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Treating Locally Advanced Rectal Cancer

Panelists: Johanna C. Bendell,MD, Sarah Cannon Research Institute; Dirk Arnold, MD, PhD, KTB Klinik fur Tumorbiologie GmbH & Co. KG ; Heinz-Josef Lenz, MD, FACP, USC Center for Molecular Pathway and Drug Discovery; Zev A. Wainberg, MD, UCLA Medical Center
Published: Friday, Dec 14, 2018



Transcript: 

Johanna C. Bendell, MD: Now moving along to rectal cancer. We’ve had some patients asking about surgery and radiation therapy and whether it’s necessary. The Germans have been instrumental in setting the standard of care for how we treat rectal cancer, both in terms of chemoradiation therapy and surgery. What’s the right surgery? Can you give us a background on what the standard is and why?

Dirk Arnold, MD, PhD: We should talk about locally advanced rectal cancer. This starts with the problem of defining locally advanced rectal cancer. There is broad agreement worldwide that we should use an MRI [magnetic resonance imaging]–based decision-making model regarding a T3 or T4 tumor, plus/minus lymph nodes. Those with lymph nodes, we can discuss for the rest of the day, because we do not know whether lymph nodes being assessed by MRI or rectal ultrasound mean anything at all. It is limited, therefore, to T3 and T4 disease defined by an MRI. The next question is for the locally advanced disease: What about the circumferential resection margin in the perirectal fat? Can this be resected in total?

For these patients, it is of interest to discuss multidisciplinary treatments. At early stages, it is clearly likely to do surgery or endoscopic resection up front. For these locally advanced diseases, which are in 60% to 70% of patients, the optimal perioperative treatment and best surgical option is a total mesorectal excision, which has been established at centers. There are many countries that have established training programs, or proctor programs, where surgeons were trained to perform the surgery and report it with a pathologist on a quality assurance basis.

There’s been a lot of effort in European countries on programs like this. This alone, with the optimal surgery, has reduced the risk of relapse dramatically. We now speak of local relapsed percentages being around 5%, and we can discuss whether, in these cohorts, if radiotherapy or chemoradiation is still necessary.

Johanna C. Bendell, MD: What’s your take?

Dirk Arnold, MD, PhD: There we come, really, to a complex discussion, since the understanding in many countries is, with many clinical trials supporting this, that we overtreat many patients with the uniform use of chemoradiation preoperatively. I would say there are many European countries or many local countries where they have a tradition of saying, “The outcome of early T3, T3A, T3B”—meaning with a minimal infiltration in the perirectal fat and complete free-circumferential resection margin; it may be an overtreatment to use chemoradiation there. Many countries are traditionally overtreating these patients and applying uniform chemoradiation.

Johanna C. Bendell, MD: Does that change what you do? Does that make you more inclined to do adjuvant chemoradiation therapy, even though you have had data?

Dirk Arnold, MD, PhD: We don’t use adjuvant. It’s not belonging to, say, the normal course of treatment. The question is, what would we do preoperatively? Nothing? Should we give short-time radiation, which is done in the Nordic countries and some European countries? Should we give chemoradiation, or should we use this novel approach and use systemic treatment? We need to enhance our efficacy in our choice of the best systemic treatment, because we do know that some patients are at risk of
 relapse—not locally, but most of them relapse, let’s say, with distant metastases. It therefore makes sense to install preoperative chemotherapy in some patients.

Johanna C. Bendell, MD: We’re bringing in oxaliplatin now, right? We’re seeing data pulling oxaliplatin into this neoadjuvant approach and talking more about using oxaliplatin in the adjuvant setting?

Heinz-Josef Lenz, MD, FACP: Dirk mentioned an important point. I think in the United States, the role of radiation is more focused on the distal tumors of less than 5 cm for sphincter-sparing surgeries and so on. For T3 and high rectal, we don’t do radiation anymore. The question is, is there a role in the low rectal, and what distance is the staging? That needs to be looked at, and the United States decided for total neoadjuvant treatment with systemic chemotherapy. There are data with chemotherapy alone, because these patients die of metastatic disease. We can better control the disease not only systemically but also locally. The complete pathologic response would seem to be higher than with chemoradiation. We then develop better chemoradiation sensitizers for patients who may benefit from radiation. It’s an interesting approach, ,because we have not advanced chemoradiation sensitization for some of these patients.

