 Kidney Cancer patients fare better with tumor removal only according to an article appearing in Health Day and Yahoo News. Kidney cancer patients who have only the tumor removed, not the entire kidney, have higher survival rates according to a new study. That research involves more than 7,000 Medicare patients with early stage kidney cancer who underwent surgery to remove either the entire organ or only the tumor and a small margin of healthy tissue around it. Early stage kidney cancers are becoming more common and are often discovered by chance when patients receive an X-ray or CT scan for an unrelated condition. According to Dr. David Miller, assistant professor of urology at University of Michigan Medical School, this study does not suggest that every patient with early stage kidney cancer should get a partial nephrectomy. The American Cancer Society estimates that nearly 65,000 people in the U.S. will be diagnosed with kidney cancer this year. Nearly 14,000 will die from the disease. I'd like to thank the Kidney Cancer Association, the organizers and the participants in the meeting for the opportunity to talk today about outcomes for patients with locally advanced disease. Patients with locally advanced disease are patients who are at high risk of developing metastatic disease after nephrectomy. We'll talk about lymph node invasion, tumors that extend into the venous system, tumors that extend beyond the capsule into the perinephric fat, tumors that extend into adjacent organs and also the role of adjuvant systemic therapy. We'll begin with invasion of lymph nodes. Historically we saw this much more often, but nowadays with the advent of cross-sectional imaging CT scanners in most ERs, we're finding patients a lot earlier with smaller lesions. So this is a pretty rare event, maybe three to five percent. We also know the incidence is based on how well you look. If you do a limited lymph node dissection, you find less than if you do a more extensive lymph node dissection. Most patients with nodal disease will also have distant metastatic disease. We know that it's more common in patients with higher stage disease. This study at UCLA looked at 661 patients and patients who had T3 or T4 disease, so tumors that weren't confined to the kidney, there's a 20 percent rate of tumor in the lymph nodes. We also know this is more common with higher ferment grade in patients. This is another study at UCLA, two-thirds of patients who had lymph node negative disease had low grade disease, whereas two-thirds of patients with no positive disease had high grade disease, and this was also confirmed in other studies. So the important thing to realize is that patients with kidney cancer into their lymph nodes are more likely to die from cancer. This is a study out of the Mayo Clinic, a large study, and if you notice that the survival for patients who do not have lymph node invasion is significantly better than for patients who do have lymph node invasion. So we know that when we see this at the time of surgery, it's a bad thing. So within patients who have lymph node metastasis, we know that the histological subtype matters, the number of lymph nodes probably matters, as well as the lymph node density and extra nodal extension. So this is a study out of MD Anderson looking at patients who have papillary renal cell. Papillary subtype has actually a better prognosis if you have disease within your lymph nodes. As you can see here, the patients who had papillary disease had a 65 percent survival at five years compared to the patients who had clear cell, who did not do very well. This is another study at MD Anderson looking at the survival was dependent on the number of positive lymph nodes. They had 40 patients and looked at the survival, and it was much better if you only had one lymph node positive, or if you had more than one lymph node positive, you did worse. The concept of a lymph node density has also been shown to be predictive of how well a patient does after surgery. This is a study out of Italy looking at lymph node density. What the definition is, is the ratio of the number of nodes to the total of nodes involved. And this may be actually a better indicator of the quality of surgery, because in more sense of dissections you're going to get more lymph nodes and have a larger denominator. Total extension is also something people think is important. This is when the tumor extends beyond the lymph node, outside of the lymph node. And this study found that this was also an important variable. So the benefits of a lymph node dissection we think are two-fold. Number one, it provides more accurate staging so we can identify patients who are at risk of disease. And it also may provide a therapeutic benefit in patients who do not have distant metastasis and only have metastasis in their lymph node, and we may be able to cure these patients with surgery alone. However, with any surgical procedure there's always potential complications. We found in a couple large studies that the complications were generally not increased in patients with lymph node dissection at the time and effrectomy compared to an effrectomy alone. Nonetheless, we worry about things like bleeding, bowel injury, kyla societies, which is a large lymph leak after surgery, and ultimately death. Unfortunately, the available studies of patients with kidney cancer and lymph node dissection all have major limitations. All these studies are retrospective, so we're looking backwards with one notable exception. They're mostly with small numbers of