Abstract
Purpose:
The combination of cisplatin and radiation or cetuximab and radiation improves overall survival of patients with locoregionally advanced head and neck carcinoma. NRG Oncology conducted a phase 3 trial to test the hypothesis that adding cetuximab to radiation and cisplatin would improve progression-free survival (PFS).
Methods and Materials:
Eligible patients with American Joint Committee on Cancer sixth edition stage T2 N2a-3 M0 or T3–4 N0–3 M0 were accrued from November 2005 to March 2009 and randomized to receive radiation and cisplatin without (arm A) or with (arm B) cetuximab. Outcomes were correlated with patient and tumor features. Late reactions were scored using Common Terminology Criteria for Adverse Events (version 3).
Results:
Of 891 analyzed patients, 452 with a median follow-up of 10.1 years were alive at analysis. The addition of cetuximab did not improve PFS (hazard ratio [HR], 1.06; 95% confidence interval [CI], 0.89–1.26; P = .74), with 10-year estimates of 43.6% (95% CI, 38.8–48.4) for arm A and 40.2% (95% CI, 35.4–45.0) for arm B. Cetuximab did not reduce locoregional failure (HR, 1.21; 95% CI, 0.95–1.53; P = .94) or distant metastasis (HR, 0.79; 95% CI, 0.54–1.14; P = .10) or improve overall survival (HR, 0.97; 95% CI, 0.80–1.16; P = .36). Cetuximab did not appear to improve PFS in either p16-positive oropharynx (HR, 1.30; 95% CI, 0.87–1.93) or p16-negative oropharynx or nonoropharyngeal primary (HR, 0.94; 95% CI, 0.73–1.21). Grade 3 to 4 late toxicity rates were 57.4% in arm A and 61.3% in arm B (P = .26).
Conclusions:
With a median follow-up of more than 10 years, this updated report confirms the addition of cetuximab to radiation therapy and cisplatin did not improve any measured outcome in the entire cohort or when stratifying by p16 status.
Introduction
Before the understanding of the role of the human papilloma virus (HPV) in the epidemiology, etiology, and prognosis of squamous cell carcinomas of the head and neck,1 significant efforts were undertaken to intensify therapy to improve overall survival (OS). For example, the acceleration of radiation therapy (RT) improved locoregional control over conventionally fractionated RT.2,3 A meta-analysis of trials of locoregional therapy with or without systemic therapy, the combination, particularly concurrent cisplatin, has been shown to improve OS over RT alone by approximately 7% at 5 years.4 However, further intensification with the combination of accelerated RT and concurrent cisplatin did not improve OS.5
In a similar locoregionally advanced head and neck cancer population, a phase 3 randomized trial of RT with or without cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, demonstrated a 9% improvement in 5-year survival with the addition of cetuximab.6 Nevertheless, with either approach, OS at 5 years was less than 50%. Furthermore, both promising phase 2 efficacy with the combination of RT, cisplatin, and cetuximab in the locoregionally advanced setting7 and a phase 3 trial showing the significantly improved response rate of cetuximab with cisplatin8 in the metastatic setting raised interest in exploring the combination of these drugs with RT.
Therefore, the NRG Oncology investigators launched a phase 3 trial (RTOG/NRG Oncology 0522) to examine the efficacy of RT with cisplatin with or without cetuximab. The primary results at 5 years were previously reported9; herein we report results with 10 years of follow-up.
Methods and Materials
Protocol and treatment
Patient selection criteria and demographics have previously been described.9 Briefly, patients with squamous cell carcinoma of the oropharynx, larynx, or hypopharynx with T2 N2–3 M0 or T3–4 any N M0 by American Joint Committee on Cancer (sixth edition) were enrolled. Patients were stratified by primary site (larynx vs nonlarynx), nodal status (N0 vs N1-N2b vs N2c-N3), Zubrod status (0 vs 1), use of intensity modulated RT (IMRT) (no vs yes), and receipt of pretreatment positron emission tomography/computed tomography (no vs yes). Patients were randomly assigned to RT with cisplatin without or with cetuximab in a 1:1 ratio.
If treated with 3-dimensional (3D) conformal RT, patients received 72 Gy in 42 fractions given over 6 weeks, with twice-daily radiation for the last 12 treatment days.2 If treated with IMRT, patients received 70 Gy in 35 fractions given over 6 weeks, with twice daily radiation once per week during weeks 2 to 6.3
In both arms, cisplatin was dosed at 100 mg/m2 given on day 1 and 22 of RT. If randomized to cetuximab, loading dose of 400 mg/m2 was given the week before RT, followed by 250 mg/m2 weekly during RT. Imaging was performed at 8 to 9 weeks posttreatment, at 6 months, and then annually, with physical examination every 3 months for 2 years, every 6 months through year 5, and then annually to assess tumor status and toxicity.
