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AUA2022: BEST POSTERS Deferred Cytoreductive Nephrectomy in Patients with Metastatic Renal Cell Carcinoma Treated with Nivolumab Plus Ipilimumab
By: Maki Yoshino, MD; Hiroki Ishihara, MD, PhD; Tsunenori Kondo, MD, PhD; Toshio Takagi, MD, PhD | Posted on: 01 Sep 2022
Cytoreductive nephrectomy (CN) has played a central role in metastatic renal cell carcinoma (mRCC) treatment in cytokine therapy settings.1,2 However, recently 2 trials, the CARMENA and SURTIME trials, rejected the superiority of up-front CN in the molecular-targeted therapy era.3,4 An increase is anticipated in the number of patients without prior nephrectomy, owing to the findings of these trials. Additionally, immune checkpoint inhibitor-based treatment exhibits higher effects on tumor shrinkage in patients without prior nephrectomy,5-8 resulting in the increased likelihood of considering the indication of CN during therapy, namely deferred CN (dCN). However, data regarding the dCN’s therapeutic role during immune checkpoint inhibitor-based treatment remain limited.
Table 1. Patient characteristics based on nephrectomy status
| Variables | All (41 pts) | dCN (7 pts) | uCN (21 pts) | Non-CN (13 pts) | p Value |
|---|---|---|---|---|---|
| No. male sex (%) (reference female) | 27 (65.9) | 6 (85.7) | 13 (61.9) | 8 (61.5) | 0.434 |
| Median age (yrs) (IQR) | 64.0 (53.5–71.5) | 56.0 (47.0–64.0) | 64.0 (53.5–69.5) | 70.0 (56.5–73.0) | 0.131 |
| No. histopathology (%): | 0.599 | ||||
| Clear cell carcinoma | 31 (75.6) | 5 (71.4) | 18 (85.7) | 8 (61.5) | |
| Nonclear cell carcinoma | 6 (14.6) | 1 (14.3) | 3 (14.3) | 2 (20.0) | |
| Papillary renal cell carcinoma | 3 (7.31) | 0 (0) | 2 (9.52) | 1 (7.7) | |
| Other | 3 (7.31) | 1 (14.3) | 1 (4.76) | 1 (7.7) | |
| Unknown | 4 (9.76) | 1 (14.3) | 0 (0) | 3 (23.1) | |
| No. IMDC risk (%): | 0.0286* | ||||
| Intermediate | 19 (46.3) | 1 (14.3) | 14 (66.7) | 4 (30.8) | |
| Poor | 21 (51.2) | 5 (71.4) | 7 (33.3) | 9 (69.2) | |
| Unknown | 0 | 1 (14.3) | 0 | 0 | |
| No. KPS <80 (%) (reference >80) | 10 (24.4) | 2 (28.6) | 4 (19.0) | 4 (30.8) | 0.712 |
| Median mg/dL serum CRP levels | 3.06 (0.37–11.6) | 5.11 (2.73–12.8) | 1.10 (0.16–2.47) | 10.7 (4.5–13.5) | 0.0028 |
| No. metastatic organ sites (%) (reference solitary) | 28 (68.3) | 5 (71.4) | 13 (61.9) | 10 (76.9) | 0.641 |
| No. liver metastasis presence (%) (reference absence) | 5 (12.2) | 1 (14.3) | 3 (14.3) | 1 (7.70) | 0.824 |
| No. bone metastasis presence (%) (reference absence) | 8 (19.5) | 1 (14.3) | 7 (33.3) | 0 (0) | 0.0183 |
| Median days between diagnosis and systemic therapy initiation (IQR) | 22 (15–41) | 15 (8–22) | 40 (24–63) | 16 (9.5–21) | 0.001 |
| Median mos followup (IQR) | 12 (7–21) | 19 (18–20) | 12 (5–25) | 11 (6–20) | 0.258 |
KPS, Karnofsky Performance Status.
*Analyzed with the exclusion of 1 patient in the dCN group without IMDC risk data.
To clarify the prognostic impact of dCN, we retrospectively evaluated 41 patients with synchronous mRCC who received nivolumab plus ipilimumab as first-line therapy at our 5 affiliated institutions between September 2016 and July 2021. During the followup period with a median period of 12.0 months, 7 of the 41 (17%) patients received dCN. The dCN was performed at a median of 10.4 months after the initiation of nivolumab plus ipilimumab treatments. Of the remaining 34 patients, 21 (51%) underwent nephrectomy prior to nivolumab plus ipilimumab treatments (ie uCN group) and 13 (32%) did not receive nephrectomy (ie the non-CN group). When the patient characteristics were compared based on their nephrectomy status, the patients diagnosed with poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk or those with high serum C-reactive protein levels were significantly more frequent in the dCN and non-CN groups (p=0.0286 and p=0.0028, respectively; Table 1).
