Metastatic kidney cancer has a high mortality rate, few good treatment options, and an escalating incidence in the United States. That's the bad news. None of the news is terrific, but there is news that is cautiously optimistic and improving.
Walter M. Stadler, MD, Associate Professor and Director of the Genitourinary Oncology Program at the University of Chicago, noted in an interview for this article that renal cell cancer is especially problematic because it is not a single entity but rather a collection of various types of histology with different molecular genetics.
Gary D. Grossfeld, MD, Director of the Genitourinary Oncology Program at Marin General Hospital in California, said that in general the news about kidney cancer is “pretty depressing—The mainstay of treatment is immunotherapy, but the problem there is that low doses are not particularly effective, and high doses are very problematic because of the severe toxicity.”
Nevertheless, he said, “Some promising treatments are on the horizon.” At the most recent ASCO Annual Meeting, “for the first time in several years, there was excitement about the future, a kind of general buzz about the disease that hasn't been there for a while.”
David R. Minor, MD, Associate Clinical Professor of Medicine at the University of California, San Francisco, and President of the California Kidney Cancer Foundation, which he founded in 1994, agreed: “Because the outlook for this disease was so grim, very little research was done until about a decade ago. And it wasn't until three years ago that there was an explosion of interest in new targeted therapies.”
Controversy about Primary Tumor Resection
Nephrectomy is a basic element of treatment. Patients with a good prognosis (who have early-stage disease and/or only one site of metastasis) are the best candidates for surgical resection. In fact, 40% of them have five or more years of disease-free survival.
In an Education Session at the most recent ASCO Annual Meeting, David P. Wood, MD, Professor of Surgery in the Section of Urology at the University of Michigan, discussed two almost identical randomized Phase III trials of nephrectomy followed by the use of interferon alpha-2b vs just interferon-2b alone (the Southwest Oncology Group 8949 study and the European Organization for Research and Treatment of Cancer 30947 study). The purpose was to determine if cytoreductive surgery enhanced survival.
The results showed that patients who had surgery before receiving interferon had improved overall survival compared with patients treated with just interferon: 12.6 vs 7.8 months. Fifty-three percent of patients in the surgical arm were alive at one year, compared with 36.4% in the nonsurgical arm.
There were, however, several significant surgical complications: cardiac events, infection, hypertension, and “cerebellar syndrome,” and one patient receiving interferon only died.
Dr. Wood said that, based on these studies, an argument could be made that all patients with metastatic renal carcinoma should have nephrectomy before systemic therapy. But these patients had small, easily resectable tumors, whereas the majority have larger unresectable tumors and would not benefit much from surgery.
Even if there was a slight survival advantage, surgery of a large renal cell carcinoma, with its attendant risks and morbidity, may not be worth an extra month or two.
Dr. Grossfeld noted that the controversy about primary tumor resection has been going on for years. Then along came these randomized Phase III trials. But is this sufficient motivation for patients to undergo major surgery?
“Oh yes,” Dr. Grossfeld replied, disagreeing somewhat with Dr. Wood. “Some patients get far more than four months, especially younger ones and those who are relatively healthy. We don't offer the surgery to patients who are too sick to benefit from it, and no one to whom we offer it turns it down.”
Because some renal cell carcinoma tumors regress spontaneously, the disease has been classified as immunogenic, which could therefore respond to immune-modulating therapies.
So far, interleukin(IL)-2 is the only agent approved for treatment in the United States. It is usually administered as a high-dose bolus regimen of 600,000 IU/kg every eight hours for five days, repeated for four to eight cycles.
This produces a consistent overall response rate of 15%, half of which are complete responses. The majority of these complete responses are durable—more than 80% lasting a decade or more.
Dr. Minor said he has been giving IL-2 since 1988 and has had success with a different regimen: 18,000,000 IU/m2 as an intravenous infusion over 24 hours every day for five days, repeated for four to eight cycles. He accompanies the IL-2 with low-dose interferon.
“I've treated 40 patients this way over 10 years, for a total response rate of 30%—12% complete and 18% partial,” he said. “More than 10% of the patients are still alive and free of disease. And I should add that this is the treatment used most often in France.”
Dr. Minor acknowledged that success comes with a price: IL-2 is a very toxic agent. Patients can get iatrogenic septic shock, life-threatening hypotension, kidney failure, and lung inflammation. About 1% of patients die of adverse events.
“In fact,” he said, “it's so toxic that it's tolerable and useful only in patients who are under age 60 or 65—because after that there is a high incidence of occult vascular disease—and who have very good performance status.”
Phase II trials with lower doses of IL-2, with or without interferon, have been done to avoid some of the toxicity of high doses, he noted. Some have response rates comparable to the high-dose regimen, but durability is not as good.
