What was the 3-year overall survival difference in HPV positive patients vs. HPV negative patients according to the results of RTOG 0129 (Ang et al. NEJM 2010), a phase III randomized control trial of locally advanced squamous cell carcinoma of the head and neck?
Head and Neck
General Head And Neck
RTOG 0129 (Ang et al. NEJM 2010) was a phase III randomized controlled trial with an original intention to compare accelerated fractionation radiation therapy with concurrent chemotherapy vs. conventionally fractionated radiation therapy with concurrent chemotherapy.
Eligible patients included those with untreated stage III/IV squamous-cell carcinoma of the oropharynx, hypopharynx, or larynx without evidence of distant disease, Zubrod (ECOG) performance status of 0 or 1, and adequate bone marrow, hepatic, and renal function. Stratification was based on performance status, tumor site, and nodal status. Patients were than randomized into one of the following arms:
Conventional fractionation with concurrent chemotherapy: 70 Gy in 35 fractions over 7 weeks. Chemotherapy was cisplatin100mg/m2 days 1, 22, 43 (3 cycles)
Accelerated fractionation with concurrent chemotherapy: 72 Gy in 42 fractions over 6 weeks. Chemotherapy was cisplatin100mg/m2 days 1, 22, 43 (2 cycles)
With a median follow-up of 4.8 years they reported 3-year overall survival: 70.3% accelerated vs. 64.3% conventional p=0.18. There was also no significant difference in the two arms between progression free survival, patterns of failure, acute grade 3/4 toxicity, or late toxic events.
More importantly, the authors performed a retrospective analysis of the association between tumor HPV status and survival among the patients enrolled in the study. Their results were practice changing and led to a paradigm shift in the treatment of head and neck cancer.
3-yr overall survival per tumor HPV status: 82.4% HPV positive vs. 57.1% HPV negative, p < 0.001
3-yr progression-free survival per tumor HPV status: 73.7% HPV positive vs. 43.4% HPV negative, p < 0.001
3-yr local regional relapse per tumor HPV status: 13.6% HPV positive vs. 35.1% HPV negative, p < 0.001
3-yr distant metastasis per tumor HPV status: 8.7% HPV positive vs. 14.6% HPV negative, p = 0.23
A recursive partitioning analysis was completed and classified patients into low, intermediate, and high risk of death on the basis of:
Number of pack years (tobacco smoking)
HPV positive tumor, less than or equal to 10 pack years of smoking
HPV positive tumor, greater than 10 pack years of smoking, and N0-N2 disease
HPV positive tumor, greater than 10 pack years, and N2b-N3 disease
HPV negative tumor, less than or equal to 10 pack years, and T2-T3 tumor
HPV negative tumor, less than or equal to 10 pack years, and T4 tumor
HPV negative tumor, and greater than 10 pack years
3-year overall survival according to risk classification: 93% low vs. 71% intermediate vs. 46% high
Conclusion: There was no statistically significant difference in outcomes between the conventional fractionation arm and accelerated fractionation arm. Therefore, conventional fractionation with concurrent cisplatin (100 mg/m2 on days 1, 22, 43) should be considered the standard of care in locally advanced head and neck cancer. In addition, HPV status is prognostic and when taken together with T-stage, N-stage, and smoking history can be used to risk stratify patients.