The total tumor size decreased in all the targeted lesions (median 51.5%; Fig. 1, A) in all patients receiving dCNs. Upon analyzing the primary and metastatic lesions, the tumors in primary lesions shrank in all the patients (median 38.7%; Fig. 1, B), and 6 (86%) patients (except Patient E) exhibited tumor shrinkage (median 69.4%; Fig. 1, C). A ≥30% shrinkage in the primary lesions was observed in 6 (86%) patients whose metastatic lesions concurrently shrank by ≥30%, including 2 (29%) patients with complete responses (Fig. 1, B and C).
Table 2. Clinical characteristics and perioperative outcomes in patients undergoing dCN
| Pt | Age (yrs) | Sex | Clinical Stage | No. IMDC Risks at Diagnosis | Mos to Surgery | Procedure | Operating Time (mins) | Blood Loss (ml) | Complications | Pathological Diagnosis | Length of Stay (days) | Postop Followup (mos) | Current Treatment | Current Outcome |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| A | 56 | M | cT3aN0M1 | 5 | 4 | RAPN | 199 | 50 | None | Viable cells present | 4 | 19 | None | CR |
| B | 47 | M | cT3bN0M1 | 5 | 10 | ORN | 239 | 1,290 | CD grade 2 (transfusion) | Viable cells present | 7 | 10 | Nivolumab | SD |
| C | 57 | M | cT4N1M1 | N/A | 11 | LRN | 200 | 50 | None | Viable cells present | 4 | 12 | Nivolumab | CR |
| D | 41 | M | cT1aN0M1 | 1 | 12 | RAPN | 203 | 50 | None | Viable cells absent | 4 | 9 | None | SD |
| E | 51 | M | cT2bN0M1 | 3 | 1 | ORN | 171 | 2,055 | CD2 (transfusion) | Viable cells present | 8 | 18 | Cabozantinib | PR (on cabozantinib) |
| F | 64 | F | cT3aN1M1 | 5 | 11 | LRN | 189 | 20 | None | Viable cells absent | 6 | 7 | None | CR |
| G | 76 | M | cT3aN2M1 | 3 | 8 | ORN | 199 | 315 | CD2 (transfusion) | Viable cells present | 8 | 5 | Nivolumab | SD |
CD, Clavien–Dindo. CR, complete response. LRN, laparoscopic radical nephrectomy. N/A, not available. ORN, open radical nephrectomy. PR, partial response. RAPN, robot-assisted partial nephrectomy. SD, stable disease.
The dCN had a median surgery time of 191 minutes and median blood loss volume of 50 ml (Table 2). Three (43%) patients required blood transfusions (Clavien-Dindo grade 2), while the remaining 4 (57%) did not experience complications. The median length of postoperative hospital stay was 6 days. Regarding the pathological findings in the resected kidneys, no viable cells were observed in 2 cases.
During the followup period, 13 (32%) patients died. Patients in the dCN group had the highest overall survival (OS) rate compared to the uCN and non-CN groups (1-year rate 100% vs 72.4% vs 58.2%, p=0.158; Fig. 2). Specifically, the OS rate tended to be higher in the dCN group compared to the uCN group (p=0.0587) and the non-CN group (p=0.0613). No difference was observed in the OS rate between the uCN and non-CN groups (p=0.815). The rates of complete responses during therapy among the 3 groups were 43% (3/7), 14% (3/21), and 0% (0/13) in the dCN, uCN, and non-CN groups, respectively. Thus, the rate of complete response was significantly higher in the dCN group (p=0.01).
This study had several limitations. First, the retrospective nature of our analysis, in addition to the small sample size and relatively short followup period, potentially affected our findings. Moreover, our institutions have no consensus criteria for dCN. In all the dCN patients, the CN was unplanned and frontline systemic therapy with nivolumab plus ipilimumab was preferred at the time of mRCC diagnosis. dCN was conducted because the patients’ primary and metastatic lesions presented sufficient response. Thus, a strong selection bias was inevitably introduced.
Collectively, the present data showed that dCN followed by frontline nivolumab plus ipilimumab therapy was associated with improved OS in the patients with synchronous mRCC. dCN may be an effective treatment option for a subset of patients who exhibit favorable responses for a certain period in primary lesions, with the simultaneous shrinkage of metastatic lesions.
- Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345(23):1655-1659.
- Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358(9286):966-970.
- Mejean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med. 2018;379(5):417-427.
- Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5(2):164-170.
- Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384(9):829-841.
- Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378(14):1277-1290.
- Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1116-1127.
- Motzer RJ, Penkov K, Haanen J et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380(12):1103-1115.