RTOG-0129 was a Phase 3 Randomized Trial – Accelerated-Fractionation Radiotherapy vs. Standard-Fractionation

RTOG-0129:
- Was a phase 3 randomized trial (enrolled 2002 to 2005) conducted by the Radiation Therapy Oncology Group:
  - That tested whether accelerated-fractionation radiotherapy improves outcomes over standard-fractionation radiotherapy:
    - When each is given concurrently with cisplatin in locally advanced (stage III to IV) head and neck squamous-cell carcinoma
- Its primary comparison was negative :
  - The two radiotherapy schedules produced equivalent survival:
  - But its retrospective HPV analysis became a landmark:
    - Establishing tumor HPV status as a strong independent prognostic factor in oropharyngeal cancer
Design:
- Population:
  - Patients with locally advanced (stage III to IV) squamous-cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx:
    - 743 randomized:
      - 738 analyzed
- Standard-fractionation arm:
  - 70 Gy in 2 Gy fractions once daily, 5 days / week over 7 weeks (35 fractions), with cisplatin 100 mg/m² on days 1, 22, and 43 (3 cycles)
- Accelerated-fractionation arm (concomitant boost):
  - 72 Gy over 6 weeks — 1.8 Gy / fraction to the large field, plus a second daily 1.5 Gy boost fraction during the last 12 treatment days — with cisplatin 100 mg/m² on days 1 and 22 (2 cycles)
- Technique:
  - IMRT was not permitted:
    - Treatment used 2D / 3D conformal radiotherapy
- Median follow-up was 4.8 years in the original report, with long-term follow-up of 7.9 years in later analyses
Primary result (fractionation):
- There was no significant difference between arms
- The 3-year overall survival was 70.3% with accelerated fractionation versus 64.3% with standard fractionation (P=0.18; HR for death 0.90, 95% CI 0.72–1.13), and rates of high-grade acute and late toxicity were similar
- This supported the conclusion that accelerated fractionation offers no efficacy advantage over conventional fractionation when combined with concurrent cisplatin
Landmark HPV finding:
- Among patients with oropharyngeal cancer, 63.8% (206/323) had HPV-positive tumors
- These patients were younger, more often white, had fewer pack-years, and smaller primaries:
  - 3-year overall survival:
    - 82.4% (HPV-positive) vs 57.1% (HPV-negative); P<0.001
    - After adjustment for age, race, tumor / nodal stage, tobacco, and treatment:
      - HPV-positive status conferred a 58% reduction in risk of death (HR 0.42, 95% CI 0.27–0.66)
    - The 8-year overall survival rate was 70.9% vs 30.2% (HR 0.30, 95% CI 0.21–0.42)
References:
- Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N Engl J Med. 2010.
- Ang KK, Harris J, Wheeler R, et al. Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer. N Engl J Med. 2010.
- Lacas B, Bourhis J, Overgaard J, et al. Role of Radiotherapy Fractionation in Head and Neck Cancers (MARCH): An Updated Meta-Analysis. Lancet Oncol. 2017.
- De Felice F, Bonomo P, Sanguineti G, Orlandi E. Moderately accelerated intensity-modulated radiation therapy using simultaneous integrated boost: Practical reasons or evidence-based choice? A critical appraisal of literature. Head Neck. 2020.
- Driessen CM, Janssens GO, van der Graaf WT, et al. Toxicity and efficacy of accelerated radiotherapy with concurrent weekly cisplatin for locally advanced head and neck carcinoma. Head Neck. 2016.
- National Comprehensive Cancer Network. Head and Neck Cancers. 2026.
  Chow LQM. Head and Neck Cancer. N Engl J Med. 2020.
- Budach V, Tinhofer I. Novel Prognostic Clinical Factors and Biomarkers for Outcome Prediction in Head and Neck Cancer: A Systematic Review. Lancet Oncol. 2019.