ECE and Z11. Has anything changed?

[scarbrtj]

I truly think you ARE trolling...

EORTC 22922 randomized patients to IM/SC-RT or not.
A small proportion of the patients had axillary RT, evenly distributed between both arms.

There were 1.3% axillary recurrences with IM/SC-RT, while in the control group that rate was 1.9%.

All you can say is that irradiation of the IM/SC DECREASED axillary recurrence rates by 0.6%. That's it.

You can draw ZERO conclusions on the role of axillary RT here.

My personal interpretation is that irradiating the SC probably delivered dose to the higher levels of the axilla, thus eliminating disease there. Not all of us place the border at the same level when delivering SC-RT. And even if it was a trial with a protocol describing treatment techniques and field borders, things happen and dose may have been delivered to the axilla when targetting the SC, according to technique
..

Hey, I think we are finally in agreement, and glad someone else said it...
"All you can say is that irradiation of the IM/SC DECREASED axillary recurrence rates by 0.6%. That's it."
Not irradiating the axilla decreases axillary recurrences (to the tune of NNTNNNT*=200)
That's what I do. I don't irradiate the axilla thereby decreasing axillary recurrences. Pas de problème. #microtroll
Arthur Clarke said, "Any sufficiently advanced technology is indistinguishable from magic."
And that's what we have loads of in rad onc: axillary recurrence risk-reducing technology.
*number needed not to treat

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[evilbooyaa]

I don't push it on left sided patients, personally, esp if we are talking low nodal burden in a pt with a lateral tumor

Agreed. We generally evaluate feasibility with wide tangents, but will omit if DVH gives us any issues (contralateral breast, too high DVH, mean heart, etc.) for any lateralized (especially upper outer quadrant) primary that is pN1. All pN2 or higher get it. Although some folks are omitting IM routinely, with the justification of 'when have you seen an isolated IMN recurrence'. I don't inherent disagree with them and it does increase dosimetric toxicity.

 

[scarbrtj]

'when have you seen an isolated IMN recurrence'.

My personal experience. YMMV.

Agreed. We generally evaluate feasibility with wide tangents, but will omit if DVH gives us any issues (contralateral breast, too high DVH, mean heart, etc.) for any lateralized (especially upper outer quadrant) primary that is pN1. All pN2 or higher get it. Although some folks are omitting IM routinely, with the justification of 'when have you seen an isolated IMN recurrence'. I don't inherent disagree with them and it does increase dosimetric toxicity.

I would upvote this if I could...
1) It's not tethered to any hard data per se (esp the "all pN2 or higher get it"; there's maybe more benefit from local RT for pN1 than pN2 e.g.)
2) It overall exposes less patients to RNI (esp IMN containing RNI) vs routinely offering it to all N+; the best heart and lung dosimetry/DVHs in breast cancer RNI are where doses of zero Gy are prescribed

 

[scarbrtj]

Trying to draw conclusions on axillary recurrence rates from trials where (almost) all patients received ALND and then went on to receive regional RT or not and then trying to "project" these recurrences rates to the current setting of "sentinel-node-biopsy --> positive node --> what to do?" is not trivial. Certainly the axillary recurrence rates in high-risk patients, who were truly underrepresented in Z0011 and are now managedwith sentinel-node-biopsy without any further treatment of the axilla are higher.

Presented without comment re: EORTC 22922, save for this: most of the women in the EORTC trial were node negative while 100% of the women in Z0011 were node positive... and Z0011 patients had lower rates of axillary recurrence (0.4-0.9%) than the EORTC patients (1.3-1.9%). As a technical matter, this would mean on average Z0011 was a higher risk population than that in the EORTC trial. (No line of conventional logic consistently works re: the axilla in breast cancer... and in the EORTC trial SLN patients tended to have better mean DFS but more heterogenous outcomes w/ RNI.)

 

[Palex80]

It‘s because the EORTC patients had an ALND. You are comparing apples with oranges...

 

[scarbrtj]

It‘s because the EORTC patients had an ALND. You are comparing apples with oranges...

