Adjuvant autologous renal tumour cell vaccine and the risk of tumour progression in patients with renal-cell carcinoma after radical nephrectomy: phase III, randomised controlled trial

Author: Jocham D, et al.
Source:Lancet, 363, Feb 2004, pg 594

Background

• Over 31,000 new cases of renal cell carcinoma are expected in the United States this year
• Approximately 75% of renal cell carcinomas are local or regional upon diagnosis, with the remaining 25% being metastatic
• Standard therapy is radical or partial nephrectomy, with no effective adjuvant therapy established
• Though no adjuvant therapy has proven efficacious, there is a role for an effective intervention, as patients with T2 (tumors localized but > 7cm) or T3 (regional disease outside of the kidney) tumors have a progression free survival of only 65%
• Autologous vaccines have been studied as a possible adjuvant in patients with renal cell carcinoma, though their role in curative treatment is yet to be established
• This trial reports on results of a randomized trial comparing vaccinations using an autologous renal cell tumor vaccine to a control group

Materials and Methods

• Fifty-five institutions in Germany enrolled 558 patients preoperatively to receive either autologous renal cell vaccines or no further adjuvant therapy (no placebo)
• Patients were randomized following surgery, and only those with histologically confirmed pT2-3bpN0-3M0 renal cell carcinoma were eligible. It should be noted that this study used the 1993 staging system, which included as T2 and tumor >2.5 cm (which would be T1 tumors until >7cm in the latest staging system)
• The vaccine was prepared using tumor cells from each individual patient. Tumor cells were incubated with Interferon g, as it has been shown that incubation with interferon g causes the vaccine to become more immunogenic. To ensure the tumor cells were innocuous, they were repeatedly frozen to –82 C, with confirmation of their sterility.
• Vaccinations with the prepared vaccine were given six times at four week intervals
• Primary endpoint was progression, defined as local recurrence, distant metastasis or death
• Secondary outcome was the effect on quality of life and adverse event rate
• Results were analyzed as intention to treat
• Minimum follow up for all patients was 4.5 years

Results

• One hundred seventy four patients were withdrawn from study because they did not meet the pathologic criteria for study. Nine patients were withdrawn because of inability to prepare the vaccine. Therefore, the intention to treat population was 379 patients. An additional 36 were withdrawn due to protocol violations, leaving the patients treated per protocol at 343.
• Five year progression free survival (PFS) was 77.4% in the vaccine group compared to 67.8% in the control group, with a corresponding hazard ratio of 1.58 in favor of the vaccine group
• For patients with T2 tumors, 5 year PFS was 81.3% vs. 74.6%, again favoring the vaccine group
• For patients with T3 tumors, 5 year PFS was 67.5% vs. 49.7%, again favoring the vaccine group
• Out of a total of 1053 vaccine doses administered in 177 patients, 12 vaccine-related adverse events were noted in two different patients
• Quality of life scores were similar between the vaccine and control groups before nephrectomy, at 6 months, 24 months, 36 months, and 48 months after nephrectomy

Authors' Conclusions

• Adjuvant treatment with an autologous renal tumor cell vaccine after radical nephrectomy reduced the risk of tumor progression compared with surgery alone in patients with renal cell carcinoma
• Patients with risk factors for progression, such as large tumor size and high tumor grade had an even greater benefit from adjuvant treatment
• An autologous renal cell tumor vaccine can be considered for patients undergoing a nephrectomy for a non-metastatic renal cell carcinoma of more than 2.5 cm

Scientific Implications

Various methods of tumor vaccines have been studied in many different cancers with varying success. Until the time of publication of this trial, the major successes have been with prophylactic vaccinations (specifically against viruses that are implicated in cervical cancer and hepatoma). Perhaps a large reason that treatment vaccines have not found great success is that they are tried as second and third line treatments. They are often given to patients who have very advanced disease and a weakened immune system to react to the vaccine due to the various chemotherapy regimens to which they have been exposed. This trial reports on results of using an autologous vaccine against a patient's own renal cell carcinoma. The results are impressive, as the progression free survival was significantly higher in those patients receiving the vaccine. This is in contrast to other negative studies that had smaller patient populations and a different method of vaccine preparation. Weaknesses of the trial include the fact that they did not verify an immune response using a surrogate marker such as delayed type hypersensitivity reactions. The authors defend this correctly by stating the fact that these reactions are not reliable. The main limitation in the broad acceptance of these results is simply the applicability of the results. A relative minority of patients will have access to large institutions that have the means and technology to produce an individual vaccine such as was administered in this trial. Although this remains a major hurdle to overcome in the field of tumor immunotherapy, these results are impressive and should be considered in a disease that has limited other reliable options in terms of adjuvant therapy.