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Defining Disease Volume in Metastatic Prostate Cancer

Panelists: Joe OSullivan, MD, Queen's University; Nicholas James, MBBS, PhD University of Birmingham; Noel Clarke, MBBS, Christie Hospital
Published: Wednesday, Dec 05, 2018



Transcript: 

Noel Clarke, MBBS, FRCS, ChM: From a biological standpoint, it is fascinating that the burden is such a watershed that it formats into stage III; the patient falls off a cliff. The biological question is, at what point does the primary tumor stop feeding the metastases and instead, the metastases start feeding one another? Is there some immunological threshold that is overwhelmed, and suddenly things begin to deteriorate? Or is there some other effect we don’t understand?

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I wonder if it’s a dose effect because the doses in the STAMPEDE trial weren’t renal radical radiation doses, whereas there’s some retrospective data suggesting that there’s a threshold of the sort of radical therapy doses. There’s a 70-grade type of biological equipment that might be more effective.

Nicholas James, MD: If you look at the RTL1 trial, which is the MRC’s [Medical Research Council] trial, it compared 64 grade with 74 grade, that had big and early readouts in terms of prostate-specific antigen [PSA] relapsed-free survival [RFS], which was better with the higher dose. Even with 15 years of follow-up, it has never translated into a metastatic progression-free survival [PFS] difference, let alone an OS [overall survival] difference. You trade extra radiation dose for less hormone therapy later.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Exactly.

Nicholas James, MD: But in the paper that we’ve written, we’ve concluded that it wouldn’t, because we picked 2 doses for the RT part of this, grade 55 and -20, which is broadly equivalent to grade 64 and -32 on alpha beta ratios. We picked that because, when we set up, not everybody had an intensity-modulated radiation therapy [IMRT] and image-guided radiation therapy [IGRT], and we didn’t want to subject people to 37 fractions of conformal radiotherapy, which PEACE I has done. That face will be interesting in due course. We knew the toxicity was manageable, but, in the meantime, everybody’s got IMRT. The CHHiP [conventional or hypofractionated high-dose intensity modulated radiotherapy for prostate cancer] trial has shown that grade 74 and -37 is equivalent to grade 60 and -20.

Considering these 2 sets of results, I think it would be advisable to give stage 60 and -20, not -55 and -20, as the local therapy, which will be our default for moving forward through our next stage of STAMPEDE.

Noel Clarke, MBBS, FRCS, ChM: The question of volume and risk is another thing this has unearthed, and we haven’t given a huge amount of thought to this before we started doing the analyses for abiraterone acetate and M1RT [multidimensional item repo component] in STAMPEDE. Charted has a volume stratification, but it’s not looking at volume but numbers.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Correct.

Noel Clarke, MBBS, FRCS, ChM: It quantifies according to 4 and an axial-nonaxial, and any visceral goes automatically into the high risk. It doesn’t take any account at all of lymph nodes. If you then look at latitude, which looks at risk, and arbitrarily produces Gleason 8, or above 3 bone metastases, and any visceral, again, there is no lymph node classification at all. When you look at the outcome from patients who were presenting bone-only, bone lymph node, and visceral, the bone and lymph node combination is as lethal as visceral at first presentation. We just published on this, on the latest SEER [surveillance, epidemiology, and end results program] data involving over 17,000 patients, and you can see clearly that it doesn’t matter how many lymph nodes are present; they just need bone and lymph node in any number, which automatically causes them to fall to a worse prognosis category.

We haven’t addressed this concept of tumor burden, and that’s another thing that we’re hoping to look at within STAMPEDE, where we’ve got this large body of imaging data, which is well classified and quantified. We hope to be able to answer some of these questions.

Nicholas James, MD: We also pulled in thousands of scans into Manchester. Directed by Gerhardt Attard, MD, PhD, we’re busy pulling in thousands of blocks of data. We’ll be able to perform radiogenomic research on an industrial scale with this data. We’re going to have an absolute data bonanza to play with here. I entirely agree with everything said.

