Click here to view next page of this article

 

New Treatments for Bladder Cancer

Renal cell carcinoma constitutes about 3% of all malignancies, so it’s not a common tumor. There’s about 25,000 cases annually in the United States that that results in about 10,000 deaths. There’s a male to female predominance of 2:1 and there’s a similar incidence in both black and white populations.

Now the von Hippel-Lindau syndrome is not a major health problem in the United States but it was useful in defining the genetic abnormalities that occur in both an inherited form of renal cell carcinoma as well as an acquired form. In general, those abnormalities occur on chromosome 3. This just summarizes some of the features of the von Hippel-Lindau syndrome. A multi-focal, bilateral clear cell carcinoma of the kidney occurs in about 35% of the patients.

These are the subtypes of renal cell carcinoma. The majority of the renal cell carcinomas are what we call clear cell carcinomas. About 70% of patients. The papillary version, which is also referred to as a chromophilic tumor, occurs in about 20% of the patients.

Presentations; typically about half the patients will present with stage I or II disease. I think we are seeing more and more patients presenting with an incidental finding of renal cell carcinoma, because they are having CAT scans of the abdomen obtained for various reasons, and we are seeing patients in whom renal cell carcinomas are picked up incidentally on those scans. About one-quarter of the patients present with stage III disease.

Now I mentioned briefly the sarcomatoid variant of renal cell carcinoma. Again, this is a variant of the clear cell type. Renal cell carcinoma itself is rare and of the renal cell carcinomas, only 5% or so represent sarcomatoid histology. So this is a rare tumor but I think it’s important to be aware of it. The cells have a sarcomatoid appearance and the way you can distinguish this tumor from a sarcoma of the kidney is that the sarcoma of the kidney will not have any clear cell features associated with it. It will be a pure sarcoma.

There is a relationship between the proportion of the tumor that exhibits the sarcomatoid pattern. These two lines represent patients whose tumor was either 50% sarcomatoid and 50% regular renal cell carcinoma or greater, and then one of these lines is 75%. So when you have more than 50% of the tumor as a sarcomatoid histology.

Now when patients develop metastatic disease, there’s a number of papers that have been written about how to assess their prognosis. And to be honest, these papers I think have been used primarily when pharmaceutical companies are trying to come up with a historical control group to compare for their studies, but they are useful to recognize. There’s really no surprises here. These are the major risk factors for poor prognosis and ECOG performance status.

Now the role of surgery in renal cell carcinoma is a little controversial. I think probably more controversial with me than perhaps with other speakers you may have up here. But certainly in stage I and II radical nephrectomy is the only effective therapy. Regional lymphadenectomy provides no clear survival benefit, although clearly there would be prognostic information gained if the regional lymph nodes were sampled. Especially if more than one lymph node was involved, I think given the natural history of this disease those patients would be stage IV NED.

For stage IV, the party line is that you do a palliative nephrectomy only for symptoms. I think this is still considered probably to be the standard answer to this question. So if patients are having hematuria or pain, a nephrectomy would be indicated for that. There is some experience in patients who have had resection of solitary, especially pulmonary, metastases that occur a long time after having their initial diagnosis.

Now as far as treatment of metastatic disease; I think you are all aware that chemotherapy has little activity, as reported in the literature, in this disease. This is some data that Phil Keebler reviewed a number of years ago and reports the dismal activity of a number of different agents in renal cell carcinoma. There was some activity reported in a small series of patients with FUDR, patients who had been treated with nitrosoureas and vinblastine have response rates of less than 10%. Although these regimens were used a lot when I was in my training.

The other drug that has been tried in renal cell carcinoma is alpha interferon and a large number of investigators have looked at a large number of interferon preparations. Generally, in the regimens that you can give as an outpatient and are tolerated by the patients, I think a response rate of about 10-15% is a reasonable number to carry around in your head.

The other thing I need to touch upon is the frequency of spontaneous remissions. There’s been a lot of talk about this in the literature and when Bloom reviewed 1,100 patients back in 1973 - his own group of 195 patients and then six other studies - and reported on the times that spontaneous regressions were reported in these studies. He found two in his own series where he was specifically looking for it and then one in the other series.

Now it was in this context that interleukin-2 came on the scene and as you know, interleukin-2 is a T-cell growth factor. The clinical material is a 15.5 kilodalton peptide and obviously in vivo it’s produced by the helper T-cells. In May of 1992 the FDA approved interleukin-2 for the treatment of metastatic renal cell carcinoma.

This is the response duration curve and the median duration of response for the CR’s has not yet been met. There were only seven patients, but only three of them have relapsed. For the partial responses; there are a number of patients with partial responses who had very good partial responses, greater that 95% tumor shrinkage.

Now some of the most interesting and promising preclinical data in history have revolved around this very fantastic synergy between interleukin-2 and interferon in mice. This resulted in a lot of interest in looking at this combination in the clinic.

Since two drugs weren’t better than one, then why not try three drugs and see if that’s not better than one? Zapodian and Sella have both reported on a regimen using interleukin-2, interferon and 5-FU. This is a much more intense regimen, has to be given as an inpatient.

This is a report by a group looking at predictive factors for response to biological response modifiers and this group III here are patients with sarcomatoid histology regardless of their performance status, presence of bone metastases or whatever. In that group they had very poor response to biological based therapies. This is a summary, again from the M.D. Anderson paper, and those two patients who I mentioned earlier were then treated with a doxorubicin-containing chemotherapy and both of them actually received CY-VA-DACT.

I just want to say one word about some patients who have very poorly differentiated tumors at the time of diagnosis and have a clinically demonstrable, very rapidly progressing disease. Those patients I tend not to try to treat with immunotherapy.