Oligometastatic vs Oligoprogressive RCC Treatment Strategies - Chad Tang
October 7, 2024
Leslie Ballas interviews Chad Tang about the use of stereotactic body radiation therapy (SBRT) in metastatic renal cell carcinoma (RCC). Dr. Tang discusses two key approaches: treating oligometastatic disease (up to five metastatic sites) and oligoprogressive disease (one to three progressing sites). He presents data from recent studies showing SBRT's potential to delay the need for systemic therapy in oligometastatic RCC and to extend the efficacy of existing systemic treatments in oligoprogressive cases. Dr. Tang highlights the benefits of SBRT, including lower costs, reduced toxicity, and fewer hospital visits compared to standard systemic therapies. The conversation covers practical considerations such as the definition of oligometastatic disease, the impact of metastasis site on outcomes, and the management of systemic therapies during radiation treatment. Dr. Tang states the need for further research, particularly randomized phase III trials, to solidify SBRT's role in RCC management.
Biographies:
Chad Tang, MD, Associate Professor, Genitourinary Radiation Oncologist,The University of Texas MD Anderson Cancer Center, Houston, TX
Leslie Ballas, MD, Director, Hematologic/Bone Marrow Transplant/Cellular Therapies Disease Research Group, Cedars-Sinai Medical Center, Los Angeles, CA
Biographies:
Chad Tang, MD, Associate Professor, Genitourinary Radiation Oncologist,The University of Texas MD Anderson Cancer Center, Houston, TX
Leslie Ballas, MD, Director, Hematologic/Bone Marrow Transplant/Cellular Therapies Disease Research Group, Cedars-Sinai Medical Center, Los Angeles, CA
Read the Full Video Transcript
Leslie Ballas: Hi, I'm Leslie Ballas. I'm a Radiation Oncologist at Cedars-Sinai Medical Center in Los Angeles, and it is my great pleasure to introduce Dr. Chad Tang, an Associate Professor at MD Anderson Cancer Center in the Departments of Radiation Oncology, Translational Molecular Pathology, as well as the Department of Investigational Cancer Therapeutics. He is a true expert in radiation for renal cell carcinoma, and he is going to talk to us a little bit today about the use of SBRT in renal cell carcinoma for metastatic disease.
Thank you so much, Dr. Tang, for joining us.
Chad Tang: Thank you, Dr. Ballas. I appreciate the kind introduction. I'm really excited to be here on UroToday to talk about some of these really interesting topics.
So I'm going to focus on two areas: oligometastatic and oligoprogressive disease, because they have the most data supporting them. So jumping right in, let's talk about oligometastatic RCC. These are patients with up to five sites of metastatic disease, and we recently reported on a phase II single-arm study looking at these patients. What we did was we took patients with up to five sites of metastatic disease, who had no prior systemic therapy or stopped it one month ago, and they had radiation to all sites. At the time of progression, patients were assessed radiographically, and if they had oligoprogressive disease—that is, up to three sites—they could reenter this loop and be treated again off systemic therapy. However, at the time of polymetastatic progression (greater than three sites), they then had to restart systemic therapy in order to control the disease.
What we showed in this initial study was that the toxicities were quite favorable, first off—only 10% Grade 3 to 4 toxicities. Progression-free survival was favorable at about 20 months median survival, and systemic therapy was also favorable with the majority of patients not requiring systemic therapy at the time of study closure.
As you can see on the swimmer's plot, patients had an initial amount of radiation, and about 12 months later they had a subsequent amount of radiation, and this continued continuously until polymetastatic progression was observed. So after these results were published, we enrolled another 120 patients and we rapidly analyzed these results for the review.
So why is this important? It's because the frontline systemic therapy options for metastatic renal cell carcinoma is usually a combination of two drugs—two immunotherapies, or immunotherapy and tyrosine kinase inhibitors—and at least in the U.S., this is quite expensive, at least in the six digits in terms of per-year costs, and it's an indefinite use. Toxicities in the pivotal phase III trials were also significant, ranging between 40 to 80% Grade 3s, and the patient has to come back, usually monthly if not more, for infusions and for labs for that infusion.
In contrast, if we do a systemic therapy-sparing strategy with SBRT, the costs are usually much lower per round of SBRT, with lower toxicities for the patients. Healthcare visits do require some, but the patient only has to be here for one to two weeks per round of SBRT. I want to emphasize that to date there is no evidence that systemic therapy after MDT is less effective.
So moving on to the next topic. This is oligoprogressive renal cell carcinoma. This entity is a newly defined entity and it basically entails a patient with any number of metastatic lesions, when active systemic therapy is rendered to a state where there's only one to maybe three to five lesions that are progressing. This paradigm has been tested in two prospective trials in RCC, where patients who had oligoprogressive RCC received radiation to all progressive sites and then continued the same line of systemic therapy, which they were technically progressing on.
