First-Line Chemotherapy in Advanced Bladder Cancer
Insights From: Daniel J. George, MD, Duke University Medical Center
Daniel J. George, MD: For patients who present with either metastatic transitional cell carcinoma bladder cancer or start out with more localized disease that then recurs as metastasis, many of these patients are ineligible for cisplatin-based chemotherapy which, historically, has been our only really proven therapy to prolong survival. Cisplatin, I really want to distinguish here from carboplatin. This is one of those tumors where these 2 agents are not equivalent, and cisplatin has really shown the survival benefits, the response benefits, and the duration of response that we haven’t been able to reproduce with carboplatin for whatever reason.
So, when we look at our patient population, the first thing we do in this metastatic setting is ask, can these patients tolerate cisplatin-based chemotherapy? And sadly, probably half or more of our patients don’t and there’s a variety of reasons why. The most common reason probably has to do with their kidney function. And many of our patients have either had issues with creatinine clearances that are low because of coexisting comorbidities or if they have an upper tract lesion, had one kidney removed. But whatever the reason, we see a significant percentage of our patients with creatinine clearances less than 50. When you have a creatinine clearance less than 50, we’re generally going to have to modify your dose of cisplatin down to a level where it may be just difficult to either tolerate or be able to respond. Between 50 and 60, we’re able to manage many of those patients. Above 60, we can usually give full-dose cisplatin without difficulty. So, that’s typically our range when we’re looking at patients, and sadly, that’s a population, because they’re older and with these comorbidities, where platinum treatment is often difficult.
A second criteria that gets in the way of many of our patients, believe it or not, is hearing. A lot of our patients are men. Older men have a lot of difficulty with hearing loss, and that can be really disruptive from a quality-of-life perspective. If they’ve already got significant hearing loss, cisplatin chemotherapy can really completely disrupt and block all hearing, which is a major concern for many of these folks. Neuropathy is another. A lot of these folks—again, older patients—have neuropathy from either spinal stenosis, arthritis, or other causes, like diabetes and other conditions, that can really make neuropathy debilitating if it worsens, and platinum chemotherapies are notorious for worsening peripheral neuropathy.
And then, lastly, is performance status. Many of our patients will come in with metastatic disease that’s symptomatic. And, particularly if they’ve got metastatic sites that are symptomatic in bone or key visceral organs, they may not be able to tolerate cisplatinum-based chemotherapy simply because of a performance status of 2 or worse.
When I’m dealing with a patient who has a platinum-ineligible bladder cancer, it’s a real challenge. Historically, the only options we’ve really had for these patients have been chemotherapies that have no real proven survival benefit and relatively limited response benefit. Probably the best chemotherapy option for these patients has been carboplatin/gemcitabine. So, that has been a de facto standard of care for these patients. There are some patients who are absolutely platinum refractory, just cannot tolerate any platinum, period, because of maybe really severe neuropathy or issues with really poor performance status.
But for patients who have softer reasons or more reasons for being cisplatin-ineligible, but we think maybe could tolerate carboplatinum—kidney function, creatinine clearance that is more in that gray zone of, say, 30 to 50, patients who have perhaps some hearing loss but it’s not severe—these are patients who we’ll offer a carboplatin/gemcitabine combination to. And I think that’s still appropriate for a number of folks. These patients can respond to therapy. That therapy can be palliative. We can see response rates typically around a 30% range for these patients. So, that’s a reasonable response, and they’re still candidates for immunotherapy after that. Particularly for patients who I see that I think are symptomatic, are having a lot of pain, or weight loss, or other kind of physical complications associated with their cancer, and who I think can tolerate a platinum-based chemotherapy like carboplatinum/gemcitabine, I’ll still consider that. It works quickly. We can see responses in a relatively short period of time, and I know that I’ve still got a rescue strategy with my I-O therapies to follow.