How to Select Patients with Biochemical Relapse in Whom Salvage Radiation Therapy Can be Postponed? "Presentation" - Barbara Alicja Jereczek-Fossa
November 15, 2024
At the 2024 Advanced Prostate Cancer Consensus Conference (APCCC), Barbara Alicja Jereczek-Fossa examines timing decisions for post-prostatectomy salvage radiation, addressing PSA definitions and risk stratification tools. She emphasizes the importance of early intervention while discussing personalized treatment approaches and ongoing trials.
Biographies:
Barbara Alicja Jereczek-Fossa, MD, PhD, Director, Division of Radiotherapy, European Institute of Oncology, Associate Professor in Radiation Oncology, University of Milan, Italy
Biographies:
Barbara Alicja Jereczek-Fossa, MD, PhD, Director, Division of Radiotherapy, European Institute of Oncology, Associate Professor in Radiation Oncology, University of Milan, Italy
Read the Full Video Transcript
Barbara Alicja Jereczek-Fossa: Good morning to everybody. I'm really honored to be part of this panel, and really a big thank you to the committee for the invitation. Thank you also for the question, for the title, because it's quite tricky to ask the radiation oncologist, "How to select patients with biochemical relapse in whom salvage radiation therapy can be postponed?" So when not to do radiotherapy. Okay, it's here. These are my disclosures. All outside this lecture.
It's a really interesting time for this area, for this space, because in the last years we've got really many randomized trials, some of them are already published, some of them are ongoing, answering the questions on biochemical relapse after surgery. And indeed, it is a very difficult, very heterogeneous patient population because we don't even have one unique definition of undetectable PSA after surgery. We have at least 12 definitions of biochemical recurrence. Here you see the definitions by major societies, and these definitions range from 0.05 to 0.4. So even the definition is not yet unique.
And indeed it's a very heterogeneous patient population. We see how different prognosis, how different outcomes are between different patients. So far we have many clinical prognostic factors correlated to the outcome. Actually, two of them are really validated in all studies. It is PSA doubling time and grade group. Based on these two, I would say, conventional clinical risk factors, EAU distinguishes two categories of biochemical recurrence. Either it may be low risk when PSA doubling time is longer than 1 year and a grade group less than 4, or high-risk group if it is shorter PSA doubling time and high grade group. Very easy. And it was validated—compliments for this study—by young academic urologists from EAU.
Despite all the limitations of this large cohort, it was a prospective study. No information on ADT, no imaging. But this study shows that salvage radiotherapy improves survival in patients with high-risk biochemical recurrence, and this benefit was not so clear in patients with low-risk biochemical recurrence after surgery.
We know that there are some patients, candidates for observation only—patients with low-risk recurrence—and other patients are candidates for salvage radiotherapy, with or without systemic therapy. Some of the patients, and it will be discussed today, are maybe candidates for systemic treatment only. In this area we have one trial; it is a small Japanese trial comparing salvage radiotherapy with salvage hormonal treatment. Salvage radiation was better. Obviously all these options are applied to the patients with no or negative imaging. In case of positive imaging, the treatment will be different, and I will not discuss it here.
So which are the patients when we can avoid, I would say even postpone, radiotherapy? Definitely patients with short life expectancy, frail patients, comorbidity, low-risk patients. But based on what? We don't have yet new genomic classifiers or AI ready, but I will show you some data already coming out. Genomic testing is already available. They are still not available everywhere. And we know that even in the States, only 1% of the patients undergoing surgery will get the genomic classifier. But these numbers, fortunately, are growing, especially in young patients. Today, they are mostly used for your initial diagnosis and choice of adjuvant treatment, but not for the choice of salvage therapy.
Decipher has been validated on a big study from Switzerland by Alan Dal Pra, showing that patients with high genomic classifier score had improved outcomes with early salvage when compared to late salvage radiotherapy. So what we know about Decipher in this space, we know that with high score, more than 0.6, patients may benefit with addition of ADT, maybe more intense earlier treatment, multimodal treatment, new trials. When it is a low score, like 0.6 or less, de-escalation could be a choice. These kinds of genomic classifiers are already included in some guidelines. Here you see tables from guidelines' recommendations where genomic classifiers are already here on the list together with other clinical factors or, for example, BRCA mutation status.
