Presenter: K. Ang, University of Texas M. D. Anderson Cancer Center, Houston, TX
Accelerated fractionation of radiotherapy and concurrent chemoradiotherapy have both been shown to improve outcomes in locally advanced HNC patients compared to standard fractionated radiotherapy alone.
RTOG 9003 was a phase III randomized trial that compared 4 different radiation therapy fractionation schemes. The study showed a significant benefit in local-regional control with hyperfractionated therapy or accelerated fractionation with concomitant boost compared to standard fractionated radiotherapy (Fu et al. IJROBP, 2000).
Several randomized clinical trials as well as a meta-analysis published by Pignon et al. (Lancet, 2000) have demonstrated an overall survival benefit with the addition of chemotherapy to radiation as part of definitive therapy for HNC.
However, it is unknown if accelerated fractionation confers a benefit for HNC patients when combined with concurrent chemotherapy.
RTOG 0129 was a phase III randomized trial comparing two different regimens of concurrent chemoradiation.
Analysis of the primary endpoints were reported at the 2009 ASTRO annual meeting and there was no observed significant difference in overall survival among patients receiving accelerated fractionation and concurrent chemotherapy versus standard fractionation with concurrent chemotherapy.
The current analysis retrospectively examined the impact of tumor, patient, and therapeutic variables on patient outcomes.
The RTOG 0129 was a multi-institutional phase III randomized trial that was designed to compare the combination of accelerated fractionation radiotherapy vs. standard fractionated radiotherapy when both are combined with concurrent cisplatin chemotherapy for locally advanced HNC.
Patients with Stage III or IV Squamous Cell Carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx were randomized to one of two treatment arms:
Accelerated fractionation radiotherapy with concomitant boost (AFX-C), consisting of 72 Gy delivered in 42 fractions over 6 weeks with 2 cycles of concurrent cisplatin, delivered on days 1 and 22 (100 mg/m2).
Standard fractionation (SFX) radiotherapy consisting of 70 Gy delivered in 35 fractions over 7 weeks with 3 cycles of concurrent cisplatin given on days 1,22, and 43 (100 mg/m2).
The primary endpoint of this trial was to detect a 25% improvement in overall survival (OS).
The current report is of an unplanned secondary analysis which was intended to further examine the potential impact of tumor, patient, and therapeutic variables on OS, progression free survival (PFS), and local regional progression (LRP).
Eligibility criteria for this subset analysis included:
Patients were required to have been alive > 3 months post enrollment without disease progression
Receipt of therapy as per protocol or with minor deviations (Defined as: 1-3 cycles of cisplatin, RT dose > 63 Gy or ? 90 % of the prescribed dose, and overall RT duration ? 9 weeks).
Overall survival was calculated via the Kaplan-Meier method and compared via log-rank tests.
Cox-proportional hazards models were used to estimate hazard ratios, adjusting for patient, tumor, and treatment variables.
743 patients were enrolled in the trial from 7/02-6/05, and 721 patients were included in the final analysis after 22 patients were either found to be ineligible or withdrew consent.
The two study arms were found to be well-balanced in terms of patient and tumor characteristics.
60% of the patients enrolled had oropharyngeal primary cancers.
80-86% of the patients were male
There was no difference observed in the trial’s primary endpoint (5 year survival: 59% vs. 56%; HR: 0.90, 0.72-1.13; p=0.18).
656 patients (91%) were eligible for the current secondary analysis
Median f/u for these patients was 4.8 years
Compared to patients receiving 3 cycles of cisplatin, patients receiving only 1 cycle of cisplatin had significantly inferior OS [hazard ratio (HR) 2.1, 95% CI 1.35-3.32,)] and PFS (HR 1.8, 95% CI 1.19-2.82), and greater rates of local-regional relapse (HR 1.9, 95% CI 1.07-3.34).
Patients receiving SFX with 2 cycles of cisplatin were more likely to experience local-regional relapse compared to those patients receiving the total prescribed dose of chemotherapy (HR 1.7, 95% CI 1.20-2.54).
Delayed completion of radiotherapy (Total course given over 8-9 weeks vs. 6-7 weeks) was also associated with inferior overall survival (HR 2.2, 95% CI 1.33-3.46).
When analyzed as a continuous variable, each day of RT delay compromised OS, PFS, and LRP by 5%, 4%, and 4% (p=0.001, 0.006, and 0.02), respectively.
No treatment variables were found to significantly affect the rates of distant metastases.
Rates of grade 3-4 late toxicities did not significantly differ by treatment variables.
In this unplanned secondary subset analysis of patients enrolled in the RTOG 0129 trial, the authors found that patients receiving only 1 cycle of cisplatin had inferior OS, PFS, and LRR compared to patients receiving the total prescribed dose of cisplatin.
Delayed completion of radiotherapy also had a significant effect on patient overall survival.
The RTOG 0129 trial was designed to examine the potential benefit of altered fractionation in the setting of concurrent chemoradiation for locally advanced head and neck cancer.
The results of the primary analysis show no difference in OS, PFS, or LRR between the two groups and therefore the standard of care for these patients remains concurrent chemoradiation with standard fractionation.
This secondary analysis examines the impact of tumor, patient, and treatment variables on patient outcomes including OS, PFS, LRR, and the development of distant metastasis.
The authors found that patients receiving only 1 cycle of cisplatin, and/or those experiencing delayed completion of radiotherapy had inferior overall survival.
However, the results of this study have several limitations:
This analysis was an unplanned retrospective subset analysis that is inherently subject to potential bias.
It is likely that patients receiving only 1 cycle of cisplatin, or delayed completion of radiotherapy, experienced additional complications during their treatment course that could explain these protocol violations and are not accounted for in the analysis.
Therefore, while the study suggests that a single cycle of cisplatin is inadequate and delays in completion of radiotherapy may have adverse consequences, both conclusions that may impact practice significantly, these results should be interpreted cautiously given the potential inherent biases of the study.
Jan 15, 2014 - Patients with head and neck cancers treated with intensity-modulated radiation therapy (IMRT) experience significant improvements in cause-specific survival compared with patients treated with non-IMRT techniques, according to a study published online Jan. 13 in Cancer.