No more PMRT for cN1 ypN0 breast cancer?

[TheWallnerus]

De-escalation of radiotherapy after primary chemotherapy in cT1–2N1 breast cancer (RAPCHEM; BOOG 2010–03): 5-year follow-up results of a Dutch, prospective, registry study​

Background​

Primary chemotherapy in breast cancer poses a dilemma with regard to adjuvant locoregional radiotherapy, as guidelines for locoregional radiotherapy were originally based on pathology results of primary surgery. We aimed to evaluate the oncological safety of de-escalated locoregional radiotherapy in patients with cT1–2N1 breast cancer treated with primary chemotherapy, according to a predefined, consensus-based study guideline.

Methods​

In this prospective registry study (RAPCHEM, BOOG 2010–03), patients referred to one of 17 participating radiation oncology centres in the Netherlands between Jan 1, 2011, and Jan 1, 2015, with cT1–2N1 breast cancer (one to three suspicious nodes on imaging before primary chemotherapy, of which at least one had been pathologically confirmed), and who were treated with primary chemotherapy and surgery of the breast and axilla were included in the study. The study guideline comprised three risk groups for locoregional recurrence, with corresponding locoregional radiotherapy recommendations: no chest wall radiotherapy and no regional radiotherapy in the low-risk group, only local radiotherapy in the intermediate-risk group, and locoregional radiotherapy in the high-risk group. Radiotherapy consisted of a biologically equivalent dose of 25 fractions of 2 Gy, with or without a boost. During the study period, the generally applied radiotherapy technique in the Netherlands was forward-planned or inverse-planned intensity modulated radiotherapy. 5-year follow-up was assessed, taking into account adherence to the study guideline, with locoregional recurrence rate as primary endpoint. We hypothesised that 5-year locoregional recurrence rate would be less than 4% (upper-limit 95% CI 7·8%). This study was registered at ClinicalTrials.gov, NCT01279304, and is completed.

Findings​

838 patients were eligible for 5-year follow-up analyses: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 5-year locoregional recurrence rate in all patients was 2·2% (95% CI 1·4–3·4). The 5-year locoregional recurrence rate was 2·1% (0·9–4·3) in the low-risk group, 2·2% (1·0–4·1) in the intermediate-risk group, and 2·3% (0·8–5·5) in the high-risk group. If the study guideline was followed, the locoregional recurrence rate was 2·3% (0·8–5·3) for the low-risk group, 1·0% (0·2–3·4) for the intermediate-risk group, and 1·4% (0·3–4·5) for the high-risk group.

Interpretation​

In this study, the 5-year locoregional recurrence rate was less than 4%, which supports our hypothesis that it is oncologically safe to de-escalate locoregional radiotherapy based on locoregional recurrence risk, in selected patients with cT1–2N1 breast cancer treated with primary chemotherapy, according to this predefined, consensus-based study guideline.

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[TheWallnerus]

 

[TheWallnerus]

 

[RADONC4285]

I am not sure this trial changes a great deal of what I would do for most patients. The majority of cN1 patients are postmenopausal and have ER+ and HER2 negative tumors. Neoadjuvant chemotherapy should only be given if oncotype is high. Are you comfortable skipping RT for those with oncotype high based on this? I wouldn't be without more data based on genomics.

 

[Fpg1245]

Plus surgeons are getting away from ALNDs on the whole so…not sure I would omit just yet

 

[TheWallnerus]

I am not sure this trial changes a great deal of what I would do for most patients. The majority of cN1 patients are postmenopausal and have ER+ and HER2 negative tumors. Neoadjuvant chemotherapy should only be given if oncotype is high. Are you comfortable skipping RT for those with oncotype high based on this? I wouldn't be without more data based on genomics.

Yeah. I would be absolutely comfortable skipping PMRT in a lady who’s cT1 and a solitary node who goes through neoadj chemo and becomes pCR. Single lymph node positive ladies were always a soft call for PMRT anyways, the vast bulk of the “proven” benefit there coming from a certain Danish study. For women who are LN positive in one node and have a pCR? Radiation therapy doesn’t help them. (I said what I said!) I see the study applying to a somewhat narrow subset: small T, small N women who get ypN0 (and these are usually not ER+ ladies who achieve that). I would additionally point out though: no women (including ypN2-3) got sclav or IMN RT in the study and look at those LRRs.

