WEDNESDAY, January 17, 2001

"Making Surgery as Easy, Effective and Informative as Possible"

The advent of anesthesia and antiseptic techniques in the late 1800ís made it possible for physicians to perform surgical techniques. The surgical dogma was to eradicate all possible areas of tumor, as breast cancer over time would have a pattern of spread, locally along the skin. Areas next to the tumor wre removed as well. Fairly radical surgical techniques were developed, the Halstead radical mastectomy. This procedure dictated that the more tissue removed, the better: the muscle of the chest wall, the muscles over the ribs and a lot of axillary lymph nodes. This was considered the price one paid for a cure. It wasnít until the 1970ís that there was even a consideration to reduce the amount of surgery. Bernard Fisher, M.D., a surgeon at the University of Pittsburgh started studying the biology of cancer. He proposed that cancer cells might have a slow growth rate and it might be possible in early stage breast cancer to do much less surgery, just a mastectomy. The National Surgical Adjuvant Breast and Bowel Project (NSABP) was started by Dr. Fisher and his colleagues. Their first project was a randomized study that compared a radical mastectomy to a modified radical mastectomy (no pectoralis muscle taken) which really changed the cosmetic and functional outcome. The concern was that the less radical surgery would not control the cancer as well, and Dr. Fisher was vilified by his colleagues for the effort, because it is much easier to add treatment than to limit it. The study showed no difference in longer term survival. Over the next ten years it did change the standard of care. The next series of NSABP trials, comparing lumpectomy and radiation to mastectomy, met with the same criticism, and even today has not been adopted as the standard of care in many parts of the country. It is estimated that 70% of women diagnosed with early stage breast cancer are probably candidates for breast conserving surgery, but the rates are unequal throughout the U.S., with approximately 30-40% receiving it in the South compared to about 50% on the coasts.

Over time, we have come to realize that the important characteristics of good, adequate surgery which should result in a good prognosis are careful staging, (consisting of a thorough examination, mammogram, MRI), minimal but adequate surgery, (breast conserving if possible), and negative margins of at least 3mm. In about 20-30% of cases negative margins are impossible to achieve because of multifocal sites of tumor, or diffuse calcifications present on mammogram, or because the tumor is of large size. The other aspect of importance in surgery is sampling the axillary lymph nodes. The radical and modified radical mastectomy both included aggressive lymph node dissections. Three general anatomical areas under the arm (Level I, II, and III) are based on the distance from the pectoralis muscle (Level I) up through the auxillary vein (Level III). The higher you go, the more nodes will be removed, with different numbers of nodes present in different people. Generally Level I and II are enough for a good diagnostic sample to determine whether or not the lymph nodes are involved. The best test is for the surgeon to actually feel the nodes and decide whether (s)he needs to go to Level III.

A newer technique, sampling the sentinel lymph nodes arose from earlier work in melanoma. With skin melanomas, it is not possible to know to which nodes the skin is draining, so the surgeons added blue dye to track which nodes were in the path of the tumor. Dr. Armando Guiliano at John Wayne Cancer Center decided this should work for breast cancer. He did many cases in which he looked for the sentinel lymph node but also did a full dissection. He found the sentinel node to be fairly predictive (80 to 90%) for cancer, with accuracy being dependent on the experience of the surgeon. The American College of Surgeons recommends that surgeons do 30 cases of both sentinel lymph nodes and full dissection; if all negative SLN yield negative nodes on the dissection, then they can start to do only SLN without dissection. Sometimes with medial tumors, the drainage can be both to the internal mammary nodes as well as the axillary (sentinel) node, so you could miss a tumor if you only check the axillary nodes. However, removal of the nodes themselves is not a therapy, it is more a marker of risk. People who do not have a lymph node dissection do not necessarily have a compromised survival. What it does do is reduce the risk of a local recurrence in the axilla. Sentinel node has now become the treatment of choice, but it is important to keep in mind that we do not have long term data on patients. Less surgery should mean less lymphedema, but we donít want this at the price of increased axillary and metastatic recurrence. Experts in the field still do not consider this to be the standard of care, even though it is right on the cusp of becoming so. A lot of research is built around the sentinel lymph node. UCSF is participating in a national study that is looking at what happens to the patient when a lymph node dissection is not done even when the sentinel lymph node is positive.

In three large studies for early stage breast cancer, there seem to be the same benefit whether chemotherapy is used before (neoadjuvant therapy) or after surgery. A higher percentage (40 vs 50%) of those receiving neoadjuvant therapy were able to have breast conserving surgery. Other indications for neoadjuvant would include presentation with a large breast mass, or skin involvement or inflammatory changes. It is possible to predict prognosis based on the completeness of the response after surgery, that is, patients who have a good response to surgery tend to do better in the long run. Neoadjuvant is also a laboratory tool which allows us to understand more about what happens to tumor cells when they receive chemotherapy. We know very little about how chemotherapy and hormonal therapy drugs work in principle. The kinds of things which go on in the cell when it is subjected to chemotherapy is very complicated. Being able to study cells real time, before and after treatment, we can get a lot of insight into what is really going on, allowing us to identify markers which may help us predict how someone is going to do. Genetic profiling or signatures will allow us to see if genes that are turned "off" or "on" can correlate with response to therapy and will eventually allow for individualization of care.

