Richard J. Bleicher, MD, FACS, presents a discussion on local control and ductal carcinoma in situ (DCIS). He reviews 4 abstracts and a spotlight session on updates on strategies for axillary management.
So we're going to talk about um local control in D. C. I. S. And there wasn't anything tremendously groundbreaking but we should go over some of these issues. We will talk about four specific abstract and a spotlight session which I'm just going to give you the very highlighted bullet points for that. So the first abstract we're gonna go through is radioactive iodine seed placement in the villa would send the lymph node biopsy after neo adjuvant chemotherapy and breast cancer. Results of the prospective multi center rice's trial. So rice is basically this was a trial for clinically known positive patients treated with neo adjuvant chemotherapy. And we know that such patients have a pcr at about a third of cases in the excel up. Um And obviously if you have a pcr they don't benefit from an axe to section. But the problem is how do you avoid an excellent axillary dissection and still identify residual disease? Um Any axillary lymph node dissection substitute is going to need a low false negative rate and a high negative predictive value. And the authors went through three different things here. They correlated the data for three different procedures now. Um Tad which is targeted axillary dissection is basically a technology where we place a seed into a positive node and that seed after neo adjuvant chemotherapy is then localized to see whether the disease in that node ends up having achieved a pcr or not. That's tad or targeted acts or dissection. You can see that there is 100% I'd rate 2-4% false negative rate and a negative predictive value. That's quite good marry which is a trial that was done with a radioactive iodine. See that's the same as Tad was similar with a slightly higher false negative rate and by the way a false negative rate under 10% is considered acceptable. And sentinel node biopsy which we all know um Is not quite as good as this in the neo adjuvant setting after chemotherapy is given. And so you can see the identification rate is lower. The false negative rate is over 10% which is considered unacceptable. And the negative predictive value is only fair. So the racist trial schema was a prospective multi center validation trial looking at clinically no positive and pathologically note positive patients treated with neo adjuvant chemotherapy and they excluded a positive. In fact lenticular or super particular notes. Um uh when iodine 125 radioactive seed was placed in the positive note by radiology under ultrasound. And they had neo adjuvant chemotherapy. The time of the surgery they localized that I won 25 seed. They performed to send on a biopsy. Sometimes it was the same nodes and they also didn't act to section. And this was a non inferiority trial where the upper bound needed to be within 6.25%. Now, if we look at the actual data data points from this, the identification rate or what they call success rate of the seeds and the notes was 98% of the patients ended up having a PCR in the axillary in just over a third of cases. And um some of the patients requested that there be no axillary dissection. And because of the way this was analyzed, they need to exclude does Um identification of either a single note or a mark lymph node but not both. Was happened in 16% of the cases and residual disease was found only in a central note or only in a mark note. In 19%,, the mark lymph node was the central node in 70% of cases. And the false negative rate you can see here was very good at 3.5% and the negative predictive value at 94%. Unfortunately they did not achieve non inferiority because it was above the upper confidence bounds above 6.24%. And so if you add the data from this trial to the rest of these, it's really in line with mary and todd and this is basically the same thing you're talking about. The same type of procedure will re localize the seed after neo adjuvant chemotherapy. And so it's got a high identification rate, a low false negative rate. Well under the required 10% and a good negative predictive value. And so the authors concluded that rice's or tad is the most suitable staging procedure after neo adjuvant chemotherapy and clinically no positive breast cancer. So there were a few good questions that were asked first. How many positive notes did you allow to be clipped before Neo Adjuvant chemotherapy. There was no maximum number of suspicious lymph nodes, but most patients ended up having four or fewer suspicious lymph nodes before Neo Adjuvant chemotherapy. How was the central no done? Um and the author said that the trial recommended dual tracer but they could do it as desired. So 94% had radio tracer with or without blue dye, but 6% had blue die alone where any radioactive seeds not identified in the excel up, all patients, the author said had the seeds identified. But there were quite a few that had the seeds sitting and adequacy issue and not lymph nodes. So in these they found the seed but they couldn't identify the lymph node. So a few considerations we need to look at. Um so they didn't achieve non inferiority but it's probably just simply due to lack of power because they needed 248 patients. They only consented 252, leaving very little room for attrition. 