Upfront Systemic Therapy, Deferred Surgery Pass Muster in Advanced Kidney Cancer

CHICAGO — Perioperative immunotherapy for advanced kidney cancer did not adversely affect outcomes with cytoreductive nephrectomy and appeared to have several beneficial effects, a small multicenter study showed.

Primary immunotherapy significantly reduced median tumor size and thrombus length and improved tumor thrombus level and mean RENAL score. Immunotherapy led to pathologic downstaging in 25 of 56 cases. Two-thirds of patients achieved the composite outcome of complete surgical resection with negative margins and no 30-day postoperative complications, which was associated with improved 2-year survival.

“While there are multiple trials ongoing, our data support further investigation of the utility of presurgical immunotherapy and the impact of surgical quality on outcomes in advanced and metastatic renal cell carcinoma [RCC],” said medical student Kevin Hakimi, of the University of California San Diego, at the American Urological Association meeting.

A second report at the meeting showed no untoward effects of perioperative systemic therapy on surgical complication rates for patients with advanced/metastatic kidney cancer. The results support upfront systemic therapy and deferred cytoreductive surgery as a viable approach to treatment, said Shawn Dason, MD, of the Ohio State University in Columbus.

The two studies addressed the unresolved issue of whether systemic therapy should follow surgery or vice versa. Moreover, results of the randomized, multicenter CARMENA trial called into question the value of cytoreductive surgery, showing that patients with advanced/metastatic kidney cancer had better survival with single-agent sunitinib (Sutent).

“Immunotherapy has emerged as a first-line option for patients with metastatic RCC,” Hakimi noted. “Surgical quality has not been formally evaluated in the context of a cytoreductive nephrectomy following primary immunotherapy for metastatic RCC. We wanted to look at surgical quality as a proxy following primary immunotherapy in advanced RCC.”

Investigators performed a retrospective analysis of patients with advanced/metastatic RCC, image-guided biopsy of the primary tumor or metastases, and combination immuno-oncology therapy. Cytoreductive surgery was offered in the context of a multidisciplinary team involving urologic oncology and genitourinary medical oncology.

The primary outcome was “bifecta,” a composite of complete surgical resection and no postoperative complications within the first 30 days after surgery. Survival, change in tumor dimensions and RENAL score, and pathologic downstaging were secondary outcomes. Most of the patients were intermediate risk, a majority had received nivolumab (Opdivo) plus ipilimumab (Yervoy) as their initial immunotherapy, and the median duration of treatment was 8.1 months.

Primary immunotherapy was associated with:

• Decreased tumor size: 9.4 vs 5.9 cm (P<0.001)
• Decreased thrombus length: 6.0 vs 2.0 cm (P=0.02)
• RENAL score: 9.2 vs 8.4 and a significant shift from complex toward simple (P<0.001)

In addition, preoperative immunotherapy was associated with improvement in tumor thrombus level and led to pathologic downstaging in 44.6% of cases versus pretreatment stage (P<0.001 for both).

Surgery was radical nephrectomy in 48 of the cases and partial nephrectomy in the other eight cases. Hakimi said surgery resulted in negative margins in 85.7% (48 patients) with no intraoperative complications and a 30-day postoperative complication rate of 26.8% (15 of 56), and 67.9% of procedures (38 of 56) met the bifecta composite outcome.

A multivariable analysis showed significant associations between change in renal mass and pathologic downstaging and achieving bifecta (P=0.043, P=0.047). Bifecta, pathologic downstaging, and change in renal mass size were all predictors of improved progression-free survival. Patients who achieved bifecta had a 24-month survival of 84% versus 71% for those who did not (P=0.019).

Though cytoreductive nephrectomy and systemic therapy both make important contributions to outcomes in advanced RCC, optimal sequencing remains unclear, which was the focus of Dason’s study.

“Sequencing decisions are complex, and if perioperative outcomes differed between approaches, this may be something that could be incorporated as part of the decision making,” he said. “Current systemic therapies are kind of new with limited perioperative data available, so the objective of our study was to assess the contemporary perioperative outcomes between the two approaches.”

Data for the analysis came from the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) for 2019-2021. The primary analysis included patients who received systemic therapy within 90 days of nephrectomy. The primary outcome was major complications.

The NSQIP query identified 586 patients who had upfront surgery and 166 who had deferred cytoreductive nephrectomy.

Comparing upfront with deferred surgery, the investigators found no significant difference in major complications (8% vs 5%), overall complications (33% vs 39%), or infectious complications (7% vs 5%). Operative time was about 3 hours for both groups. The timing of surgery had no significant effect on the rate of conversion from minimally invasive to open surgery, use of adjunctive procedures, discharge to a care facility, or length of hospital stay.

“These data are consistent with several series from the current and prior systemic-therapy eras,” said Dason. “We know that selected patients do have a marked desmoplastic reaction, and we have a hard time predicting who these patients may be, certainly something worthy of future study, as these patients might have an adverse outcome.”

“These data support the perioperative safety of deferred cytoreductive nephrectomy and certainly the safety of enrollment in trials where deferred cytoreductive nephrectomy is part of the paradigm,” he added.