High-Risk Prostate Cancer: 80Gy + ADT Extends Survival Without Added Toxicity - Christophe Hennequin
February 27, 2024
Leslie Ballas and Christophe Hennequin explore the findings of the GETUG-AFU 18 randomized trial, which evaluated the impact of radiotherapy dose escalation in high-risk prostate cancer patients receiving long-term androgen deprivation therapy (ADT). Conducted between 2009 and 2013, the trial randomized 500 patients to receive either 70 Gy or 80 Gy, revealing significant improvements in progression-free survival, cancer-specific survival, and a notable 10% increase in overall survival at 10 years for those receiving the higher dose. Despite advancements in radiotherapy techniques, such as IMRT, and the emergence of hypofractionation and SBRT, this study underscores the critical role of dose escalation combined with long-term ADT in curing over 80% of high-risk patients, challenging current practices and emphasizing the need for further research to adapt these findings to modern treatment protocols.
Biographies:
Christophe Hennequin, MD, PhD, Radiation Oncologist, Saint Louis Hospital, Paris, France
Leslie Ballas, MD, GU Radiation Oncologist, Cedars-Sinai Medical Center, Los Angeles, CA
Biographies:
Christophe Hennequin, MD, PhD, Radiation Oncologist, Saint Louis Hospital, Paris, France
Leslie Ballas, MD, GU Radiation Oncologist, Cedars-Sinai Medical Center, Los Angeles, CA
Read the Full Video Transcript
Leslie Ballas: Hi, my name is Leslie Ballas and I am a GU radiation oncologist at Cedars-Sinai Hospital in Los Angeles. I'm joined today by Dr. Christophe Hennequin, who is joining us as part of the GETUG-AFU study group that presented an abstract long-term results of dose escalation 80 versus 70 Gy, combined with long-term androgen deprivation in high-risk prostate cancer patients. This is the GETUG-AFU 18 randomized trial. Thank you so much for joining us today.
Christophe Hennequin: It's a pleasure. And so on behalf of the GETUG Group, as I said, I present this morning the result of this large randomized trial evaluating the role of dose escalation of radiotherapy in high-risk prostate cancers. So we included about 500 patients between 2009 and 2013, and randomized between 70 Gy versus 80 Gy. And both groups received long-term androgen deprivation therapy, long-term ADT. In fact, most of the previous trials evaluating the role of dose escalation did not use ADT or used short-term ADT. And this is the originality of these trials to use combinations of long-term ADT and dose escalations.
And we expected, in fact, 197 events and we observed only 92 events. Even with the long follow-up, 9.5 years. This is good news for patients, because in this group of patients we can cure more than 80% of the patients now. And the result of the trials are very clear. We improve not only progression-free survival, biochemical control, and so on. We improve also cancer-specific survival and overall survival. But 10% increase in overall survival at 10 years. So this is a major advance. In fact, most of the radiation oncologists know that dose is very important and gave actually a high dose for these patients. But it's the first trial level one evidence showing that it is beneficial for the patients to increase the dose of radiation in combination with long-term ADT.
Leslie Ballas: Congratulations on this important study. The results were exciting to see since many dose escalation trials in radiotherapy have shown benefits in biologic progression-free survival. The long-term results of RTOG 0126 showed a benefit in distant metastasis-free survival. But there are very few that have shown benefit in overall survival. Why do you think that you saw that in your study whereas it hasn't been seen in others?
Christophe Hennequin: This is a good question. I don't know why we have only included high-risk patients. In many other trials investigating the role of dose escalation, an intermediate group is included. And so, the number of events such as deaths are not so high as in the high-risk groups. So maybe this is one explanation. We have to work again with our database to better define prognostic factors such as the Gleason score or PSA levels to see exactly what is the population who benefit from this high dose.
Leslie Ballas: And also exciting in your results is the fact that the grade two and higher toxicity, both GI and GU, was not increased with the 80 Gy dose escalation. Is that correct?
Christophe Hennequin: Exactly, exactly. I must say that we have made this trial 10, 15 years ago now, and at this moment in France, IMRT was not so usual as now. And some patients were treated with 3D RT and not with IMRT. And in fact, there is an imbalance between both arms with more patients treated with IMRT in the 80 Gy group than in the 70 Gy group. It could explain the fact that we have no difference in toxicity and quality of life between both arms.
Leslie Ballas: Did you do any stratification based on radiation factor or radiation technique?