Transcript Edited for Clarity 

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Transcript: 

Noel Clarke, MBBS, FRCS, ChM: From a biological standpoint, it is fascinating that the burden is such a watershed that it formats into stage III; the patient falls off a cliff. The biological question is, at what point does the primary tumor stop feeding the metastases and instead, the metastases start feeding one another? Is there some immunological threshold that is overwhelmed, and suddenly things begin to deteriorate? Or is there some other effect we don’t understand?

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: I wonder if it’s a dose effect because the doses in the STAMPEDE trial weren’t renal radical radiation doses, whereas there’s some retrospective data suggesting that there’s a threshold of the sort of radical therapy doses. There’s a 70-grade type of biological equipment that might be more effective.

Nicholas James, MD: If you look at the RTL1 trial, which is the MRC’s [Medical Research Council] trial, it compared 64 grade with 74 grade, that had big and early readouts in terms of prostate-specific antigen [PSA] relapsed-free survival [RFS], which was better with the higher dose. Even with 15 years of follow-up, it has never translated into a metastatic progression-free survival [PFS] difference, let alone an OS [overall survival] difference. You trade extra radiation dose for less hormone therapy later.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Exactly.

Nicholas James, MD: But in the paper that we’ve written, we’ve concluded that it wouldn’t, because we picked 2 doses for the RT part of this, grade 55 and -20, which is broadly equivalent to grade 64 and -32 on alpha beta ratios. We picked that because, when we set up, not everybody had an intensity-modulated radiation therapy [IMRT] and image-guided radiation therapy [IGRT], and we didn’t want to subject people to 37 fractions of conformal radiotherapy, which PEACE I has done. That face will be interesting in due course. We knew the toxicity was manageable, but, in the meantime, everybody’s got IMRT. The CHHiP [conventional or hypofractionated high-dose intensity modulated radiotherapy for prostate cancer] trial has shown that grade 74 and -37 is equivalent to grade 60 and -20.

Considering these 2 sets of results, I think it would be advisable to give stage 60 and -20, not -55 and -20, as the local therapy, which will be our default for moving forward through our next stage of STAMPEDE.

Noel Clarke, MBBS, FRCS, ChM: The question of volume and risk is another thing this has unearthed, and we haven’t given a huge amount of thought to this before we started doing the analyses for abiraterone acetate and M1RT [multidimensional item repo component] in STAMPEDE. Charted has a volume stratification, but it’s not looking at volume but numbers.

Joe O’Sullivan, MD, FRCPI, FFRRCSI, FRCR: Correct.

Noel Clarke, MBBS, FRCS, ChM: It quantifies according to 4 and an axial-nonaxial, and any visceral goes automatically into the high risk. It doesn’t take any account at all of lymph nodes. If you then look at latitude, which looks at risk, and arbitrarily produces Gleason 8, or above 3 bone metastases, and any visceral, again, there is no lymph node classification at all. When you look at the outcome from patients who were presenting bone-only, bone lymph node, and visceral, the bone and lymph node combination is as lethal as visceral at first presentation. We just published on this, on the latest SEER [surveillance, epidemiology, and end results program] data involving over 17,000 patients, and you can see clearly that it doesn’t matter how many lymph nodes are present; they just need bone and lymph node in any number, which automatically causes them to fall to a worse prognosis category.

We haven’t addressed this concept of tumor burden, and that’s another thing that we’re hoping to look at within STAMPEDE, where we’ve got this large body of imaging data, which is well classified and quantified. We hope to be able to answer some of these questions.

Nicholas James, MD: We also pulled in thousands of scans into Manchester. Directed by Gerhardt Attard, MD, PhD, we’re busy pulling in thousands of blocks of data. We’ll be able to perform radiogenomic research on an industrial scale with this data. We’re going to have an absolute data bonanza to play with here. I entirely agree with everything said.

Transcript Edited for Clarity 
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