227 had the procedure and only 217 agreed to the acts to section which were the ones that ended up needing to be analyzed. So they probably just didn't achieve the numbers. Now rice's, as I've mentioned a couple times now is a form of Tad and it uses a radioactive seed but we don't really need the radio activity. There are multiple ways to do this localization without it. So we've got the elusive and video device which uses a GPS like technology. This is what we do with localization at Fox Chase. We've got the end of MAg magazine which is magnetic. We've got a savvy scout which is radar detection. We've got the whole logic localizer which is our fight and we've got needle or wire traditional localizations which we're all familiar with. I would say that this does confirm tad with or without a sentinel node biopsy as being standard. Um It has the highest identification rates and the lowest false negative rates. So here we have additional bolstering to how we can handle sentinel node biopsies and determination of the status of the Exelon after neo adjuvant chemotherapy. So the next slide is shows the title for their second abstract which is updated long term results of an Astros all versus tamoxifen for the prevention of breast cancer in postmenopausal women with locally excised ductal carcinoma in sight to or the Ibis to D. C. I. S. Trial. Um so we all know that Roma taste inhibitors are better than tamoxifen for hormone receptor positive invasive breast cancer treatment and tamoxifen reduces hormone receptor positive DCs recurrences by about a third. We also have a recent low dose tamoxifen trial five mg a day for three years that showed a 52% reduction versus placebo in hormone receptor positive D. C. I. S. Now be 35 trial had nine years of follow up and showed a 27% reduction by an astronaut as versus tamoxifen for hormone receptor positive D. C. I. S. And this was mostly seen in the late post treatment follow up period Ibis to was also initially analyzed at seven years with again for hormone receptor positive D. C. I. S. And it did show an 11% recurrence reduction by an Astros all as versus tamoxifen but that was not significant. So the plan here was to update the analysis analyzed by breast cancer subtype and check for adverse events. And um this ended up being a trial of postmenopausal women 40 to 70 who had locally excised here positive D. C. I. S. Within six months. They could also, instead of having D. C. I. S. Have atypical hyperplasia or L. C. I. S. Alone. And it was 2003 to 2012. They were randomised as you see here to five years of an ass result or tamoxifen. And there was followed for five years by clinic visits questionnaires, registry data. And this analysis looked at a median follow up of 11.6 years. The primary endpoint was invasive in DCs recurrences. And you can see the secondary endpoints listed here. Um I won't go through the numbers but the groups were well balanced and um you can see the bottom line here for five year and 11-year recurrences. The bottom line is that 9.7% for an Astros. All 8.5 for Tamoxifen. But no difference still at 11 years out. Um Most things were not significant. All recurrences. DCs recurrences even when broken down by subtypes invasive recurrences. Even when broken down by subtypes E. R. Negative recurrences for er positive recurrences there was a significant 44% reduction within Astra's all in the early first five years but not after that. And the same thing with her two negative recurrences dropping this by 60%. There was no difference in non breast cancers other than endometrial and ovarian interestingly. There was higher endometrial and higher ovarian cancers in the tamoxifen group for fractures. This was 34% higher in an Astra saw and for a C. V. A stroke and T. I. A. This was also higher for an Astros all significantly breast cancer and other causes of death were not significant between the groups. And so the conclusion was that there's no recurrence difference and Astra's all versus tamoxifen for ear positive. DCs was essentially the same. And um there was a late benefit of an astronaut and be 35 that we didn't see here in ibis too. So we have a little bit of a conflict. There is no effect on breast cancer deaths for tamoxifen. They saw an excess of endometrial and interestingly ovarian cancers and the anastrozole group actually had an excess of fractures and tia and strokes. Ultimately the authors concluded that side effects are really going to be what helps patients with D. C. I. S. To make an informed decision about which treatment to pursue so few good questions. Why were there more strokes in the anastrozole arm? And the authors felt that this was because of an increase in hypertension in that arm. Um They also said that it's believed that tamoxifen may improve endothelial function and vessel dilatation. But the reason is not clear ovarian cancer is not associated with tamoxifen. So one questioner asked how certain is the association seen here and the author said that every site reported this. So they believe it to be a true diagnostic association. They do have pathology review ongoing. But so far all of the ovarian cancers have been confirmed. Finally they asked about how many patients were entered with only a tibia or L. C. I. S. As they could have that as an entry criteria instead of D. C. I. S. And the author said less than 2% had atypical hyperplasia or L. C. I. S. All the rest had D. C. I. S. Considerations. Well with no difference between anastrozole tamoxifen for receptor positive D. C. I. S. The choice might be boiled down to side effect profile. So pick your poison. Um Would you rather have fractures Cv a stroke or tia or would you rather have endometrial cancer? Or potentially here ovarian cancer? Um So we now have competing data between B. 35 ibis too. And so the question is which do you pursue? And which do you believe ultimately? Regardless of the fact that we didn't see a difference here, it does seem like an astronaut has the advantage including among these side effects. The third abstract