Two such randomized trials were conducted at the NCI Surgery Branch and the Cytokine Working Group. The former compared low-dose IL-2 in two different regimens (IV bolus every 8 hours, and subcutaneous injection 5 days a week) with high-dose bolus IL-2.
The high-dose regimen had a significantly better overall response rate, but it carried no survival advantage.
The latter trial compared high-dose bolus IL-2 with a low-dose subcutaneous injection combined with interferon. The overall response rate was twice as high for the high-dose regimen, but again, there was no improvement in overall survival.
Adoptive immunotherapy is cellular based. Hematopoietic stem cells or ex-vivo manipulated cell populations can be adoptively transferred with a therapeutic purpose.
Various strategies for kidney cancer have been evaluated:
- ▪ Lymphokine-activated killer cells.
- ▪ Natural killer cells.
- ▪ Mini-allogeneic transplantation.
- ▪ Vaccine-primed lymph node cells (VPLN).
One such investigation in advanced disease involved nonmyeloablative allogeneic stem cell transplantation in patients who did not respond to IL-2. Fifteen of 33 patients responded, four of whom had a complete response.
The metastases, however, did not regress until an average of five months after transplant—and after withdrawal of immunosuppression and establishment of T-cell chimerism. This implies an immunologic basis for the response.
In a study presented at the ASCO 2004 Annual Meeting, Bruce G. Redman, DO, PhD, Professor of Medicine at the University of Michigan, reported on another form of adoptive immunotherapy using ex-vivo anti-CD3-activated lymphocytes isolated from autologous tumor VPLN.
After transfer of these cells, patients received 360,000 IU/kg of IL-2 every eight hours for five days. Nine of 34 patients responded.
Angiogenesis is almost certainly a factor in kidney cancer metastasis. The disease may be an ideal target for evaluation of antiangiogenesis because clear cell carcinomas show inactivation of the VHL gene, which leads to overexpression of hypoxia-inducible factor-1-α. This then causes induction of proangiogenic substances, including vascular endothelial growth factor (VEGF).
The important angiogenic proteins are: basic fibroblast growth factor (bFGF); VEGF, which can have up to a 37-fold increase in expression in renal cell carcinoma; and tumor necrosis factor alpha (TNF-α).
The level of serum VEGF is correlated with clinical stage and histopathologic grade, and patients with a VEGF level greater than 343.4 pg/ml have a poor prognosis for survival.
In addition, there is a positive correlation between tumor size and interleukin-6, TNF-α, and interleukin-1b.
Thalidomide (or its metabolite) is currently under investigation as an antiangiogenic. The drug has been shown to decrease TNF-α, VEGF, and bFGF and to stimulate the production of IL-2.
For example, a Phase II trial of thalidomide at 100 mg per day was conducted in patients with advanced melanoma, renal cell cancer, ovarian cancer, and breast cancer. Seventeen percent of the renal cancer patients had a partial response, and one patient continued the response at 11 months.
Thalidomide was found to reduce the level of circulating VEGF, although it is unclear how this phenomenon and tumor response are related.
William D. Figg, PharmD, Head of the Molecular Pharmacology Section in the NCI's Cancer Therapeutics Branch in the Center for Cancer Research, said that thalidomide has many properties, but that it is not a very potent antiangiogenic.
It will probably give us some insight into the nature of proteins, and right now it is the gold standard in the treatment of myelodysplastic syndrome and multiple myeloma. So we know it works in some liquid tumors, but I doubt that it has much of a beneficial effect in solid tumors.
“But having said that,” he continued, we're trying to develop more potent analogs of thalidomide that might be effective in kidney cancer and other solid tumors. The first optimized analogs are still in preclinical studies, and of course we don't know which will make it to clinical trials.
Thalidomide is a possible option for patients with advanced solid and plasma cell tumors, he said, and although it may have some activity in renal cell cancer, its role has not been defined.
He pointed to two ongoing studies of interferon with or without thalidomide (a Phase III trial by the Eastern Cooperative Oncology Group and a Phase II one by Cancer Research UK), the results of which should provide a better understanding of the role of thalidomide in kidney cancer.
Bevacizumab, a humanized monoclonal antibody against VEGF, approved for colorectal cancer, has been evaluated in clear cell renal carcinoma. Patients were randomized to high-dose (10 mg/kg), low-dose (3 mg/kg), or placebo every two weeks. When placebo patients' disease progressed they were allowed to cross over to a treatment arm.
The primary endpoint was progression-free survival. Responses were seen in only the high-dose arm, and because of the crossover, it was impossible to detect a survival advantage. A Phase III trial of interferon with or without bevacizumab is underway.
