Renal cell carcinoma accounts for 85% of all kidney cancers. Standard therapy for the disease in nonmetastatic stages is usually radical nephrectomy. However, "there has been, up to now, no adjuvant therapy available to improve outcomes for those patients," Dr. Doehn said.
For patients with tumors confined to the kidney, relapse rates approach 50%. For recurring or metastatic disease, the prognosis is worse. Moreover, current pharmacological treatments for patients with disease progression all carry substantial potential for severe side effects.
Between January 1997 and August 1998, researchers enrolled 558 patients with stage pT2-3b pN0-3 M0 renal cell tumors who were scheduled for radical nephrectomy at 55 hospitals throughout Germany. Prior to surgery, patients were randomized to receive postoperatively six consecutive doses of a vaccine consisting of cells from their own tumors or standard postoperative management (watchful waiting). Eligible patients (n = 379) had organ-confined tumors greater than 2.5 cm or tumors that were regionally advanced but not metastatic.
The vaccine was prepared separately for each patient from a sterilized tumor specimen obtained during nephrectomy. Specimens were transferred to a German company, LipoNova (Hanover), where cell suspensions from the tumor were prepared and incubated with gamma-interferon and tocopherol acetate (vitamin E), then washed several times and frozen repeatedly to kill the cells. The resulting lysate, containing about 5 million tumor cells/mL, was shipped frozen to the relevant center and stored until use.
Intradermal inoculations with the vaccine began 4 weeks after surgery and were repeated every 4 weeks thereafter for a total duration of 6 months. The study’s primary endpoint was time to progression. Patients were evaluated at 6-month intervals and followed for a minimum of 4 to 5 years. Five-year progression-free survival for vaccinated subjects was 77.4% vs 67.8% for controls (P = .0204); progression-free survival rates at 70 months were 72% and 59.3%, respectively.
At 70 months of follow-up, neither arm had reached median progression-free survival. The point at which 25% of the vaccinated and control subjects had progressed was 63.2 months and 42.1 months, respectively. Patients with larger or higher-grade tumors saw an even greater benefit. Full results of the study were recently published in The Lancet (363:594-599, 2004).
There were only 12 adverse reactions attributable to the vaccine, and none of them were severe, Dr. Doehn said. Given the poor prognosis and poor treatment options for patients with progression, he added, any treatment that succeeds in prolonging progression-free survival—especially if its toxicity profile is mild— would appear promising.
The vaccine is now undergoing review by the European Medical Evaluations Agency. To date, Dr. Doehn said, no other late-phase trial testing a therapeutic vaccine in renal cell cancer has shown substantial clinical response rates. He noted that a competing vaccine, composed of heat shock proteins extracted from patients’ tumors, is being administered in an adjuvant setting in a multicenter phase III trial with even higher patient enrollment. Results of that trial, sponsored by Antigenics, Inc. (New York City) and featuring survival as its primary clinical endpoint, are expected early next year.
Dr. Doehn believes that a therapeutic vaccine is more likely to be effective in the adjuvant setting. "Many research groups do find evidence of immunological reactivity," he said. "I think lack of efficacy in trials of patients with advanced disease is a matter of tumor burden."
