is to eradicate micrometastases. Whatever definitive therapy the patient undergoes, they should still be considered if they’re eligible for cisplatin. I use cisplatin-based chemotherapy because that’s where the level 1 evidence is. I give them neoadjuvant chemotherapy regardless of whether they’re going to undergo a radical cystectomy or a trimodality therapy with radiation. I also use it for patients with upper-tract disease.

This was on a study that we did when I was at Memorial Sloan Kettering Cancer Center about 14 years ago. We started a trial for neoadjuvant cisplatin-based chemotherapy for patients with upper-tract disease. We recently published this in JCO [Journal of Clinical Oncology]. We found that there were good responses in these patients. Generally, they did well with cisplatin-based chemotherapy. It’s better to get cisplatin-based chemotherapy before they undergo nephroureterectomy. When they have both kidneys is when to give them cisplatin-based chemotherapy.

Shilpa Gupta, MD: Mamta, is that a perspective you share, or you have a different approach?

Mamta Parikh, MD, MS: I take a very similar approach to Andrea’s. For upper-tract tumors, I try to treat with neoadjuvant chemotherapy if patients are cisplatin candidates because that might be their only chance to get a cisplatin-based regimen. Otherwise, my approach is similar. I favor accelerated MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin]. Also, because of ease in terms of the time to completing therapy and getting to surgery, it’s a little faster with that approach compared with gemcitabine-cisplatin. Some patients prefer it for that reason as well. If patients have cardiac comorbidities, I lean away from accelerated MVAC [methotrexate, vinblastine sulfate, doxorubicin hydrochloride, cisplatin] because of anthracycline use in that regimen compared with gemcitabine-cisplatin.

Shilpa Gupta, MD: Andrea, you brought up a great point about neoadjuvant therapy prior to trimodality. In the United States, it’s not widely used. In the United Kingdom and Europe, they use it and go by its Alliance for Clinical Trials in Oncology trial, which uses precisely that approach. Petros, are you are routinely doing that also? We try to do that if patients are candidates, but as a routine, it’s underutilized in the United States.

Petros Grivas, MD, PhD: I agree, Shilpa. That’s a great point. I’m glad Andrea mentioned this because it’s a big debate and a different practice across different centers. I know colleagues in Canada who routinely use neoadjuvant chemotherapy before TMT. It’s a reasonable approach, and it mechanistically makes sense. You try to eradicate micrometastases with a standard-dose systemic therapy before you focus on locoregional therapy because micrometastases is potentially life-threatening for the patient. It makes sense. The challenge we have is the lack of clinical trial data supporting that approach. Trials in the past were done and did not show benefit with neoadjuvant chemotherapy followed by trimodality therapy. But there were challenges in those trials. They were in the previous era. There were some theological challenges, and physicians weren’t able to answer the question. We don’t have data supporting it.

Because of that, at our institution, UW [University of Washington] Fred Hutchinson Cancer Center, when we do TMT, we do it without neoadjuvant chemotherapy after maximal TURBT [transurethral resection of a bladder tumor]. We have trials, like the SWOG/NRG S1806, openly looking at chemoradiation plus atezolizumab, but I definitely understand the rationale why some centers do neoadjuvant chemotherapy. Ideally, I’d like to see a trial answer this question. The challenge is we need resources. Can such a trial can be done in the modern era in terms of resources? It’s a very reasonable consideration. It’s a matter of clinical data supporting that reasonable practice.

Transcript edited for clarity.

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