 

[Burt Radnolds]

5 year follow up, 'nuff said

 

[TheWallnerus]

When is the last time a study showed no statistical difference between RT/no RT at 5y but statistical significance appeared at 10y in favor of RT. One of the log-rank’s assumptions (for the null) is that there is no difference between the curves at any and ALL time points. It’s … quite unlikely … that significant differences (between curves) appear at 10y vs 5y. More likely is what happened eg in the “Upfront Outback” trial; at first, differences, and later, not.

 

[deleted1111261]

5 year follow up, 'nuff said

When has a breast study changed after the 5 year ? I can’t think of one

 

[TheWallnerus]

When has a breast study changed after the 5 year ? I can’t think of one

Americans: we need 10-15y data

UK: we are treating 6 out of 10 breast cancer patients across all stages with 5 fractions

 

[medgator]

When is the last time a study showed no statistical difference between RT/no RT at 5y but statistical significance appeared at 10y in favor of RT. One of the log-rank’s assumptions (for the null) is that there is no difference between the curves at any and ALL time points. It’s … quite unlikely … that significant differences (between curves) appear at 10y vs 5y. More likely is what happened eg in the “Upfront Outback” trial; at first, differences, and later, not.

I think it took longer fu with the ebctcg meta-analysis to show an OS benefit based on LC earlier on right?

 

[TheWallnerus]

I think it took longer fu with the ebctcg meta-analysis to show an OS benefit based on LC earlier on right?

I think this is ... a good point. OTOH, we are talking meta-analysis on data from trials that started accruing in the 70s and 80s. Because lifestyle, staging, surgical philosophy, and systemics have changed so profoundly since then (and breast cancer survival has steadily improved on account of that), it's also not a bad point that one day we may have to stop referring to pro-RT studies in this disease from last century.

 

[deleted1111261]

I think it took longer fu with the ebctcg meta-analysis to show an OS benefit based on LC earlier on right?

Um, your example is a meta-analysis?

 

[medgator]

Um, your example is a meta-analysis?

A pretty well known one? Did this not make the headlines at most programs when it came out?

Effect of radiotherapy after mastectomy and axillary surgery on 10-year recurrence and 20-year breast cancer mortality: meta-analysis of individual patient data for 8135 women in 22 randomised trials

Postmastectomy radiotherapy was shown in previous meta-analyses to reduce the risks of both recurrence and breast cancer mortality in all women with node-positive disease considered together. However, the benefit in women with only one to three positive ...

www.ncbi.nlm.nih.gov

 

[RADONC4285]

Yeah. I would be absolutely comfortable skipping PMRT in a lady who’s cT1 and a solitary node who goes through neoadj chemo and becomes pCR. Single lymph node positive ladies were always a soft call for PMRT anyways, the vast bulk of the “proven” benefit there coming from a certain Danish study. For women who are LN positive in one node and have a pCR? Radiation therapy doesn’t help them. (I said what I said!) I see the study applying to a somewhat narrow subset: small T, small N women who get ypN0 (and these are usually not ER+ ladies who achieve that). I would additionally point out though: no women (including ypN2-3) got sclav or IMN RT in the study and look at those LRRs.

It's not only thr Danish studies. Both EORTC and MA.20 showed a benefit to RNI for women with 1 to 3 nodes. Like half the patients had 1 Ln. Granted only one of the trials allowed mastectomy, but the point is that RNI makes a difference even in small nodal burden. Someone who has a PCR likely has less benefit, but again my point is these days it would be pCR in a patient with high oncotype most of the time

 

[deleted1111261]

Ok, let me try again

Has any individual breast study changed after the 5 year ?

 

[TheWallnerus]

t's not only thr Danish studies. Both EORTC and MA.20 showed a benefit to RNI for women with 1 to 3 nodes.

There was no overall survival benefit in either study further confirming the "Alternative Hypothesis." The most statistically significant results from these studies were on the toxicity side. But I think you're mixing metaphors a bit (NB: my post was entitled "No more PMRT for cN1 ypN0 breast cancer?"). MA20/EORTC 22922 didn't appear until 2015 and were not the raison d'être for PMRT in pN1 disease. Prior to ~2010-15, it was not routine to give PMRT to cT1-2N1 patients. It was the (yet another, different) EBCTCG meta-analysis whose results* (if you dig a little deeply the results were driven strongly by the Danish data) caused the switcheroo as it were.

