Immunotherapy and Peripheral - Blood Transplant for Metastatic Renal Cell Carcinoma

Nonprostate Urologic Oncology

REVIEWING THE LITERATURE Nonprostate Urologic Oncology Immunotherapy and Peripheral-Blood Transplant for Metastatic Renal Cell Carcinoma Belur Patel, MD, Kiarash Michel, MD, Arie Belldegrun, MD, FACS University of California, Los Angeles, School of Medicine [Rev Urol. 2000;2(1):32-33, 38] M anagement of metastatic renal cell carcinoma (RCC) continues to be of strong research interest. Three articles looking into the question of administering immunotherapy or providing an allogeneic peripheral-blood stem cell transplant for patients with metastatic RCC are reviewed. Interleukin-2 Based Immunotherapy for Metastatic Renal Cell Carcinoma With the Kidney in Place Wagner JR, Walther MM, Linehan WM, et al. J Urol. 1999;162:43-45. In a retrospective analysis, the authors evaluated the response, morbidity, and survival of 51 patients with metastatic RCC who were treated with interleukin-2 (IL-2) and who had the primary renal tumor in place. There were 15 women and 36 men with an age range of 35 to 53 years; 84% of these had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or less. The mean number of IL-2 courses administered per patient was 1.6, with a range of 1 to 5 courses. Three patients (6%) had either a complete or a partial response of the extrarenal metastases and underwent radical nephrectomy; no other patients had a nephrectomy. Of these 3 patients, 1 had complete response that lasted for 88 months, while the other 2 had partial responses lasting 4 and 11 months, respectively, after nephrectomy. The overall survival for all patients ranged from 1 to 86 months, with a median of 13 months. The major toxicities encountered were diarrhea in 23 patients (45%), hypotension in 21 (41%), decreased urinary output 32 REVIEWS IN UROLOGY WINTER 2000 in 16 (31%), and pulmonary toxicity in 15 (29%). This report highlights several important points: • The primary RCC does not respond well to immunotherapy. • Responses to immunotherapy occur in metastatic deposits when the primary kidney tumor is in place. • Nephrectomy can be performed safely in patients who respond to immunotherapy. • IL-2 toxicities are similar in patients who receive treatment after nephrectomy. • Response rates are lower in patients treated with the kidney in place (6%), in contrast to patients who undergo therapy after nephrectomy.1 Reference 1. Rosenberg SA, Lotze MT, Yang JC, et al. Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. Ann Surg. 1989;210: 474-485. Laparoscopic Cytoreductive Nephrectomy as Preparation for Administration of Systemic Interleukin-2 in the Treatment of Metastatic Renal Cell Carcinoma: A Pilot Study Walther MM, Lyne JC, Libutti SK, Linehan WM. Urology. 1999;53:496-501. This study explores the role of nephrectomy and optimizing the time to administering immunotherapy in patients with metastatic RCC. Walther and associates explored the feasibility of laparoscopic surgery for renal tumor removal and for reducing the time to immunotherapy administra- Nonprostate Urologic Oncology tion. The study compared three groups of patients: 19 had open nephrectomy, 6 had laparoscopic cytoreductive surgery, and 5 had laparoscopic-assisted surgery. All patients had similar characteristics in terms of age, sex, ECOG status, and tumor size. In the laparoscopic cytoreductive group, the tumor was removed following morcellation in the sac. There were no significant differences in complications rates among the three groups, and no tumor seeding of the port sites or abdomen was seen with morcellation of the tumor. Those patients undergoing laparoscopic surgery had significantly longer surgery times than those who had open surgery. A statistical difference was noted for patients undergoing laparoscopic cytoreductive surgery in terms of decreased use of pain medication and shorter time to discharge, compared with those who had either open or laparoscopic-assisted surgery. The median time between surgery and immunotherapy initiation was 37 days for patients undergoing tumor morcellation, while those having open and laparoscopic-assisted surgery had median times of 67 and 60 days, respectively. The authors have presented an interesting evaluation of the feasibility of laparoscopic surgery for RCC with no increased morbidity