Large, Grade 4 Kidney Tumors Pose Risk of Early Cancer-Specific Mortality

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Possible guidance for use of adjuvant immunotherapy in high-risk, non-metastatic disease

by
Charles Bankhead, Senior Editor, MedPage Today
November 12, 2024

LOUISVILLE, Ky. — Large tumor size and high disease grade were associated with an increased risk of early cancer-related death in patients with high-risk, non-metastatic kidney cancer.

Patients with grade 4 tumors larger than 10 cm had an early cancer-specific mortality (CSM) rate of 41% — defined as cancer-related death within 24 months of nephrectomy — compared with 14% of all other patients. Extension into the inferior vena cava (IVC) thrombus, a rare but frequently fatal condition, did not increase the likelihood of early CSM.

The findings could help inform decision making regarding use of adjuvant immune checkpoint blockade in patients with high-risk, non-metastatic renal cell carcinoma (RCC), reported Mitchell T. Hayes, MD, of the Moffitt Cancer Center in Tampa, Florida, at the International Kidney Cancer Symposium.

“Patients with high-level thrombi have a high risk of perioperative death, which is more likely related to bleeding or some aspect of the surgery,” said Hayes. “We wanted to know more about cancer death at a later point in time, so we can really begin to think about who benefits from adjuvant immunotherapy. We don’t want to count patients who died from bleeding, vascular complications.”

“We found that when you combine just two variables — large, bulky, grade 4 tumors — there’s a statistically significant increased risk of non-perioperative death after surgery,” he continued. “We wanted to look at our own institutional cohort in light of recent trials of adjuvant immunotherapy. To all urologists who might not be sending everybody for adjuvant immunotherapy discussions, if you’re going to send anybody, maybe these patients with larger, grade 4 tumors definitely should have these discussions.”

The recent KEYNOTE-564 trial showed a survival benefit with adjuvant pembrolizumab (Keytruda) in high-risk RCC, but not all patients need adjuvant therapy, noted Priyanka Chablani, MD, of the University of Pittsburgh Medical Center.

“Some patients who are at low risk of recurrence and get adjuvant therapy might develop hypophysitis or adrenalitis or thyroiditis and then require long-term supplements to live with these effects,” she said. “It’s still unclear who really needs adjuvant therapy. We need more biomarkers.”

“I like how it was pretty clear here — greater than 10 cm, grade 4 tumors,” Chablani noted. “Sarcomatoid tumors, where even with T2 tumors we think about referring for adjuvant therapy, did not have an association, although you only had three patients. We need more studies like this and more biomarkers to understand who really should be getting adjuvant therapy.”

Hayes and colleagues retrospectively reviewed records of 134 consecutive patients treated from 2000 to 2019 who met KEYNOTE-564 inclusion criteria: clear cell histology; pT2G4 or sarcomatoid N0M0, pT3+ N0M0, or pTany N+M0; and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The primary outcome was cancer-specific death within 24 months of nephrectomy.

Men accounted for 70% of the patients, median age was 66, and median follow-up was 72 months. A third of patients had IVC thrombus, a third had tumors ≥10 cm, and three-fourths had grade 3-4 tumors. Tumors>10 cm had a statistically significant association with early CSM (P=0.035), as did grade 4 disease (P=0.046).

Age at surgery, tumor thrombus classification, performance status, systemic symptoms at diagnosis, sarcomatoid features, rhabdoid features, and T4 disease did not significantly influence the likelihood of early CSM.

Hayes and colleagues acknowledged limitations to their study, primarily small numbers (17 patients total with large, grade 4 tumors), the retrospective design of the study, and reliance on data from two affiliated institutions.