NCCN Clinical Practice Guidelines in Prostate Cancer Radiation Therapy: External Beam Radiation Therapy - Zachary Klaassen
March 16, 2023
In this UroToday Journal Club, Zachary Klaassen discusses the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology, specifically looking at radiation therapy and focusing on an overview of the role of radiotherapy, a discussion of external beam radiotherapy, and a brief discussion of stereotactic body radiation therapy. The NCCN guidelines emphasize that SBRT and IMRT likely have similar toxicity profiles, whereas proton therapy has a decreased rate of GU toxicity but an increased rate of GI toxicity.
Biographies:
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Biographies:
Zachary Klaassen, MD, MSc, Urologic Oncologist, Assistant Professor Surgery/Urology at the Medical College of Georgia at Augusta University, Georgia Cancer Center
Read the Full Video Transcript
Christopher Wallis: Hello, and thank you for joining us for this UroToday discussion of the NCCN clinical practice guidelines in oncology, with a focus on prostate cancer. We are discussing the recently presented and published 2022 guidelines, which came out in September of 2021, and today, we're discussing radiation therapy, and this is broken down into two parts. The first of which is presented here.
I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. And joining me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.
Examining the radiotherapy section of the NCCN prostate cancer guidelines, we can see that there are six main components. Today, we are going to discuss the first three, focusing on an overview of the role of radiotherapy, a discussion of external beam radiation therapy, and a brief discussion of stereotactic body radiation therapy.
In terms of an overview, there are a variety of radiation approaches that may be used in prostate cancer, including external beam radiotherapy, which was initially relatively accrued in, and now very sophisticated with the use of IMRT and hypofractionated image-guided SBRT. Additionally, proton radiation or brachytherapy may be used, and sometimes, these are used in combination. Now, propensity-score match comparison, the NCCN guidelines emphasize that SBRT and IMRT likely have similar toxicity profiles. Whereas proton therapy has a decreased rate of GU toxicity, but an increased rate of GI toxicity. Perhaps, most important from a healthcare perspective, given these similar clinical outcomes, proton therapy is substantial, more expensive than IMRT, which is itself, somewhat more expensive than SBRT.
When we consider first external beam radiotherapy, this is a field that has had a rapid evolution over the past few decades. And these improvements in technical aspects of the delivery of radiotherapy have resulted in increased radiation doses, which can be safely administered. So one of the first advances was the use of a 3D-CRT, which allowed the integration of CT images for treatment positioning and targeting. IMRT represents a second-generation 3D technique, which has demonstrated reduced GI toxicity and rates of salvage therapy, compared with 3D-CRT. However, there is an increased cost associated with the use of IMRT.
One of the advances that the improvements in technology have allowed is the use of hypofractionation. So hypofractionated IMRT has been compared with conventional fractionation. Highlighted here, is the HYPRO trial which is just one of many Phase III trials performed in this space, and together evidence for efficacy suggests similar or noninferior outcomes. While we examine toxicity, there is some variability between trials, although the overall suggestion is that toxicity rates are similar between conventional and hypofractionated IMRT. Differences between trials, particularly, with respect to toxicity, have been postulated to be due to differences in the fractionation schedules, themselves.
As a result of these data and others, the panel supported the role of hypofractionated IMRT as an alternative to conventional fractionation. You can see here, in the table below, that moderate hypofractionation is the preferred approach across nearly all NCCN risk groups, and a variety of dose and fractionation schedules can be considered.
The panel then moved to discuss the role of localization, recommending that daily prostate localization with image-guided radiotherapy is essential for target margin reduction and treatment accuracy. A number of imaging approaches can be used, including, ultrasound, implanted fiducials, electromagnetic targeting, and tracking, or the use of an endorectal balloon. The use of such localization improves cure rates and decreases complications, by allowing more targeted delivery of radiotherapy.
Dose escalation has been shown in many trials, as well as registry data, to improve biochemical outcomes. And one of the first important studies that came from Dr. Kuban and colleagues, showed that recurrence-free survival improved substantially when radiation dose was escalated from 70 Gy to 78 Gy. And as a result, the panel concluded that 70 Gy is no longer adequate. instead, 75.6 to 79.2 Gy for lowest disease, and up to 81 Gy for intermediate to high-risk disease should be used.
