SLIDES & TRANSCRIPTS
Friday, December 5, 2003

Open RPLND is the Gold Standard for Low Stage NSGCT

Joel Sheinfeld, M.D.

I would like to begin. In 1995, Dave Swanson wrote a very good editorial entitled low-stage testis cancer is still potentially lethal.

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And he wrote this editorial in response to a report from Indiana University on patients with clinical stage 1 suffering late relapse who in three-quarters of these patients could not be salvaged.

Interestingly 31 of these patients had had a prior RPLND. Two-thirds relapsed in the retroperitoneum despite the fact that three-quarters had received platinum-based therapy and the message here was in a subset of patients effective chemotherapy will not compensate for suboptimal surgery.

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Unfortunately, late relapse has emerged as a very significant problem in testis cancer, and the retroperitoneum is the most common site for this problem. This appears to be a phenomenon really of the modern age from 1978 forward, about three-quarters of these patients. About one-third of them start off with low stage disease. These are very difficult patients to salvage. They are chemorefractory. Prior exposure to chemotherapy negatively impacts their outcome and an uncontrolled retroperitoneum is a predisposing factor.

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The retroperitoneum in germ cell cancer is the first and often the only site of metastatic disease, and clearly control of these nodes remains critical. Yet in low-stage germ cell tumor [the retroperitoneum] remains very, very difficult to assess.

We have improved significantly detecting and predicting distant spread but have not made significant progress in evaluating the retroperitoneum.

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One-third of clinical stage 1 patients are under staged. One-third of [stage] 2As have negative nodes, and these are [from] multiple large series.

On the other hand systemic staging has improved significantly.

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It does not appear that there is really a clear consensus on what represents stage 1. You can see here a gray zone in terms of transverse diameter and even when you add other variables including location and pathology of the primary and so forth, predictive models fall short about 20 to 30 percent of the time. So, there is no clear consensus on what [stage] 1 and 2A are

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and, in fact, three expert radiologists could not agree on what constituted a positive node at a given size.

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If one looks at the CAT scan era from 1979 forward 25 years and multiple generations of CAT scanners, you see that 30 percent of clinical stage 1 are pathologic [stage] 2 and that is not really very different than the pre-CAT scan era. This is a sobering statistic.

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On the other hand, systemic staging has improved dramatically. We are picking up unsuspected pulmonary nodules with CAT scans of the chest

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and most importantly I think we have learned to integrate serum tumor markers in decision making and patient selection criteria.

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And, in fact, if you look at our patient selection criteria over the years in multiple time, 1989 to 1993, 1994 to 1998, and 1999 forward, you can see that right about here [referring to slide] we stopped operating on patients with elevated markers, and you can also see a shift [from stage] 2B patients to [stage] one patients. So, [there has been] a significant change in our selection criteria for primary node dissections.

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On the other hand, the selection criteria - the pathology, in terms of the orchiectomy specimen, if anything, has become more adverse in terms of lymphovascular invasion. You see a significant increase. So, the pathology has gotten worse, but we have eliminated patients with elevated markers.

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What has this translated into? What you see is that the proportion of pathologic stage 1 versus pathologic [stage] 2 has remained constant over the years. However, the nature, the proportion, of [stage] N1s and N2s has changed significantly. The amount of [stage] N zeros remains fairly constant, not significant, but you see a significant increase in [stage] N1 at the expense of a decrease in N2s, particularly after we stopped doing [surgery on patients with] positive markers. But even if you exclude patients with elevated markers, these trends are true, and if you exclude patients with [positive] markers and clinical stage 2B you see the same trend.

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If you look at criteria predictive for relapse, and this excludes all patients that receive adjuvant chemotherapy, overwhelmingly patients with positive markers relapse. Clearly pathologic stage 2 will relapse more than stage 1 but, interestingly, embryonal predominance and lymphovascular invasion do not predict for systemic relapse. Positive markers do,

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and so what you see starting in 1999 forward [is] this has become more of a loco-regional problem. You see that systemic relapses in patients without adjuvant therapy, these[receiving adjuvant therapy] are excluded, are very uncommon occurrences, relapses.

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This is true in pathologic stage 1, one relapse

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and N1, minimal volume disease, again, few relapses. So, not only is the proportion of PN1s (pathologic stage N1) increasing but they are better. They are relapsing less.