Here is an excerpt from the 2015 JNCCN:

The recommendation for strong consideration of chest wall and supraclavicular irradiation in women with 1 to 3 involved ALNs generated substantial controversy among panel members. The use of regional nodal irradiation is supported by a subgroup analysis of studies from the Danish Breast Cancer Cooperative Group. In this analysis, a substantial survival benefit was associated with postmastectomy radiation therapy for women with 1 to 3 positive ALNs. Some panel members believe chest wall and supraclavicular irradiation should be used routinely after mastectomy and chemotherapy in this subgroup of patients. However, other panel members believe radiation should be considered in this setting but should not be mandatory, because studies do not show an advantage. This is an unusual situation in which high-level evidence exists but is contradictory. Results of an Early Breast Cancer Trialists’ Collaborative Group meta-analysis showed that radiotherapy after mastectomy and axillary node dissection reduced both recurrence and breast cancer mortality in the women with 1 to 3 positive lymph nodes, even when systemic therapy was administered. The consensus panel for women with 1 to 3 involved ALNs and tumors greater than 5 cm or tumors with pathologic margins is that postmastectomy radiation therapy to the chest wall, infraclavicular, and supraclavicular areas should be strongly considered. The panel also recommends strong consideration of ipsilateral internal mammary field radiation therapy in these patients (category 2B).​

​

* based on studies accruing between 1964-1986

 

[Burt Radnolds]

I wrote my initial response flippantly while sitting at a restaurant with my kids and mostly to provocate. I now follow up while watching TV on my couch, still sans literature review.

We are definitely not moving the needle much in these low volume disease treatment responders. I'm all about getting out the game whenever I can. You could just stop radiating regional nodes for the rest of your career and your damage done would be negligible (but not zero). A few comments though, many of these studies such as ma20, eortc 22922, and yes the much maligned but oft quoted ebctcg meta-analyses reported out their results at 10-15 years. Did they even report 5 year outcomes?? The whole shaking your fist at WHEN DID ANYTHING EVER CHANGE FROM 5 TO 10 seems hollow when some studies have just waited for their data to mature.

Breast can be the long game. I've seen many patients recur late late late with local or regional disease only.

5 years is trash. These patients can be on endocrine therapy for that entire duration that smudges out any result.

 

[TheWallnerus]

I wrote my initial response flippantly while sitting at a restaurant with my kids and mostly to provocate. I now follow up while watching TV on my couch, still sans literature review.

We are definitely not moving the needle much in these low volume disease treatment responders. I'm all about getting out the game whenever I can. You could just stop radiating regional nodes for the rest of your career and your damage done would be negligible (but not zero). A few comments though, many of these studies such as ma20, eortc 22922, and yes the much maligned but oft quoted ebctcg meta-analyses reported out their results at 10-15 years. Did they even report 5 year outcomes?? The whole shaking your fist at WHEN DID ANYTHING EVER CHANGE FROM 5 TO 10 seems hollow when some studies have just waited for their data to mature.

Breast can be the long game. I've seen many patients recur late late late with local or regional disease only. My grandmother had a 20 year regional recurrence that eventually took her life.

5 years is trash. These patients can be on endocrine therapy for that entire duration that smudges out any result.

Flippant is fine lol. There was a slow, but steady, separation of the curves both for OS and LC seen in the meta-analyses that were not seen in the trials themselves. I will grant you that. But grant me this... here I have superimposed the RAPCHEM curve onto the 2014 EBCTG for the appropriate comparator subgroup of N1 patients. Breast cancer patients (specifically T1-2N1 patients) in the 21st century recur at very different rates than breast cancer patients in the 20th century, irrespective of the radiotherapy package.

The superimposed RAPCHEM graph:

 

[Burt Radnolds]

Flippant is fine lol. There was a slow, but steady, separation of the curves both for OS and LC seen in the meta-analyses that were not seen in the trials themselves. I will grant you that. But grant me this... here I have superimposed the RAPCHEM curve onto the 2014 EBCTG for the appropriate comparator subgroup of N1 patients. Breast cancer patients (specifically T1-2N1 patients) in the 21st century recur at very different rates than breast cancer patients in the 20th century, irrespective of the radiotherapy package.

I think we see eye to eye and alluded to that in my post

 

[bigman1]

This is a HUGE issue. I still treat them all as there's no good evidence for me not to treat, Tumour scatter about chemo scares me. Med onc is literally THE worst area of medicine and all their patients hate them.