The panel then provided a comparison of radiotherapy versus surgical treatment in localized prostate cancer, highlighting that radiotherapy advantages include, the avoidance of surgical complications and anesthetic complications. Additionally, radiotherapy techniques are relatively, widely available, and there is a low risk of incontinence and quote, "a good chance of short-term preservation of erectile function".
However, the panel highlighted that radiotherapy may have substantial disadvantages, including a prolonged treatment course when conventional fractionation is used, and high rates of temporary bladder or bowel dysfunction. Further, there's a low, but definite, risk of protracted proctitis, and the erectile dysfunction risk may increase over time. Finally, late rectal complications should be considered, although, these are related primarily, to the volume of the rectum that is treated.
And one way to decrease treatment of the rectum is the use of spacers. And biomaterials have been approved as spacers between the prostate and rectum. Use of these decreases rectal toxicity with late grade two rates dropping from 5.7% to 0%. Additionally, their suggestion is that the use of attrition may actually benefit sexual toxicity. However, these are expensive and may have rare complications, including rectal perforation and urethral damage.
The panel then highlighted some contraindication stakes from beam radiotherapy in terms of more absolute contraindications. These include pelvic radiotherapy, which has been previously administered, active inflammatory disease of the rectum, and a permanent indwelling Foley catheter. In contrast, relative contraindications include very low bladder capacity, chronic, moderate, or severe diarrhea, bladder outlet obstruction, and inactive ulcerative colitis.
I'm now going to hand it over to Zach to walk us through the role of external beam radiotherapy in a variety of different prostate cancer indications.
Zachary Klaassen: Thanks Chris. So if we look at external beam radiotherapy for earlier disease, the panel suggests that external beam radiotherapy is one of the principal treatment options for clinically localized prostate cancer. The panel consensus is that similar progression-free survival between external beam radiotherapy and radical prostatectomy in low-risk disease is achievable. Looking at data from the NRG/RTOG 0126 trial, dose-escalation from 70.2 to 79.2 Gy demonstrated a decreased risk of biochemical recurrence, however, with an increased late toxicity profile, and no effect on overall survival.
Now we will talk about external beam radiotherapy for patients with high-risk and very high-risk disease. So in these patients, a combination of ADT plus radiotherapy should be employed. There have been several studies that have looked at the addition of ADT to radiotherapy, which is associated with improved disease, specific survival, and overall survival, as well as the addition of radiotherapy to ADT, again, associated with improved DSS and OS.
Notably, a PSA nadir greater than 0.5 after radiotherapy plus ADT for six months of treatment is a poor prognostic sign and is associated with a 72% increased risk of all-cause mortality. For these patients, prophylactic nodal irradiation should also be considered.
Next, we'll talk about external beam radiotherapy for node-positive disease. And the panel suggests that external beam radiotherapy with neoadjuvant, concurrent, or adjuvant ADT, is the preferred option for patients with clinical N1 disease, and may also include consideration of ADT alone, or ADT plus abiraterone. On the right, you can see a patient CT scan and mapping plan for external beam radiotherapy to the node-positive disease.
Next, we'll talk about external beam radiotherapy to the primary tumor in low-volume M1 disease. And for this discussion, we turned to the STAMPEDE arm H trial, which was published in Lancet Oncology in 2018. This trial was a big trial that had 4,697 patients that were randomized to the trial platform. 2,636 were allocated to other research arms that were not eligible. So ultimately 2,061 patients were randomized, including 1,029 to the standard of care arm, and 1,032 to the standard of care plus radiotherapy arm.
And you can see here, that these were also broken down into metastatic burden, low versus high. If we look to the right, you can see that in the entire population, there was no difference in overall survival for the control group, versus the radiotherapy group. When we look at the failure-free survival, the radiotherapy arm, which is in blue, compared to the control arm, in red, had improved failure-free survival with a hazard ratio of 0.76, and a 95% confidence interval of 0.68 to 0.84.