Two studies highlighted here are the Cheung et al. study done in Canada, which enrolled patients with up to five mets, required clear cell components, and was closed early because they required a TKI monotherapy, which changed to doublet therapy during the study enrollment period. So they had 38 patients. Another study by Dr. Raquib Hannan at UT Southwestern, which enrolled patients with up to three sites of disease with mixed systemic therapies, and this trial enrolled 20 patients.
These two independent studies have remarkably similar results despite their differences, and what they both showed was that time until having to switch from the line that the patient was on to a next line of systemic therapy was 12 to 11 months, and that the Grade 3 severe toxicities were quite modest at zero to 5%.
So in summary, this is an exciting time for radiation to aid in the disease management of metastatic RCC. In these two areas, we have two prospective studies—one I showed and another by UT Southwestern—that demonstrate the potential of metastasis-directed therapy to defer the initiation of systemic therapy for more than a year, potentially much longer, and that these approaches where we spare systemic therapy are generally less toxic, less expensive, and require less hospital visits than the doublet standard upfront systemic therapy. However, notably, randomized phase III data is needed in this space.
For metastasis-directed therapy with systemic therapy, there have been the two trials that I presented previously for radiation to oligoprogressive sites demonstrating the potential to defer systemic therapy escalation for approximately one year, and this is important because the earlier lines of systemic therapy are generally more effective and have less side effects than later lines. So thank you.
Leslie Ballas: Thank you so much. That was excellent. I have a couple of questions. I noticed in your trial that you presented, looking at metastasis-directed therapy initially in the oligometastatic space, you define that as five sites of metastasis or less, and then when it became oligoprogression, it became three sites of metastasis or less. I'm wondering—I think that people are accepting the definition of five or fewer sites of metastasis as an oligometastatic definition, but I feel like, why does it differ between oligometastatic disease and oligoprogressive disease? Do you have a sense of does three versus five really matter in this space?
Chad Tang: These are excellent questions. This area, this entity of oligometastatic, and even more recently, oligoprogressive, are new entities that we are trying to define. You brought up three and five. These are arbitrary cutoffs. We had to do an arbitrary cutoff for a trial, and I think what you're seeing is the result of that. I must note that probably better than looking at the number of mets on your imaging are biologic markers, and that's something we sorely need for both oligometastasis and oligoprogression, which we're all working on, because we believe ultimately radiograph is a poor surrogate of really the disease state and what's happening.
Leslie Ballas: Yeah. Tell me, did you find, or is there any data to show, that the site of the metastasis makes a difference in terms of MDT? Most notably, I would think CNS would be one of the ones that you'd wonder about.
Chad Tang: Yeah, another excellent question. So we did look in our expanded trial, which we are currently preparing at the sites. We couldn't find a site that was immediately associated with a worse outcome. There is some preclinical data suggesting that metastases that come to rarer sites like pancreas or exocrine glands can be a little bit more indolent genetically, but that also needs to be teased out with other factors as well. One of my patients that has done really well with this strategy presented, for example, with a brain metastasis that was resected, and 13 years later, multiple rounds of MDT, they still never received systemic therapy. So sometimes you're a little surprised by the outcomes based on the organ site.
Leslie Ballas: Yeah, biology of the tumor clearly makes a difference. On a practical level, what is your recommendation to your medical oncology colleagues in terms of if someone is on systemic therapy and going to get MDT, do you ask them to hold the systemic therapy or do you let them continue on the IO but not the TKI? How do you manage that?
Chad Tang: Yeah, so as you mentioned, there are two main systemic therapies that we see most commonly in these patients—that is, an IO and a TKI. There's been a number of phase I, II, and even some III trials in which radiation has been paired directly with IO, and they have shown toxicities that are added but not synergistic, so we don't generally hold IO during radiation. TKIs, however, they do inhibit wound healing afterwards, so we have made it our practice to hold it a few days before, during radiation, and a few days after, and that can vary depending on the half-life of the TKI in question. For example, axitinib has a very short half-life, while cabo can be a longer half-life, but as a general rule of thumb, probably one or two days before and one or two days after restarting, and that's only when we're doing SBRT and a luminal organ is involved that could be injured, form ulcers, and would require repair afterwards.
Leslie Ballas: Thank you. One other practical question for our radiation oncology colleagues. Renal cell carcinoma has been thought to be radioresistant, and that's why SBRT has been a great treatment option for patients with renal cell carcinoma. Do you know if it makes a difference if we treat with one fraction of radiation, three fractions, five fractions, ten fractions? Do you have any data on that in the MDT space?