“We've been using it for kidney cancer for a while now,” Dr. Minor said, “and in some patients it gets rid of all the cancer cells. In other patients, it significantly lengthens the time to disease progression.”
Cell growth regulatory pathways are new areas of investigation in cancer development and progression. One of the best studied is the RAS signaling pathway.
More than 20 agents that target the RAS pathway are now in development or clinical trials. The one with the greatest interest in kidney cancer is Bayer's BAY 43–9006 (sorafenib), an inhibitor of RAF kinase and VEGF receptor.
It prevents tumor growth by two mechanisms: inhibition of tumor cell proliferation and tumor angiogenesis, and the FDA recently granted the agent Orphan Drug status.
Interim results of a Phase II single-agent trial of sorafenib in patients with advanced renal cell carcinoma were presented at the most recent ASCO Annual Meeting by Mark Ratain, MD, Professor of Medicine and Associate Director for Clinical Sciences at the University of Chicago's Cancer Research Center.
The study showed a high level of durable disease stabilization and tumor shrinkage. “As we continue to evaluate BAY 43–9006, I am excited about the potential it may offer in the fight against this form of kidney cancer,” Dr. Ratain said.
The study had a unique design: It is called a discontinuation trial and consists of two stages: a 12-week induction phase followed by a randomization phase with a parallel BAY 43–9006 open-label phase.
During the first stage, all study participants received the drug orally at 400 mg twice a day. Subsequently, patients whose tumor burden was within 25% of the pretreatment measurement were randomized to either sorafenib or placebo for another 12 weeks.
In addition, patients who had tumor shrinkage of more than 25% at the Week-12 evaluation continued treatment with open-label sorafenib. Patients with tumor shrinkage of less than 25% were dropped from the study.
At the 12-week evaluation, 89 of 106 patients had a tumor response, of whom 37 had tumor shrinkage greater than 25%. Thirteen of them had shrinkage of at least 50%.
Thirty-eight patients had disease stabilization and were randomized. The other 31 patients had disease progression or were discontinued for other reasons.
Thirty-seven patients received sorafenib in the open-label phase, and their median time to progression was 48 weeks. Of these, 88% were progression-free at six months. Confirmatory radiology scans done by independent reviewers will be completed at the end of the study.
The most commonly reported adverse events included mild to moderate hand-foot syndrome, rash, diarrhea, and hypertension, all of which were manageable and reversible.
Dr. Stadler said that an international Phase III trial of sorafenib vs placebo in second-line treatment has already accrued 880 patients and expects more.
Several trials of agents that block the VEGF receptor signal are under way, the most promising of which is Pfizer's SU 011248 in cytokine-refractory metastatic disease. SU 011248 is a tyrosine kinase inhibitor active against VEGF receptors and platelet-derived growth factor.
It is administered orally at 50 mg per day for four weeks every six weeks. Antitumor activity has been seen, as well as some minimal partial responses.
SU 11248 is the subject of two major trials, Dr. Stadler noted. The first is a single-arm, Phase II study that has completed accrual with about 100 to 150 patients. No data are available yet.
The second is a confirmatory Phase III study comparing interferon and SU 011248. “These data will probably be ready in a little over a year, and Pfizer will be looking for accelerated approval,” he said.
He added that both drugs are interesting and both have a beneficial effect. “It remains to be seen whether either of them will actually improve survival—probably they won't. They will not cure kidney cancer, but they will increase the time to disease progression, and that's progress.”
“All in all,” Dr. Minor summed up, “Things are looking up for kidney cancer. We can cure some of it and turn some into a manageable disease that patients can live with for many years. That's a lot better than what it used to be.”
Scope of the Problem
By the time it is diagnosed, renal cell carcinoma has almost always metastasized because there are so few warning signs or evidence of early disease.
The incidence of disease, both localized and advanced, has increased by 126% since 1950, perhaps due to better imaging techniques, although Dr. David Minor said that no one really knows why.
Kidney cancer is actually several different entities, the most common of which is clear cell carcinoma (70% of localized disease and 95% of metastatic disease), which arises from the proximal tubules and 3p depletions and inactivation of the von Hippel-Lindau pathway.
Papillary renal cancers also arise from proximal tubules and are characterized by trisomy of chromosomes 7, 16, and 17. Chromophobe tumors arise from intercalated cells of the collecting duct and have monosomy 1, 2, 6, and 10.
Dr. Walter Stadler noted that the majority of clinical trials for metastatic disease have not differentiated among histologic subtypes. Thus, findings usually refer only to clear cell carcinoma, leaving researchers in the dark about efficacy for other subtypes.
The natural history of the disease is so variable that many clinical trials divide patients into those with a poor, intermediate, or good prognosis. These groupings can be used as a stratification tool in clinical practice as well.