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Neoadjuvant Therapy in Muscle-Invasive Bladder Cancer

Panelists:Raoul S. Concepcion, MD, FACS, Urology Associates; Michael S. Cookson, MD, MMHC, University of Oklahoma Health Sciences Center; Daniel P. Petrylak, MD, Yale School of Medicine; Daniel I. Quinn, MBBS, PhD, FRACP, FACP, University of Southern California; Neal D. Shore, MD, FACS, Carolina Urologic Research Center; Charles J. Ryan, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Tuesday, Aug 09, 2016


Transcript:

David I. Quinn, MBBS, PhD:
I believe that carboplatin-based regimens do not have any merit in the neoadjuvant setting. And from that perspective, I would agree with Dan on that: go straight to cystectomy. You get your staging; you get your disease sorted out. You can make decisions on therapy after that. I think it’s important for us to try and get the cisplatin in. In some of the bigger centers, like Yale and USC, if I’m seeing a patient who’s got a creatinine clearance between, say, 45 and 60 ml/min, I’m typically going to use a split-dose regimen of cisplatin and gemcitabine and hydrate the patients very aggressively. And the only caveat is that this lady, if she has a little bit of renal impairment, she’s got obstructive renal impairment. I’m much happier with that once we’ve relieved the obstruction than with patients who have medical kidney disease. Someone who has long-term diabetes, hypertension, or prior nephritis is much more likely to get into trouble with a modified dose of cisplatin than someone who’s been obstructed where we’ve “fixed the plumbing.” So, I think there are some judgment calls there.

It’s interesting. In southern California, we’re getting referred patients who are in that range of clearance, because the community urologists would give carboplatin plus something in the past. The community oncologists are talking to the community urologists, and they’re saying, “Okay, send them to a center where they’ve got 24-hour cancer nursing and care, and where they can admit them overnight and look after them.” My personal preference is, in this lady, if she’s got a relatively normal creatinine, we would put a nephrostomy in her. And a week later, we would probably start dose-dense MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) because we get four cycles in, in 8 weeks. I think there is a dose-density advantage and that comes from data in the metastatic setting, where Cora Sternberg did a study that showed there was improved survival, certainly after 5 years, with dose-dense MVAC compared to standard MVAC. So, that’s become a preference for many of us in the larger centers for patients with normal renal function; it’s done quicker. We get through it in 8 weeks instead of 12—or in the case of MVAC, 12 to 16—and it probably is a better treatment.

Raoul S. Concepcion, MD: Can you do the same with gemcitabine/cisplatin?

David I. Quinn, MBBS, PhD: You can, but the advantages are not demonstrated in a phase III trial in metastatic disease. We have phase II data in that setting, and we also have phase II data in the neoadjuvant-type setting. It’s doable, but for some reason related to the gemcitabine, you tend to run into more problems with low platelet count over time. So, it’s a little more cumbersome. And for some reason, the condensed MVAC given with growth factor support, GCSF (granulocyte-colony stimulating factor), is better tolerated, both in the metastatic and also the neoadjuvant setting, than the old standard MVAC.

Raoul S. Concepcion, MD: Mike, I think we all agree. And, again, I think urology is coming around to this. The routine standard of care for muscle-invasive bladder cancer, for the most part, with normal renal function should be giving neoadjuvant chemotherapy. So, once the patient gets referred back to you from medical oncology, what is your approach? Do you do a repeat cystoscopy, repeat scans, a repeat biopsy, or do you just wait and say, “In 4 weeks, your bladder is out”? And in this particular patient, 53 years old, female, sexually active: talk us through a little bit about what you present as potential surgical options.

Michael S. Cookson, MD, MMHC: I think the point that was stated earlier about the ability to try and get the platinum in, in the face of non-optimal renal function, is really important. I know they mentioned it, but it needs to be done more often. When you looked at the perioperative use of chemotherapy, in the United States, it’s about 40%. That includes the up-front and the adjuvant setting. We need to do it more up front; it’s better tolerated; patients do it. Having said that, she receives her chemotherapy. Traditionally, if they receive MVAC in the four cycles, usually after about the second cycle, a CT scan is obtained. In this particular case, you’d have a marker with that lymph node, but you’d want to make sure she was responding. They might switch therapies and do something different if it wasn’t. Once they’re referred back, usually we’re planning to remove their bladders.

Most of the studies that have been done—even in the absence of residual disease, based on the clinical impression—still show residual disease, 20% or 30%, including involvement of the lymph nodes even if you’re pT0. So, I think that we go into the plan with the idea that cystectomy is coming once they complete their therapy. You do occasionally get patients who want to forego the cystectomy. We try to emphasize to them that this is a multimodality therapy. I don’t think that we would be successful in curing this particular patient without cystectomy. Cystectomy includes extended lymph node dissection, so that would be offered to her, as well. And then choice of diversion would be a personal preference for her. If it’s a locally advanced tumor and we’re worried about recurrence, we tend to do continent reservoirs. And this lady may be that type of patient. Ileal conduit is the most commonly performed diversion in the United States, and, again, it depends on the particulars and some of the intraoperative findings that would persuade us to go one way or the other.

Raoul S. Concepcion, MD: What about vaginal sparing? Because the traditional anterior exenteration is obviously the anterior vaginal wall, bladder, and uterus.