 

[bigman1]

"Primary chemotherapy" for solid tumours is the worst approach you could ever take oncologically.

 

[Palex80]

5 year follow up, 'nuff said

Bury this thread and resurrect it in 5 years!

 

[Palex80]

Ok, let me try again

Has any individual breast study changed after the 5 year ?

I believe some of the „omission of RT“ trials in early-stage, low risk breast cancer, which means tamoxifen +/- RT showed similar rates of locoregional recurrences at 5 years between both arms, but LRC-rates went up, once tamoxifen was terminated.

 

[madchemist89]

Regarding the table above, in ypno patients, there is already a fully accrued phase iii trial, b51. We will just have to wait for these results.

 

[deleted1111261]

I believe some of the „omission of RT“ trials in early-stage, low risk breast cancer, which means tamoxifen +/- RT showed similar rates of locoregional recurrences at 5 years between both arms, but LRC-rates went up, once tamoxifen was terminated.

Calgb and prime 2 both separated by 5 years and were statistically significant.

“But we need >5 years!”

It’s always the case for breast. I used to be one of them. But, 5 years tells the story. If you base practice on 5 year follow up for RCTs for breast cancer patients, you will be treating your patients with highest level of evidence.

 

[TheWallnerus]

Calgb and prime 2 both separated by 5 years and were statistically significant.

“But we need >5 years!”

It’s always the case for breast. I used to be one of them. But, 5 years tells the story. If you base practice on 5 year follow up for RCTs for breast cancer patients, you will be treating your patients with highest level of evidence.

Sometimes one needs 5 year data; sometimes one don't.

If you like your five year data, you can keep your five year data:



But if you don't like 5 year data...



I think arthritis data is stronger than adjuvant RT data in early stage N+ ypN0 breast at this point.

 

[Burt Radnolds]

This was a prospective study without any sort of randomization. They took an educated guess at what reasonable local management would be and their results look pretty good.

All this talk of 5 vs 10 year follow up is funny. There is no control arm for it to become significantly different from. The results will absolutely be different at 10 years. We know from basically every breast study in existence that LRF slowly goes up over time.

Will it stay below a reasonable threshold? Probably.

 

[TheWallnerus]

All this talk of 5 vs 10 year follow up is funny. There is no control arm for it to become significantly different from.

You need a with-RT control arm when without RT arm had a 2% LRF at 5 years? Ok. If we are being super strict.

The results will absolutely be different at 10 years. We know from basically every breast study in existence that LRF slowly goes up over time.

The LRF goes up slowly over time in BOTH irradiated and unirradiated patients (see above). So while waiting to see a between-arm difference at ten years that didn’t appear at 5, the “runners” (arms) usually beginning “running” at the same speed and the between-arm-delta doesn’t change as much toward the tail of the curve as it did at the beginning.

Be all that as it may…
It has struck me, looking back into the history of pro-PMRT for ladies with 1-3 nodes positive and getting chemo (lots of melphalan!), that all the randomized data supporting PMRT comes from ~1200 ladies across ~20-30 studies treated between about 1965 and 1985. And even then when we cull all that data together (again as shown above in the EBCTCG), in the unirradiated ladies the incidence of per-year LRF in years 5-10 is <1% (was ~17% at 5y and ~21% at 10y… and, again, this number is now ~2% at 5y for women chemotherapized but unirradiated in the modern era… showing how much things have changed IMHO).

 

[Palex80]

Be all that as it may…
It has struck me, looking back into the history of pro-PMRT for ladies with 1-3 nodes positive and getting chemo (lots of melphalan!), that all the randomized data supporting PMRT comes from ~1200 ladies across ~20-30 studies treated between about 1965 and 1985. And even then when we cull all that data together (again as shown above in the EBCTCG), in the unirradiated ladies the incidence of per-year LRF in years 5-10 is <1% (was ~17% at 5y and ~21% at 10y… and, again, this number is now ~2% at 5y for women chemotherapized but unirradiated in the modern era… showing how much things have changed IMHO).