Another new tool, and I think the hope for the near future, is AI. Definitely we will have these tools. Here's one of the first studies from the Netherlands showing this new deep learning-based biomarker well correlated. Here there is data from two separate institutions, and this novel deep learning-based biomarker based on the prostatectomy tissue analysis, it was well correlated with the velocity of biochemical recurrence.
We are not yet there. We don't know which are really low-risk patients in which we can avoid or postpone radiotherapy. We are waiting for novel prognostic factors. I would just mention some pitfalls of postponing radiotherapy, salvage radiotherapy. Definitely these patients will still need some kind of follow-up. It may create some kind of anxiety. They see they are growing, slowly but constantly growing PSA. We know this PSA, it is, we call it in Italy. And what is most important is losing the window of opportunity because we have one single high-efficacy treatment. What do I mean? If we have a patient with PSA 0.1, 0.2 and we give him salvage radiotherapy, many of these patients, up to 80–90%, will be, again, cured. So it's a second chance to be cured and they will not need any other treatment. If we wait for PSA 0.5 or 1, as some studies show, it means that this patient will enter in the area of chronic disease, chronic treatment with all these long-lasting, sometimes lifelong treatments and toxicity.
So if we go through the guidelines again, here is European Societies, the rating for avoiding radiotherapy or monitoring only is very weak and it is very high for not delaying salvage therapy if it is indicated or even not waiting for the threshold. So as soon as you have the impression—I say impression because it's many factors you keep in mind—if you have the impression of the indication for early salvage, go for it. Do it.
There are many trials in this area, and here I'll just take one which actually answers the question of the lecture. This is the trial from Australia and New Zealand, the DIPPER trial. Patients with low-risk biochemical recurrence, negative imaging, are randomized between surveillance and early radiotherapy given at 0.2, 0.5 PSA of this level. So it'll answer the question of the topic.
And this brings me to the conclusions that biochemical recurrence is a very heterogeneous area. EAU risk categories may be helpful in patient stratification. Selected low-risk patients may not need salvage radiotherapy. We know that they are not all the same patients, and we need to keep in mind that this salvage treatment is a unique opportunity to impact survival and delay metastasis. So we should be very careful to avoid risking losing the window of opportunity. In the near future, I'm sure we'll have risk-adapted and image-based salvage treatment strategies. Thank you very much, and thank you to my group as well.
Barbara Alicja Jereczek-Fossa: Good morning to everybody. I'm really honored to be part of this panel, and really a big thank you to the committee for the invitation. Thank you also for the question, for the title, because it's quite tricky to ask the radiation oncologist, "How to select patients with biochemical relapse in whom salvage radiation therapy can be postponed?" So when not to do radiotherapy. Okay, it's here. These are my disclosures. All outside this lecture.
It's a really interesting time for this area, for this space, because in the last years we've got really many randomized trials, some of them are already published, some of them are ongoing, answering the questions on biochemical relapse after surgery. And indeed, it is a very difficult, very heterogeneous patient population because we don't even have one unique definition of undetectable PSA after surgery. We have at least 12 definitions of biochemical recurrence. Here you see the definitions by major societies, and these definitions range from 0.05 to 0.4. So even the definition is not yet unique.
And indeed it's a very heterogeneous patient population. We see how different prognosis, how different outcomes are between different patients. So far we have many clinical prognostic factors correlated to the outcome. Actually, two of them are really validated in all studies. It is PSA doubling time and grade group. Based on these two, I would say, conventional clinical risk factors, EAU distinguishes two categories of biochemical recurrence. Either it may be low risk when PSA doubling time is longer than 1 year and a grade group less than 4, or high-risk group if it is shorter PSA doubling time and high grade group. Very easy. And it was validated—compliments for this study—by young academic urologists from EAU.
Despite all the limitations of this large cohort, it was a prospective study. No information on ADT, no imaging. But this study shows that salvage radiotherapy improves survival in patients with high-risk biochemical recurrence, and this benefit was not so clear in patients with low-risk biochemical recurrence after surgery.
