What is the evidence behind giving radiation therapy in patients with lymphovascular invasion (LVI) and perineural invasion (PNI)?

Evidence for Radiation Therapy in Lymphovascular Invasion (LVI) and Perineural Invasion (PNI)

Adjuvant radiation therapy should be offered to patients with lymphovascular invasion (LVI) and perineural invasion (PNI) due to their association with increased risk of locoregional recurrence and decreased survival outcomes.

Risk Stratification for Radiation Therapy

Perineural Invasion (PNI)

• PNI is a well-established adverse pathologic feature that significantly increases risk of locoregional recurrence and decreases survival 1

• Two distinct presentations of PNI exist:

  • Histologic/pathologic PNI (pPNI): Microscopic finding on pathology
  • Clinical PNI (cPNI): Symptomatic/radiographic evidence of nerve involvement

• Risk stratification for PNI:

  1. High risk (strong indication for RT):

     • Named nerve invasion
     • Multifocal PNI
     • Clinical symptoms of PNI
     • PNI in head and neck locations
     • PNI with other high-risk features (positive margins, high-grade tumors)

  2. Intermediate risk (consider RT):

     • Focal PNI as sole risk factor
     • PNI in desmoplastic melanoma

Lymphovascular Invasion (LVI)

• LVI is considered an intermediate-risk feature that increases risk of nodal metastasis and recurrence 1, 2
• LVI is often grouped with PNI as an indication for adjuvant radiation therapy in intermediate-risk groups 1

Evidence from Clinical Trials and Guidelines

The ECOG 3311 trial, a phase II randomized controlled trial of HPV-positive oropharyngeal cancer, provides the most recent high-quality evidence for radiation dosing in patients with intermediate risk factors including PNI and LVI 1:

• Patients with intermediate risk factors (including PNI/LVI) were randomized to:
  • 50 Gy adjuvant radiation
  • 60 Gy adjuvant radiation
• Results showed comparable 2-year progression-free survival:
  • 50 Gy arm: 94.9% (90% CI, 91.3-98.6)
  • 60 Gy arm: 96.0% (90% CI, 92.8-99.3)

This suggests that a reduced dose of 50 Gy may be sufficient for patients with intermediate risk factors like PNI and LVI in HPV-positive oropharyngeal cancer.

Radiation Treatment Recommendations

For Perineural Invasion:

1. Coverage:

   • Cover the surgical bed and the involved nerve pathway 1
   • For named nerve invasion, extend coverage to the skull base with intermediate dose (46-54 Gy) 1

2. Dose:

   • Standard fractionation: 60-66 Gy to high-risk areas 1, 3
   • For intermediate-risk HPV+ oropharyngeal cancer: 50 Gy may be sufficient 1

For Lymphovascular Invasion:

1. Coverage:

   • Surgical bed and regional nodal basins at risk

2. Dose:

   • Similar to PNI recommendations
   • For intermediate-risk HPV+ oropharyngeal cancer: 50 Gy may be sufficient 1

Cancer-Specific Considerations

Head and Neck Cancers

• PNI and LVI are strong indications for adjuvant RT 1
• In salivary gland malignancies, postoperative RT is strongly recommended for tumors with PNI or LVI 1
• For HPV-positive oropharyngeal cancer, reduced-dose radiation (50 Gy) may be appropriate for intermediate risk factors including PNI and LVI 1

Cutaneous Malignancies

• For cutaneous squamous cell carcinoma, PNI is a clear indication for adjuvant RT 3
• In melanoma, PNI (particularly in desmoplastic neurotropic melanoma) may warrant consideration of adjuvant RT 1
• For cutaneous head and neck carcinomas with PNI, surgery plus RT provides high local control rates (90% for pPNI) 4

Prognostic Impact

Multiple studies demonstrate the negative prognostic impact of PNI and LVI:

• PNI is an independent predictor for overall survival (HR 1.7) and disease-free survival (HR 1.84) in oral cavity SCC 5
• LVI is associated with decreased overall survival (HR not specified) 2
• Patients with early node-negative oral cavity SCC with PNI showed improved survival with adjuvant radiation (p=0.022) 5

Treatment Algorithm

1. Assess risk factors:

   • Determine if PNI/LVI is present
   • Evaluate other risk factors (margins, grade, nodal status)
   • Consider tumor type and location

2. Determine radiation indication:

   • High-risk features (named nerve invasion, multifocal PNI, clinical PNI): Strongly recommend RT
   • Intermediate-risk features (focal PNI/LVI alone): Consider RT based on tumor type and location

3. Select radiation dose:

   • Standard dose: 60-66 Gy at 2 Gy/fraction
   • For HPV+ oropharyngeal cancer with intermediate risk: Consider 50 Gy
   • For named nerve invasion: Include nerve pathway to skull base with 46-54 Gy

4. Timing:

   • Start within 6-7 weeks after surgery
   • Complete within 85 days of surgery

Conclusion

The evidence strongly supports the use of adjuvant radiation therapy in patients with PNI and LVI, particularly in head and neck cancers. The presence of these features significantly increases the risk of locoregional recurrence and decreases survival outcomes. Treatment decisions should be based on the specific tumor type, location, and presence of other risk factors.