Chad Tang: Yeah, so to the radiation colleagues out there, there are some data suggesting that the alpha/beta is, for renal cell, about 2.6, so that would lend itself to a little bit of hypofractionation to have a better effect. But I think there's a lot of diverse biology within renal cell, as can be seen by some can be indolent, some can be quite aggressive metastatic, and even in renal cell, clear cell and other histologies are also very different in biology. So I would say it's a little unclear, but generally more dose per fraction has been suggested to be more effective, but I don't know if that applies to all renal cells and all renal cell histologies.
Leslie Ballas: Fair enough. Well, thank you so much for sharing your expertise with us today. The data you showed is really exciting, and it's a great time for renal cell carcinoma and the addition of radiation into that space. So thank you so much for talking with us and explaining what's going on.
Chad Tang: Thank you so much. It's been a pleasure.
Leslie Ballas: Hi, I'm Leslie Ballas. I'm a Radiation Oncologist at Cedars-Sinai Medical Center in Los Angeles, and it is my great pleasure to introduce Dr. Chad Tang, an Associate Professor at MD Anderson Cancer Center in the Departments of Radiation Oncology, Translational Molecular Pathology, as well as the Department of Investigational Cancer Therapeutics. He is a true expert in radiation for renal cell carcinoma, and he is going to talk to us a little bit today about the use of SBRT in renal cell carcinoma for metastatic disease.
Thank you so much, Dr. Tang, for joining us.
Chad Tang: Thank you, Dr. Ballas. I appreciate the kind introduction. I'm really excited to be here on UroToday to talk about some of these really interesting topics.
So I'm going to focus on two areas: oligometastatic and oligoprogressive disease, because they have the most data supporting them. So jumping right in, let's talk about oligometastatic RCC. These are patients with up to five sites of metastatic disease, and we recently reported on a phase II single-arm study looking at these patients. What we did was we took patients with up to five sites of metastatic disease, who had no prior systemic therapy or stopped it one month ago, and they had radiation to all sites. At the time of progression, patients were assessed radiographically, and if they had oligoprogressive disease—that is, up to three sites—they could reenter this loop and be treated again off systemic therapy. However, at the time of polymetastatic progression (greater than three sites), they then had to restart systemic therapy in order to control the disease.
What we showed in this initial study was that the toxicities were quite favorable, first off—only 10% Grade 3 to 4 toxicities. Progression-free survival was favorable at about 20 months median survival, and systemic therapy was also favorable with the majority of patients not requiring systemic therapy at the time of study closure.
As you can see on the swimmer's plot, patients had an initial amount of radiation, and about 12 months later they had a subsequent amount of radiation, and this continued continuously until polymetastatic progression was observed. So after these results were published, we enrolled another 120 patients and we rapidly analyzed these results for the review.
So why is this important? It's because the frontline systemic therapy options for metastatic renal cell carcinoma is usually a combination of two drugs—two immunotherapies, or immunotherapy and tyrosine kinase inhibitors—and at least in the U.S., this is quite expensive, at least in the six digits in terms of per-year costs, and it's an indefinite use. Toxicities in the pivotal phase III trials were also significant, ranging between 40 to 80% Grade 3s, and the patient has to come back, usually monthly if not more, for infusions and for labs for that infusion.
In contrast, if we do a systemic therapy-sparing strategy with SBRT, the costs are usually much lower per round of SBRT, with lower toxicities for the patients. Healthcare visits do require some, but the patient only has to be here for one to two weeks per round of SBRT. I want to emphasize that to date there is no evidence that systemic therapy after MDT is less effective.
So moving on to the next topic. This is oligoprogressive renal cell carcinoma. This entity is a newly defined entity and it basically entails a patient with any number of metastatic lesions, when active systemic therapy is rendered to a state where there's only one to maybe three to five lesions that are progressing. This paradigm has been tested in two prospective trials in RCC, where patients who had oligoprogressive RCC received radiation to all progressive sites and then continued the same line of systemic therapy, which they were technically progressing on.
Two studies highlighted here are the Cheung et al. study done in Canada, which enrolled patients with up to five mets, required clear cell components, and was closed early because they required a TKI monotherapy, which changed to doublet therapy during the study enrollment period. So they had 38 patients. Another study by Dr. Raquib Hannan at UT Southwestern, which enrolled patients with up to three sites of disease with mixed systemic therapies, and this trial enrolled 20 patients.
These two independent studies have remarkably similar results despite their differences, and what they both showed was that time until having to switch from the line that the patient was on to a next line of systemic therapy was 12 to 11 months, and that the Grade 3 severe toxicities were quite modest at zero to 5%.