When we look at the subgroup analysis by metastatic burden, we can see that there was a significant improvement in overall survival for low metastatic burden patients, with a hazard ratio of 0.68, and a 95% confidence interval of 0.52 to 0.90. Importantly, this survival benefit was not seen in the high burden group, as you can see here with the hazard ratio of 1.07, and a not statistically significant 95% confidence interval.
So the panel recommends that external beam radiotherapy to the primary lesion can be considered for those with low-volume disease, but that recommends against treatment in patients with high-volume disease.
Next, we'll talk about stereotactic body radiation therapy. And the rationale for this approach is that there is a relatively slow prostate cancer proliferation. And because it's similar or lower than surrounding tissue, extreme hypofractionation should result in similar cancer control, without the increased risk of late toxicity.
SBRT is typically delivered in high doses, with the radiotherapy fraction of fewer than five fractions for the total treatment plan. And single-center studies in early Phase II trials show excellent biochemical progression-free survival and similar early toxicity to standard radiotherapy. However, some analyses have suggested a higher GU toxicity than regular radiotherapy.
A number of Phase III studies have been initiated to compare SBRT to conventional regimes. And preliminary results show comparable GU and GI toxicity. The HYPO-RT-PC trial showed non-inferior, failure-free survival in intermediate high-risk disease patients for patients that receive 42.7 Gy in seven fractions, versus 78 Gy in 39 fractions. So SBRT can be considered as an alternative where there is appropriate technology, physics, and clinical expertise, at the particular site. Certainly, longer-term and multi-center data are required to evaluate the late toxicity for SBRT.
So to summarize this portion of the NCCN guidelines discussing external beam radiotherapy, as well as SBRT, we note that external beam radiotherapy is one of the principal treatment options in localized disease. And hypofractionation, including that applied to SBRT, can be considered for these patients. Dose escalation is the standard of care, in terms of low-risk patients receiving 76 to 79 Gy, in intermediate and high-risk patients receiving up to 81 Gy. Very high-risk and high-risk patients should have a combination with ADT. And external beam radiotherapy is the preferred approach, with ADT plus or minus abiraterone, for patients with clinical N1 disease. Finally, as we discussed in the STAMPEDE arm H trial, external beam radiotherapy can be considered in patients with low-volume M1 disease.
We thank you for your attention to this UroToday NCCN prostate cancer guideline discussion on radiotherapy, specifically, external beam radiotherapy and SBRT.
Christopher Wallis: Hello, and thank you for joining us for this UroToday discussion of the NCCN clinical practice guidelines in oncology, with a focus on prostate cancer. We are discussing the recently presented and published 2022 guidelines, which came out in September of 2021, and today, we're discussing radiation therapy, and this is broken down into two parts. The first of which is presented here.
I'm Chris Wallis, an Assistant Professor in the Division of Urology at the University of Toronto. And joining me today is Zach Klaassen, Assistant Professor in the Division of Urology at the Medical College of Georgia.
Examining the radiotherapy section of the NCCN prostate cancer guidelines, we can see that there are six main components. Today, we are going to discuss the first three, focusing on an overview of the role of radiotherapy, a discussion of external beam radiation therapy, and a brief discussion of stereotactic body radiation therapy.
In terms of an overview, there are a variety of radiation approaches that may be used in prostate cancer, including external beam radiotherapy, which was initially relatively accrued in, and now very sophisticated with the use of IMRT and hypofractionated image-guided SBRT. Additionally, proton radiation or brachytherapy may be used, and sometimes, these are used in combination. Now, propensity-score match comparison, the NCCN guidelines emphasize that SBRT and IMRT likely have similar toxicity profiles. Whereas proton therapy has a decreased rate of GU toxicity, but an increased rate of GI toxicity. Perhaps, most important from a healthcare perspective, given these similar clinical outcomes, proton therapy is substantial, more expensive than IMRT, which is itself, somewhat more expensive than SBRT.