patients. There's a selection bias anytime these patients underwent lymph node dissection. These are probably more healthy patients because we're doing a more extensive surgery. There's a lack of standardized template, so people don't agree on what type of surgery we should be doing. There's a lack of standardized pathologic examination. That can really skew the results. And there's also a lack of defined post-surgical treatments. So which lymph nodes need to be removed for kidney cancer? This is a key question. The initial studies were done in the 1930s and they were done on normal kidneys. In normal kidneys, the lymphatics follow the arteries back into the renal sinus and drain into the regional lymph nodes. However, kidney cancer is an abnormal situation. We know that kidney cancers make a lot of blood vessels that can alter the drainage patterns. We also know that the lymphatic drainage in the perinephric fat is not the same as in the kidney itself. So as the tumor spreads, this may actually alter the drainage pattern. So there's many different possibilities for what we will remove at the time of surgery. This shows the hyalur dissection and this just, this is kind of the most limited lymph node dissection we perform where we just take the lymph nodes that are right along the renal vessels. This is a little bit more extensive where we take some of the lymph nodes along the aorta or the inferior vena cava. And then the extended lymph node dissection. This shows the left side of the section where we take all the lymph nodes along the aorta from the diaphragm down to the bifurcation. And on the right side, we take all the lymph nodes that are next to the vena cava and also between the aorta and the vena cava. This is a little bit easier way to look at it. Let's see if my mouse works here. So this is the before and after picture of lymph node dissection. The large artery in the middle, the white structure, is the aorta that carries all the blood from your heart down to your lower extremities. And the vena cava is the blue structure where the white towel is, which carries all the blood back from your lower extremities to your heart. This is an extended lymph node dissection. You can see all the lymph nodes that have been removed from this patient. I'm sorry? They're on this side. You can see that white structure in the middle. It's hard to distinguish them from the fat in there as well. So here you can see the lymph nodes right here and kind of up. And this is the aorta here. And here's the vena cava going back. So we take all the tissue that's in the middle on these sides. So there's several studies which support performing lymph node dissection. This is a study at UCLA which looked at 900 patients who underwent lymph node dissection. And they saw there was a five month increase in median survival if patients had any type of lymph node dissection. There was no benefit for patients who didn't have clinically negative nodes, meaning if we couldn't see them on CT scan beforehand, there was no benefit to doing it. Most patients with positive lymph nodes were identified preoperatively, about 90%. This is a study out of Andy Anderson, which is just impressed looking at patients who had tumor in their lymph nodes, but did not have any evidence of distant metastasis. And this study showed, importantly, that some patients had a durable cure with surgery alone. So 22% of the patients, one of every five patients who had a lymph node dissection alone, were cured with a 44 month follow up. And again, most of these patients were identified preoperatively. So there are some studies that also question the benefit of lymph node dissection. This is a study out of Italy, looking at patients who had lymph node dissection and comparing them to patients who underwent an nephrectomy alone. Interestingly, the numbers are pretty small here, and most of them only have the only one patient who had a positive node on pathology. So these are probably not the patients who we think would benefit to begin with. But they found no survival difference. This is the only randomized trial. This is a trial out of Europe where they randomized patients to nephrectomy or nephrectomy plus lymph node dissection, and they found no difference in cancer-specific survival. Again, they were looking at patients who we probably wouldn't think would benefit from lymph node dissection to begin with, patient with small localized tumors. So in summary, do patients benefit from lymph node dissection? We think yes, and if you have enlarged lymph nodes on your preoperative imaging, or if you have interoperative evidence of lymph node disease, we do not think there's a benefit if there's organ-confined tumors or no clinical evidence of lymph node involvement on your preoperative and intraoperative assessment. And it's a possibility in patients who have advanced tumors and no evidence of lymph node involvement that these patients may get some benefit. Moving on to tumor thrombus. Tumors that invade the venous system. This occurs about 40 to 10% of the time. It can occur just in the kidney or move into the vena cava and all the way up into the heart. Only about 1% of them reach into the heart into the right atrium. Associated symptoms include lower extremity swelling, right-sided varicoseal, and that's a dilation of the veins around the man's testis. Pulmonary embolus, a blood clot in the lungs. Capit medusa, which is a dilation of the veins around your amylochus, your belly button. Protein present in the urine. You can also get advanced cardiac lung symptoms if it's a higher level thrombus. And non-function really is at the end. So there's many different classifications of tumor thrombus. This is from the Mayo Clinic. You can see as the tumor extends out of the kidney here, it can be just in the renal vein or can stand into the vena cava or eventually up and into the heart causing the most severe symptoms. So surgery in these patients is difficult. The first resection was reported in 1919. This was once considered at death science. Modern theories have the mortality of less than 5%. It does increase if the thrombus is above the diaphragm. 