Statistical analysis
Primary endpoint and sample size derivation
The primary endpoint was progression-free survival (PFS). The primary hypothesis was the combination of radiation, cisplatin, and cetuximab improves PFS compared with radiation and cisplatin. In October 2008, the study sample size was increased from 720 to 945 and the primary endpoint was changed from disease-free survival to PFS (ie, second primary tumors were not considered a failure and persistent disease was not considered a failure at day 1). The targeted sample size of 945 patients (900 eligible) was based on detecting a 25% reduction in the risk of failure for PFS with 84% statistical power, a 1-sided test at the 0.025 significance level, and 3 interim efficacy and futility analyses.
Secondary endpoints
Secondary endpoints included in this report were OS, locoregional failure (LRF), distant metastasis (DM), late toxicity, and feeding tube utilization. LRF was defined as locoregional recurrence or progression (including salvage surgery for the primary site with tumor present or unknown, neck dissection >15 weeks after the end of RT with tumor present or unknown), death due to study cancer (index cancer), or unknown causes as first event; DM and death due to other causes were competing events. The planned subset analysis to evaluate the treatment effect within p16 subgroups was also updated here. This analysis was limited to patients with oropharyngeal cancer (OPC) with known p16 status or non-OPC.
Statistical methods
Statistical analysis was based on an intent-to-treat approach with all eligible patients. Failures for efficacy endpoints were previously defined.7 PFS and OS rates were estimated by the Kaplan-Meier method and tested using the 1-sided log-rank test at the 0.025 level. LRF and DM rates were estimated using the cumulative incidence method and tested using the 1-sided failure-specific log-rank test at the 0.025 level. Hypotheses for secondary endpoints tested whether the combination of radiation, cisplatin, and cetuximab had better clinical outcomes compared with radiation and cisplatin. Hazard ratios (HRs) were estimated from Cox models. Adverse events (AEs) were graded with the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. AEs reported as definitely, probably, or possibly related to protocol treatment (or with missing attribution) were considered treatment related. The acute and late periods were defined as ≤90 and >90 days from start of RT, respectively. Late AE rates were compared by Fisher’s exact test. The numbers of late grade 3 to 4 AEs (with each term counted once) were compared by Wilcoxon rank-sum test. To test for a differential treatment effect by p16 status, a Cox regression model was used with the following covariates: (1) assigned treatment; (2) p16 status; and (3) assigned treatment by p16 status interaction. Exploratory multivariable analyses within subgroups defined by p16 status and tumor site were also performed for all clinical outcomes. All tests were 2-sided 0.05 unless otherwise noted.
Results
RTOG/NRG Oncology 0522 opened to patient accrual on November 22, 2005, and closed on March 3, 2009, after enrolling 940 patients from 151 institutions. Forty-nine patients were excluded from analysis (47 were ineligible; 2 had no follow-up), leaving 891 analyzable patients, including 235 p16-positive and 86 patients with p16-negative OPC. Median follow-up for 452 surviving patients was 10.1 years, compared with 3.8 years in the initial report. Patient demographics, tumor characteristics, treatment characteristics, and acute and late toxicity were previously reported.9
Outcomes
PFS events have been reported in 512 patients, compared with 371 for the initial report. The addition of cetuximab did not improve PFS (HR, 1.06; 95% confidence interval [CI], 0.89–1.26; P = .74). Five- and 10-year PFS estimates were 56.0% (95% CI, 51.3–60.7) and 43.6% (95% CI, 38.8–48.4) for RT and cisplatin and 52.9% (95% CI, 48.2–57.7) and 40.2% (95% CI, 35.4–45.0) for RT and cisplatin/cetuximab, respectively (Fig. 1A). Patterns of first failure are shown in Table E1.
Fig. 1.
(A) Kaplan-Meier estimates of progression-free survival, (B) cumulative incidence estimates of locoregional failure, (C) cumulative incidence estimates of distant metastasis, and (D) Kaplan-Meier estimates of overall survival.
