Breast RNI and IMN coverage Discussion.... Again. Breast is the worst x 4?

[TheWallnerus]

I would participate in shared decision making with the patient regarding pros/cons of B51 data in terms of treating WBI alone vs WBI + RNI

Shared decision making is a great answer. I should have said that!

Comparing Rabinovitch's slide which is a discussion of comparing one RT regimen to another is not an equal comparison to thinking of outcomes between omission of RT vs delivering RT

Of course not an "equal comparison to thinking of outcomes between omission of RT vs delivering RT," just simply throwing it in the mix as an amuse bouche of the temporality of 5 vs 10 y outcomes in terms of significance vs insignificance

See PRIME and CALGB for pretty significant differences in numerical risks of recurrence between 5 and 10-year data.

Again I think I'm being unintentionally misunderstood (imagine that!). There are differences in the "instantaneous recurrence rate" of 5 and 10y data in every breast cancer trial I can think of. But this is not my point. My point is that the positivity or negativity of a breast cancer, or any, trial's actuarial (i.e. logrank or Cox hazards, from the KM curves) outcomes rarely change with 10y median followup vs 5y median followup. CALGB was positive/statistically significant at 5y for LRR, and with the 10y update it was still significant; overall survival was not significant at 5y, and it was still not significant at the 10y update. Same exact story for PRIME. (Including other metrics like distant DFS, etc.: everything negative at 5y was still negative at 10y.) So negative actuarial results rarely become positive over time, especially if we are talking 5 vs 10 years. It is uncommon—yet more likely—that positive results become negative over time. E.g., in the "Upfront Outback," any of the positive results at 5 years (say, significantly more distant recurrences if radiation happened before chemo and more local recurrences if chemo happened before radiation) disappeared at 10 years.

So about one of the least controversial things I can ever say around here would be, should be: on the basis of the 5y results from B51 (and biostats principles and assumptions), there is a <<5% chance that the 10y update will show a significant benefit of RNI for LRR, distant DFS, or OS.

RT to a TNBC cN1 patient --> ypN0 after NAC is actively killing them.

I wanted to say this, but thought "quit while ahead."

B51 protocol states that clinical nodal involvement may be assessed by mri, pet, ct, etc. please see section 5.2.5 of the protocol. Under ineligibility criteria please see section 5.3.4

This is the kind of thinking Antonin Scalia would have loved

---

Members don't see this ad.

 

[MidwestRadOnc]

As you note, T3 (EPE vs SVI) by MRI on prostate is different than saying 15 nodes involved on MRI and thus > N1 (actually N3 if you're counting nodes).



I hear you and not a knock on you specifically. I just think that, of any patient who might ever benefit from RNI in this clinical situation, suggesting that it's a TNBC patient (and not a ER+/Her2- patient) is actively refuted by the data. Like HR is WORSE with RT. RT to a TNBC cN1 patient --> ypN0 after NAC is actively killing them. HR 2.3, statistically significant, CI does not cross 1, when RT is added. Some would say not to over-interpret forest plot data. I disagree. A p-value that is significant may be fragile, but is not underpowered. Findings may be spurious, but just as spurious as with a larger sample size.

What is the proposed mechanism how RNI causes survival to worse at 5 years for TNBC compared to no RNI? There is either a mechanism or else it is a statistical fluke (like the last time I went to the casino and lost 10 out of 11 hands of blackjack playing perfectly. Statistically that should almost never happen, teeny tiny P-value, <1 in 5000 chance. But it did. Dealer draws out a 21 on a 20. Again. Then again. My wRVUs drift away.)

 

[evilbooyaa]

So about one of the least controversial things I can ever say around here would be, should be: on the basis of the 5y results from B51 (and biostats principles and assumptions), there is a <<5% chance that the 10y update will show a significant benefit of RNI for LRR, distant DFS, or OS.

Across all patients, I agree. Given > 75% of patients were NOT ER+/Her2- (either Her2+ or TNBC), I agree that, in all comers, no role of RNI.

