What is the recommended treatment protocol for a patient with stage II-III anal cancer eligible for the RTOG0915 (Radiation Therapy Oncology Group) trial using IMRT (Intensity-Modulated Radiation Therapy)?

RTOG 0915 Treatment Protocol for Stage II-III Anal Cancer

For patients with stage II-III anal cancer eligible for IMRT-based treatment, the standard protocol consists of dose-painted intensity-modulated radiation therapy (IMRT) with simultaneous integrated boost (SIB) delivering 50.4-54 Gy to the primary tumor over 28-30 fractions, combined with concurrent 5-fluorouracil (1000 mg/m²/day as 96-hour infusion) and mitomycin-C (10 mg/m² bolus) on days 1 and 29. 1, 2

Radiation Therapy Specifications

Dose Prescription by Stage

For T2N0 disease:

• Elective nodal volumes: 42 Gy in 28 fractions (1.5 Gy/fraction)
• Anal tumor planning target volume: 50.4 Gy in 28 fractions (1.8 Gy/fraction) 2, 3

For T3-T4 or node-positive disease:

• Elective nodal volumes: 45 Gy in 30 fractions (1.5 Gy/fraction)
• Metastatic nodes ≤3 cm: 50.4 Gy in 30 fractions (1.68 Gy/fraction)
• Metastatic nodes >3 cm: 54 Gy in 30 fractions (1.8 Gy/fraction)
• Anal tumor planning target volume: 54 Gy in 30 fractions (1.8 Gy/fraction) 2, 3

Technical Requirements

IMRT is the required radiation modality because it significantly reduces acute grade 3+ toxicity compared to conventional techniques, particularly decreasing grade 3 gastrointestinal events (21% vs 36%, P=0.008) and grade 3 dermatologic events (23% vs 49%, P<0.0001). 4

Volumetric modulated arc therapy (VMAT) or helical tomotherapy is preferred over fixed-gantry IMRT with sliding window technique, as the latter shows significantly higher acute grade 3+ toxicity rates (38.5% vs 15.3%, P=0.049). 5

Daily image-guided radiotherapy must be utilized to ensure accurate dose delivery and minimize toxicity. 5

Target Volume Delineation

Include the following in radiation fields:

• Primary tumor with 2-5 cm margin
• Entire mesorectum (except very early tumors)
• Presacral lymph nodes
• Internal iliac lymph nodes
• Obturator lymph nodes
• Inguinal lymph nodes must be included even without obvious involvement, as the risk of inguinal nodal involvement is at least 20% in T3 disease and higher for tumors below the dentate line. 4

Chemotherapy Regimen

Standard Protocol

Primary regimen:

• 5-fluorouracil: 1000 mg/m²/day as continuous 96-hour infusion on days 1-4 and days 29-32
• Mitomycin-C: 10 mg/m² IV bolus on day 1 (and possibly day 29) 4, 1, 2

Alternative oral regimen (acceptable substitute):

• Capecitabine: 825 mg/m² orally twice daily, Monday through Friday, on each day of radiation therapy for 4-6 weeks
• Mitomycin-C: 10 mg/m² IV bolus on day 1 4, 1

Alternative for Mitomycin-Intolerant Patients

For patients unable to tolerate mitomycin-C (Category 2B):

• Cisplatin: 60 mg/m² IV on days 1 and 29
• 5-fluorouracil: continuous infusion as above 4, 1

However, cisplatin-based regimens are inferior: The RTOG 98-11 trial demonstrated significantly worse 5-year disease-free survival with cisplatin compared to mitomycin (57.8% vs 67.8%, P=0.006) and worse overall survival (70.7% vs 78.3%, P=0.026). 4

Critical Treatment Principles

Avoid Treatment Breaks

Treatment must be delivered continuously without planned breaks. The RTOG 92-08 trial demonstrated that planned 2-week treatment breaks were associated with increased locoregional failure rates and lower colostomy-free survival compared to continuous treatment. 4 Treatment breaks ≥3 days should occur in <15% of patients. 6

Do Not Use Induction or Maintenance Chemotherapy

Neither induction chemotherapy before chemoradiation nor maintenance chemotherapy after completion has shown benefit. The RTOG 98-11 and UK ACT II trials both demonstrated no improvement in progression-free survival, overall survival, or colostomy rates with these approaches. 4, 1

Avoid Dose Escalation Beyond 59 Gy

Radiation doses >59 Gy provide no additional benefit. The ACCORD 03 trial showed no improvement in colostomy-free survival with higher doses, and RTOG 92-08 confirmed this finding. 4

Expected Outcomes with RTOG 0915 Protocol

Long-term efficacy at 8 years:

• Overall survival: 68%
• Disease-free survival: 62%
• Colostomy-free survival: 66%
• Local-regional control: 84% 2

Acute toxicity rates:

• Grade 3 gastrointestinal: 8-10%
• Grade 3 dermatologic: 13-17%
• Grade 3 hematologic: 11-12%
• Grade 4 hematologic: 2% 2, 7, 3

Late toxicity rates at 4 years:

• Grade 2 events: 55%
• Grade 3 events: 16%
• Grade 4 events: 0%
• Grade 5 events: 4% (not treatment-related) 2

Pre-Treatment Counseling Requirements

Mandatory patient counseling includes:

• Infertility risks with information on sperm banking or oocyte/egg/ovarian tissue banking
• Risk of early treatment-induced menopause
• Changes to sexual function
• Daily vaginal dilator use during treatment to reduce radiation doses to sexual organs and prevent vaginal stenosis 4

Response Assessment

Clinical evaluation should occur 8-12 weeks after completion of chemoradiation. Response may be slow, with persistent disease potentially continuing to regress up to 26 weeks after treatment initiation. Patients with persistent but non-progressive disease should be followed closely rather than proceeding immediately to salvage surgery. 4, 1