LRF events have been reported in 279 patients, compared with 212 for the initial report. Fifty-five of the new events were death without documented locoregional progression (17 study cancer and 38 unknown), which were defined as LRF events per protocol. In total, 52 patients (11.6%) in the RT/cisplatin arm and 43 patients (9.7%) in the RT and cisplatin/cetuximab arm had death without progression due to study cancer or unknown. The addition of cetuximab did not reduce LRF (HR, 1.21; 95% CI, 0.95–1.53; P = .94). Five- and 10-year LRF estimates are 22.7% (95% CI, 18.9–26.7) and 28.5% (95% CI, 24.2–32.9) for RT and cisplatin and 28.8% (95% CI, 24.5–33.1) and 34.8% (95% CI, 30.3–39.5) for RT and cisplatin/cetuximab, respectively (Fig. 1B).
DM events have been reported in 116 patients, compared with 102 for the initial report. The addition of cetuximab did not reduce DM (HR, 0.79; 95% CI, 0.54–1.14; P = .10). Five- and 10-year DM estimates are 13.9% (95% CI, 10.9–17.4) and 15.0% (95% CI, 11.8–18.6) for RT and cisplatin and 10.8% (95% CI, 8.1–14.0) and 11.8% (95% CI, 9.0–15.1) for RT and cisplatin/cetuximab, respectively (Fig. 1C).
Four-hundred thirty-nine deaths have been reported, compared with 261 for the initial report. The addition of cetuximab did not improve OS (HR, 0.97; 95% CI, 0.80–1.16; P = .36). Five- and 10-year OS estimates are 65.0% (95% CI, 60.5–69.5) and 49.9% (95% CI, 45.0–54.8) for RT and cisplatin and 65.9% (95% CI, 61.4–70.5) and 50.0% (95% CI, 45.1–54.9) for RT and cisplatin/cetuximab (Fig. 1D). The most common cause of death was the index cancer (41.5%), followed by unknown (23.0%) and death due to other cause (22.6%) (Tables E2 and E3).
Comparison of subgroups by p16 status
Patients with p16-positive OPC have significantly longer PFS compared with p16-negative OPC (HR, 0.54; 95% CI, 0.39–0.75; P = .0002). Five- and 10-year PFS estimates are 68.6% (95% CI, 62.6–74.5) and 57.7% (95% CI, 51.1–64.3) and 44.8% (95% CI, 34.1–55.5) and 36.8% (95% CI, 26.2–47.3) for OPC p16-positive and p16-negative, respectively (Fig. E1). The difference between PFS for p16-negative OPC and non-OPC was not statistically significant (P = .22; Fig. E2).
We therefore included non-OPC patients in the p16-negative group, as done in most contemporary clinical trials, for evaluation of the treatment effect. For PFS, the unadjusted treatment effect HRs are 1.30 (95% CI, 0.87–1.93) and 0.94 (95% CI, 0.73–1.21) for the p16-positive and p16-negative groups, respectively (P = .18 for interaction; Fig. 2A). The adjusted for age, Zubrod, T category, N category, and pack-years treatment effect HRs are quite similar to the unadjusted ones. In the p16-positive subgroup the adjusted HR was 1.35 (95% CI, 0.89–2.06), and for the p16-negative subgroup the adjusted HR was 1.03 (95% CI, 0.78–1.35) (P = .29 for interaction). Five- and 10-year estimates by p16 subgroup are shown in Table 1.
Fig. 2.
Kaplan-Meier estimates of (A) progression-free survival, (B) local-regional failure, (C) distant metastasis, and (D) overall survival by p16 status and assigned treatment including patients with nonoropharyngeal cancer in the p16-negative group.
Table 1.