ER+/Her2-, I think open question. I forget what else on that forest plot looked like potential benefit of RT, but IIRC that was the only one where HR didn't cross 1.

 

[evilbooyaa]

What is the proposed mechanism how RNI causes survival to worse at 5 years for TNBC compared to no RNI? There is either a mechanism or else it is a statistical fluke (like the last time I went to the casino and lost 10 out of 11 hands of blackjack playing perfectly. Statistically that should almost never happen, teeny tiny P-value, <1 in 5000 chance. But it did. Dealer draws out a 21 on a 20. Again. Then again. My wRVUs drift away.)

There is no oncologic benefit.
Any toxicity that occurs worsens quality of life.
Some percentage of those affect quantity of life.
Maybe there is some interaction between AC-TC +/- Immunotherapy and radiation that is exacerbating the issue.
Maybe folks weren't doing DIBH and monitoring MHD sufficiently?

The why is unknown. It's mostly immaterial, to me. There can be 100 hypotheses that'll take 100 researchers 100 careers to figure out. But we know what the clinical data says in this situation. Clinical data, from a randomized controlled clinical trial.

Maybe it's a fluke.

It's one thing to suggest that maybe it's a fluke and there is no survival detriment of RNI in TNBC patients --> ypN0 after NAC. But, they did have like a few HUNDRED of those patients (25% of 2k) on the trial. And still saw that. Interaction p-value positive showing difference in effect based on stratification group. So 500 black jack hands later. 90% losses. Means you're going against a crooked dealer/casino.

But to suggest that it's a fluke and that not only is there no survival detriment of RNI in TNBC patients --> ypN0 after NAC, but a complete flipping of the HR so that there is now an ADVANTGE of doing RNI in TNBC patients --> ypN0 after NAC.... that's some strong belief in dogma. Dogma that was written in stone prior to the routine use of neoadjuvant chemotherapy.

Dogma that we need to throw in the trash where it belongs.

 

[RadOncDoc21]

Love me some breast cancer debates, never gets old!

 

[Ray D. Ayshun]

Well, once again, may deral things, but this could perhaps be considered a pro-RT trial. In the NEJM no less

Loading…

www.nejm.org

 

[Bequerel]

Well, once again, may deral things, but this could perhaps be considered a pro-RT trial. In the NEJM no less

Loading…

www.nejm.org

Am I missing something…isn’t this old news? I was expecting the date to be 2004 not 2024

 

[Ray D. Ayshun]

Am I missing something…isn’t this old news? I was expecting the date to be 2004 not 2024

Id say we take what we can get.

 

[RadOncDoc21]

Id say we take what we can get.

You know in one year they will say radiation kills babies! At the very end, they will explain how but only after patients are telling me about it from the news.

 

[TheWallnerus]

Well, once again, may deral things, but this could perhaps be considered a pro-RT trial. In the NEJM no less

Loading…

www.nejm.org

For funsies here's the 5y DFS results of this study overlaid on the 10y DFS results from ACOSOG Z0011.

In the SENOMAC trial (blue/yellow above): "[For] patients with clinically node-negative breast cancer who had sentinel-node macrometastases, most... received nodal radiation therapy." In Z0011 (green/orange above): "In an unplanned analysis of the subset of the 228 patients with detailed radiation records available, those treated with nodal-field irradiation experienced no difference in disease-free survival, overall survival, or locoregional recurrence compared with those who did not receive irradiation."

 

[taserlaser]

As you note, T3 (EPE vs SVI) by MRI on prostate is different than saying 15 nodes involved on MRI and thus > N1 (actually N3 if you're counting nodes).



I hear you and not a knock on you specifically. I just think that, of any patient who might ever benefit from RNI in this clinical situation, suggesting that it's a TNBC patient (and not a ER+/Her2- patient) is actively refuted by the data. Like HR is WORSE with RT. RT to a TNBC cN1 patient --> ypN0 after NAC is actively killing them. HR 2.3, statistically significant, CI does not cross 1, when RT is added. Some would say not to over-interpret forest plot data. I disagree. A p-value that is significant may be fragile, but is not underpowered. Findings may be spurious, but just as spurious as with a larger sample size.