Why is surgery used at diagnosis, but not at metastasis? After people become metastatic, the role of treating the primary tumor has been questioned. There is a particular time in the growth of a tumor where you really do have an opportunity to impact on its spread, this is in the early stages. Once you have metastasis, there is already systemic spread. Going in surgically at that point doesnít seem to have the clinical impact on a patientís longevity and survival. We do not know at what precise point in someoneís clinical course surgery is no longer effective. Inflammatory breast cancer represents a real gray zone in this area. Radiation may be effective; if the area is extremely localized.

If a tumor disappears with adjuvant therapy, how do you know where to operate? Surgeons will usually put in a clip at the time of biopsy, sometimes with a radiopaque marker. There is usually some residual tumor and they will go in and get it out.

Are frozen sections usually accurate? About 10% of the time a tumor considered negative on frozen section will turn out to be positive on fuller dissection. Historically, nodes have been cut in two and examined. The sentinel node is evaluated in much more detail, many more and deeper cuts. Because of the more refined dissection, we are now finding positive nodes that would have been considered negative ten years ago finding cancers at very early stages and very small sizes. This has an impact on decisions regarding adjuvant therapy because with a very small risk of recurrence the benefit of therapy will be smaller.

What about "smart" probes? These are fiberoptic needles which use radioactive tracers to locate the sentinel node and sample it without removing the node.

Can surgery actually seed the tumor to other parts of the body? This is a phenomenon that can really happen. Tumors can form along the track of the biospy needle. No one has ever really studied whether micrometastatic cells can be released while manipulating the tumor during surgery. The Tibetans are very much against biopsies and surgeries for this very reason. This is an area where we obviously disagree. In fact, by removing the primary tumor source, you lower the ongoing risk of tumor seeding. The best evidence that surgical removal of the tumor is the best course of action is just to observe the natural history of neglected breast cancers. The prognosis for women who present late, with metastatic conditions is far worse than those who have mammography and have their tumors removed at an early stage.

Hasnít it been shown in animal models that moving the tumor does increase tumor activity? The time it takes a tumor to grow in an animal is so much shorter than in a human that it is hard to extrapolate any findings from animal studies to people. Some general concepts can be demonstrated with animal models, but it is very hard to estimate the net benefit.

Is there any difference in having a needle biospy or a surgical biopsy? If the needle is placed by an experienced technician and read by an experienced cytopathologist, the accuracy is about the same. At centers without this expertise, it is better to get a core or open biopsy. It is also possible for a needle biopsy to be inconclusive, requiring an open biopsy.

What about the long term side effects of post mastectomy? Long term side effects of chemotherapy and surgery that are not related to traditional outcomes like metastatic recurrence and survival are only now beginning to be incorporated into our long term follow-up studies. There is a big void in our knowledge regarding things that are important to breast cancer survivors like quality of life and post mastectomy pain syndrome. A small amount of literature is beginning to emerge regarding issues like menopausal symptoms in women on chemotherapy, and lymphedema rates in women after surgery. CALGB now has a core committee on quality of life issues. Adding these issues to protocols is increasing the cost, but it is worth it to get the information on functionality, pain, cognition, depression, etc. In some cases it is possible to determine if a specific side effect is caused by the surgery or the chemotherapy, but this is not always possible.

What does it mean when the surgeon says he "got it all"? Usually this refers to the technical issue of the surgical margins, there being no obvious tumor seen under the microscope. This is an indication of a better prognosis and a lower incidence of local recurrence. But there is more to it. Even with the entire tumor removed, someone with ten positive nodes is going to have a worse prognosis. Outcomes are still best described by a probability model, which gives a percentage probability for recurrence or death, but patients prefer individual information which is not possible. There is always an element of uncertainty. It is better to think that the patient is cured, but has a chance of recurrence, with certain treatments maximizing the chance of doing well.

What about sentinel node biopsy in DCIS? Ductal carcinoma in situ (DCIS) means that the cancer cells are confined to the duct. The risk of metastasis is very slight. With high grade DCIS, there is always the possibility that there is a focus of invasion that has been missed. In about 1-2% of these cases you might actually find positive nodes if a lymph node dissection is done, but the role of a positive node is in DCIS is unknown. Even with positive nodes a patient should anticipate a good prognosis.

What about PET scans? PET, or Positron Emmision Tomography, is a young field. We donít know how well it performs in detecting metastasis or quantifying the amount of tumor in the breast. It does seem to correlate with disease. More literature is available in lung and colon cancer than in breast cancer. If a CT scan is equivocal, you might consider using a PET.

Is Taxol valuable in early stage breast cancer? Taxol is not curative, but is known to induce a transient remission in metastatic breast cancer. The question is: In early stage breast cancer, might it add value to the chemotherapies that are already in use? Two major studies have compared adriamycin/cytoxan alone with adriamycin/cytoxan followed by four cycles of taxol for patients with positive nodes. One study showed an improvement in outcome with the addition of taxol, about a 5% benefit in patients whose tumors are estrogen receptor negative. A second study done by NSABP is currently not showing a benefit from taxol. The actual amount of benefit that people get from taxol is still under debate. We need more studies in order to narrow the confidence interval, and be accurate.

© © © © Next meeting will be Wednesday, February 14^th . The topic will be "Quality of Life after Breast Cancer". The meeting will take place at the new Cancer Center, 1600 Divisidero, 3^rd Floor Conference Room.