Five- and 10-year estimates of PFS, LRF, DM, and OS
| Endpoint | Primary sites | RT + cisplatin | RT + cisplatin + cetuximab | ||
|---|---|---|---|---|---|
| 5-y estimate (95% CI) | 10-y estimate (95% CI) | 5-y estimate (95% CI) | 10-y estimate (95% CI) | ||
| PFS | All | 56.0% (51.3–60.7) | 43.6% (38.8–48.4) | 52.9% (48.2–57.7) | 40.2% (35.4–45.0) |
| p16-positive OPC | 73.7% (65.5–81.9) | 62.8% (53.5–72.2) | 63.9% (55.4–72.4) | 53.1% (43.9–62.3) | |
| Non-OPC or p16-negative OPC | 42.7% (35.3–50.0) | 27.0% (20.1–33.9) | 43.7% (36.1–51.3) | 29.4% (22.1–36.7) | |
| LRF | All | 22.7% (18.9–26.7) | 28.5% (24.2–32.9) | 28.8% (24.5–33.1) | 34.8% (30.3–39.5) |
| p16-positive OPC | 10.8% (5.9–17.5) | 14.1% (8.2–21.4) | 25.4% (18.0–33.4) | 27.6% (19.8–35.9) | |
| Non-OPC or p16-negative OPC | 32.1% (25.3–39.1) | 40.0% (32.5–47.3) | 31.8% (24.8–39.0) | 38.3% (30.6–45.9) | |
| DM | All | 13.9% (10.9–17.4) | 15.0% (11.8–18.6) | 10.8% (8.1–14.0) | 11.8% (9.0–15.1) |
| p16-positive OPC | 10.0% (5.3–16.5) | 10.0% (5.3–16.5) | 7.4% (3.6–13.0) | 8.4% (4.3–14.3) | |
| Non-OPC or p16-negative OPC | 17.7% (12.4–23.7) | 19.7% (14.1–26.0) | 12.9% (8.3–18.5) | 12.9% (8.3–18.5) | |
| OS | All | 65.0% (60.5–69.5) | 49.9% (45.0–54.8) | 65.9% (61.4–70.5) | 50.0% (45.1–54.9) |
| p16-positive OPC | 84.5% (77.7–91.3) | 69.6% (60.5–78.6) | 78.7% (71.4–85.9) | 66.4% (57.6–75.1) | |
| Non-OPC or p16-negative OPC | 50.0% (42.4–57.5) | 33.1% (25.8–40.4) | 53.3% (45.6–61.1) | 35.7% (28.0–43.4) | |
Abbreviations: CI = confidence interval; DM = distant metastasis; LRF = locoregional failure; OPC = oropharyngeal cancer; OS = overall survival; PFS = progression-free survival; RT = radiation therapy.
For LRF, the unadjusted treatment effect HRs were 1.95 (95% CI, 1.07–3.55) and 0.92 (95% CI, 0.65–1.29) for the p16-positive and p16-negative groups, respectively (P = .03 for interaction; Fig. 2B). In the p16-positive subgroup the adjusted HR was 2.05 (95% CI, 1.09–3.83), and for the p16-negative subgroup the adjusted HR was 1.04 (95% CI, 0.72–1.49) (P = .07 for interaction).
For DM, the unadjusted treatment effect HRs were 0.87 (95% CI, 0.37–2.04) and 0.64 (95% CI, 0.37–1.10) for the p16-positive and p16-negative groups, respectively (P = .56 for interaction; Fig. 2C). In the p16-positive subgroup the adjusted HR was 0.90 (95% CI, 0.38–2.13), and for the p16-negative subgroup the adjusted HR was 0.76 (95% CI, 0.43–1.36) (P = .76 for interaction).
For OS, the unadjusted HRs were 1.08 (95% CI, 0.68–1.69) and 0.92 (95% CI, 0.71–1.20) for the p16-positive and p16-negative groups, respectively (P = .56 for interaction; Fig. 2D). Adjusted for the same covariates, in the p16-positive subgroup the adjusted HR was 1.05 (95% CI, 0.65–1.69) and for the p16-negative subgroup the HR was 0.96 (95% CI, 0.72–1.29) (P = .77 for interaction).
Multivariable analyses
Table 2 shows multivariable analysis for PFS, LRF, and OS in all primary sites, in patients with OPC, in patients with p16-positive OPC, and in patients with non-OPC or p16-negative OPC. For all primary sites, factors significantly associated with poorer PFS were age >50, >10 pack-years, p16-negative OPC, non-OPC, and N2c or N3 disease; factors significantly associated with increased LRF were p16-negative OPC, non-OPC, T4 disease, and N2c or N3 disease; factors significantly associated with poorer OS were age >50, Zubrod 1, >10 pack-years, p16-negative OPC, non-OPC, and N2c or N3 disease. For OPC, factors significantly associated with poorer PFS were Zubrod 1, >10 pack-years, p16-negative status, and N2c or N3 disease; factors significantly associated with increased LRF were p16-negative status and N2c or N3 disease; factors significantly associated with poorer OS were age >50, Zubrod 1, and p16-negative status. For p16-positive OPC, the only factor significantly associated with poorer PFS was Zubrod 1; the only factor significantly associated with increased LRF was cetuximab treatment; factors significantly associated with poorer OS were age >50 and Zubrod 1. For non-OPC or p16-negative OPC, the only factor significantly associated with poorer PFS was N2c or N3 disease; the only factor significantly associated with increased LRF was N2c or N3 disease; factors significantly associated with poorer OS were age >50, >10 pack-years, and N2c or N3 disease.
Table 2.