This is something I've been thinking about more over the week. Why could this be the case? MA-20 showed more of a benefit with RNI in hormone negative tumours, so had the opposite finding.

Has something changed from MA-20 to B-51 cohort? Perhaps availability and use of immunotherapy in TNBC? Does RNI actively impede an important immune response in these cases? Or is this spurious? Does taking the time to treat with RT delay more useful systemic therapy? Just odd to me that we have two large randomized RNI trials with opposing results in this population, and trying to think about why this might or could be.

 

[RadOncDoc21]

This is something I've been thinking about more over the week. Why could this be the case? MA-20 showed more of a benefit with RNI in hormone negative tumours, so had the opposite finding.

View attachment 385062

Has something changed from MA-20 to B-51 cohort? Perhaps availability and use of immunotherapy in TNBC? Does RNI actively impede an important immune response in these cases? Or is this spurious? Does taking the time to treat with RT delay more useful systemic therapy? Just odd to me that we have two large randomized RNI trials with opposing results in this population, and trying to think about why this might or could be.

Because it’s breast cancer… too many variables and too much noise to really see a signal!

 

[drowsy12]

This is something I've been thinking about more over the week. Why could this be the case? MA-20 showed more of a benefit with RNI in hormone negative tumours, so had the opposite finding.

View attachment 385062

Has something changed from MA-20 to B-51 cohort? Perhaps availability and use of immunotherapy in TNBC? Does RNI actively impede an important immune response in these cases? Or is this spurious? Does taking the time to treat with RT delay more useful systemic therapy? Just odd to me that we have two large randomized RNI trials with opposing results in this population, and trying to think about why this might or could be.

B51 is a specific unique question to a particular subset of patients. I don’t think of this population as the same as MA20 at all, because it’s not.

I totally agree with you in terms of MA20, ER negative patients had the strongest benefit

 

[taserlaser]

B51 is a specific unique question to a particular subset of patients. I don’t think of this population as the same as MA20 at all, because it’s not.

I totally agree with you in terms of MA20, ER negative patients had the strongest benefit

You are right in that it is a totally different population. I guess I would have thought that given the high propensity for nodal spread, more likely to have occult disease. I guess systemic therapy is THAT good, esp if already shown to have a pCR. But what a dichotomy - if there is still disease, need RT, and if has had a response, ?harms?. Just mulling it out and still digesting everything.

 

[drowsy12]

You are right in that it is a totally different population. I guess I would have thought that given the high propensity for nodal spread, more likely to have occult disease. I guess systemic therapy is THAT good, esp if already shown to have a pCR. But what a dichotomy - if there is still disease, need RT, and if has had a response, ?harms?. Just mulling it out and still digesting everything.

I take less stock in the ‘harms’ part

But to me the story makes sense. If people have a PCR, what are we hoping to improve with RT? What microscopic disease are we treating? The results of B51 prove it.

 

[CurbYourExpectations]

I take less stock in the ‘harms’ part

But to me the story makes sense. If people have a PCR, what are we hoping to improve with RT? What microscopic disease are we treating? The results of B51 prove it.

Should be thinking about what systemic and radiation without surgery we can do.

 

[evilbooyaa]

This is something I've been thinking about more over the week. Why could this be the case? MA-20 showed more of a benefit with RNI in hormone negative tumours, so had the opposite finding.

View attachment 385062

Has something changed from MA-20 to B-51 cohort? Perhaps availability and use of immunotherapy in TNBC? Does RNI actively impede an important immune response in these cases? Or is this spurious? Does taking the time to treat with RT delay more useful systemic therapy? Just odd to me that we have two large randomized RNI trials with opposing results in this population, and trying to think about why this might or could be.

MA.20 didn't have neoadjuvant chemotherapy.
B51 did.

