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Edited comments by Dr Wood
Validation of sentinel lymph node biopsy
Data continue to be presented at our scientific meetings validating the efficacy of sentinel lymph node biopsy (SLNB). Individual institutional series demonstrate better technical ability of the surgeons performing SLNB. The change from peritumoral to subareolar injection of blue dye has made it virtually impossible not to identify a sentinel node. For those who perform numerous biopsies, there's probably no need to use anything other than blue dye. For those who do it less frequently, there's a great advantage to using a "double-dye technique" with technetium sulfur colloid. With two labels, it's even easier to identify the sentinel lymph node.
Phase III trials evaluating SLNB
NSABP-B-32 is evaluating whether the abandonment of axillary node dissection in patients with negative nodes is detrimental. NSABP-B-04 was a very small study done years ago, which failed to demonstrate the virtue of axillary dissection. Despite the inadequate power of B-04, it is difficult to understand why the NSABP would address this issue in preselected lymph node-negative patients.
We participate, to a limited extent, in the American College of Surgeons' (ACOS) trial, which asks very different questions than B-32. The ACOS study aims to determine whether there is any advantage to removing nonpalpable involved lymph nodes. Clearly, radiation to the breast radiates the lower part of the axilla. Sentinel lymph node biopsy removes almost one-half of involved lymph nodes - so, even in the node-positive patients, only about one-half will have any other lymph nodes involved - and radiation probably sterilizes most of those. What do we gain by the additional dissection? This is a very important clinical question. I applaud the ACOS in undertaking this trial.
I am comfortable presenting the ACOS trial to a patient, but frankly, if pressed, I don't have personal therapeutic equipoise about it. I would prefer to see a woman with a positive sentinel node have an axillary dissection. It gets a little tougher when the patient asks you that old question, "How would you want your sister treated?" I explain that, although I would choose axillary dissection, I have colleagues who would not, and I think either choice is legitimate. The only way to find out for our daughters' generation is to do the clinical trial.
Ironically, I would not be comfortable entering a patient or someone in my family in the NSABP trial. The data are entirely clear that patients with negative sentinel lymph nodes - if more than one node is examined - are so unlikely to have unidentified positive nodes that I don't believe the morbidity of axillary dissection, even in very good hands, is justified.
Contraindications to SLNB
I see three contraindications for SLNB. For DCIS, if one is not doing mastectomy, I see no role for SLNB. Another contraindication would be in cases of invasive cancer with palpable nodes prior to a core biopsy, because the lymphatics may be blocked and dye can go off to uninvolved secondary nodes, making the sentinel node appear negative.
The third area in which we do not know how to perform the procedure is in the rare cases in which the tumor truly begins in the axilla. Radioisotope shines through, and blue dye runs in all directions. Even if you place the dye in the subareolar location, I'm not sure it goes to the same node that a metastasis from an axillary tail in the mid-axilla would go.
It is clear that SLNB can be done after induction chemotherapy, but it is not clear whether it is as effective. Studies purporting to demonstrate its effectiveness have a false-negative rate of eight percent to 12 percent. In a good series, the false-negative rate should be one percent to three percent. This suggests to me that SLNB is less effective after induction chemotherapy. Numerous studies will sort that out, but at present, we're doing SLNB prior to induction chemotherapy.
Intraoperative radiation therapy
Intraoperative radiation therapy (IORT) can be administered in a variety of ways. Dr Veronesi performs IORT with a linear accelerator, pulling the breast together inside the wound with a couple of stitches and then radiating it. The dosimetry with this technique is very difficult because radiation is given right at the moment, and you can only try to reconstruct it after the fact. Other modes of administration include the intracavitary balloon radiation device or intraoperative radiation with catheters.
Intraoperative radiation therapy will likely help prevent local recurrence of DCIS or very small breast cancers within the first year to two years. However, over the next eight years, more than 50 percent of the recurrences are likely to occur at a considerable distance from the lumpectomy site. So, the early results from IORT trials will likely be wonderfully positive, and a negative result won't emerge for five years to 10 years. By that time, the whole world will have begun using these intracavitary forms of radiation therapy. It is disconcerting that "the horse will be out of the barn" before we have real data to demonstrate the safety of these procedures.
Nonprotocol role of ductal lavage for patients at high risk
Ductal lavage offers an interesting way of gathering material for research, but we do not have a clear clinical indication for this procedure. In performing ductal lavage as part of a study at Northwestern, Dr Seema Khan found that numerous breast cancers were lavage negative, while in many lavages with atypical cells, no abnormality could be found. Cells present within ducts may appear abnormal over time, and ductal smears often appear atypical with no associated clear abnormality. I definitely do not see a role for ductal lavage in a nonprotocol situation.
The advocates of ductal lavage have backed away from the idea that it is a diagnostic test and now suggest that its real role is in risk assessment. But, if the ductal lavage reveals no abnormality, are you going to tell a woman at high risk that she shouldn't consider an intervention with tamoxifen or entry into the STAR trial? I see no clinical basis for the use of ductal lavage.
Integration of adjuvant endocrine therapy into surgical practice
Surgeons have enough to do without trying to take on the superb work done by our medical oncology colleagues with cytotoxic agents. However, the use of hormonal agents is so easily integrated into our ordinary care of patients, that I believe it will continue to be a part of the surgical oncologist's role today. In terms of surgeons' comfort in prescribing aromatase inhibitors, I have not seen a difference in women utilizing tamoxifen compared to an aromatase inhibitor. Women on both agents do well with few side effects.
The ATAC trial is a very exciting study. Dr Mike Baum is once again leading the pack with another class of agents in a massive trial. Should we now use anastrozole instead of tamoxifen for all our postmenopausal patients? That's a difficult question. The older the woman, the more satisfied I am using anastrozole. I still have concerns about the younger postmenopausal woman. There's no question that we can prevent the bone fractures that can occur in women on anastrozole with bisphosphonates. Surgeons need to be alert regarding this issue.
In the adjuvant setting, I'm not enthusiastic about using aromatase inhibitors other than anastrozole outside of a clinical trial. We really need Phase III data for the other aromatase inhibitors with sufficient follow-up.
Anthracyclines, taxanes and dose-dense adjuvant chemotherapy
The last three years have brought about some very clear answers to three big questions. The first is: Do anthracyclines really make a big difference? And yet another study shows that anthracyclines really are dramatically better than CMF-based therapy, not just a little bit. The second question is: Does the addition of taxanes add to the benefit seen with the anthracycline-based combinations? We now have two studies - the NSABP and breast Intergroup studies - each with over 3,000 women, clearly demonstrating that taxanes add benefit. The third answered question revolves around the benefit seen with the dose-dense approach to chemotherapy, which was recently demonstrated by CALGB-9741.
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