We know that there are some patients, candidates for observation only—patients with low-risk recurrence—and other patients are candidates for salvage radiotherapy, with or without systemic therapy. Some of the patients, and it will be discussed today, are maybe candidates for systemic treatment only. In this area we have one trial; it is a small Japanese trial comparing salvage radiotherapy with salvage hormonal treatment. Salvage radiation was better. Obviously all these options are applied to the patients with no or negative imaging. In case of positive imaging, the treatment will be different, and I will not discuss it here.
So which are the patients when we can avoid, I would say even postpone, radiotherapy? Definitely patients with short life expectancy, frail patients, comorbidity, low-risk patients. But based on what? We don't have yet new genomic classifiers or AI ready, but I will show you some data already coming out. Genomic testing is already available. They are still not available everywhere. And we know that even in the States, only 1% of the patients undergoing surgery will get the genomic classifier. But these numbers, fortunately, are growing, especially in young patients. Today, they are mostly used for your initial diagnosis and choice of adjuvant treatment, but not for the choice of salvage therapy.
Decipher has been validated on a big study from Switzerland by Alan Dal Pra, showing that patients with high genomic classifier score had improved outcomes with early salvage when compared to late salvage radiotherapy. So what we know about Decipher in this space, we know that with high score, more than 0.6, patients may benefit with addition of ADT, maybe more intense earlier treatment, multimodal treatment, new trials. When it is a low score, like 0.6 or less, de-escalation could be a choice. These kinds of genomic classifiers are already included in some guidelines. Here you see tables from guidelines' recommendations where genomic classifiers are already here on the list together with other clinical factors or, for example, BRCA mutation status.
Another new tool, and I think the hope for the near future, is AI. Definitely we will have these tools. Here's one of the first studies from the Netherlands showing this new deep learning-based biomarker well correlated. Here there is data from two separate institutions, and this novel deep learning-based biomarker based on the prostatectomy tissue analysis, it was well correlated with the velocity of biochemical recurrence.
We are not yet there. We don't know which are really low-risk patients in which we can avoid or postpone radiotherapy. We are waiting for novel prognostic factors. I would just mention some pitfalls of postponing radiotherapy, salvage radiotherapy. Definitely these patients will still need some kind of follow-up. It may create some kind of anxiety. They see they are growing, slowly but constantly growing PSA. We know this PSA, it is, we call it in Italy. And what is most important is losing the window of opportunity because we have one single high-efficacy treatment. What do I mean? If we have a patient with PSA 0.1, 0.2 and we give him salvage radiotherapy, many of these patients, up to 80–90%, will be, again, cured. So it's a second chance to be cured and they will not need any other treatment. If we wait for PSA 0.5 or 1, as some studies show, it means that this patient will enter in the area of chronic disease, chronic treatment with all these long-lasting, sometimes lifelong treatments and toxicity.
So if we go through the guidelines again, here is European Societies, the rating for avoiding radiotherapy or monitoring only is very weak and it is very high for not delaying salvage therapy if it is indicated or even not waiting for the threshold. So as soon as you have the impression—I say impression because it's many factors you keep in mind—if you have the impression of the indication for early salvage, go for it. Do it.
There are many trials in this area, and here I'll just take one which actually answers the question of the lecture. This is the trial from Australia and New Zealand, the DIPPER trial. Patients with low-risk biochemical recurrence, negative imaging, are randomized between surveillance and early radiotherapy given at 0.2, 0.5 PSA of this level. So it'll answer the question of the topic.
And this brings me to the conclusions that biochemical recurrence is a very heterogeneous area. EAU risk categories may be helpful in patient stratification. Selected low-risk patients may not need salvage radiotherapy. We know that they are not all the same patients, and we need to keep in mind that this salvage treatment is a unique opportunity to impact survival and delay metastasis. So we should be very careful to avoid risking losing the window of opportunity. In the near future, I'm sure we'll have risk-adapted and image-based salvage treatment strategies. Thank you very much, and thank you to my group as well.