Selecting for biology and selecting for those who sterilize in the nodes is a HUGE biological selection that MA.20 did not do. These are two completely distinct patient cohorts.

TNBC is a bad risk factor and warrants RNI. UNLESS you sterilize the nodes with NAC. Residual ypN1 patients should still get RNI. Additionally, adding carboplatin and immunotherapy improves outcomes in TNBC, so not surprised that RT is less helpful.

Her2 USED to be a bad risk factor until Her2+ directed therapies came out.

To me, the thought of ER+/Her2- disease still benefiting is that we know this group is less likely to have a pCR to chemo, and thus perhaps those paitents still require what would've been routinely given in the non-neoadjuvant setting.

 

[Ray D. Ayshun]

Where are people standing on hypofx PMRT in patients who might get reconstruction, or who got immediate reconstruction?

 

[HolySmokes]

Waiting for RT CHARM results. Until then 50/25 for recon patients.

 

[evilbooyaa]

Where are people standing on hypofx PMRT in patients who might get reconstruction, or who got immediate reconstruction?

I mean I'm still doing 50/25 for RNI as the most standard answer.... which may be why I'm not an academic breast attending

 

[Ray D. Ayshun]

I mean I'm still doing 50/25 for RNI as the most standard answer.... which may be why I'm not an academic breast attending

I've been doing rni in general in 15 or 16 fx. The only situations I don't is with reconstruction based on the fact that the aforementioned trials exist. At the same time, I could make an argument in the same vein as the 26/5 daily apbi instead of Livi. I feel like we all know that 40-42/15-16 RNI is fine in any context. And I'm hardly an academic breast attending.

 

[evilbooyaa]

I've been doing rni in general in 15 or 16 fx. The only situations I don't is with reconstruction based on the fact that the aforementioned trials exist. At the same time, I could make an argument in the same vein as the 26/5 daily apbi instead of Livi. I feel like we all know that 40-42/15-16 RNI is fine in any context. And I'm hardly an academic breast attending.

Is there new published ph III data on 40-42.5 in 15-16 RNI besides the paucity of patients treated on the START trials? Besides the chinese trial that was plenary at ASTRO a few years ago where they treated the CW with electrons (not an American practice)? I remember Colorado had a ph II (amongst others, I'm sure), but do we have ph III data of specifically RNI pts?

Not saying it's wrong, but are we extrapolating? Or do we have definitive data suggesting its equal (or better!) like the Whelan trial or the START trials established WBI w/ 15-16 fx as 'the' standard?

 

[TheWallnerus]

 

[RadOncDoc21]

Have to admit, I haven’t done a cme in awhile but outside of decreasing fractions, have we found any new indications for RT lately or are we still in a bear market?

 

[taserlaser]

Is there new published ph III data on 40-42.5 in 15-16 RNI besides the paucity of patients treated on the START trials? Besides the chinese trial that was plenary at ASTRO a few years ago where they treated the CW with electrons (not an American practice)? I remember Colorado had a ph II (amongst others, I'm sure), but do we have ph III data of specifically RNI pts?

Not saying it's wrong, but are we extrapolating? Or do we have definitive data suggesting its equal (or better!) like the Whelan trial or the START trials established WBI w/ 15-16 fx as 'the' standard?

RHEAL (ongoing) was originally designed to address this exact question (5 weeks vs 3 weeks RT) for RNI/PMRT, but with publication of UK-FF was redesigned as standard arm being 15 fr and experimental arm of 5 fr.

 

[taserlaser]

Is there new published ph III data on 40-42.5 in 15-16 RNI besides the paucity of patients treated on the START trials? Besides the chinese trial that was plenary at ASTRO a few years ago where they treated the CW with electrons (not an American practice)? I remember Colorado had a ph II (amongst others, I'm sure), but do we have ph III data of specifically RNI pts?

Not saying it's wrong, but are we extrapolating? Or do we have definitive data suggesting its equal (or better!) like the Whelan trial or the START trials established WBI w/ 15-16 fx as 'the' standard?