40 to 70% of these patients without mastectomy can be cured with surgery alone, and that's an important point. So it's important to do accurate imaging for these patients. We need to know the extent of the thrombus. This can be done with a multi-detector CT scan or MRI. While the patient is in surgery, we also do a transesophageal echocardiogram to make sure that the thrombus does not move during surgery. So what surgery entails for these patients, we'll start with the lower level thrombuses. We get control of the renal artery. We then ligate the lumbar veins. Here you can see in the first tile, this is the thrombus extending into the vena cava. We get control above and below and on the contralateral kidney. We then make an incision in the vena cava and remove the entire thrombus as well as the kidney. And then we repair the vena cava where we took the thrombus out. And then we breathe the sigh of relief and go home and everyone's happy. And when it gets higher, it requires mobilization and deliver, which occasionally requires including the hepatic blood supply. This is why these are more dangerous surgeries. In the level fourth thrombus, this actually may require open heart surgery, requiring a sternotomy and multiple surgical teams involved. It places patients at increased risk for bleeding, stroke, and heart attack. But it's important to realize that surgery can provide a durable cure in these patients without Mestac disease. So even though the surgery can be very complicated and difficult, some patients will survive and greater than 50% of these patients will survive with just surgery alone and not have any recurrence of their disease. There's some controversy because some studies show that the level of the thrombus is important. Other studies show that this just may be a result of low numbers or the failure to evaluate other predictors of bad outcomes. We know that perinephoric fat invasion is a bad predictor. Lymphs node involvement, sarcomatoid features, which are aberrant differentiation in pathology, as well as invasion into the blood vessel wall. And so this is one study, it's a small study which show that the thrombus level impacted survival. Development Mestac disease was seen in 10 to 49 patients with a thrombus below the diaphragm and four of seven patients who had a thrombus higher. This is another study which did not show the same thing, which showed that the level of the thrombus did not affect survival. This was a little bit larger study. And this is probably the largest study, almost 1200 patients from 13 different institutions in Europe. Again, they showed there was no difference based on the level in the IVC, but there was a difference for the patients who just had a thrombus in the renal vein compared to the patients who had a thrombus higher than the renal vein. So there's other factors which may affect survival in patients with venous invasion. This is a study at UCLA looking at 300 patients and they found that metastatic disease, either distant or in the lymph nodes was the strongest predictor survival, as well as the patient's performance status, how well they were able to do their normal activities. Invasion into the lymph nodes, sarcomatoid features, and perinephric fat evasion. We looked at our own experience at MD Anderson and found that in 605 patients over the last 15 years, similar things were predictive. So if you had a clear cell subtype that was actually better than if you had different subtypes, higher grade tumors did worse. Perinephric fat evasion was important, sarcomatoid de-differentiation, lymphdomatastasis and distant metastasis were all predictive. One other interesting thing we found was that microscopic tumor, which was present at the margin of resection in the vein, was also predictive of increased local recurrence and metastatic progression. So we think that it's important to resect the veins widely when at all possible. And this shows the top line here is patients who had negative margins on their vein. This is freedom from, these are patients who don't recur locally, and it's higher in patients who do have a positive vein margin. The same thing was true when we look at patients who progress to metastatic disease. If you have a negative vein margin, you do better than if you have a positive vein margin. So in summary, patients who have venous involvement are at a high risk to develop metastatic disease. Significant proportion of patients without metastatic disease when they first present can be cured by surgery alone, which is encouraging. Surgery requires careful planning and should involve experienced surgeons. And in general, the prognosis has not changed by the level of the thrombus, except in patients who have a renal vein thrombus only. So when the tumor starts to extend outside of the kidney into the perinephric fat, it also indicates a bad prognosis for the patient. This is a study looking at patients who had a tumor thrombus and about half