A number of patients in EORTC got SNB only (who had no sign. benefit from RNI), or just a "partial" dissection, or were pN0. There were almost twice the number of pN0 patients in EORTC than there were N+ (and they were all N+ in Z0011) patients in the whole Z0011 trial. And there were half as many SNB only patients in the EORTC trial as in Z0011. And with all that RNI, and a fair amount of SNB-only/"partial" dissections, certainly no better outcome(s) than Z0011. Thing is, I can remember a time and I'm sure you can too, when a patient that was T2 and who walked in the clinic with one out of one lymph nodes positive (with microscopic ECE!) we would've kind of freaked out over and called very high risk. "My God, her axilla is going to explode in disease." Now we get to call them "low risk" right off the bat. Neat. I wonder how that happened.

 

[Palex80]

Thing is, I can remember a time and I'm sure you can too, when a patient that was T2 and who walked in the clinic with one out of one lymph nodes positive (with microscopic ECE!) we would've kind of freaked out over and called very high risk. "My God, her axilla is going to explode in disease." Now we get to call them "low risk" right off the bat. Neat. I wonder how that happened.

We started irradiating the axilla.

 

[scarbrtj]

We started irradiating the axilla.

"We." I'm going to predict you're in Sweden? Nearby? I think this approach, "We irradiate the axilla now that the ALND is uncommon" is prob more popular there than anywhere. "We" here in the U.S. don't really do that, of course, for years now. I remember when one of the Z0011 trialists said "Surgeons must ask themselves whether they are more comfortable using their own clinical impressions and retrospectively derived nomograms to make the decision about performing an axillary dissection for a positive sentinel node than they are with the use of criteria employed in a prospective, randomized trial." You (me, not we, obviously) could paraphrase this into "Rad oncs must ask themselves whether they are more comfortable using their gut & nomograms than data." If the irradiating of axillae is futile, toxic, associated with more deaths... IDK as the kids say.

Country matters for a person's beliefs. Almost no Americans think the moon landing was fake. However, three quarters of all Russians think it was fake.

Instead of the Z0011 trial maybe we should call it the Apollo 11 trial. Bernie Fisher (first man on the cancer data moon) might approve.

 

[Palex80]

"We" here in the U.S. don't really do that, of course, for years now.

Oh, really?

 

[xrthopeful]

For a while, before EORTC/MA20, a lot of US centers were being fairly selective about which patients in the 1-3 nodes subset they gave PMRT too. But ever since those trials were published, the pendulum has really swung; the majority of breast rad oncs treat comprehensively with RNI.

Scarbtj doesn’t speak for the ‘US’, he speaks for his practice and his patients

 

[evilbooyaa]

For a while, before EORTC/MA20, a lot of US centers were being fairly selective about which patients in the 1-3 nodes subset they gave PMRT too. But ever since those trials were published, the pendulum has really swung; the majority of breast rad oncs treat comprehensively with RNI.

Scarbtj doesn’t speak for the ‘US’, he speaks for his practice and his patients

As another US rad onc that has pretty strongly disagreed with Scarb throughout this thread, I agree with the above post. I'll add that the EBCTCG meta-analysis also pushed more people to treat nodes (full 3-field) with 1-3 nodes.

I do not know (as in personally) a single rad onc that treats breast (n=10+), in the setting of the case described, of 1/1+ LN (let's skip the ECE for purposes of discussion) isn't either 1) doing high tangents to cover the entirety of levels 1/2 axilla under the humeral head, or 2) doing full 3-field, with the SCV field extending laterally under the humeral head (+/- on IMN coverage, that's more heterogeneous). I have seen exactly one case of somebody (not me, because I would likely never do this) doing high tangents with IMN coverage.

People routinely skip coverage of dissected axilla (s/p ALND) in the absence of high risk features (which the cut-offs for what is considered high-risk is more heterogeneous)

 

[scarbrtj]

For a while, before EORTC/MA20, a lot of US centers were being fairly selective about which patients in the 1-3 nodes subset they gave PMRT too. But ever since those trials were published, the pendulum has really swung; the majority of breast rad oncs treat comprehensively with RNI.