It depends...
The Dutch have shown some other data too, in the past:

Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials - PubMed

The survival benefit after postmastectomy RT was substantial and similar in patients with 1-3 and 4+ positive lymph nodes. Furthermore, it was not strictly associated with the risk of loco-regional recurrence, which was most pronounced in patients with 4+ positive nodes. The indication for RT...

pubmed.ncbi.nlm.nih.gov

I do not think that looking only at locoregional control rates is the optimal endpoint for trials on PMRT.
You may find it odd, but there are two important arguments here:
a) PMRT may be more valuable in reducing distant metastases (MA.20 gave a hint in that direction)
b) Really distinguishing LR failures is tricky in breast cancer. These patients do not undergo routine imaging to look at nodes and disease progression if often picked up when symptomatic distant metastases arise. It is quite possible that the effect of PMRT is being missed, simply because we do not perform any imaging in those women (not that I am advocating in favor of doing any, I am just stating that it is difficult to measure an endpoint, if you are not examining it at all in a systematic way).

 

[TheWallnerus]

It depends...
The Dutch have shown some other data too, in the past:
View attachment 359166

Is the benefit of postmastectomy irradiation limited to patients with four or more positive nodes, as recommended in international consensus reports? A subgroup analysis of the DBCG 82 b&c randomized trials - PubMed

The survival benefit after postmastectomy RT was substantial and similar in patients with 1-3 and 4+ positive lymph nodes. Furthermore, it was not strictly associated with the risk of loco-regional recurrence, which was most pronounced in patients with 4+ positive nodes. The indication for RT...

pubmed.ncbi.nlm.nih.gov

I do not think that looking only at locoregional control rates is the optimal endpoint for trials on PMRT.
You may find it odd, but there are two important arguments here:
a) PMRT may be more valuable in reducing distant metastases (MA.20 gave a hint in that direction)
b) Really distinguishing LR failures is tricky in breast cancer. These patients do not undergo routine imaging to look at nodes and disease progression if often picked up when symptomatic distant metastases arise. It is quite possible that the effect of PMRT is being missed, simply because we do not perform any imaging in those women (not that I am advocating in favor of doing any, I am just stating that it is difficult to measure an endpoint, if you are not examining it at all in a systematic way).

Top left graph germane to “argument” here and the Danish data is subsumed, I assume, in the EBCTCG graph.

I get your points about LRF. If PMRT is going to improve survival it’s got to affect more than just LRF. (However we will never achieve OS advantages in arenas where LRF is less than 5% long term but I digress.) But we are radiation oncologists, and you know what Monica Morrow said about us…

 

[RickyScott]

I am not sure this trial changes a great deal of what I would do for most patients. The majority of cN1 patients are postmenopausal and have ER+ and HER2 negative tumors. Neoadjuvant chemotherapy should only be given if oncotype is high. Are you comfortable skipping RT for those with oncotype high based on this? I wouldn't be without more data based on genomics.

It shows where things are headed. Can we omit xrt today? I don’t know, but drugs are only improving and I am confident that at some point in my career these patients will not be getting xrt.

 

[medgator]

Top left graph germane to “argument” here and the Danish data is subsumed, I assume, in the EBCTCG graph.

I get your points about LRF. If PMRT is going to improve survival it’s got to affect more than just LRF. (However we will never achieve OS advantages in arenas where LRF is less than 5% long term but I digress.) But we are radiation oncologists, and you know what Monica Morrow said about us…

View attachment 359168

Local recurrences can be obnoxious to patients, can't they?

 

[TheWallnerus]

Local recurrences can be obnoxious to patients, can't they?

Absolutely. Is it now a tautology that overall survival advantages from RT will always be less than LC advantages? I think so. And in this trial (a subset of) women with positive nodes and no RT had a one in fifty chance of LRF at 5y, which suggests to me a NNT of at best approximately 100 for LC advantage w/ RT in that subset. OS NNT… in the thousands?

To a large extent I’m musing. But as Ricky Scott said, “where we are headed” is what I am pondering.

 

[TheWallnerus]

It shows where things are headed. Can we omit xrt today? I don’t know, but drugs are only improving and I am confident that at some point in my career these patients will not be getting xrt.

On the basis of this and many other reports, I would omit PMRT in a lady who had evidence of N1 pre chemo, a small primary, and who was ypN0 post chemo. I don’t need to be hit over the head, or the boob. Next up: HER2 patients (and triple negative even) with pCR. Like a quote I read from a med onc: “We’ve followed 2000 patients with HER2 disease and have yet to see a single local failure.”