the patients had thrombus alone and about the other half had thrombus in association with fat invasion. After surgery, the patients who only had a thrombus with no fat invasion had a significantly improved survival of 70 months compared to patients who had thrombus and fat invasion who only survived about 25 months. So what that tells us is that fat invasion is a very bad prognostic factor. Again, this is a European study looking at almost 2,000 patients. They know that it's difficult to identify preoperatively. CT scans and MRIs don't pick this up. This is something that we pick up only pathologically. It's an important risk factor across all stages of disease and it affects survival in patients. It's something we have to consider after nephrectomy. So in summary, patients with fat invasion are at a higher risk to have disease recurrence and radiographic staging is inadequate to distinguish between patients with or without perinephric fat invasion. So when the tumors get out of the kidney and invade adjacent organs, you might also suspect this is a bad prognostic sign. This is a patient who has a kidney tumor, which is invading into the liver here. This is also something that's relatively rare. These T4 tumors, because kidney tumors are more likely to compress the other organs rather than invade into it. And these patients have a very poor prognosis with five years of rivals between five and 20%. Complete surgical excision is very important in these patients, including the involved organs if you're gonna give any chance of cure. So your organs and structures at risk, the adrenal gland, which sits on top of the kidney is one organ which is frequently involved. The posterior abdominal wall, the paraspinus muscles, which go along your vertebral column, the diaphragm, the spleen, the duodenum, the pancreas, and the colon, including the blood supply, which goes through the mesentery. This study looked at 38 patients with advanced disease. They found that the liver was the most common location for invasion. And their median survival was less than a year after resection. The only significant factor in these patients, which predicted death was a positive surgical margin. So this tells us that it's very important to take out the entire tumor as well as any adjacent organs in these patients. So can we predict this invasion preoperatively? This is a study out of MD Anderson, Dr. Margulis on Dr. Wood, looking at 30 patients with clinical T4 disease. They found that they were wrong more than they were right. As far as 60% of the time, it was downstage on final pathology. And their conclusion was that you cannot adequately predict a T4 tumor by preoperative and interoperative imaging. So when we compare adrenal invasion, which is a common area, a common plan that it invades to, compared to the perinephric invasion, this is a retrospective study of 1,000 patients. Almost 200 had perinephric fat invasion and about 2.5% had direct adrenal invasion. We found that survival was much worse with adrenal invasion compared to perinephric fat invasion. So perinephric fat invasion is bad and adrenal invasion is worse. So a summary on the adjacent organ invasion, kidney cancer compresses much more often than invades. So many times we think something in, while we're in clinic is invasive and we're wrong. There's a poor prognosis with invasion of adjacent organs. The majority of patients with T4 disease also have metastatic disease. Surgical resection, complete surgical resection is the only chance for a cure in these patients. And there's a lot of studies lacking in T4 disease, mostly because this is rare and it's hard to identify preoperatively. And adrenal invasion is worse than perinephric fat involvement. So the next portion of this talk is on adjuvant therapy, systemic therapy an hour later. With the recent success of targeted agents and the dramatic responses and increases in patient survival, people are asking, is there a benefit to start patients who are high risk on these therapies right after nephrectomy? The definition of adjuvant therapy to be distinguished from neo-adjuvant therapy which Dr. Wood will be talking about later, is taking some form of therapy after complete surgical resection to decrease the risk of recurrence. And again, we think this is most indicated in high risk patients. We've seen earlier that high risk patients are these patients, patients with venous invasion, lymph node involvement, large tumors, invasion into the adjacent organs or perinephric fat involvement. So many different therapies have been tried. His recently local therapy, hormonal therapy, immunotherapy during the cytokine era, certain tumor vaccines and thalidomide have also all been tried and the short answer is none of these have worked. So there's no survival benefit to any of these therapies that have been seen. That really the big question is with targeted therapy, is there gonna be some benefit? And for the large part, the jury is still out. There have been many different studies ongoing and not much has been reported as of yet. So this is one trial called the Eryzer trial looking at monoclonal antibody G250. We're still waiting the results of this trial. One interesting thing that did come out of this trial is a PET scan which is specific for kidney cancer. This is very promising. This was reported last year's AUA. You can see this detects kidney cancer. A lot of times when things are very small, we have a difficult time detecting them on a conventional CT scan. This is not yet FDA approved. This is another