When we consider first external beam radiotherapy, this is a field that has had a rapid evolution over the past few decades. And these improvements in technical aspects of the delivery of radiotherapy have resulted in increased radiation doses, which can be safely administered. So one of the first advances was the use of a 3D-CRT, which allowed the integration of CT images for treatment positioning and targeting. IMRT represents a second-generation 3D technique, which has demonstrated reduced GI toxicity and rates of salvage therapy, compared with 3D-CRT. However, there is an increased cost associated with the use of IMRT.
One of the advances that the improvements in technology have allowed is the use of hypofractionation. So hypofractionated IMRT has been compared with conventional fractionation. Highlighted here, is the HYPRO trial which is just one of many Phase III trials performed in this space, and together evidence for efficacy suggests similar or noninferior outcomes. While we examine toxicity, there is some variability between trials, although the overall suggestion is that toxicity rates are similar between conventional and hypofractionated IMRT. Differences between trials, particularly, with respect to toxicity, have been postulated to be due to differences in the fractionation schedules, themselves.
As a result of these data and others, the panel supported the role of hypofractionated IMRT as an alternative to conventional fractionation. You can see here, in the table below, that moderate hypofractionation is the preferred approach across nearly all NCCN risk groups, and a variety of dose and fractionation schedules can be considered.
The panel then moved to discuss the role of localization, recommending that daily prostate localization with image-guided radiotherapy is essential for target margin reduction and treatment accuracy. A number of imaging approaches can be used, including, ultrasound, implanted fiducials, electromagnetic targeting, and tracking, or the use of an endorectal balloon. The use of such localization improves cure rates and decreases complications, by allowing more targeted delivery of radiotherapy.
Dose escalation has been shown in many trials, as well as registry data, to improve biochemical outcomes. And one of the first important studies that came from Dr. Kuban and colleagues, showed that recurrence-free survival improved substantially when radiation dose was escalated from 70 Gy to 78 Gy. And as a result, the panel concluded that 70 Gy is no longer adequate. instead, 75.6 to 79.2 Gy for lowest disease, and up to 81 Gy for intermediate to high-risk disease should be used.
The panel then provided a comparison of radiotherapy versus surgical treatment in localized prostate cancer, highlighting that radiotherapy advantages include, the avoidance of surgical complications and anesthetic complications. Additionally, radiotherapy techniques are relatively, widely available, and there is a low risk of incontinence and quote, "a good chance of short-term preservation of erectile function".
However, the panel highlighted that radiotherapy may have substantial disadvantages, including a prolonged treatment course when conventional fractionation is used, and high rates of temporary bladder or bowel dysfunction. Further, there's a low, but definite, risk of protracted proctitis, and the erectile dysfunction risk may increase over time. Finally, late rectal complications should be considered, although, these are related primarily, to the volume of the rectum that is treated.
And one way to decrease treatment of the rectum is the use of spacers. And biomaterials have been approved as spacers between the prostate and rectum. Use of these decreases rectal toxicity with late grade two rates dropping from 5.7% to 0%. Additionally, their suggestion is that the use of attrition may actually benefit sexual toxicity. However, these are expensive and may have rare complications, including rectal perforation and urethral damage.
The panel then highlighted some contraindication stakes from beam radiotherapy in terms of more absolute contraindications. These include pelvic radiotherapy, which has been previously administered, active inflammatory disease of the rectum, and a permanent indwelling Foley catheter. In contrast, relative contraindications include very low bladder capacity, chronic, moderate, or severe diarrhea, bladder outlet obstruction, and inactive ulcerative colitis.
I'm now going to hand it over to Zach to walk us through the role of external beam radiotherapy in a variety of different prostate cancer indications.
Zachary Klaassen: Thanks Chris. So if we look at external beam radiotherapy for earlier disease, the panel suggests that external beam radiotherapy is one of the principal treatment options for clinically localized prostate cancer. The panel consensus is that similar progression-free survival between external beam radiotherapy and radical prostatectomy in low-risk disease is achievable. Looking at data from the NRG/RTOG 0126 trial, dose-escalation from 70.2 to 79.2 Gy demonstrated a decreased risk of biochemical recurrence, however, with an increased late toxicity profile, and no effect on overall survival.
