ALND vs No ALND in pts with limited SLN metastatic breast ca. No OS difference?

[radioh3ad]

NYTimes article
http://www.nytimes.com/2011/02/09/health/research/09breast.html?hp

"Some prominent institutions wouldn't even take part in it," Dr. Giuliano said, though he declined to name them. "They're very supportive now. We don't want to hurt their feelings. They've seen the light."

.... ballsy

JAMA this Wed
http://jama.ama-assn.org/content/305/6/569.short

Context Sentinel lymph node dissection (SLND) accurately identifies nodal metastasis of early breast cancer, but it is not clear whether further nodal dissection affects survival.

Objective To determine the effects of complete axillary lymph node dissection (ALND) on survival of patients with sentinel lymph node (SLN) metastasis of breast cancer.

Design, Setting, and Patients The American College of Surgeons Oncology Group Z0011 trial, a phase 3 noninferiority trial conducted at 115 sites and enrolling patients from May 1999 to December 2004. Patients were women with clinical T1-T2 invasive breast cancer, no palpable adenopathy, and 1 to 2 SLNs containing metastases identified by frozen section, touch preparation, or hematoxylin-eosin staining on permanent section. Targeted enrollment was 1900 women with final analysis after 500 deaths, but the trial closed early because mortality rate was lower than expected.

Interventions All patients underwent lumpectomy and tangential whole-breast irradiation. Those with SLN metastases identified by SLND were randomized to undergo ALND or no further axillary treatment. Those randomized to ALND underwent dissection of 10 or more nodes. Systemic therapy was at the discretion of the treating physician.

Main Outcome Measures Overall survival was the primary end point, with a noninferiority margin of a 1-sided hazard ratio of less than 1.3 indicating that SLND alone is noninferior to ALND. Disease-free survival was a secondary end point.

Results Clinical and tumor characteristics were similar between 445 patients randomized to ALND and 446 randomized to SLND alone. However, the median number of nodes removed was 17 with ALND and 2 with SLND alone. At a median follow-up of 6.3 years (last follow-up, March 4, 2010), 5-year overall survival was 91.8% (95% confidence interval [CI], 89.1%-94.5%) with ALND and 92.5% (95% CI, 90.0%-95.1%) with SLND alone; 5-year disease-free survival was 82.2% (95% CI, 78.3%-86.3%) with ALND and 83.9% (95% CI, 80.2%-87.9%) with SLND alone. The hazard ratio for treatment-related overall survival was 0.79 (90% CI, 0.56-1.11) without adjustment and 0.87 (90% CI, 0.62-1.23) after adjusting for age and adjuvant therapy.

Conclusion Among patients with limited SLN metastatic breast cancer treated with breast conservation and systemic therapy, the use of SLND alone compared with ALND did not result in inferior survival.

Trial Registration clinicaltrials.gov Identifier: NCT00003855

How are your home institutions reacting?

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[Gfunk6]

We knew about it for a while since it was previously published in abstract form. Results are promising but median follow up is too short for early stage breast cancer. I look forward to an update with at least 10 year follow-up for LR and 15 year for OS.

 

[medgator]

Monica Morrow gave a talk on this when she came to our hospital for a lecture.

The important thing to remember is that this cohort of patients received "tangential whole-breast irradiation", which likely sterilized micrometastatic disease in a good part of the axilla (Levels I and II). It's important to keep that in mind when extrapolating this data to other groups of patients (i.e. those you are considering partial breast on, or those who decide to forgo XRT).

And, like gfunk said, more LT follow-up is needed.

edit: Here's a good paragraph from the conclusion:

The Z0011 trial did not include patients undergoing mastectomy, those undergoing lumpectomy without radiotherapy, those treated with partial-breast irradiation, those receiving neoadjuvant therapy, and those receiving whole-breast irradiation in the prone position, in which the low axilla is not treated. In those patients, ALND remains standard practice when SLND identifies a positive SLN. However, ALND may no longer be justified for women who have clinical T1-T2 breast cancer and hematoxylin-eosin–detected metastasis in the SLN and who are treated with breast-conserving surgery, whole-breast irradiation, and adjuvant systemic therapy.

Also, it's unclear as to how her-2/neu figures into this.

 

[Cancerdancer]

We knew about it for a while since it was previously published in abstract form. Results are promising but median follow up is too short for early stage breast cancer. I look forward to an update with at least 10 year follow-up for LR and 15 year for OS.

The most impressive thing is that they published the LRR rate last year in Annals of Surgery (PMID: 20739842) and then got a separate JAMA publication reporting OS. Same # pts, same length of followup. Pretty silly to act like the OS would be different (and that this outcome is new knowledge) when they just published no diff in LRR for a regional therapy, and didn't add any f/u. Apparently reporting more than one oncologic outcome in the same paper is, like, so 90's...