trial, the Assure trial which finished accrual last fall. We're waiting on the results of this. This randomized patients to either synitinib enseraphanib or a combination with the placebo. One issue that we did see in these patients were that a lot of patients left treatment not because they were finished treatment and not because they progressed but because they were having difficulty with toxicity. So we have identified the fact that patients who take these targeted agents and don't have any metastatic disease have a significant adverse effect profile. This is another study which is expected to primary result in June 2017. This is the S-Track trial looking at patients with synitinib or a placebo. This trial is the Source trial. Again, the primary result is expected in 2012. Randomizing patients to either three years of serraphanib, one year serraphanib or placebo. This is the new GSK trial looking at posopenib in the adjuvant setting. And this is the newest trial looking at everolimus for renal cell cancer. Randomizing patients to either placebo or everolimus after nephrectomy. So in summary, adjuvant therapy we're currently waiting on the results of several trials which have been with agents which are shown promised in the metastatic setting. The toxicity for treatment is a major issue with a lot of patients stopping adjuvant treatment with targeted agents. Thank you. On April 16th this year, the National Cancer Institute is releasing the latest cancer statistics. Our statistics that we're currently releasing are from 1973 all the way to 2009. We are just now releasing data from 2009 and this reflects the complicated process that we go through to collect the data and ensure the quality of the information that we collect. So the 2009 information on overall mortality shows a continuation of the decline in mortality rates that we've seen since the late 1990s. The top four cancers that we see are prostate cancer, breast cancer, colorectal cancer and lung cancer. And together these four sites make up over 50% of the cancers that we find in our data set. All the mortality rates for all of those cancers in men and women for colorectal cancer and lung cancer are all decreasing and that's a continued decrease from what we've seen in the last few years. For incidents, for lung cancer, for both men and women it's decreasing. Prostate cancer is decreasing. Colorectal cancer is decreasing and breast cancer is relatively stable. Two cancer sites where we've seen persisting differences between white women and black women are cervical cancer and breast cancer. Cervical cancer, the rates are declining for both incidence and mortality in both groups. However, blacks remain at higher risk than whites for incidence and mortality. For breast cancer it's a complex picture where whites have higher level of incidence, risk of developing breast cancer, but blacks have higher mortality rates and the difference in mortality between white and black women has been increasing over time rather than decreasing. Lung cancer incidence is declining this year in both men and women and mortality is declining in men and women as well. However, the trends are very different for men than they are for women. Men have much higher rates but had a decline that started earlier and has continued. Women have had lower rates but they've been fairly level lately and have only shown a decline in the last few years. But with the 2009 data point we do see a statistically significant decline in incidence and mortality for women as well as men. These trends reflect patterns of smoking in the U.S. where men had higher rates of smoking than women and perhaps stopped smoking earlier. It typically takes a long time between the smoking behavior and changes in that behavior and when we see the impact on cancer incidence and mortality. The data that we base our statistics on are from the SEAR registry program. And SEAR stands for Surveillance Epidemiology and End Results. When we started SEAR back in 1975 we had nine registries but as time has gone on we've added more registries to get a better representation of the population as far as having adequate covers of different race groups, urban areas versus rural areas and now in 2009 we have 18 registries and 28% of the population. SEAR is also part of a larger national program of cancer registries that also includes the registries that are managed by CDC. Together they cover the vast majority of the United States and each state in the US has a cancer registry. SEAR registries are really a fundamental component of the data system for cancer research and monitoring and surveillance. They're really widely used by researchers, public policy and of course the public to understand their prognosis after diagnosis. It is also a basis of many different annual reports that come out. They really describe the cancer burden in the United States. It's part of the annual report to the nation which describes incidents and mortality for the whole US and it also plays an important role in reports such as the American Cancer Society's facts and figures where they estimate the number of cases that they expect to be diagnosed in the current year and the number of cases they expect to die in the current year for different cancer sites. Join us again next month for another edition of Kidney Cancer News. I'm Keri Konoski wishing you good health. Join us again next month for another edition of Kidney Cancer News produced by the Kidney Cancer Association. Find us on the web at kidneycancer.org. This is Dick Lashbroke speaking.