So in summary, this is an exciting time for radiation to aid in the disease management of metastatic RCC. In these two areas, we have two prospective studies—one I showed and another by UT Southwestern—that demonstrate the potential of metastasis-directed therapy to defer the initiation of systemic therapy for more than a year, potentially much longer, and that these approaches where we spare systemic therapy are generally less toxic, less expensive, and require less hospital visits than the doublet standard upfront systemic therapy. However, notably, randomized phase III data is needed in this space.
For metastasis-directed therapy with systemic therapy, there have been the two trials that I presented previously for radiation to oligoprogressive sites demonstrating the potential to defer systemic therapy escalation for approximately one year, and this is important because the earlier lines of systemic therapy are generally more effective and have less side effects than later lines. So thank you.
Leslie Ballas: Thank you so much. That was excellent. I have a couple of questions. I noticed in your trial that you presented, looking at metastasis-directed therapy initially in the oligometastatic space, you define that as five sites of metastasis or less, and then when it became oligoprogression, it became three sites of metastasis or less. I'm wondering—I think that people are accepting the definition of five or fewer sites of metastasis as an oligometastatic definition, but I feel like, why does it differ between oligometastatic disease and oligoprogressive disease? Do you have a sense of does three versus five really matter in this space?
Chad Tang: These are excellent questions. This area, this entity of oligometastatic, and even more recently, oligoprogressive, are new entities that we are trying to define. You brought up three and five. These are arbitrary cutoffs. We had to do an arbitrary cutoff for a trial, and I think what you're seeing is the result of that. I must note that probably better than looking at the number of mets on your imaging are biologic markers, and that's something we sorely need for both oligometastasis and oligoprogression, which we're all working on, because we believe ultimately radiograph is a poor surrogate of really the disease state and what's happening.
Leslie Ballas: Yeah. Tell me, did you find, or is there any data to show, that the site of the metastasis makes a difference in terms of MDT? Most notably, I would think CNS would be one of the ones that you'd wonder about.
Chad Tang: Yeah, another excellent question. So we did look in our expanded trial, which we are currently preparing at the sites. We couldn't find a site that was immediately associated with a worse outcome. There is some preclinical data suggesting that metastases that come to rarer sites like pancreas or exocrine glands can be a little bit more indolent genetically, but that also needs to be teased out with other factors as well. One of my patients that has done really well with this strategy presented, for example, with a brain metastasis that was resected, and 13 years later, multiple rounds of MDT, they still never received systemic therapy. So sometimes you're a little surprised by the outcomes based on the organ site.
Leslie Ballas: Yeah, biology of the tumor clearly makes a difference. On a practical level, what is your recommendation to your medical oncology colleagues in terms of if someone is on systemic therapy and going to get MDT, do you ask them to hold the systemic therapy or do you let them continue on the IO but not the TKI? How do you manage that?
Chad Tang: Yeah, so as you mentioned, there are two main systemic therapies that we see most commonly in these patients—that is, an IO and a TKI. There's been a number of phase I, II, and even some III trials in which radiation has been paired directly with IO, and they have shown toxicities that are added but not synergistic, so we don't generally hold IO during radiation. TKIs, however, they do inhibit wound healing afterwards, so we have made it our practice to hold it a few days before, during radiation, and a few days after, and that can vary depending on the half-life of the TKI in question. For example, axitinib has a very short half-life, while cabo can be a longer half-life, but as a general rule of thumb, probably one or two days before and one or two days after restarting, and that's only when we're doing SBRT and a luminal organ is involved that could be injured, form ulcers, and would require repair afterwards.
Leslie Ballas: Thank you. One other practical question for our radiation oncology colleagues. Renal cell carcinoma has been thought to be radioresistant, and that's why SBRT has been a great treatment option for patients with renal cell carcinoma. Do you know if it makes a difference if we treat with one fraction of radiation, three fractions, five fractions, ten fractions? Do you have any data on that in the MDT space?
Chad Tang: Yeah, so to the radiation colleagues out there, there are some data suggesting that the alpha/beta is, for renal cell, about 2.6, so that would lend itself to a little bit of hypofractionation to have a better effect. But I think there's a lot of diverse biology within renal cell, as can be seen by some can be indolent, some can be quite aggressive metastatic, and even in renal cell, clear cell and other histologies are also very different in biology. So I would say it's a little unclear, but generally more dose per fraction has been suggested to be more effective, but I don't know if that applies to all renal cells and all renal cell histologies.
Leslie Ballas: Fair enough. Well, thank you so much for sharing your expertise with us today. The data you showed is really exciting, and it's a great time for renal cell carcinoma and the addition of radiation into that space. So thank you so much for talking with us and explaining what's going on.
Chad Tang: Thank you so much. It's been a pleasure.