Scarbtj doesn’t speak for the ‘US’, he speaks for his practice and his patients

1) "Comprehensively with RNI." What form of RNI? SC/IM? SC/IM/axilla? Axilla/IM? IMN only? Axilla only?
2) Why restrict RNI to N+? More patients were pN0 than N1, N2, or N3 on EORTC's putatively positive trial e.g. (And there was an association of no benefit from RNI for pN3 in EORTC.) As the NCCN guidelines point out, "consider" RNI for pN0. Who does this???

3) When/what situations do the majority of breast rad onc treat comprehensively with RNI? More radiation for breast cancer is delivered by non-breast rad oncs than breast rad oncs. What do you think the non-breast rad oncs do? RNI patterns are sporadic in the U.S. and across the planet. Or were; maybe consensus now but perhaps only for pN1. Consensus with controversy, depending on clinical scenario. Some are "obsessed" with locoregional control. Even @Krukenberg mentioned MA20 is a "negative" trial; so some are less obsessed, not afraid to court controversy. Again, I have asked, what is the data that axillary RT actually does anything good? In a spirit of helpfulness @xrthopeful says I willfully ignore RNI's benefit of DFS, etc etc. Help me ignore the bad aspects of axillary RT. Help me ignore Z0011 which has completely changed practice patterns re: the axilla in the U.S. Help me ignore that axillary recurrence rates are ~1% across the breast cancer landscape. Help me ignore the lack of any association with RT technique/RNI after SNB. Help me ignore more toxicity, more second cancers associated with axillary RT. Help me ignore the association of axillary with decreased survival. I can ignore it, would ignore it, if shown any reasonably good data. For the totality of the data conflicts with the NCCN guideline to "strongly consider" axillary RT.

As another US rad onc that has pretty strongly disagreed with Scarb throughout this thread


I do not know (as in personally) a single rad onc that treats breast (n=10+), in the setting of the case described, of 1/1+ LN (let's skip the ECE for purposes of discussion) isn't either 1) doing high tangents to cover the entirety of levels 1/2 axilla under the humeral head, or 2) doing full 3-field, with the SCV field extending laterally under the humeral head (+/- on IMN coverage, that's more heterogeneous). I have seen exactly one case of somebody (not me, because I would likely never do this) doing high tangents with IMN coverage.

People routinely skip coverage of dissected axilla (s/p ALND) in the absence of high risk features (which the cut-offs for what is considered high-risk is more heterogeneous)

Strongly disagree? I'd do tangents, lots of others would do tangents only too. Whether they're "high" or not has never been associated with anything meaningful, clinically, and they just don't do what you think they're doing (meaningfully covering the axilla). But yeah, sure, I do high tangents. I'm with Michelle Obama: when they go low we go high. I love high tangents. I think the second part of your answer is quite similar in spirit to what I've been saying which is, if you try to talk about this in any logical way, or get strident, you come away with a headache and the sense that differing techniques re: locoregional therapy play no substantial part in breast cancer outcomes nowadays. Better to just stick with the data.

 

[evilbooyaa]

Scarb, in all honesty, it's like talking to a brick wall with you in regards to this topic. If you don't believe in RFS (even though the 'official' endpoint was OS, which was negative) benefit of RNI per MA.20 and insist on doing tangents that don't purposefully cover all of level 1 and 2 axilla (the textbook definition of high tangents), then we're never going to agree on this.

RT in the current era is for LC in the breast, and RFS with RNI. This is why N+ patients are getting RNI (undissected axilla, SCV, +/- IMN) in my practice. The only adjuvant scenario I routinely do high tangents in is SLNB+ with micrometastatic disease.

This is my practice. Neither one of us are going to 'convince' the other to change theirs in the setting of current data.

 

[KHE88]

1) "Comprehensively with RNI." What form of RNI? SC/IM? SC/IM/axilla? Axilla/IM? IMN only? Axilla only?
2) Why restrict RNI to N+? More patients were pN0 than N1, N2, or N3 on EORTC's putatively positive trial e.g. (And there was an association of no benefit from RNI for pN3 in EORTC.) As the NCCN guidelines point out, "consider" RNI for pN0. Who does this???

