Treatment is guided by IMDC risk and centres on immune-checkpoint combinations, with cytoreductive nephrectomy now reserved for selected patients after the CARMENA era. Histology should be confirmed (by biopsy) before systemic therapy.
Prognostic Models
| Model | Era | Factors | Risk groups (median OS) |
|---|---|---|---|
| MSKCC (Motzer) | Cytokine | KPS <80, diagnosis-to-treatment <1 yr, Hb below LLN, corrected Ca >10, LDH >1.5× ULN | 0 favourable (30 mo), 1–2 intermediate (14 mo), ≥3 poor (5 mo) |
| IMDC (Heng) | Targeted | K-PINCH: KPS <80, Platelets >ULN, Interval <1 yr, Neutrophils >ULN, Calcium >10, Hb below LLN | 0 favourable (not reached), 1–2 intermediate (27 mo), ≥3 poor (9 mo) |
IMDC uses four Motzer factors (dropping LDH) plus neutrophils and platelets.
Cytoreductive Nephrectomy
In the cytokine era CN improved survival (SWOG 8949 + EORTC 30947). In the targeted era, CARMENA showed sunitinib alone was non-inferior to CN + sunitinib in intermediate/poor-risk disease (it does not apply to favourable-risk), and SURTIME favoured deferred CN (systemic therapy first). The 2019 CUA offers upfront CN to patients with good performance status (ECOG ≤1 / KPS ≥80), a resectable primary, limited metastatic burden, minimal metastatic symptoms, and no active CNS metastases — and avoids it with rapidly progressing disease or limited life expectancy. Non-optimal candidates receive systemic therapy first, with CN if they respond well. Lymphadenectomy is not recommended for cN0 disease.
Metastasectomy and Local Therapy
About a third of metachronous metastases are resectable, and complete metastasectomy can give long-term survival in selected patients — best with isolated metastases, a >2-year interval from nephrectomy, and favourable sites (lung most common, thyroid, bone, pancreas, adrenal). SBRT can treat oligometastatic or oligoprogressive disease, and radiotherapy palliates a symptomatic primary or metastatic sites.
Systemic Therapy
First-line choice follows IMDC risk:
| IMDC risk | Preferred first-line |
|---|---|
| Favourable | Axitinib + pembrolizumab (alternatives: avelumab/axitinib, sunitinib, pazopanib) |
| Intermediate / poor | Nivolumab + ipilimumab, or axitinib + pembrolizumab |
The key immunotherapy trials are CheckMate 214 (nivolumab + ipilimumab > sunitinib in intermediate/poor-risk), CheckMate 9ER (nivolumab + cabozantinib > sunitinib), and CLEAR (lenvatinib + pembrolizumab > sunitinib). Ipilimumab blocks CTLA-4 and nivolumab/pembrolizumab block PD-1; nivolumab + ipilimumab gives the highest complete-response rate (~9%).
- VEGF tyrosine-kinase inhibitors — sunitinib and pazopanib (equivalent in COMPARZ, but pazopanib causes more hepatotoxicity and sunitinib more fatigue, cytopenias, and hand-foot syndrome), plus sorafenib, axitinib (AXIS — second-line), and cabozantinib (VEGFR/MET/AXL). Class effects: hypertension, fatigue, diarrhoea, hand-foot syndrome, and — with sunitinib — hypothyroidism (monitor TSH). Bevacizumab is an anti-VEGF-A antibody.
- mTOR inhibitors — temsirolimus (first-line only in poor-risk, ARCC) and everolimus (later-line; first-line everolimus is inferior, RECORD-3). Sequence a VEGF-TKI first, then an mTOR inhibitor.
- Cytokines (historical) — high-dose IL-2 gives durable complete responses in 7–9% of ccRCC but with serious toxicity (vascular-leak syndrome; 2–5% mortality), so only high-dose regimens are used; IFN-α has been largely supplanted. Conventional chemotherapy is ineffective in ccRCC.
Second-line therapy depends on prior treatment (after immune-checkpoint therapy → cabozantinib or axitinib; after a VEGF-TKI → nivolumab or cabozantinib). Non-clear-cell RCC (~15–25%) has no standard therapy — enrol in a trial, otherwise treat as for clear-cell (IO combinations or sunitinib).
Bone-Modifying Agents
For bone metastases, zoledronic acid (avoid in renal dysfunction; monitor renal function) or denosumab (anti-RANK-ligand) reduce skeletal-related events. Give calcium and vitamin D (watch for hypocalcaemia, though paraneoplastic hypercalcaemia can coexist) and arrange a dental examination first (osteonecrosis-of-the-jaw risk).
Self-Test
1. What are the IMDC (Heng) risk factors and groups? K-PINCH: KPS <80, platelets >ULN, interval to treatment <1 yr, neutrophils >ULN, calcium >10, haemoglobin below LLN. Favourable 0, intermediate 1–2, poor ≥3 factors.
2. How did CARMENA and SURTIME change the role of cytoreductive nephrectomy? CARMENA showed sunitinib alone is non-inferior to CN + sunitinib in intermediate/poor-risk disease; SURTIME favoured deferred CN (systemic therapy first) — so CN is now reserved for selected good-risk patients.
3. What do nivolumab and ipilimumab target? Nivolumab targets PD-1; ipilimumab targets CTLA-4.
4. Name the VEGF and mTOR inhibitors used in RCC. VEGF — sunitinib, sorafenib, pazopanib, axitinib, cabozantinib, bevacizumab; mTOR — temsirolimus, everolimus.
5. What is the preferred first-line therapy in metastatic clear-cell RCC? Favourable-risk — axitinib + pembrolizumab; intermediate/poor-risk — nivolumab + ipilimumab or axitinib + pembrolizumab.