we're going to take a look at is the Prime two randomized trial which stands for post operative radiotherapy and minimum risk elderly. Um Wide local excision and adjuvant hormonal therapy with or without whole breast radiation and women 65 older with early invasive breast cancer is the 10 year results. So prime one showed that radiation is well tolerated and we already know that C. L. G. B. 93 43 showed that breath in breast conservation surgery and patients having tamoxifen with or without radiation And then low risk patients. There was a a 7% reduction in 10 years in local recurrence from 9% to 2%. The prime to trial was a similar design and initially was found to have a reduction of 2.8% in low risk holder patients. So our purpose here is to assess the whole breast radiation impact on local control at 10 years after breast conservation and adjuvant endocrine therapy and low risk older patients. And the follow up medium was 7.3 years. The primary endpoint was its lateral breast tumor recurrence rates and the secondary endpoints I've listed here. The original sample size needed was 870. They shot for 1000 and increased it to 1300 because they felt that they would need to detect a 3% difference in in breast tumor recurrence of five years. So 1300 women over 65 with unilateral invasive breast cancer were signed up for the trial. The tumors had to be three cm or under. They had to have breast conservation. They had to be pathologically note negative by any axillary assessment and the margins had to be a millimeter or over which was done before the current guidelines. Um, They had to be receptive positive treated with endocrine therapy either before or after surgery. And patients with prior cancers were excluded, as were those having both grade three and lymph vascular invasion. Okay. Um, They were randomized to whole breast radiation. You can see the fraction nation and the dose here and whole breast radiation um uh assuming and no breast whole breast radiation in the other arm. The results were well balanced between the arms. I won't read through that. But you've got your demands listed here basically. Local recurrence was significantly different. Um They didn't collect location so we don't know whether this has something has an effect on what we know about A PB and regional recurrence was also significantly different. Again, the radiation providing a local control benefit. There was no difference in overall metastases, free survivals, contra lateral breast cancers or new non breast cancers. They did do an unplanned subgroup analysis in the non radiation group for er high or low looking at local recurrence. In the low er there was a 20% recurrence versus high er a 9% recurrence. So the difference was really half of that. Um So the conclusions in breast tumor recurrence rate was about 10% with whole breast radiation and under 1% without most deaths were not due to breast cancer, 93% of them. And so the authors felt that the omission is an option for PT one or two three centimeter and under grade 1 to 2 tumors as theirs. No president, no evidence that this there is a risk of metastasis or a problem with overall survival. Questions related to this trial. They were asked if they looked at patients h less than versus soldiers set than 70. The answer is no. And they also didn't look at comorbidities. They asked about her too and they said that during the recruitment her to was not standard. Although her two positive and negative patients were included. Um They asked about endocrine therapy compliance and cardiac toxicity and they stated that they didn't collect that. And they also asked about the rate of mastectomy in the No radiation group. And they said that they do have some data on salvage. And they looked at the survival difference from that and there was no difference Basically. Um you know, we've got no difference survival. But uh while we appreciate the author's conclusions at 10% recurrence rate or 9% difference may not be trivial to some patients in terms of having to go through breast cancer treatment again. Um This is generally consistent with prior data, but whether the lack of survival benefit justifies the modality necessitates, I would say an individual discussion with patients. So finally, we've got the big 307 trial or randomized phase three study of radiation doses infraction nation and non low risk DCs of the breast and whole breast radiation after breast conservation for DCs we know reduces local recurrence and there was no high level evidence for optimal dose fraction nation for D. C. I. S. So the objective was really to look at boost and fraction nation. Um By time to local recurrence in non low risk D. C. I. S. Having breast conservation. And um it was they looked at a whole breast versus whole breast plus sequential boost and conventional versus hyper fraction nation. And you can see the dosage here. Secondary objectives were time to disease room recurrence, radiation toxicity, overall survival. And they've previously published quality of life and cosmetic analysis. So uh D. C. I. This was D. C. I. S. Respected by breast conservation with a millimeter or larger margins plus if they were under 70 that was sumi under 50 that was fine. Or if they were 50 and older they had to have at least one of these symptomatic presentation palpable tumor multifocal disease size of a centimeter and a half. And over intermediate or high grade central necrosis committed histology. Or the surgical margins still had to be under 10 millimeters. So it would have to be between one and 10 millimeters. This is a multi center parallel randomized, controlled on blinded trial and was stratified multiple ways. The centers chose to participate in