3) When/what situations do the majority of breast rad onc treat comprehensively with RNI? More radiation for breast cancer is delivered by non-breast rad oncs than breast rad oncs. What do you think the non-breast rad oncs do? RNI patterns are sporadic in the U.S. and across the planet. Or were; maybe consensus now but perhaps only for pN1. Consensus with controversy, depending on clinical scenario. Some are "obsessed" with locoregional control. Even @Krukenberg mentioned MA20 is a "negative" trial; so some are less obsessed, not afraid to court controversy. Again, I have asked, what is the data that axillary RT actually does anything good? In a spirit of helpfulness @xrthopeful says I willfully ignore RNI's benefit of DFS, etc etc. Help me ignore the bad aspects of axillary RT. Help me ignore Z0011 which has completely changed practice patterns re: the axilla in the U.S. Help me ignore that axillary recurrence rates are ~1% across the breast cancer landscape. Help me ignore the lack of any association with RT technique/RNI after SNB. Help me ignore more toxicity, more second cancers associated with axillary RT. Help me ignore the association of axillary with decreased survival. I can ignore it, would ignore it, if shown any reasonably good data. For the totality of the data conflicts with the NCCN guideline to "strongly consider" axillary RT.



Strongly disagree? I'd do tangents, lots of others would do tangents only too. Whether they're "high" or not has never been associated with anything meaningful, clinically, and they just don't do what you think they're doing (meaningfully covering the axilla). But yeah, sure, I do high tangents. I'm with Michelle Obama: when they go low we go high. I love high tangents. I think the second part of your answer is quite similar in spirit to what I've been saying which is, if you try to talk about this in any logical way, or get strident, you come away with a headache and the sense that differing techniques re: locoregional therapy play no substantial part in breast cancer outcomes nowadays. Better to just stick with the data.

The burden of proof is on you to demonstrate that it is safe to de-escalate off trial and not radiate a site of known disease that has not had full surgical oncologic management, not on us to demonstrate that it isn't. This would require prospective randomized evidence, ideally with long term follow-up and confirmatory trials. And in this setting, I honestly believe proving a mechanism is also necessary as it goes against general principles on cancer treatment.

Massive liberties are being taken with the findings of the Poortmans study here, as Palex pointed out, and I think it's worth repeating the authors' own words from the discussion again:

"Since the regional nodes are functionally interconnected, it was decided to include the medial supraclavicular nodes, thereby in fact randomizing
between complete nodal treatment (axillary surgery and irradiation of nondissected nodes) and axillary surgery alone. Therefore, we cannot determine whether internal mammary irradiation or medial supraclavicular irradiation contributed more to the outcome."

This was NOT a study investigating axillary RT vs. no axillary RT in the finding of a positive sentinel node, and it is wrong to draw a conclusion on this finding from this study. Almost as wrong as trying to draw that from the dumpster fire that is known as Z-11.

It's also worth noting, that even with a carefully designed trial that specifically tests axillary vs. no axillary RT in the setting of a positive LN Bx, that long term follow-up is crucial in the setting of hormone positive breast cancer and systemic/endocrine therapy.

And it's also worth noting what a positive trial with a p-value < 0.05 means. A finding with a p-value < 0.05 does NOT mean that the question is definitively answered. It means that the finding is "statistically significant" and worthy of further investigation with repeat trials. Of course, this never happens as academics are rewarded for novel research, not confirmatory/repetitive research. Regardless, even with a single positive trial finding, the answer isn't fully elucidated, and for this question, we don't even have that.

With that, I retire from this discussion.

 

[scarbrtj]

@evilbooyaa @KHE88 I agree. "Neither one of us are going to 'convince' the other to change theirs in the setting of current data" says it... and I am not a good convincer. Nor am I easily convinced. Extraordinary claims require extraordinary evidence.

The burden of proof is on you to demonstrate that it is safe to de-escalate off trial and not radiate a site of known disease that has not had full surgical oncologic management, not on us to demonstrate that it isn't.

