Phase iii randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma

Abstract

Background. Treatment with interleukin‐2 (IL‐2) and lymphokine‐activated killer cells (LAK) resulted in responses in some patients with advanced renal cell carcinoma (RCC). However, the relative therapeutic benefit of the addition of LAK to IL‐2 was unknown. Methods. A randomized Phase III trial was conducted in patients with RCC comparing continuous intravenous infusion (CI) IL‐2 alone with CI IL‐2 plus LAK. Interleukin‐2 was administered at 3 × 106 U/m2/day on days 1–5, 13–17, 21–24, and 28–31. Patients on the LAK treatment arm underwent leukapheresis on days 8–10 and LAK cell reinfusion on days 13–15. The results are reported with long‐term follow‐up. The published experience with IL‐2 alone or with the addition of LAK was investigated in a quantitative literature survey. The response proportions were studied by schedule (high dose bolus, moderate dose, low dose) and by concomitant administration of LAK. Results. Seventy‐one patients were treated, 36 on the IL‐2 arm and 35 on the IL‐2 plus LAK arm. Four patients (6%) had major responses (two complete, two partial). The median survival of all patients was 13 months (95% confidence interval [CI], 9–18 months). There were no differences between treatment arms with regard to response (P=0.61) and survival (P=0.67). More patients on the LAK arm experienced pulmonary toxicity (P=0.008). The overall weighted response proportion was 16% (95% CI, 8%‐24%) for the 39 published series of 1291 patients treated with IL‐2. The 95% confidence intervals for response proportion overlapped when compared by schedule and by administration of LAK. Conclusions. The dose and schedule of IL‐2 used in this study resulted in a low level of antitumor activity and the addition of LAK did not improve the response rate against RCC. Given the infrequent, but reproducible, responses with IL‐2 and interferon‐based regimens, continued investigation of these agents is warranted as is the study of new cytokines. Alternative treatment strategies should be studied in RCC and new agents and treatment regimens that appear promising in Phase II studies must be studied in randomized tria.

Immunotherapy of Metastatic Renal Cell Cancer

“…Estimates of CR and PR are generally in the 6% to 8% and 15% to 20% range, respectively, in larger series. [4][5][6][7] Smaller series with better rates, such as reported by Atzpodien et al, 38 appear difficult to reproduce, again probably related to case selection. Long-term survivorship is concentrated in subjects with CRs, and some improvement is also observed for PRs.…”

“…Initial enthusiasm from an apparent high frequency of response in small single-arm series 93,94 waned as larger randomized series showed an absence of sustained benefit with the addition of the LAK component to the therapy and even the potential for enhanced toxicity. 5,95,96 If the native immune system cannot be stimulated, primed, or augmented to reject renal cancer, could a foreign one be used? The technique of allogeneic minitransplantation uses an immunologically similar but not identical donor.…”

Phase I/II study of thalidomide in combination with interleukin‐2 in patients with metastatic renal cell carcinoma

“…12 Metastatic RCC (MRCC) is comparatively more resistant to cytotoxic therapy and radiotherapy than other cancers. [13][14][15][16][17][18][19][20][21][22] Reviews of more than 100 trials have failed to associate a single agent with consistent levels of antitumor activity, 13,22 and to our knowledge no single-agent or combination regimen is currently accepted as the standard of care. 6,13 To our knowledge, the most effective treatment currently available is immunotherapy with interferon-␣ (IFN-␣) or interleukin-2 (IL-2), which produce an objective response in 6 -21% of patients.…”

Böbrek Hücreli Karsinomlu Hastaların Demografik Özellikleri ve Tedavi Sonuçları: Tek Merkez Deneyimi

“…Law ve arkadaşlarının 1995'te yaptığı çalışmada nefrektomi oranı %86 iken 2009 da yapılan bir diğer çalışmada bu oran %89 olarak bildirilmişti. 7,14 Biz, tanıda metastazı olmayan, nefrektomi yapılan hastalarda ortanca GS'yi 52 ay, evre 4 hastalarda ortanca GS'yi 9 ay bulduk. Daha önceki çalışmalarda da evre 4 hastalarda ortanca GS 8-12 aydı.…”

“…Fakat bu tedavilerde ortanca genel sağkalım süreleri yaklaşık 12 ay olup, %20'den daha az yanıt sağladılar. 7 Ancak, son yıllarda metastatik BHK'nin moleküler biyolojisi ve genetiğinin daha iyi anlaşılmasıyla vasculer endotelial growth factor (VEGF) ve mammalian target of rapamycin (mTOR) gibi tedavide hedef alınabilecek birçok moleküler yol belirlenmiştir. Metastatik BHK tedavisinde VEGF reseptörlerini inhibe eden küçük moleküllü tirozin kinaz inhibitörlerinin (sunitinib, sorafenib, pazopanib, axitinib) ve dolaşımdaki VEGF'i nötralize eden monoklonal antikorların (bevasizumab), ayrıca mTOR yolağı inhibitörlerinin (temsirolimus, everolimus) kullanılması bu alandaki gelişmelerin belki de yeni bir başlangıcı olmuştur.…”