this trial in one of three randomization categories. And they had to do that prior to study activation. So the first randomization a center could choose would be all four um in blue whole breast radiation versus uh standard fraction nation versus in green hyper fracture nation boost in red versus no boost in white. So basically those four possibilities in combination, right? Um standard versus type of fracture nation boost versus no boost. And the four combinations you see here. Um randomization be would be a center would choose to have a standard fraction nation and just randomized between boost and no boost and uh randomization. CIA center could choose would be hyper fraction nation randomized between boost and no boost and I won't go through it but they analyze different sets for different measures to come up with their final analysis. So for especially for our radiation oncology colleagues in the audience um CT based radiation therapy planning was mandatory and um the whole breast radiation was tangential with photon beams. The boost was cT contouring of protocol defined tumor bed target volumes. Electrons or photons were allowed. Interstitial breaking therapy was not allowed And they designed this to detect a 3% difference in five year local recurrence rates between the boost groups. Um nearly 1600 patients were required. This was an intent to treat analysis and 1600 randomized patients were enrolled between 2007 and 14 with a median follow up of 6.6 years. I won't go through the numbers because we're running out of time. But the patients were very well balanced. The results are here the five year freedom from local recurrence was different with a boost versus no boost, but was not different between Hyper fraction nation and conventional fraction ation. They did a test for interaction between the boost infraction nation and that came up not significant. The 5-year freedom from Disease Recurrence was also again significant for boost for snow boost. But hippo versus conventional fraction nation did not show any difference in terms of side effects acutely. We saw a difference in radiation dermatitis and those getting a boost, but fatigue, breast pain and pneumonitis were not significant in late side effects. We see a difference in breast pain in duration and fibrosis and atlantic tasas in those getting a boost. But um pneumonitis, cardiac issues and second malignancy were not significant. So they concluded that a boost reduces the local recurrence of non lowest DCs patients treated with breast conservation. Independent. A fraction nation and fracture nation didn't change the local recurrence. The boost increased fibrosis. But it turned out when they analyzed is the Great Three toxicity was uncommon and so long term follow up is needed. Two very good questions that were asked by the audience number one, why an eight fraction boost in this hyper fractionated schedule? And they said that this was consensus by committee and from their analysis of prior literature, the second was a sort of a comment question. It's not really a surprise that a boost improves recurrence, but should 25 patients receive this treatment to prevent one local recurrence which does not affect distant recurrence of survival. So remember there was a 4% benefit. Well they said they previously published that there was more than a two-fold increase in adverse cosmetic outcome with a boost. Um And no difference in cosmetic outcomes between conventional hype a fraction nation. But despite this the boost didn't affect the quality of life. So their thought was this is something that needs to be discussed with patients. It's a valid question and it will sort of have to be figured out. Okay. Um Final slide the spotlight session looking at abstract on the management of X. The X. L. A. And early disease. We have six points that were pointed out One trial called the Senate are one trial confirmed. Z. 11 but this trial happened to have 20% mastectomy patients. Unlike the 11 that had none. There was a trial that looked at sentinel node biopsy. And when that changes chemotherapy patients in er positive patients over 70 turns out it rarely does. Another study looked at sent on a biopsy in patients who had ankle type and when centeno biopsy changed the chemotherapy recommendations. Beyond that. Anka type only happened only change recommendations for chemotherapy and 5% of cases. But it did change radiation in 15% of cases. The tailored axillary surgery trial or tasked. This was yet another tad like trial. Um And it showed again the tad placental. No biopsy has a low false negative rate confirming the righteous trial we saw earlier actually recurrences low if three or more subtle, no biopsies and dual tracer are used basically. This study said we don't need to do tad we can do it if we've got these criteria and so we don't need to place clips. And then finally a study that showed that clip notes don't change management and clinically end zero or N one patients before neo adjuvant chemotherapy. Overall takeaways for local control. Rice's Tad with an I won 25 seed which is not needed bolstering Tad after neo adjuvant chemotherapy ibis to showed an astra salt equal to tamoxifen for receptor positive D. C. I. S. Side effects may end up really ultimately making the choice. Prime two confirmed a recurrence benefit for radiation but not survival for invasive breast cancer and low risk older patients. And the big 307 studies showed you are bad boost, improves local recurrence by 4% in non low risk DCs, whether it's worth the side effects. However, with no survival benefit requires discussion. So thank you for your attention and I'm happy to take questions when the time is appropriate.