Christophe Hennequin: No, sorry. No. The stratification factors were about lymphadenectomy or not and about the center. There was no stratification about the technique. So you have to look more accurately at the role of the technique of radiotherapy in the results.
Leslie Ballas: And in terms of GI toxicity with that stratification factor in mind, whether or not they had lymph node radiation because they were clinical node-negative versus pathologic node-negative where they did not require pelvic lymph node radiation. Was there any difference?
Christophe Hennequin: No, no difference at all between patients who received pelvic radiations or not. In fact, most of the bowel toxicity was rectitis, proctitis, and so on, bleeding. Not due to bowel toxicity.
Leslie Ballas: So you finished accruing to this trial I believe in 2013.
Christophe Hennequin: That's right.
Leslie Ballas: And the world of prostate radiation has changed dramatically. I can't even remember the last person that I gave 80 Gy or the equivalent to. How do you think that we should interpret your results to this study in the setting of moderate hypofractionation, in the setting of certain practitioners giving SBRT to high-risk patients, flame-style DIL boosts? How do we dose escalate in our current setting?
Christophe Hennequin: This is a good question and I have no answer to that. Sure. I don't want to make again a fractionation, fortification to patients. So we have to use hypofractionations, and the question is, what hypofractionated dose is equivalent to 80 Gy. And there is a big debate about the alpha-beta ratio of prostate cancer. And we do not know if it's 1.5, 3 Gy or 5 Gy, and it matters because equivalence is completely different if we get an alpha-beta ratio of 1.5 or 5 Gy, so we have to better define what is the equivalent dose of 80 Gy with hypofractionated, and moreover about SBRT. If five fractions are equivalent to 40 Gy, to 80 Gy, I don't know. So this is a good question.
The second important problem is the use for very high-risk patients because of the STAMPEDE trial, we know that to add abiraterone to long-term ADT is important for very high-risk patients. And what is the role of the dose with the combinations of [inaudible] and long-term ADT? We don't know exactly.
Leslie Ballas: And a similar-
Christophe Hennequin: We have also one question, but many others are coming.
Leslie Ballas: Yeah, and similarly, your high-risk patient definition is from an era of conventional imaging.
Christophe Hennequin: Exactly.
Leslie Ballas: And so with obviously the widespread use of PSMA, whether you are treating the highest-risk patients, or patients who are truly clinically node-negative is another question. Do we need simultaneous integrated boosts if a PSMA shows a positive lymph node? And obviously, there are a lot of current ongoing trials looking at some of those questions.
Christophe Hennequin: Sure. And it shows that if we select better our patients with a PSMA PET scan, obviously the role of local control will be more important. And probably the role of dose is also important.
Leslie Ballas: I think, again, your group and you yourself deserve incredible congratulations on completing this important study. It lets us understand how important local therapy is despite long-term ADT. And I just want to say thank you again for being here and presenting these results. Is there anything else you want to communicate to the community?
Christophe Hennequin: No, no. I think it's an important result, but we have many works to do to apply it to the clinics.
Leslie Ballas: Hi, my name is Leslie Ballas and I am a GU radiation oncologist at Cedars-Sinai Hospital in Los Angeles. I'm joined today by Dr. Christophe Hennequin, who is joining us as part of the GETUG-AFU study group that presented an abstract long-term results of dose escalation 80 versus 70 Gy, combined with long-term androgen deprivation in high-risk prostate cancer patients. This is the GETUG-AFU 18 randomized trial. Thank you so much for joining us today.
Christophe Hennequin: It's a pleasure. And so on behalf of the GETUG Group, as I said, I present this morning the result of this large randomized trial evaluating the role of dose escalation of radiotherapy in high-risk prostate cancers. So we included about 500 patients between 2009 and 2013, and randomized between 70 Gy versus 80 Gy. And both groups received long-term androgen deprivation therapy, long-term ADT. In fact, most of the previous trials evaluating the role of dose escalation did not use ADT or used short-term ADT. And this is the originality of these trials to use combinations of long-term ADT and dose escalations.
And we expected, in fact, 197 events and we observed only 92 events. Even with the long follow-up, 9.5 years. This is good news for patients, because in this group of patients we can cure more than 80% of the patients now. And the result of the trials are very clear. We improve not only progression-free survival, biochemical control, and so on. We improve also cancer-specific survival and overall survival. But 10% increase in overall survival at 10 years. So this is a major advance. In fact, most of the radiation oncologists know that dose is very important and gave actually a high dose for these patients. But it's the first trial level one evidence showing that it is beneficial for the patients to increase the dose of radiation in combination with long-term ADT.