As important as fractionation, I would love to see a VMAT/IMRT vs non-IMRT for RNI pts. We have IMRT data for intact breast, like my rant earlier, but hard to move people in that direction for more complicated setups & anatomy, sigh. Or even more toxicity rates from IMRT vs non-IMRT patients on recent SIB/concommitant boost trials. I’m sure someone will do an analysis at some point but that data is difficult to find for this population last I looked - if anyone has good citations, please add - would love to read them.

 

[evilbooyaa]

RHEAL (ongoing) was originally designed to address this exact question (5 weeks vs 3 weeks RT) for RNI/PMRT, but with publication of UK-FF was redesigned as standard arm being 15 fr and experimental arm of 5 fr.

How is the standard arm for RNI 15fx felt to be OK? The few START patients?

The leaps in evidence people are making when it justifies their nation's incentive program (same pay regardless of # of tx, so use the least amount possible) is mind-boggling. It's just the opposite of the US system, but only US docs are 'money-grubbing'.

View attachment 385542

I look forward to their supplemental tables which will have buried the things that ARE actually different between 26/5 and 40/15 (and worse for 26/5), a-la original FAST-FORWARD paper.

 

[evilbooyaa]

As important as fractionation, I would love to see a VMAT/IMRT vs non-IMRT for RNI pts. We have IMRT data for intact breast, like my rant earlier, but hard to move people in that direction for more complicated setups & anatomy, sigh. Or even more toxicity rates from IMRT vs non-IMRT patients on recent SIB/concommitant boost trials. I’m sure someone will do an analysis at some point but that data is difficult to find for this population last I looked - if anyone has good citations, please add - would love to read them.

The average RO accepts a MHD of 8+ Gy w/ VMAT when they wouldn't ever approach that with 3D. I think VMAT for RNI routinely is a bad idea.

 

[Ray D. Ayshun]

The average RO accepts a MHD of 8+ Gy w/ VMAT when they wouldn't ever approach that with 3D. I think VMAT for RNI routinely is a bad idea.

Doing vmat rni right now. Mhd is 1.9, lad max is 12.5. not sure what the planning issues are elsewhere.

 

[TheWallnerus]

If a rad onc went a whole career and never VMAT’d to chase IMNs I wonder how many women they’ll have wound up killing (assume 60 breast patients a year).

 

[drowsy12]

The average RO accepts a MHD of 8+ Gy w/ VMAT when they wouldn't ever approach that with 3D. I think VMAT for RNI routinely is a bad idea.

8 gy??

I have not seen that. Sounds like a planning issue

 

[MidwestRadOnc]

Yeah, I have never seen an RNI plan that I was unable to get MHD < 4 Gy on with VMAT. My dosimetrist would never send something like that to me. I used to bend over backwards to avoid it and do elaborate electron patched plans. But then I wondered, why? Would I take a +/- 25% hot/cold spot on a photon plan?

 

[mheat3]

The average RO accepts a MHD of 8+ Gy w/ VMAT when they wouldn't ever approach that with 3D. I think VMAT for RNI routinely is a bad idea.

Agree with other comments, I have never seen MHD > 4 Gy with properly planned VMAT and in many cases (anatomy pending) can get < 2 or even lower similar to fixed fields.

 

[HolySmokes]

I treat a lot of breast and very rarely for patients who can't DIBH AND have terrible anatomy have to accept MHD of 4-5Gy but otherwise I agree, I have never seen or approved a VMAT plan with MHD of 8Gy(!!). Acute toxicity has been better with VMAT in my anecdotal opinion.

 

[evilbooyaa]

Maybe 'Average' is the wrong word.

Glad to see you guys aren't accepting higher MHD just because it's VMAT.

 

[radiation123]

How is the standard arm for RNI 15fx felt to be OK? The few START patients?

The leaps in evidence people are making when it justifies their nation's incentive program (same pay regardless of # of tx, so use the least amount possible) is mind-boggling. It's just the opposite of the US system, but only US docs are 'money-grubbing'.

