SLIDES & TRANSCRIPTS
Friday, December 13, 2002

Lymph Node Density as a Prognostic Marker

John Stein, M.D.

We have previously reported our experience in over 1,000 patients undergoing radical cystectomy. Now, despite an early and aggressive approach for bladder cancer,

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24 percent of our patients have lymph node-positive disease at the time cystectomy. These patients are clearly at high risk for tumor recurrence, specifically when we compare them to other pathologic subgroups.

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Now, risk factors for patients with known positive disease, as we reported, includes the p-stage of the primary bladder tumor,

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as well as the tumor burden, or the number of lymph node involved with tumor.

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There is a growing body of evidence that also suggests that the extent of lymphadenectomy is critical patients undergoing radical cystectomy. There are three reports in the literature, and Harry elegantly gave us a fourth report this morning looking at this.

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The Memorial group did show that of patients undergoing a radical cystectomy that had no lymph node disease, if you removed eight lymph nodes or more, you had a significantly higher proportion of survival, compared to those patients what had less than eight lymph nodes removed.

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Similarly, Poulsen and Ken Stevens in Copenhagen compared their extended lymph node resection in patients with organ-confined bladder cancer to a more limited lymph node resection.

As you can see here, those patients that have an extended lymph node dissection did significantly better. In the extended lymph node dissection group they had an average of 25 lymph nodes removed, compared to only 14 lymph nodes removed in the limited pelvic lymphadenectomy.

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Lastly, Leissner et al. also looked at their patients undergoing radical cystectomy without evidence of lymph node metastasis, and found that if you removed greater than 15 lymph nodes, you have a significantly higher recurrence-free survival.

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Now, I would like to present the concept of lymph node density. Lymph node density, by definition, is the number of lymph nodes involved with tumor, divided by the number of lymph nodes removed. Therefore, lymph node density incorporates two prognostic factors simultaneously. That is, the lymph node tumor burden or the number of involved lymph nodes, divided by the extent of lymph node dissection, or the number of lymph nodes removed.

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So we evaluated our clinical outcomes and risk factors for patients with lymph node metastasis following radical cystectomy. And we also evaluated this concept of lymph node density.

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From July 1971 through December 1997, of the 1,054 patients, again, 244 or 24 percent had known positive disease, and this is the focus of the analysis. The median age was 66 years. We had good follow-up of over 10 years in this group.

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Now, the lymph node dissection has been standard in our group, and this extends approximately 2 centimeters above the aortic bifurcation. It extends laterally to the genitofemoral nerve, distally to the lymph node of Cloquet, or the circumflex iliac vein laterally, and it should include all the obturator, as well as the presacral, and the presciatic lymph nodes.

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Now, adjuvant therapies are clearly an important component to the comprehensive treatment of bladder cancer, and have clearly evolved as well over the past 25 years. In our patients, over 50 percent with node positive disease did receive chemotherapy, primarily in an adjuvant fashion.

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When you look at the number of lymph nodes removed in this node-positive group, the median number of lymph nodes removed is 30. The median number of lymph nodes involved with tumor is two. You can also see that 86 percent of our patients had more than 15 lymph nodes removed.

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We had two peri-operative deaths and 66 early complications. This does not significantly differ from most patients with organ-confined or extravesicle lymph node-negative disease. We had no direct complications related to the topical lymphadenectomy, however, when you look in the literature, the incidence of lymphoceles and lymphedema may range in 1-3 percent.

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We analyzed the presence of carcinoma in situ for the primary pathologic subgroups, the number of lymph nodes removed, the number of lymph nodes involved, as well as lymph node density --

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and again, by definition is the number of positive lymph nodes divided by the number of lymph nodes removed.

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When you look at the overall recurrence-free survival for those patients, you can see that for the first three years the recurrence-free in overall survival curves are basically super imposable. This suggests that the vast majority of deaths during this first three years are related to bladder cancer. Following this, the recurrence curves level off, and you can see most patients die of associated co-morbidity.

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When you look at the total number of lymph nodes removed, if you had greater than 15 lymph nodes removed, you had a slightly improved recurrence-free survival compared to those with less than 15 lymph nodes removed, but this was statistically significant.

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When you have an organ-confined lymph node-positive patient, they have a higher recurrence-free survival compared to those with extravesicle and lymph node-positive disease.

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Tumor burden was also significant. If you had less than or equal to eight lymph nodes that were involved with tumor, you had a significantly improved recurrence-free survival compared to those with greater tumor burden, and this is significant.

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Lymph node density -- if you have a lymph node density of less than or equal to 20 percent, you have a significant improved recurrence-free survival compared to those with a lymph node density greater than 20 percent.

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Now, notwithstanding the limitations of an adjuvant or a prospective trial, and clearly biases, we did look at adjuvant chemotherapy in our group of patients. Those patients that did receive chemotherapy had a significantly improved recurrence-free survival.

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In a univariant analysis, we are looking at the various prognostic factors. Age, gender, urinary diversion, and the number of lymph nodes removed were not statistically significant.

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However, those patients that received adjuvant chemotherapy, the pathologic subgroup, the lymph node density, and the lymph nodes removed were all significant in a univariate analysis.

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When you look at a multivariable analysis of these same factors, the same factors including pathologic subgroup, adjuvant chemotherapy, lymph node density, and lymph nodes involved are all independent prognostic variables.

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A lymphadenectomy is a critical component to the treatment of patients with bladder cancer. It does allow for a safe anatomical dissection. It does provide pathologic staging. And it may have some therapeutic benefits. But right now, we clearly do not know the absolute limits of the dissection.

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In our group, the independent prognostic variables remain pathologic subgroup, the administration of chemotherapy, the number of lymph nodes involved, as well as lymph node density.

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I believe a lymph node dissection is important in the treatment of patients with bladder cancer. We do report long-term survival in about a third of our patients with lymph node-positive disease. We're starting to develop some idea of the prognostic variables in this high-risk group of patients.

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I think lymph node density is an important prognostic variable as it simultaneously relates to the lymph node tumor burden, as well as the number of lymph nodes removed.

I think future clinical trials, staging systems, and also other disease systems such as testes cancer, possibly renal cell carcinoma, and even prostate cancer may consider applying some of these prognostic variables.

Thank you very much.

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