 

[Gfunk6]

The most impressive thing is that they published the LRR rate last year in Annals of Surgery (PMID: 20739842) and then got a separate JAMA publication reporting OS. Same # pts, same length of followup. Pretty silly to act like the OS would be different (and that this outcome is new knowledge) when they just published no diff in LRR for a regional therapy, and didn't add any f/u. Apparently reporting more than one oncologic outcome in the same paper is, like, so 90's...

Good point! I guess we should expect the subset analyses to be published in the near future.

 

[seper]

Notion of standard tangents "sterilizing axilla" is a TRAVESTY. Much work has been published on that (good one attached).
To treat axilla without PAB you need specifically designed high tangents, which over-treat the lung.

 

[RadRadRad]

Unfortunately it will be hard to know what type of axillary RT dose was given. The paper says tangential whole breast radiation. This probably does not exclude the possibility that high tangents were prescribed by concerned radoncs.

 

[seper]

Although it would've been helpful if authors stated that axilla was not intentionally targeted, this can be inferenced from Methods.
Again, there are multiple publications on tangents and axilla dose with similar results.

Unfortunately it will be hard to know what type of axillary RT dose was given. The paper says tangential whole breast radiation. This probably does not exclude the possibility that high tangents were prescribed by concerned radoncs.

 

[Palex80]

The Dutch MIRROR-study has shown that ommiting ALND or axillary RT may lead to more LN recurrences in pN1(mic) SLN-patients.
http://meeting.ascopubs.org/cgi/content/abstract/27/18S/CRA506

 

[deleted4401]

This is a well-designed trial.

Using retrospective data to refute a randomized controlled trial seems backwards.

Most recurrences in breast cancer (70%) occur in first 5 years. The median time for axillary recurrence is 14.8 months, and as the conclusion indicates, only 7/68 axillary recurrences were seen after 5 years in the B4 trial. This had 6.3 years of follow-up. Even if every last recurrence was in the SL alone arm, still wouldn't be enough to nudge the results. No locoregional breast cancer trial (B4, all lumpectomy +/- RT trials, Tam trials) showed non-inferiority early and then went on to show that less LR treatment was worse.

This is a logical progression from the idea of the Halsted mastectomy to what we do today. The Ax dissection is more prognostic than therapeutic in this era.

These patients were well selected - cT1-T2N0 patients, ineligible if 3 or more positive SL nodes, or if fixed/matted, or if gross nodal ECE. Almost all of them received systemic therapy (either endocrine or anthracycline cytotoxic therapy). 100% of them had nodal positivity and the survival rate was in the 90s!

Cherry-picking a population to avoid excessive therapy is a good thing, and we should do it as often as possible.

I think this should be practice changing, and those that continue to say "more follow-up, more follow-up" are like the folks that dispute the Whelan hypo-fx results, and their minds will never be changed.

-S

 

[Gfunk6]

Simul, that was a very eloquent and well-reasoned response and I respect your thoughts on the subject. However, I must disagree with you on the length of follow-up required to draw practice-changing conclusions from this study.

First, your point about the perpetual naysayers and their "more follow-up, more follow-up" diatribes is well taken. However, I do think people will change their opinion with adequate follow-up. For instance, since 10-year data was published by Whelan's group in Canada we definitely perform breast hypo-frac and consider it comparable to conventional frac. My point here is that skeptics CAN be converted with good data and we are not all simply holding on to dogma for its own sake.

Second, I'd like to quote a paragraph from NSABP-04 (which you also cited):

When the B-04 trial began, it was popularly believed that five years could be viewed as a milestone and that women who lived for five years free of disease were likely to have been "cured." However, our findings demonstrate that a substantial proportion of events occurred after five years among both women with negative nodes and those with positive nodes. Twenty-five percent of all first distant recurrences and 50 percent of all contralateral breast cancers were detected after five years, which indicates the need for long-term follow-up, particularly in the evaluation of patients with a good prognosis.

This is the angle that I am coming from.

Finally, there is a level of personal comfort with data which I think varies from physician to physician. Were I to have a cT2 pt with IDC and 2/3 positive SLNs, I would be afraid not to recommend a full ALND. Does that make me a dinosaur? Perhaps, but I am a bit more conservative when reading data and would prefer to have what I perceive as reasonable follow-up. Obviously, there is also an institutional training bias.

 

[Palex80]

This is a well-designed trial.

Using retrospective data to refute a randomized controlled trial seems backwards.

I agree with you.
I just wanted to point out, that there are other studies out there (even with a lower evidence level) showing the contrary.
I think that as you already pointed out, this can be a practice-changing study. However I would always try to look a bit more deepely into each individual patient, for whom I decide to ommit axillary clearance or radiotherapy.
Use the online calculators available to estimate the risk of further lymph node involvement, be careful with young patients and aggressive tumors, etc...

We don't use high tangents to treat the axilla in my insitution, but I see on a daily basis that we have a lot of axilla in our tangents when we are targetting only the breast. It's not the entire axilla but you do have the high-risk areas often covered (most of Level I) IMHO.