Leslie Ballas: Congratulations on this important study. The results were exciting to see since many dose escalation trials in radiotherapy have shown benefits in biologic progression-free survival. The long-term results of RTOG 0126 showed a benefit in distant metastasis-free survival. But there are very few that have shown benefit in overall survival. Why do you think that you saw that in your study whereas it hasn't been seen in others?
Christophe Hennequin: This is a good question. I don't know why we have only included high-risk patients. In many other trials investigating the role of dose escalation, an intermediate group is included. And so, the number of events such as deaths are not so high as in the high-risk groups. So maybe this is one explanation. We have to work again with our database to better define prognostic factors such as the Gleason score or PSA levels to see exactly what is the population who benefit from this high dose.
Leslie Ballas: And also exciting in your results is the fact that the grade two and higher toxicity, both GI and GU, was not increased with the 80 Gy dose escalation. Is that correct?
Christophe Hennequin: Exactly, exactly. I must say that we have made this trial 10, 15 years ago now, and at this moment in France, IMRT was not so usual as now. And some patients were treated with 3D RT and not with IMRT. And in fact, there is an imbalance between both arms with more patients treated with IMRT in the 80 Gy group than in the 70 Gy group. It could explain the fact that we have no difference in toxicity and quality of life between both arms.
Leslie Ballas: Did you do any stratification based on radiation factor or radiation technique?
Christophe Hennequin: No, sorry. No. The stratification factors were about lymphadenectomy or not and about the center. There was no stratification about the technique. So you have to look more accurately at the role of the technique of radiotherapy in the results.
Leslie Ballas: And in terms of GI toxicity with that stratification factor in mind, whether or not they had lymph node radiation because they were clinical node-negative versus pathologic node-negative where they did not require pelvic lymph node radiation. Was there any difference?
Christophe Hennequin: No, no difference at all between patients who received pelvic radiations or not. In fact, most of the bowel toxicity was rectitis, proctitis, and so on, bleeding. Not due to bowel toxicity.
Leslie Ballas: So you finished accruing to this trial I believe in 2013.
Christophe Hennequin: That's right.
Leslie Ballas: And the world of prostate radiation has changed dramatically. I can't even remember the last person that I gave 80 Gy or the equivalent to. How do you think that we should interpret your results to this study in the setting of moderate hypofractionation, in the setting of certain practitioners giving SBRT to high-risk patients, flame-style DIL boosts? How do we dose escalate in our current setting?
Christophe Hennequin: This is a good question and I have no answer to that. Sure. I don't want to make again a fractionation, fortification to patients. So we have to use hypofractionations, and the question is, what hypofractionated dose is equivalent to 80 Gy. And there is a big debate about the alpha-beta ratio of prostate cancer. And we do not know if it's 1.5, 3 Gy or 5 Gy, and it matters because equivalence is completely different if we get an alpha-beta ratio of 1.5 or 5 Gy, so we have to better define what is the equivalent dose of 80 Gy with hypofractionated, and moreover about SBRT. If five fractions are equivalent to 40 Gy, to 80 Gy, I don't know. So this is a good question.
The second important problem is the use for very high-risk patients because of the STAMPEDE trial, we know that to add abiraterone to long-term ADT is important for very high-risk patients. And what is the role of the dose with the combinations of [inaudible] and long-term ADT? We don't know exactly.
Leslie Ballas: And a similar-
Christophe Hennequin: We have also one question, but many others are coming.
Leslie Ballas: Yeah, and similarly, your high-risk patient definition is from an era of conventional imaging.
Christophe Hennequin: Exactly.
Leslie Ballas: And so with obviously the widespread use of PSMA, whether you are treating the highest-risk patients, or patients who are truly clinically node-negative is another question. Do we need simultaneous integrated boosts if a PSMA shows a positive lymph node? And obviously, there are a lot of current ongoing trials looking at some of those questions.
Christophe Hennequin: Sure. And it shows that if we select better our patients with a PSMA PET scan, obviously the role of local control will be more important. And probably the role of dose is also important.
Leslie Ballas: I think, again, your group and you yourself deserve incredible congratulations on completing this important study. It lets us understand how important local therapy is despite long-term ADT. And I just want to say thank you again for being here and presenting these results. Is there anything else you want to communicate to the community?
Christophe Hennequin: No, no. I think it's an important result, but we have many works to do to apply it to the clinics.