and possible shorter recovery time before immunotherapy administration. The two articles, both from the National Cancer Institute, looked at the important and yet unresolved questions regarding immunotherapy for RCC and timing of surgery, as well as ways of reducing the treatment window for IL-2 administration after surgery. Previous studies have shown that cytoreductive surgery can be successfully and safely performed in a majority of patients and offers improved survival compared with survival in patients who had immunotherapy with the primary kidney tumor still in place.1,2 Laparoscopic surgery does present an interesting alternative, especially considering the question of disease progression because of delay in administering immunotherapy. Unfortunately, at this time the question of which is the most beneficial strategy to manage metastatic RCC remains to be answered by well-planned, randomized, prospective studies, as indicated in the articles by Wagner et al and Walther et al. Such studies may help determine whether immunotherapy before or after nephrectomy is more efficacious and whether laparoscopic surgery will shorten the time to therapy and be more effective than open nephrectomy. References 1. Franklin JR, Figlin R, Rauch J, et al. Cytoreductive surgery in the management of metastatic renal cell carcinoma: the UCLA experience. Semin Urol Oncol. 1996;14:230-236. 2. Figlin R, Gitlitz B, Franklin J, et al. Interleukin-2-based immunotherapy for the treatment of metastatic renal cell carcinoma: an analysis of 203 consecutively treated patients. Cancer J Sci Am. 1997;3(suppl 1):S92-S97. Successful Treatment of Metastatic Renal Cell Carcinoma With a Nonmyeloablative Allogeneic Peripheral-Blood Progenitor-Cell Transplant: Evidence for a Graft-Versus-Tumor Effect Childs RW, Clove E, Tisdale J, et al. J Clin Oncol. 1999;17(7):2044-2049. Metastatic RCC portends a poor prognosis and has demonstrated little sensitivity to chemotherapeutic regimens. Immunotherapy has been used extensively for patients with good performance status and RCC not metastatic to the CNS. The most favorable results have been noted in patients with isolated pulmonary metastases who have also had a postnephrectomy metastasis-free interval of more than 12 months. While the overall response rates of metastatic RCC to immunotherapeutic regimens may be as high as 25% to 33%, only 7% of patients with metastatic RCC demonstrate durable complete remissions. For all other patients, no other reliable means of curative therapy are available. In this case report, the authors assess the potential utility of peripheral-blood stem cell allogeneic transplant in manifesting a graft-versus-tumor (GVT) response for treating a patient with metastatic RCC. The authors describe a 50-year-old otherwise healthy man who presented with hematuria and flank pain. After a standard work-up, a 12  13-cm left renal tumor was noted. His metastatic survey was negative. The patient underwent a left radical nephrectomy, revealing a large clear cell carcinoma, which was contained within the renal capsule. However, tumor thrombus was noted at the renal vein margin. The patient subsequently received 50 Gy of irradiation to his left flank. Within 6 months, the patient presented with a persistent nonproductive cough. After reevaluation, a CT scan of the chest revealed more than 40 pulmonary metastases. His metastatic survey was otherwise negative. The patient received interferon alfa-2b (3 MU/m2 three times per week for 10 weeks) and megestrol acetate. Repeated CT imaging revealed that the pulmonary metastases were progressing rapidly despite the interferon therapy. At this point, the patient was enrolled in the authors’ study to evaluate the GVT effect of nonmyeloablative allogeneic peripheral-blood transplantation for RCC. The patient was prepared with intravenous cyclophosphamide (60 mg/kg/d  2) followed by 5 days of intravenous fludarabine (25 mg/m2). He subsequently received 9.1  106 CD34+ cells/kg and 4.2  108 CD3+ cells/kg from his brother who had identical HLA. Cyclosporine therapy was started on transplant day 4. The cyclosporine was subsequently tapered on post-transplant day 30. A CT scan obtained on post-transplant day 30 did not reveal any progression of metastatic disease. By post-transplant continued on page 38 WINTER 2000 REVIEWS IN UROLOGY 33