 

[Palex80]

The point I was trying to make quoting the old Durch data is that the general rule of "prevent 4 recurrences and save the life of 1 patient", does not seem to always uphold. Patients with small (absolute) locoregional recurrence riks benefit little from PMRT in terms of locoregional control, but they may have a meaningful OS advantage because of it.
I should however have rather quoted this analysis, sorry for the confusion:

High local recurrence risk is not associated with large survival reduction after postmastectomy radiotherapy in high-risk breast cancer: a subgroup analysis of DBCG 82 b&c - PubMed

Translation of LR reduction into breast cancer mortality reduction after postmastectomy radiotherapy to high-risk breast cancer patients seems to be heterogeneous, with the largest translation occurring within the good prognosis group.

pubmed.ncbi.nlm.nih.gov

We do not really understand why this happens, but it seems that PMRT influences distant metastasis free survival (and OS) not only through prevention of locoregional recurrences that we can measure.

 

[Palex80]

On the basis of this and many other reports, I would omit PMRT in a lady who had evidence of N1 pre chemo, a small primary, and who was ypN0 post chemo.

I generally agree, however some more questions need to be adressed.

1. What surgical axillary management would you see as adequate to follow this route? Would you need an ALND proving „true“ ypN0? Would you also accept a TAS or even a SLN-excision showing ypN0?

2. What would you accept as initial staging? Ultrasound of the axilla (with biopsy)? MRI? PET-CT? If you may be planning to skip PMRT you should probably know a bit more about the exact initial disease extent in the nodes, wouldn’t you agree?

 

[RadOncDoc21]

Breast is the worst!

 

[TheWallnerus]

The point I was trying to make quoting the old Durch data is that the general rule of "prevent 4 recurrences and save the life of 1 patient", does not seem to always uphold. Patients with small (absolute) locoregional recurrence riks benefit little from PMRT in terms of locoregional control, but they may have a meaningful OS advantage because of it.
I should however have rather quoted this analysis, sorry for the confusion:

I have never seen the effect of RT to be greater for either DMFS or OS in an irradiated group than the LRFS effect. Never. When you say “benefit little… in terms of LR control but… have a meaningful OS adv,” I’m hearing you say *absolute* OS advantage can be > LR advantage, and I just have NEVER seen that. I don’t even know mechanistically how it would work (curing cancers that were never coming back is not magic, it’s illogical).

The unirradiated cN1 women in this study had a 2% LR failure at 5 years. This certainly sets a hard limit on the LR control advantage RT could offer here at 5 years: it would be a 2% advantage, at most. And, it also sets an *OS* advantage limit: it can not conceivably be >2%, and we both know it would be A LOT less. (There were women who had survival detriment with PMRT in the EBCTCG.)

I generally agree, however some more questions need to be adressed.

1. What surgical axillary management would you see as adequate to follow this route? Would you need an ALND proving „true“ ypN0? Would you also accept a TAS or even a SLN-excision showing ypN0?

2. What would you accept as initial staging? Ultrasound of the axilla (with biopsy)? MRI? PET-CT? If you may be planning to skip PMRT you should probably know a bit more about the exact initial disease extent in the nodes, wouldn’t you agree?

The unirradiated cN1 women in this study got SLN analysis. In my brain, I have made SLN and ALND completely totally fungible at the oncologic level in breast cancer. We all should IMHO. You can not rationally make any radiotherapy decisions on the basis of “I wish the lady had gotten her axilla dissected” anymore. “Know[ing] a bit more about the exact initial disease extent in the nodes” is bootless; it’s falling back into the angsty “but what if” arguments in the immediate post Z0011 days. Know what you can know (by PET or US or MRI or whatever), let her get “maximal” (sans RT) treatment (which should not include axillary dissection), and go on with life.

Breast is not the worst… it’s just a trap for people who think too much!

EDIT: as an aside there are a lot of similarities between our discussions regarding “truth” etc between classical and quantum physicists in the early days of quantum. I’m clearly quantum; there is no truth! Only what you observe.

 

[Palex80]

I have never seen the effect of RT to be greater for either DMFS or OS in an irradiated group than the LRFS effect. Never. When you say “benefit little… in terms of LR control but… have a meaningful OS adv,” I’m hearing you say *absolute* OS advantage can be > LR advantage, and I just have NEVER seen that. I don’t even know mechanistically how it would work (curing cancers that were never coming back is not magic, it’s illogical).

This is true. But sometimes OS-benefit can be similar to LR benefit.