The question is, who benefits and who doesn’t? We learn that the high ones do not. For the low ones, we don’t know who does. Here there are different approaches that, hopefully, give us answers in the next year.

Johanna C. Bendell, MD: So maybe we should not change anything quite yet, but we will see.

Dirk Arnold, MD, PhD: We have to improve stepwise in the different disciplines. Since the improvement was done in surgery, now it is important to improve MRI imaging. Without a really high-cost MRI imaging and standardized evaluation, it is impossible to stratify perioperative treatment. I would want to de-escalate preoperative treatment if you’re not sure that you have an elaborated program in your radiographic department, ensuring that this patient is low-risk MRI defined in a mid-surge-free rectal cancer. If you don’t get this information on that level, you should not play around with treatment intensity.

Heinz-Josef Lenz, MD, FACP: It’s important because the radiologists need to know not only MI but also MRI of the pelvis and rectum. There are usually specialized radiologists who only read these and are not the ones who read the CT [computed tomography] scans.

Johanna C. Bendell, MD: You all have advanced academic centers with specialized radiologists who read only pelvic MRIs. For our typical working oncologists out there that are seeing the rectal cancer, I think we still do want to do the neoadjuvant chemoradiation therapy until we can figure out how to define those.

Dirk Arnold, MD, PhD: I think it’s critical to know what their stage is in order to put them into the appropriate treatment category.

Johanna C. Bendell, MD: Zev, what’s your approach?

Zev A. Wainberg, MD: The standard of care is to follow the MRI stage. We also do a lot of MRI staging. For now, the standard remains to give chemoradiation neoadjuvantly. Certainly, there are several efforts that are interesting. Obviously, 1 is to eliminate radiation altogether and do total adjuvant therapy and chemotherapy and then follow with surgery.

Then there’s the other controversial element, which is to consider leaving out the surgery aspect, particularly in those patients who have disease that is going to undergo complete pathological response to any neoadjuvant chemotherapy treatment. But the subject in prospective trials that are looking at those patients who undergo a complete pathological response as determined by endoscopic evaluations is still controversial.

One of the arms in that study is to forgo the definitive surgery. So for now, that’s still obviously not considered standard of care by any means, but I’ll be very curious to see if there are certain patients for whom surgery is not necessary—particularly those who would undergo a permanent colostomy.

Johanna C. Bendell, MD: I’ve had a few patients—even despite my saying, “You know it’s very preliminary data; we’re waiting for prospective studies”—who say they just don’t…they refuse to have a bag. They don’t care if it means it’s going to recur, they don’t want the surgery. I’ve had this complete response. How, when you have those patients, do you watch them? What’s your typical surveillance? And realizing this is all; there are no data to tell us what to do.

Zev A. Wainberg, MD: There are no data, so I just watch them pretty carefully. There’s an added level of surveillance that you feel compelled to follow in those patients that haven’t had surgery. Whether it’s additional endoscopies or additional carcinoembryonic antigens [CEAs], it’s a more aggressive surveillance, certainly, than you would give someone who’s undergone definitive curative surgery.

Dirk Arnold, MD, PhD: We should not biopsy and rebiopsy.

Heinz-Josef Lenz, MD, FACP: When you look at the original articles, that’s how they’re followed up, with a repeated sigmoidoscopy. There are ongoing trials to find the most appropriate way to monitor this. You cannot see it, making it very difficult to miss.

Dirk Arnold, MD, PhD: Standard of care is radiographic follow-up and endoscopic follow-up. I would, in the first year, at 3- to 4-month intervals, do rectal endoscopies and rectal ultrasounds.

Heinz-Josef Lenz, MD, FACP: They don’t need to do preparation. They do the ultrasound, then the biopsy—whatever they want to do—and they have a certain scheme to follow.

Johanna C. Bendell, MD: Dirk, we’ve been trying now to improve our systemic component of rectal therapy by bringing oxaliplatin into the mix. What are some of the different abstracts we’ve seen lately that have looked at whether we should do it?