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What about the histology over years? That has remained fairly constant. The predominant histology is embryonal carcinoma but very importantly 20 percent of these patients have teratoma in the retroperitoneum and that has not changed.

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It is chemorefractory, obviously. Therefore all these 20 to 30 percent of patients that have teratoma will be untreated with any amount of chemotherapy.

Its biologic potential is unpredictable and the clinical outcome of patients with teratoma is related to one thing and one thing only and that is complete resection.

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If you look at patients with pathologic stage 2, you see that in almost 1000 patients from [the University of] Indiana and Memorial [Sloan-Kettering Cancer Center], 20 to 30 percent will have teratoma. These patients, again, to reiterate, will not be treated by any amount of chemotherapy.

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Furthermore, if you look at patients with teratoma in the retroperitoneum 30 to 40 percent will have disease outside the primary landing zone and outside most modified templates.

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Malignant transformation, the worst variant of teratoma, is seen about 1 percent of the time in primary node dissections in patients that have positive nodes. You see a 10-to-20-fold increase of malignant transformation at the time of late relapse.

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So, coming back to late relapse, and this is our own data of patients referred after a primary node dissection, there are several common themes. One is an over representation of teratoma.

[The]second [theme] is [that] the bulk of these [teratoma] occur in the retroperitoneum in the landing zone and effective chemotherapy doesn't compensate for incomplete resections - modified templates.

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Now, modified templates arose from several mapping studies in the seventies and eighties, and the driving force was to minimize morbidity and preserve ejaculation. And you can see that there are a variety of templates both for the right side and left side. And you can see that very restricted templates would leave a fair amount of disease, even in low volume, and particularly on the right side where there is more crossover to the left.

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Just a couple of comments about mapping studies: mapping studies are certainly very, very useful, but they are best case scenarios. There is no follow up and there is a huge leap of faith that everything that should have been resected was resected.

There is no follow up on two of the three classic studies, minimal follow up on the Vicbac(?) study, and 3 of 160 that had at least 6 months of follow up had in-field recurrences.

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Modified templates, though, I think have become much less relevant in the era of nerve-sparing surgery because once you isolate the nerves, preserve them and protect them templates really become irrelevant.

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Furthermore, you can see that over time complications have decreased significantly, both major, minor, and overall. And ejaculation is preserved greater than 95 percent of the time.

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In an effort to further reduce morbidity of this surgery laparoscopy has emerged, and Dr. Kavoussi, of course, will address this in more detail. But the real issue, and Dr. Lange brought it up, is what is the therapeutic efficacy and, more importantly, what is the therapeutic intent of many of the series.

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The reason that is a concern is because if you look in the literature the overwhelming majority of these patients, when they are found to have positive nodes, regardless of tumor volume, receive adjuvant chemotherapy. So, there are a total of three patients over the 12 years that have been untreated, although several centers have begun to study this prospectively. And you can see that 95 percent of this overall group of positive nodes all received adjuvant chemotherapy. So, it is difficult to distill the therapeutic effect from the surgery from that of the chemotherapy.

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On the other hand, the therapeutic efficacy of primary node dissection is clearly established. You see that 80 to 90 percent of patients with low volume disease are cured, and this is before the [application] of more stringent selection criteria where you see that systemic relapses have dropped dramatically. And half of the patients with high volume disease are cured as well.

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So, primary node dissection provides the most accurate categorization of the nodes. It is curative in the majority of patients with low volume disease, more so today. [In] half of those with high-volume disease, there is no mortality and minimal morbidity. Ejaculation rates are in excess of 95 percent. Surgical margins should not be compromised in an attempt to preserve ejaculation.

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If you encounter positive nodes, a bilateral dissection really remains the gold standard.

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Node dissections should always be done with therapeutic intent. And here are a number of statements made in both the open and laparoscopic literature. We have seen clearly late relapse and re-operative data clearly show that [in] a subset of patients who are undertreated surgically their outcome, their survival, is jeopardized.

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Minimizing morbidity is important but this is the bottom line. These patients with low stage, non-seminomatous germ cell tumor, virtually, should all live with very rare exception. The bar is set very, very high in this disease of young men who have a life expectancy of 40, 50, 60 years. And this is what we need to aspire to, because a less than thorough and meticulous approach

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brings us back to Dave Swanson's warning that low-stage disease is still potentially lethal.

Thank you very much.

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