.
About 1 out of 3 breast cancer patients have bone marrow involvement at presentation as a known site of disease; and women with positive nodes or ER- e.g. have an even higher risk than that. Meanwhile, they have axillary/sclav/IMN recurrence rates of ~1% (in contemporary patients especially) with or without RNI. A woman with a positive SN has a ~40% chance of IMN positivity, 30% chance of remaining disease in axilla and a 30% chance of bone marrow involvement. She'll go on to have a ~1% risk of IMN or axillary recurrence but a ~15-20% risk of distant relapse. There is no way to logically suss this versus just accepting that's the way it is. In the EORTC, recurrences rates were biggest for distant, which was bigger than second cancers other than breast cancer, which was a bigger risk than contralateral breast cancer, about the same risk of local recurrence, which was a bigger risk than node relapse. Without RNI, nodal recurrence was already the least common site of breast cancer recurrence. The logic of it's not safe not to irradiate a known site of disease doesn't really work in breast cancer. At the least RNI must be carefully meted out versus blanketly administered for all N+ e.g.

And it's also worth noting what a positive trial with a p-value < 0.05 means. A finding with a p-value < 0.05 does NOT mean that the question is definitively answered. It means that the finding is "statistically significant" and worthy of further investigation with repeat trials. Of course, this never happens as academics are rewarded for novel research, not confirmatory/repetitive research. Regardless, even with a single positive trial finding, the answer isn't fully elucidated, and for this question, we don't even have that.

This is well stated. Prior to MA20/EORTC, RNI was less practiced and less accepted. On the basis of these results...

.................................EORTC..............................................MA20.....................
OS..............73% vs 71% (p=0.4)....................83% vs 82% (p=0.4)
DFS ...........75% vs 73% (p=0.02)..................82% vs 77% (p=0.01)
BCM..........15% vs 19% (p=0.005)...............10% vs 11% (p=0.1)
Distant......70% vs 68% (p=0.02)................86% vs 82% (p=0.03)
lung tox....4% vs 1% (p<0.001)...................1% vs 0% (p=0.01)
lymphedema.....................................................8% vs 5% (p=0.001)

...practices changed. As mentioned, there's retrospective data from significant patient numbers at odds with these findings (e.g. worse DFS and OS with nodal RT), and EORTC was at odds with MA20 least as far as BCM was concerned, perhaps not surprising at these low-magnitude single digit differences. The strongest signal from the RNI trials was from toxicity; but per the EORTC "Toxicity was limited and no increased lethal side effects were seen." Comforting. Back to extraordinary claims require extraordinary evidence, and to your point: put another way, extraordinary claims require p-values of 0.005.

 

[SneakyBooger]

In the history of radiation oncology have high vs low tangents been associated with increased axillary recurrences. In Z0011 not only was it not, lack of RT at all was not. In the EORTC trial the axilla was not specifically irradiated; and not doing so decreased axillary recurrences by about a half percent. About 15 years ago I saw a sclav recurrence in a woman treated years before I got out of residency. I still have yet to encounter an isolated axillary recurrence. The thing is, I can fondly recall leaving residency and thinking the technicalities and nuances of axillary RT (“PABs”... yikes) were quite vital. The IMNs have higher rates of subclinical disease across all stages than sclav, including in Stage I. (And all Stage I patients nowadays have ~10% chance of being pN1 if the routine ALND were brought back.) Yet the IMN kind of gets left out, at least here. OP’s patient has a 20-40% chance of positive IMN node. High tangent, or low tangent, for her is theoretically deck chair rearranging on the Titanic. Fortunately data gives solace the theory is wrong. Hope none of (.y.)our patients recur in the IMNs.*

*EDIT: you know you've passed breast oral boards once you make it to the question about how to handle an IMN recurrence. AFAIK, there is no oral board question about how to handle an axillary recurrence; so perhaps at least in oral board land IMN recurrences are 100% more common than sclav or axillary recurrences IDK, I've been away from that for a while...

In 20+ years I have seen:
1 isolated axillary recurrence - excised, radiated (incl. SCV), dz free for 13 years now.
1 isolated IMN recurrence - radiated, chemo'd, 9 yrs dz free now - for this pt I remember thinking "Why is the surgeon getting a PET on this patient?" - then he found this isolated recurrence.