The unirradiated cN1 women in this study had a 2% LR failure at 5 years. This certainly sets a hard limit on the LR control advantage RT could offer here at 5 years: it would be a 2% advantage, at most. And, it also sets an *OS* advantage limit: it can not conceivably be >2%, and we both know it would be A LOT less.

2% sounds good for PMRT. Lot's of breast cancer patients used to get 6 months of chemo for a comparable OS benefit.

The unirradiated cN1 women in this study got SLN analysis.

Not really.

The unirradiated women, were the ypN0-group (Low Risk). 80% of them got ALND.

In my brain, I have made SLN and ALND completely totally fungible at the oncologic level in breast cancer. We all should IMHO. You can not rationally make any radiotherapy decisions on the basis of “I wish the lady had gotten her axilla dissected” anymore. “Know[ing] a bit more about the exact initial disease extent in the nodes” is bootless; it’s falling back into the angsty “but what if” arguments in the immediate post Z0011 days.

Oh no! I refuse to go on with this discussion, you just brought up Z0011!!!
Z0011 was in cN0, this is cN1. Totally different scenario. No study has yet established that you defer ALND in cN1 patients, many centers do TAS (which is fine probably), but SLNB only? Nope sorry, that's two steps too far, in my opinion.

Know what you can know (by PET or US or MRI or whatever), let her get “maximal” (sans RT) treatment (which should not include axillary dissection), and go on with life.

Well, "maximal" treatment can potentially include ALND then. I would prefer RT over ALND.

 

[TheWallnerus]

This is true. But sometimes OS-benefit can be similar to LR benefit.

2% sounds good for PMRT. Lot's of breast cancer patients used to get 6 months of chemo for a comparable OS benefit.

Not really.
View attachment 359176
View attachment 359175
The unirradiated women, were the ypN0-group (Low Risk). 80% of them got ALND.


Oh no! I refuse to go on with this discussion, you just brought up Z0011!!!
Z0011 was in cN0, this is cN1. Totally different scenario. No study has yet established that you defer ALND in cN1 patients, many centers do TAS (which is fine probably), but SLNB only? Nope sorry, that's two steps too far, in my opinion.


Well, "maximal" treatment can potentially include ALND then. I would prefer RT over ALND.

Correct me if I’m wrong but every time ALND has been tested against SLN there have been no significant differences in major outcomes long term. Every single time. How much data will it take for people to move on from thinking ALND accomplishes anything. ALND is very morbid compared to SLN.

EDIT: Sorry to do a late edit. But it’s reasonable to think one out of five of these cN1 ladies would have positive IMNs on dissection of the IMNs. If ALND is needed for axillary cN1, why isn’t IMN dissection too?

 

[Palex80]

Correct me if I’m wrong but every time ALND has been tested against SLN there have been no significant differences in major outcomes long term. Every single time. How much data will it take for people to move on from thinking ALND accomplishes anything. ALND is very morbid compared to SLN.

SLNB without any sort of local adjuvant therapy for cN+ has never been tested against ALND.
This is a totally new disease setting.

EDIT: Sorry to do a late edit. But it’s reasonable to think one out of five of these cN1 ladies would have positive IMNs on dissection of the IMNs. If ALND is needed for axillary cN1, why isn’t IMN dissection too?

Cause we irradiate the IMN, just like we irradiate the axilla (if it's not properly dissected).

 

[deleted1111261]

bc if it’s 1/5 of the axillary recurrences, even if axillary recurrence rate is 15% (no way that high), the IMN rate is 3% and RT not going to make a diff

 

[TheWallnerus]

SLNB without any sort of local adjuvant therapy for cN+ has never been tested against ALND

Oh Lordy. Now we are parsing between cN1 and pN1. In Z0011 there were a lot of pN1 SLN+ women that got no “local therapy” (ALND) to the axilla, and even a lot that got no RT at all (in violation of protocol). We all know how they did long term. I thought we (the Bernie Fisherian we) were teaching everyone that the axilla (and ALND especially) is prognostic, not therapeutic. Guess not. I almost can’t believe you want a lady with a single node on ultrasound and later ypN0 to get her axilla majorly surgerized (or radiotherapized) during her mastectomy when all we can truly be sure of (we can’t be sure it helps oncologically) is that her lymphedema risk and QOL will be affected.

