What is the recommended management for papillary renal cell carcinoma, including surgical and systemic therapy options based on stage and patient fitness?

Management of Papillary Renal Cell Carcinoma

For localized papillary RCC, partial nephrectomy is the preferred surgical approach for tumors ≤7 cm, while for advanced/metastatic disease, cabozantinib has emerged as the first-line standard based on superior progression-free survival over sunitinib. 1

Localized Disease Management

Surgical Approach by Tumor Size

For T1 tumors (≤7 cm):

• Partial nephrectomy is the recommended first-line treatment, preserving renal function with equivalent oncological outcomes to radical nephrectomy 1, 2
• Laparoscopic or robot-assisted approaches are preferred when technically feasible, offering reduced morbidity and shorter hospital stays compared to open surgery 1
• The 5-year survival rate for stage I disease approaches 95% 2

For T2 tumors (>7 cm):

• Radical nephrectomy becomes the preferred option 2, 3
• Open radical nephrectomy with negative margins remains standard for locally advanced disease 1
• The 5-year survival rate is approximately 88% 2

For T3-T4 tumors:

• Radical nephrectomy plus adrenalectomy is recommended 2, 3
• Lymph node dissection should be performed for clinically enlarged nodes 2, 3
• The 5-year survival rate drops to approximately 59% 2, 3

Special Considerations for Elderly Patients

• Ablative treatments (radiofrequency ablation, cryotherapy) are alternative approaches for patients ≥75 years with tumors ≤3 cm and substantial comorbidities 1
• Active surveillance is an acceptable option for patients ≥75 years with solid renal tumors <4 cm and significant comorbidities 1

Advanced/Metastatic Papillary RCC Management

First-Line Systemic Therapy

The treatment landscape for papillary RCC has fundamentally changed based on recent trial data:

Cabozantinib is now the preferred first-line agent based on the SWOG PAPMET trial, which demonstrated:

• Superior PFS: 9.0 months vs 5.6 months with sunitinib (HR 0.60,95% CI 0.37-0.97, P=0.02) 1
• Higher response rate: 23% vs 4% for sunitinib 1
• Median OS of 20 months (though not statistically significant vs sunitinib's 16 months) 1

Pembrolizumab monotherapy is an alternative option:

• Demonstrated 29% response rate in papillary RCC patients 1
• PFS of 5.5 months (95% CI 3.9-6.1 months) 1
• OS of 31.5 months (95% CI 25.5 months-NR) 1
• Particularly valuable for patients who cannot tolerate VEGFR-targeted therapy 1

For MET-driven tumors (approximately 30% of papillary RCC):

• Consider MET inhibitors like savolitinib if molecular testing confirms MET alterations (chromosome 7 gain, MET amplification, MET kinase domain variations, or HGF amplification) 1
• The SAVOIR trial showed median PFS of 7.0 months with savolitinib vs 5.6 months with sunitinib in MET-driven disease 1

Historical Context and Limitations

Important caveat: Most systemic therapy recommendations historically derived from clear cell RCC trials, with papillary RCC representing only small subsets 1. Earlier guidelines recommended sunitinib based on the ASPEN trial (n=70 papillary patients), which showed improved response rate (24% vs 5%) and PFS (8.1 vs 5.5 months) compared to everolimus 1. However, cabozantinib has now superseded this recommendation.

Second-Line Therapy Options

After progression on first-line VEGFR-targeted therapy:

• Everolimus 1
• Axitinib 1
• Sorafenib 1
• Pazopanib 1

After progression on cytokines:

• Axitinib (Level IA evidence) 1
• Sunitinib 1

Role of Cytoreductive Nephrectomy

For metastatic disease with good performance status:

• Cytoreductive nephrectomy is recommended for patients with good performance status, large primary tumors, and symptomatic primary lesions 1
• Do not perform cytoreductive nephrectomy in patients with poor performance status 1
• The 5-year survival rate for stage IV disease is approximately 20% 2, 3

Metastasectomy Considerations

Metastasectomy should be considered after multidisciplinary review for:

• Solitary or easily accessible pulmonary metastases 1
• Solitary resectable intra-abdominal metastases 1
• Long disease-free interval (≥2 years) after nephrectomy 1
• Partial response to systemic therapy before resection 1

Risk Stratification

Use the MSKCC risk model to guide treatment intensity:

Five risk factors predict shorter survival:

• Low Karnofsky performance status (<70) 1, 2
• Elevated lactate dehydrogenase 1, 2
• Low serum hemoglobin 1, 2
• Elevated corrected serum calcium 1, 2
• Time from diagnosis to therapy <1 year 1, 2

Risk groups:

• Favorable (0 risk factors): median survival 30 months 1
• Intermediate (1-2 risk factors): median survival 14 months 1
• Poor (≥3 risk factors): median survival 6 months 1

Critical Distinctions from Clear Cell RCC

Papillary RCC differs fundamentally from clear cell RCC:

• Represents 7-15% of all RCC cases 1
• Two subtypes exist: Type I (73% of cases, scarce cytoplasm) and Type II (42%, eosinophilic cytoplasm) 1
• Strong expression of α-methylacyl-CoA racemase is characteristic 1
• Not associated with VHL mutations unlike clear cell RCC 4, 5
• MET mutations are essential in hereditary forms but rare in sporadic cases 4, 5
• Despite often presenting with smaller, lower-grade tumors, long-term prognosis is comparable to clear cell RCC 6

Common Pitfalls to Avoid

Do not assume papillary RCC has a universally favorable prognosis - while historically considered more indolent, survival outcomes are comparable to clear cell RCC when matched by stage 6, 7

Do not extrapolate clear cell RCC treatment data directly to papillary RCC - the molecular biology differs significantly, and response rates to targeted therapies are generally lower 1, 8

Do not perform routine adrenalectomy or lymph node dissection for all radical nephrectomies - these are only indicated for specific clinical scenarios 1

Do not offer cytoreductive nephrectomy to poor performance status patients - this provides no benefit and increases morbidity 1