One last point:

Therapy deescalation trials are a great idea and I am a big fan of them. You can go from trial to trial and deescalate treatment, making the new deescalated therapy into standard treatment.
However there is one methological problem:
You will not suffer from statistic significant reduction in therapy efficiency between the old and new treatment at every step. But if you add up all reductions in therapy efficiency you may one day find that your new therapy (which was developed after 4 sequential therapy deescalation trials) lacks in efficiency in comparison to the standard of care 20 years ago.
Early Hodgkin disease is a good example for that:
We went down from 2xABVD +30 Gy EF-RT to 2xABVD + 30 Gy IF-RT then 2xABVD + 20 Gy IF-RT, now we want to do 2xABVD + 20 Gy IN-RT and in the future perhaps ommit the RT alltogehter. Surely the differences between these different deescalation steps in terms of efficacy may not be statistical significant, however diagnostics have evolved over these 30 years or so, that the trials have been running, meaning that we are probably bringing in more "true" early stages into the trials, than we did 30 years ago.
Do we really know in the end if 2xABVD + 30 Gy EF-RT are as good as 2xABVD?

 

[deleted4401]

Good points. Pretty soon the lowest risk Hodgkins patients aren't going to be getting any treatment at all.

S

 

[Palex80]

Two last point, that I forgot to make in my last posts.

1. We are arguing on tumor boards in favor of post-BCS radiation therapy often quoting data from the EBCTG.
http://www.ncbi.nlm.nih.gov/pubmed/16360786
Yet what we often forget is that these data, showing a great reduction in local failure and an overall survival benefit, are based on radiation therapy given in a much more aggressive way, than we do today.
Patients included in metaanalyses such as the EBCTG often received radiation treatment to the axilla, the paraclavicular and the retrosternal nodes, sometimes without taking into consideration how many nodes were involved, how big the primary tumors were, etc...
Modern day target volumes for post-BCS radiation therapy are based on some randomized therapy deescalation trials, but most of the data actually comes from retrospective series, which have looked into patterns of recurrence.
Like I said in my last post: Reducing target volume step by step is great, but if we reduce "too much", can we actually still claim, that we are preventing 20% recurrences and offering 5% overall survival benefit.


2. More than 80% of the patients in the Jama paper had a positive ER and/or PR status, meaning that about 80% of them got antihormonal therapy and probably >70% of them completed 5 years of it.
With a follow up of 6 years in the paper it could very well be that this hormonal therapy suppressed tumor activity and we are about to see the recurrences rising from microscopic lymph nodes metastases in the coming couple of years, when the patients will be off treatment.

 

[G'ville Nole]

Palex, your points are well taken. It's always a good caveat to keep in mind when quoting the literature, i.e. is your patient part of the included population and receiving the same treatment?

Looking at the issue overall survival from the flip side of the coin, while it's true that the fields were broader in a fair number of the individual trials that comprise the EBCTCG (lower energies, too, still several cobalt treatments in that group), there was also a higher rate of possible treatment related morbidity and mortality such as lung cancer and CV disease (HR of about 1.5 and 1.7 IIRC). While no hard data supports the supposition, I suspect that any ground ceded in terms of cancer specific survival by our more contemporary approach may be offset by a decrease in long term treatment related sequelae, thus conserving the observed survival benefit.

 

[Palex80]

While no hard data supports the supposition, I suspect that any ground ceded in terms of cancer specific survival by our more contemporary approach may be offset by a decrease in long term treatment related sequelae, thus conserving the observed survival benefit.

That sounds logical. Thanks for the good point, I'll try to keep that in mind.

 

[Raygun77]

Very interesting trial, thanks for starting ze discussion!

Can anyone comment on how their local breast surgeons are taking the data?

Things that caught my eye were:

~170 lost to follow up

No mention of lymphovascular involvement- could have been another variable in the fray (but may have overcomplicated things!)

Difficult to know implication for pts with 3+ sentinel nodes positive...if you had a hypothetical 64yo who underwent lumpectomy for a ~4cm tumour, receptor positive with 3/4 sentinel nodes positive, what would you recommend?

 

[Palex80]

Difficult to know implication for pts with 3+ sentinel nodes positive...if you had a hypothetical 64yo who underwent lumpectomy for a ~4cm tumour, receptor positive with 3/4 sentinel nodes positive, what would you recommend?

Breast + axillary & paraclavicular lymph nodes.

 

[Ursus Martimus]

This is a well-designed trial.

Most recurrences in breast cancer (70%) occur in first 5 years.


I think this should be practice changing, and those that continue to say "more follow-up, more follow-up" are like the folks that dispute the Whelan hypo-fx results, and their minds will never be changed.

-S

By the same logic 5 year Hungarian data on accelerated partial breast is good enough too? 5 years for a surgeon is an eternity and "good enough" since I doubt they see the patient out that far. In contrast, those clinicians who see patients that far out are the ones argue for longer followup. Long enough is relative and it depends where you sit. The other thing is most general surgeons you talk too hate doing complete ALND. I think they are pleased with the data and happy to say bye bye. The fear is the extension to patients that would not have been included in the trial. Don't discount that as weighing in the process