Now we will talk about external beam radiotherapy for patients with high-risk and very high-risk disease. So in these patients, a combination of ADT plus radiotherapy should be employed. There have been several studies that have looked at the addition of ADT to radiotherapy, which is associated with improved disease, specific survival, and overall survival, as well as the addition of radiotherapy to ADT, again, associated with improved DSS and OS.
Notably, a PSA nadir greater than 0.5 after radiotherapy plus ADT for six months of treatment is a poor prognostic sign and is associated with a 72% increased risk of all-cause mortality. For these patients, prophylactic nodal irradiation should also be considered.
Next, we'll talk about external beam radiotherapy for node-positive disease. And the panel suggests that external beam radiotherapy with neoadjuvant, concurrent, or adjuvant ADT, is the preferred option for patients with clinical N1 disease, and may also include consideration of ADT alone, or ADT plus abiraterone. On the right, you can see a patient CT scan and mapping plan for external beam radiotherapy to the node-positive disease.
Next, we'll talk about external beam radiotherapy to the primary tumor in low-volume M1 disease. And for this discussion, we turned to the STAMPEDE arm H trial, which was published in Lancet Oncology in 2018. This trial was a big trial that had 4,697 patients that were randomized to the trial platform. 2,636 were allocated to other research arms that were not eligible. So ultimately 2,061 patients were randomized, including 1,029 to the standard of care arm, and 1,032 to the standard of care plus radiotherapy arm.
And you can see here, that these were also broken down into metastatic burden, low versus high. If we look to the right, you can see that in the entire population, there was no difference in overall survival for the control group, versus the radiotherapy group. When we look at the failure-free survival, the radiotherapy arm, which is in blue, compared to the control arm, in red, had improved failure-free survival with a hazard ratio of 0.76, and a 95% confidence interval of 0.68 to 0.84.
When we look at the subgroup analysis by metastatic burden, we can see that there was a significant improvement in overall survival for low metastatic burden patients, with a hazard ratio of 0.68, and a 95% confidence interval of 0.52 to 0.90. Importantly, this survival benefit was not seen in the high burden group, as you can see here with the hazard ratio of 1.07, and a not statistically significant 95% confidence interval.
So the panel recommends that external beam radiotherapy to the primary lesion can be considered for those with low-volume disease, but that recommends against treatment in patients with high-volume disease.
Next, we'll talk about stereotactic body radiation therapy. And the rationale for this approach is that there is a relatively slow prostate cancer proliferation. And because it's similar or lower than surrounding tissue, extreme hypofractionation should result in similar cancer control, without the increased risk of late toxicity.
SBRT is typically delivered in high doses, with the radiotherapy fraction of fewer than five fractions for the total treatment plan. And single-center studies in early Phase II trials show excellent biochemical progression-free survival and similar early toxicity to standard radiotherapy. However, some analyses have suggested a higher GU toxicity than regular radiotherapy.
A number of Phase III studies have been initiated to compare SBRT to conventional regimes. And preliminary results show comparable GU and GI toxicity. The HYPO-RT-PC trial showed non-inferior, failure-free survival in intermediate high-risk disease patients for patients that receive 42.7 Gy in seven fractions, versus 78 Gy in 39 fractions. So SBRT can be considered as an alternative where there is appropriate technology, physics, and clinical expertise, at the particular site. Certainly, longer-term and multi-center data are required to evaluate the late toxicity for SBRT.
So to summarize this portion of the NCCN guidelines discussing external beam radiotherapy, as well as SBRT, we note that external beam radiotherapy is one of the principal treatment options in localized disease. And hypofractionation, including that applied to SBRT, can be considered for these patients. Dose escalation is the standard of care, in terms of low-risk patients receiving 76 to 79 Gy, in intermediate and high-risk patients receiving up to 81 Gy. Very high-risk and high-risk patients should have a combination with ADT. And external beam radiotherapy is the preferred approach, with ADT plus or minus abiraterone, for patients with clinical N1 disease. Finally, as we discussed in the STAMPEDE arm H trial, external beam radiotherapy can be considered in patients with low-volume M1 disease.
We thank you for your attention to this UroToday NCCN prostate cancer guideline discussion on radiotherapy, specifically, external beam radiotherapy and SBRT.