Michael S. Cookson, MD, MMHC: In the right patient, that can be very good. And it can preserve function. We’ve even done sparing of the gynecologic organs. In this lady, with this hydronephrosis, the node, and the locally advanced nature, I’m worried that she may need a wider excision; we may have to open the vagina. Certainly, in select patients who are going to do neo-bladders in the female setting, we want to preserve the vagina to reduce the incidence of fistula, but also to preserve the pelvic floor support.

Transcript Edited for Clarity
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Transcript:

David I. Quinn, MBBS, PhD:
I believe that carboplatin-based regimens do not have any merit in the neoadjuvant setting. And from that perspective, I would agree with Dan on that: go straight to cystectomy. You get your staging; you get your disease sorted out. You can make decisions on therapy after that. I think it’s important for us to try and get the cisplatin in. In some of the bigger centers, like Yale and USC, if I’m seeing a patient who’s got a creatinine clearance between, say, 45 and 60 ml/min, I’m typically going to use a split-dose regimen of cisplatin and gemcitabine and hydrate the patients very aggressively. And the only caveat is that this lady, if she has a little bit of renal impairment, she’s got obstructive renal impairment. I’m much happier with that once we’ve relieved the obstruction than with patients who have medical kidney disease. Someone who has long-term diabetes, hypertension, or prior nephritis is much more likely to get into trouble with a modified dose of cisplatin than someone who’s been obstructed where we’ve “fixed the plumbing.” So, I think there are some judgment calls there.

It’s interesting. In southern California, we’re getting referred patients who are in that range of clearance, because the community urologists would give carboplatin plus something in the past. The community oncologists are talking to the community urologists, and they’re saying, “Okay, send them to a center where they’ve got 24-hour cancer nursing and care, and where they can admit them overnight and look after them.” My personal preference is, in this lady, if she’s got a relatively normal creatinine, we would put a nephrostomy in her. And a week later, we would probably start dose-dense MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) because we get four cycles in, in 8 weeks. I think there is a dose-density advantage and that comes from data in the metastatic setting, where Cora Sternberg did a study that showed there was improved survival, certainly after 5 years, with dose-dense MVAC compared to standard MVAC. So, that’s become a preference for many of us in the larger centers for patients with normal renal function; it’s done quicker. We get through it in 8 weeks instead of 12—or in the case of MVAC, 12 to 16—and it probably is a better treatment.

Raoul S. Concepcion, MD: Can you do the same with gemcitabine/cisplatin?

David I. Quinn, MBBS, PhD: You can, but the advantages are not demonstrated in a phase III trial in metastatic disease. We have phase II data in that setting, and we also have phase II data in the neoadjuvant-type setting. It’s doable, but for some reason related to the gemcitabine, you tend to run into more problems with low platelet count over time. So, it’s a little more cumbersome. And for some reason, the condensed MVAC given with growth factor support, GCSF (granulocyte-colony stimulating factor), is better tolerated, both in the metastatic and also the neoadjuvant setting, than the old standard MVAC.

Raoul S. Concepcion, MD: Mike, I think we all agree. And, again, I think urology is coming around to this. The routine standard of care for muscle-invasive bladder cancer, for the most part, with normal renal function should be giving neoadjuvant chemotherapy. So, once the patient gets referred back to you from medical oncology, what is your approach? Do you do a repeat cystoscopy, repeat scans, a repeat biopsy, or do you just wait and say, “In 4 weeks, your bladder is out”? And in this particular patient, 53 years old, female, sexually active: talk us through a little bit about what you present as potential surgical options.

Michael S. Cookson, MD, MMHC: I think the point that was stated earlier about the ability to try and get the platinum in, in the face of non-optimal renal function, is really important. I know they mentioned it, but it needs to be done more often. When you looked at the perioperative use of chemotherapy, in the United States, it’s about 40%. That includes the up-front and the adjuvant setting. We need to do it more up front; it’s better tolerated; patients do it. Having said that, she receives her chemotherapy. Traditionally, if they receive MVAC in the four cycles, usually after about the second cycle, a CT scan is obtained. In this particular case, you’d have a marker with that lymph node, but you’d want to make sure she was responding. They might switch therapies and do something different if it wasn’t. Once they’re referred back, usually we’re planning to remove their bladders.

Most of the studies that have been done—even in the absence of residual disease, based on the clinical impression—still show residual disease, 20% or 30%, including involvement of the lymph nodes even if you’re pT0. So, I think that we go into the plan with the idea that cystectomy is coming once they complete their therapy. You do occasionally get patients who want to forego the cystectomy. We try to emphasize to them that this is a multimodality therapy. I don’t think that we would be successful in curing this particular patient without cystectomy. Cystectomy includes extended lymph node dissection, so that would be offered to her, as well. And then choice of diversion would be a personal preference for her. If it’s a locally advanced tumor and we’re worried about recurrence, we tend to do continent reservoirs. And this lady may be that type of patient. Ileal conduit is the most commonly performed diversion in the United States, and, again, it depends on the particulars and some of the intraoperative findings that would persuade us to go one way or the other.

Raoul S. Concepcion, MD: What about vaginal sparing? Because the traditional anterior exenteration is obviously the anterior vaginal wall, bladder, and uterus.

Michael S. Cookson, MD, MMHC: In the right patient, that can be very good. And it can preserve function. We’ve even done sparing of the gynecologic organs. In this lady, with this hydronephrosis, the node, and the locally advanced nature, I’m worried that she may need a wider excision; we may have to open the vagina. Certainly, in select patients who are going to do neo-bladders in the female setting, we want to preserve the vagina to reduce the incidence of fistula, but also to preserve the pelvic floor support.

Transcript Edited for Clarity
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Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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