 

[bigman1]

Bit off subject here and not subtle, but do we really think it is a good idea for women to be having all this (neoadjuvant) systemic therapy? The long term toxicity is far worse than any local treatment could ever cause.

 

[RickyScott]

Bit off subject here and not subtle, but do we really think it is a good idea for women to be having all this (neoadjuvant) systemic therapy? The long term toxicity is far worse than any local treatment could ever cause.

Who knows. Medoncs make that determination. Supposedly the vast majority of women would undergo toxic chemo for 4% absolute improvement in survival.

 

[bigman1]

Who knows. Medoncs make that determination. Supposedly the vast majority of women would undergo toxic chemo for 4% absolute improvement in survival.

I think thats the problem with our specialty. We will cannibalise one another over seemingly anything but will allow the other specialties to do as they please with no focus on the actual patient.

 

[Palex80]

Oh Lordy. Now we are parsing between cN1 and pN1.

Of course we are. These are two, totally distinct settings.
It's like saying you would be treating a cN0 prostate cancer with a moderare/high risk for nodal involvement the same way as you would be treating a pN1 prostate cancer.

In Z0011 there were a lot of pN1 SLN+ women that got no “local therapy” (ALND) to the axilla, and even a lot that got no RT at all (in violation of protocol).

We actually know very little about how the individual patients did, since the protocol was written so poorly that we could only guess what kind of doses were delivered to the axilla. Furthermore, the vast majority of Z0011 patients had luminal A tumors.

We all know how they did long term. I thought we (the Bernie Fisherian we) were teaching everyone that the axilla (and ALND especially) is prognostic, not therapeutic. Guess not.

ALND is both.

I almost can’t believe you want a lady with a single node on ultrasound and later ypN0 to get her axilla majorly surgerized (or radiotherapized) during her mastectomy when all we can truly be sure of (we can’t be sure it helps oncologically) is that her lymphedema risk and QOL will be affected.

I dont "want" something.
Standard of care for cN+ after neoadjuvant chemo is to perform ALND or TAS. Most probably do TAS. SLNB is certainly not supported by evidence.

The Dutch study results cannot be extrapolated to modern practice if you are going to do SLNB only. Not, when 80% of the patients had ALND on the trial. The trial basically delivered ALND to cN1/ypN0 patients and deferred RT. I would be fine omitting RNI in this situation too and would only treat chestwall if there were risk factors for local recurrence (pure response of the primary, L1, etc...)
Extrapolating this to SLNB is not backed up by these data.

There is quite good data that performing SLNB post-chemotherapy is not as reliable as performing it pre-chemotherapy.

Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study - PubMed

Brustkrebs Deutschland, German Society for Senology, German Breast Group.

pubmed.ncbi.nlm.nih.gov

Of 1737 patients who received treatment, 1022 women underwent sentinel-lymph-node biopsy before neoadjuvant chemotherapy (arms A and B), with a detection rate of 99.1% (95% CI 98.3-99.6; 1013 of 1022). In patients who converted after neoadjuvant chemotherapy from cN+ to ycN0 (arm C), the detection rate was 80.1% (95% CI 76.6-83.2; 474 of 592) and false-negative rate was 14.2% (95% CI 9.9-19.4; 32 of 226). The false-negative rate was 24.3% (17 of 70) for women who had one node removed and 18.5% (10 of 54) for those who had two sentinel nodes removed (arm C). In patients who had a second sentinel-lymph-node biopsy procedure after neoadjuvant chemotherapy (arm B), the detection rate was 60.8% (95% CI 55.6-65.9; 219 of 360) and the false-negative rate was 51.6% (95% CI 38.7-64.2; 33 of 64).

So if you ommit PMRT in a patient with ycN0 and ypN0 on SLNB means you are leaving cancer in the axilla in 14% of all patients.
This is bad.

 

[deleted1111261]

So if you ommit PMRT in a patient with ycN0 and ypN0 on SLNB means you are leaving cancer in the axilla in 14% of all patients.

That’s not what Bernie found.

 

[RadOncDoc21]

I think thats the problem with our specialty. We will cannibalise one another over seemingly anything but will allow the other specialties to do as they please with no focus on the actual patient.

It’s how we are trained. Look at the big wig ASTRO heads. Quick to judge/look down on the community docs but first to kiss the rings of their colleagues and looking for any excuse to not have to give or look for any indication to give less radiation.

I know I am catergorizing but am going based off my own personal experiences from my residency program and ASTRO meetings.