What is the best practice for treating oligometastatic (having a limited number of metastases) renal cell carcinoma (RCC) with vertebral bone metastasis in a patient classified as International Metastatic Renal Cell Carcinoma Database (IMDC) poor risk with no immediate spinal cord compression?

Management of Oligometastatic Renal Cell Carcinoma with Vertebral Bone Metastasis in IMDC Poor-Risk Patients

For IMDC poor-risk oligometastatic RCC with vertebral bone metastasis and no cord compression, initiate systemic therapy with cabozantinib-nivolumab combination immediately, add bone-modifying agents (zoledronic acid or denosumab), and consider stereotactic body radiotherapy (SBRT) to the vertebral lesion either concurrently or after establishing systemic disease control. 1

Systemic Therapy: First Priority

Start with cabozantinib-nivolumab combination therapy as the preferred first-line regimen. This recommendation is based on:

• Superior outcomes in bone metastases subgroup: In CheckMate 9ER, patients with bone metastases treated with cabozantinib-nivolumab showed improved PFS (HR 0.34; 95% CI 0.22-0.55) and OS (HR 0.54; 95% CI 0.32-0.92) compared to sunitinib. 1

• IMDC poor-risk efficacy: The combination demonstrates significant benefit in IMDC intermediate/poor-risk populations, which is your patient's category. 1

• Cabozantinib's bone-specific activity: In the VEGF-refractory METEOR trial, cabozantinib improved median OS (20.1 vs 12.1 months) and PFS (7.4 vs 2.7 months) in patients with bone metastases compared to everolimus. 1

Alternative first-line options if cabozantinib-nivolumab is contraindicated:

• Lenvatinib-pembrolizumab (PFS HR 0.42, OS HR 0.72 vs sunitinib) 1
• Ipilimumab-nivolumab (particularly if considering immunotherapy-only approach, though less bone-specific data) 1

Critical Caveat on Cytoreductive Nephrectomy

Do NOT perform immediate cytoreductive nephrectomy in IMDC poor-risk patients. 1

• 80% of expert consensus recommends initiating systemic therapy first rather than cytoreductive nephrectomy in IMDC poor-risk disease. 1

• The CARMENA trial demonstrated that sunitinib alone had longer median OS (18.4 vs 13.9 months) compared to immediate cytoreductive nephrectomy followed by sunitinib. 1

• Deferred cytoreductive nephrectomy can be considered only after achieving durable response to systemic therapy. 1

Bone-Modifying Agents: Concurrent Essential Therapy

Initiate zoledronic acid or denosumab immediately alongside systemic therapy to prevent skeletal-related events (SREs). 1, 2, 3

• These agents delay time to first SRE (fracture, spinal cord compression, need for radiation/surgery to bone) across all solid tumors including RCC. 1, 2

• Zoledronic acid specifically improved rate of SREs, annual incidence of SREs, and time to progression of bone metastases in mRCC patients. 1

• Concurrent use with VEGF TKIs has demonstrated safety in retrospective series. 1

• Important limitation: These agents do not "clear" bone metastases but prevent complications. 2

Local Therapy: SBRT for Vertebral Metastasis

Consider SBRT to the vertebral lesion in the oligometastatic setting, either concurrently with systemic therapy initiation or after establishing disease control. 1, 4, 5

Rationale for SBRT:

• Vertebral bone metastases are "frequently treated with" local therapy according to systematic reviews. 1

• SBRT is "effective in RCC and is being applied increasingly in the oligometastatic setting" for symptom control and local disease management. 5

• Retrospective studies suggest benefits of symptomatic control and potential delay in systemic therapy escalation, though prospective data are limited. 1

Timing Considerations:

• No immediate cord compression in your patient allows flexibility in SBRT timing. 4, 5

• Can initiate SBRT after 2-3 months of systemic therapy to assess systemic disease control and avoid treating a lesion that may respond to systemic therapy alone. 4, 5, 6

• Alternatively, concurrent SBRT with systemic therapy initiation is reasonable for local control, particularly if the vertebral lesion is symptomatic or at risk for future complications. 4, 5

Active Surveillance Alternative: Not Recommended in Poor-Risk Disease

Active surveillance before systemic therapy is NOT appropriate for IMDC poor-risk patients, even with oligometastatic disease. 1, 5

• Surveillance may be appropriate only for "selected patients with IMDC favourable-risk disease with low tumour burden." 1

• Your patient's poor-risk status mandates immediate systemic intervention. 1

Treatment Algorithm Summary

1. Immediate initiation: Cabozantinib 40mg daily + nivolumab 240mg IV every 2 weeks 7
2. Concurrent bone protection: Zoledronic acid or denosumab 1, 2
3. SBRT timing decision:
   • If symptomatic vertebral lesion or high fracture risk: concurrent SBRT 4, 5
   • If asymptomatic and stable: reassess after 2-3 months of systemic therapy, proceed with SBRT if lesion persists 5, 6
4. Avoid cytoreductive nephrectomy unless durable response achieved on systemic therapy 1

Common Pitfalls to Avoid

• Do not delay systemic therapy for surgical interventions in poor-risk disease—this worsens survival. 1

• Do not use single-agent TKI therapy when combination therapy is available and appropriate—cabozantinib-containing regimens are specifically preferred for bone metastases. 1

• Do not omit bone-modifying agents—they are standard of care for preventing skeletal complications. 1, 2

• Do not assume oligometastatic status alone justifies surgery or observation—IMDC risk stratification supersedes metastatic burden in treatment selection for poor-risk patients. 1