Dirk Arnold, MD, PhD: It’s relatively clear that we cannot add much, if you look through the local endpoints of complete resection—nothing has improved; pathologically complete response, nothing has improved. Regarding the systemic benefits, patients get less metastases or they recur later. Let’s say preoperative oxaliplatin can be completely abandoned.


Transcript Edited for Clarity
 

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Transcript: 

Johanna C. Bendell, MD: Now moving along to rectal cancer. We’ve had some patients asking about surgery and radiation therapy and whether it’s necessary. The Germans have been instrumental in setting the standard of care for how we treat rectal cancer, both in terms of chemoradiation therapy and surgery. What’s the right surgery? Can you give us a background on what the standard is and why?

Dirk Arnold, MD, PhD: We should talk about locally advanced rectal cancer. This starts with the problem of defining locally advanced rectal cancer. There is broad agreement worldwide that we should use an MRI [magnetic resonance imaging]–based decision-making model regarding a T3 or T4 tumor, plus/minus lymph nodes. Those with lymph nodes, we can discuss for the rest of the day, because we do not know whether lymph nodes being assessed by MRI or rectal ultrasound mean anything at all. It is limited, therefore, to T3 and T4 disease defined by an MRI. The next question is for the locally advanced disease: What about the circumferential resection margin in the perirectal fat? Can this be resected in total?

For these patients, it is of interest to discuss multidisciplinary treatments. At early stages, it is clearly likely to do surgery or endoscopic resection up front. For these locally advanced diseases, which are in 60% to 70% of patients, the optimal perioperative treatment and best surgical option is a total mesorectal excision, which has been established at centers. There are many countries that have established training programs, or proctor programs, where surgeons were trained to perform the surgery and report it with a pathologist on a quality assurance basis.

There’s been a lot of effort in European countries on programs like this. This alone, with the optimal surgery, has reduced the risk of relapse dramatically. We now speak of local relapsed percentages being around 5%, and we can discuss whether, in these cohorts, if radiotherapy or chemoradiation is still necessary.

Johanna C. Bendell, MD: What’s your take?

Dirk Arnold, MD, PhD: There we come, really, to a complex discussion, since the understanding in many countries is, with many clinical trials supporting this, that we overtreat many patients with the uniform use of chemoradiation preoperatively. I would say there are many European countries or many local countries where they have a tradition of saying, “The outcome of early T3, T3A, T3B”—meaning with a minimal infiltration in the perirectal fat and complete free-circumferential resection margin; it may be an overtreatment to use chemoradiation there. Many countries are traditionally overtreating these patients and applying uniform chemoradiation.

Johanna C. Bendell, MD: Does that change what you do? Does that make you more inclined to do adjuvant chemoradiation therapy, even though you have had data?

Dirk Arnold, MD, PhD: We don’t use adjuvant. It’s not belonging to, say, the normal course of treatment. The question is, what would we do preoperatively? Nothing? Should we give short-time radiation, which is done in the Nordic countries and some European countries? Should we give chemoradiation, or should we use this novel approach and use systemic treatment? We need to enhance our efficacy in our choice of the best systemic treatment, because we do know that some patients are at risk of
 relapse—not locally, but most of them relapse, let’s say, with distant metastases. It therefore makes sense to install preoperative chemotherapy in some patients.

Johanna C. Bendell, MD: We’re bringing in oxaliplatin now, right? We’re seeing data pulling oxaliplatin into this neoadjuvant approach and talking more about using oxaliplatin in the adjuvant setting?

Heinz-Josef Lenz, MD, FACP: Dirk mentioned an important point. I think in the United States, the role of radiation is more focused on the distal tumors of less than 5 cm for sphincter-sparing surgeries and so on. For T3 and high rectal, we don’t do radiation anymore. The question is, is there a role in the low rectal, and what distance is the staging? That needs to be looked at, and the United States decided for total neoadjuvant treatment with systemic chemotherapy. There are data with chemotherapy alone, because these patients die of metastatic disease. We can better control the disease not only systemically but also locally. The complete pathologic response would seem to be higher than with chemoradiation. We then develop better chemoradiation sensitizers for patients who may benefit from radiation. It’s an interesting approach, ,because we have not advanced chemoradiation sensitization for some of these patients.

The question is, who benefits and who doesn’t? We learn that the high ones do not. For the low ones, we don’t know who does. Here there are different approaches that, hopefully, give us answers in the next year.