I look forward to their supplemental tables which will have buried the things that ARE actually different between 26/5 and 40/15 (and worse for 26/5), a-la original FAST-FORWARD paper.

There are at least two large randomized trials that compared 40 Gy in 15 fractions to conventional fraction for breast cancer that needed RNI. Both have been presented in abstract form. Both showed good results. Abstracts attahced below.

 

[MidwestRadOnc]

I don’t know anecdotally of anybody reporting issues with 40/15 to the nodes including one doctor who did it exclusively and had about 5 pts under beam at any given time getting it. I personally have treated a half dozen with the 43.5/15 Chinese regimen with photons and 5 days of bolus and they all did fantastic with minimal toxicity. 50/25 way worse acutely IMO unless something wacky is happening post-tx but no pts complained at follow-up. I don’t buy efficacy arguments for 40/15 ok to kill breast ca in breast but not nodes at this point. I still recommend 50/25 as standard of care but have no issues with 15 fractions and personally prefer the 290 per fraction option.

 

[TheWallnerus]

I wonder how long it will be until the majority of breast cancer patients (and the majority of ENI patients!) will be five fraction in the US. I predict 2032. Five fraction breast is the Borg of rad onc if people are being honest. We should be ok if ASTRO can retcon some direct supervision.

 

[evilbooyaa]

There are at least two large randomized trials that compared 40 Gy in 15 fractions to conventional fraction for breast cancer that needed RNI. Both have been presented in abstract form. Both showed good results. Abstracts attahced below.

Thanks for the links.

As usual, non-inferiority trials strike again with massive allowances for what is considered 'non-inferior'

HypocG1 - HF had a 1.545 non-inferiority margin 'allowance'. Meaning that HF could cause lymphedema 50% (relatively) more frequently than conventional and it would still be considered non-inferior. Numerically lymphedema risk appeared similar, 24.1% vs 22.6% But that upper end of CI for HF arm could've been 33% and it still would've been non-inferior.

DBCG suggests lymphedema risks are the same.

Is the only toxicity we're worried about here lymphedema risk? Risk of brachial plexopathy? Esophagitis? DBCG shows breast induration to be numerically worse, p=0.11 - maybe because of the SIB boost?

Lots of details that would be of very strong value in published paper form before we start considering it 'THE' standard of care. But, based on this evidence (I was not aware of these trials in my previous post) I agree that it is 'A' SOC based on the abstracts linked.

 

[TheWallnerus]

Thanks for the links.

As usual, non-inferiority trials strike again with massive allowances for what is considered 'non-inferior'

HypocG1 - HF had a 1.545 non-inferiority margin 'allowance'. Meaning that HF could cause lymphedema 50% (relatively) more frequently than conventional and it would still be considered non-inferior. Numerically lymphedema risk appeared similar, 24.1% vs 22.6% But that upper end of CI for HF arm could've been 33% and it still would've been non-inferior.

DBCG suggests lymphedema risks are the same.

Is the only toxicity we're worried about here lymphedema risk? Risk of brachial plexopathy? Esophagitis? DBCG shows breast induration to be numerically worse, p=0.11 - maybe because of the SIB boost?

Lots of details that would be of very strong value in published paper form before we start considering it 'THE' standard of care. But, based on this evidence (I was not aware of these trials in my previous post) I agree that it is 'A' SOC based on the abstracts linked.

Based on evidence and guidelines definitely “A” standard and again “THE” standard in the UK

 

[drowsy12]

Yeah. I don’t think there are more trials needed for this question. The preponderance of data shows that hypofrac for RNI is totally fine. There’s no reason to believe the oncologic outcomes would be worse whether it’s Microscopic disease in the axilla or breast.


In regards to toxicity, it’s 40/15, it’s fine.


Totally fine with people sticking to conventional based on comfort level, but no one should raise eyes at chart rounds if someone’s doing hypofrac either