Johanna C. Bendell, MD: So maybe we should not change anything quite yet, but we will see.

Dirk Arnold, MD, PhD: We have to improve stepwise in the different disciplines. Since the improvement was done in surgery, now it is important to improve MRI imaging. Without a really high-cost MRI imaging and standardized evaluation, it is impossible to stratify perioperative treatment. I would want to de-escalate preoperative treatment if you’re not sure that you have an elaborated program in your radiographic department, ensuring that this patient is low-risk MRI defined in a mid-surge-free rectal cancer. If you don’t get this information on that level, you should not play around with treatment intensity.

Heinz-Josef Lenz, MD, FACP: It’s important because the radiologists need to know not only MI but also MRI of the pelvis and rectum. There are usually specialized radiologists who only read these and are not the ones who read the CT [computed tomography] scans.

Johanna C. Bendell, MD: You all have advanced academic centers with specialized radiologists who read only pelvic MRIs. For our typical working oncologists out there that are seeing the rectal cancer, I think we still do want to do the neoadjuvant chemoradiation therapy until we can figure out how to define those.

Dirk Arnold, MD, PhD: I think it’s critical to know what their stage is in order to put them into the appropriate treatment category.

Johanna C. Bendell, MD: Zev, what’s your approach?

Zev A. Wainberg, MD: The standard of care is to follow the MRI stage. We also do a lot of MRI staging. For now, the standard remains to give chemoradiation neoadjuvantly. Certainly, there are several efforts that are interesting. Obviously, 1 is to eliminate radiation altogether and do total adjuvant therapy and chemotherapy and then follow with surgery.

Then there’s the other controversial element, which is to consider leaving out the surgery aspect, particularly in those patients who have disease that is going to undergo complete pathological response to any neoadjuvant chemotherapy treatment. But the subject in prospective trials that are looking at those patients who undergo a complete pathological response as determined by endoscopic evaluations is still controversial.

One of the arms in that study is to forgo the definitive surgery. So for now, that’s still obviously not considered standard of care by any means, but I’ll be very curious to see if there are certain patients for whom surgery is not necessary—particularly those who would undergo a permanent colostomy.

Johanna C. Bendell, MD: I’ve had a few patients—even despite my saying, “You know it’s very preliminary data; we’re waiting for prospective studies”—who say they just don’t…they refuse to have a bag. They don’t care if it means it’s going to recur, they don’t want the surgery. I’ve had this complete response. How, when you have those patients, do you watch them? What’s your typical surveillance? And realizing this is all; there are no data to tell us what to do.

Zev A. Wainberg, MD: There are no data, so I just watch them pretty carefully. There’s an added level of surveillance that you feel compelled to follow in those patients that haven’t had surgery. Whether it’s additional endoscopies or additional carcinoembryonic antigens [CEAs], it’s a more aggressive surveillance, certainly, than you would give someone who’s undergone definitive curative surgery.

Dirk Arnold, MD, PhD: We should not biopsy and rebiopsy.

Heinz-Josef Lenz, MD, FACP: When you look at the original articles, that’s how they’re followed up, with a repeated sigmoidoscopy. There are ongoing trials to find the most appropriate way to monitor this. You cannot see it, making it very difficult to miss.

Dirk Arnold, MD, PhD: Standard of care is radiographic follow-up and endoscopic follow-up. I would, in the first year, at 3- to 4-month intervals, do rectal endoscopies and rectal ultrasounds.

Heinz-Josef Lenz, MD, FACP: They don’t need to do preparation. They do the ultrasound, then the biopsy—whatever they want to do—and they have a certain scheme to follow.

Johanna C. Bendell, MD: Dirk, we’ve been trying now to improve our systemic component of rectal therapy by bringing oxaliplatin into the mix. What are some of the different abstracts we’ve seen lately that have looked at whether we should do it?

Dirk Arnold, MD, PhD: It’s relatively clear that we cannot add much, if you look through the local endpoints of complete resection—nothing has improved; pathologically complete response, nothing has improved. Regarding the systemic benefits, patients get less metastases or they recur later. Let’s say preoperative oxaliplatin can be completely abandoned.


Transcript Edited for Clarity
 
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