Multivariable analysis of PFS, LRF, and OS
| Covariate | PFS | LRF | OS | |||
|---|---|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | HR (95% CI) | P value | |
| All primary sites | (n = 514; 301 events) | (n = 514; 162 events) | (n = 514; 256 events) | |||
| Cetuximab (yes vs no) | 1.11 (0.89–1.40) | .3526 | 1.24 (0.91–1.70) | .1735 | 0.98 (0.77–1.26) | .8936 |
| Age (>50 vs ≤50 y) | 1.42 (1.05–1.90) | .0210 | 0.93 (0.65–1.33) | .6946 | 1.97 (1.39–2.79) | .0001 |
| Zubrod performance status (1 vs 0) | 1.20 (0.94–1.52) | .1418 | 1.31 (0.95–1.81) | .0988 | 1.43 (1.10–1.85) | .0068 |
| Pack-years of smoking (>10 vs ≤10) | 1.43 (1.08–1.91) | .0137 | 1.22 (0.83–1.78) | .3054 | 1.44 (1.06–1.97) | .0210 |
| p16-negative versus p16-positive OPC | 1.61 (1.11–2.32) | .0116 | 2.21 (1.37–3.57) | .0011 | 2.16 (1.45–3.22) | .0001 |
| Non-OPC versus p16-positive OPC | 1.87 (1.41–2.49) | <.0001 | 2.14 (1.44–3.19) | .0002 | 2.25 (1.65–3.09) | <.0001 |
| T category (T4 vs T2–3) | 1.16 (0.89–1.52) | .2721 | 1.42 (1.01–2.01) | .0468 | 1.13 (0.84–1.51) | .4207 |
| N category (N2c-3 vs N0-2b) | 1.38 (1.09–1.74) | .0079 | 1.65 (1.20–2.26) | .0019 | 1.29 (1.00–1.67) | .0497 |
| OPC | (n = 288; 135 events) | (n = 288; 74 events) | (n = 288; 108 events) | |||
| Cetuximab (yes vs no) | 1.19 (0.84–1.69) | .3160 | 1.59 (0.98–2.56) | .0592 | 0.98 (0.66–1.44) | .9135 |
| Age (>50 vs ≤50 y) | 1.49 (0.96–2.30) | .0743 | 1.00 (0.59–1.69) | .9885 | 2.38 (1.36–4.14) | .0022 |
| Zubrod performance status (1 vs 0) | 1.58 (1.10–2.29) | .0141 | 1.30 (0.79–2.14) | .2963 | 2.16 (1.45–3.23) | .0002 |
| Pack-years of smoking (>10 vs ≤10) | 1.48 (1.04–2.11) | .0314 | 1.11 (0.68–1.79) | .6803 | 1.31 (0.88–1.96) | .1820 |
| p16-negative versus p16-positive | 1.48 (1.02–2.16) | .0394 | 2.18 (1.34–3.57) | .0018 | 2.04 (1.36–3.07) | .0006 |
| T category (T4 vs T2–3) | 1.23 (0.84–1.80) | .2875 | 1.51 (0.92–2.47) | .1030 | 1.39 (0.92–2.10) | .1224 |
| N category (N2c-3 vs N0-2b) | 1.63 (1.15–2.32) | .0061 | 1.88 (1.17–3.01) | .0087 | 1.46 (0.99–2.17) | .0570 |
| p16-positive OPC | (n = 216; 91 events) | (n = 216; 44 events) | (n = 216; 68 events) | |||
| Cetuximab (yes vs no) | 1.26 (0.82–1.94) | .2912 | 2.04 (1.08–3.85) | .0283 | 0.93 (0.57–1.53) | .7772 |
| Age (>50 vs ≤50 years) | 1.50 (0.87–2.58) | .1424 | 0.88 (0.45–1.73) | .7188 | 3.42 (1.55–7.55) | .0024 |
| Zubrod performance status (1 vs 0) | 1.74 (1.10–2.76) | .0188 | 0.99 (0.49–2.00) | .9816 | 2.60 (1.55–4.35) | .0003 |
| Pack-years of smoking (>10 vs ≤10) | 1.51 (0.99–2.29) | .0546 | 1.01 (0.55–1.87) | .9624 | 1.23 (0.76–1.99) | .4079 |
| T category (T4 vs T2–3) | 1.05 (0.63–1.75) | .8408 | 1.41 (0.70–2.82) | .3327 | 1.19 (0.68–2.09) | .5446 |
| N category (N2c-3 vs N0-2b) | 1.34 (0.87–2.06) | .1806 | 1.69 (0.93–3.09) | .0869 | 1.01 (0.61–1.69) | .9681 |
| Non-OPC or p16-negative OPC | (n = 298; 210 events) | (n = 298; 118 events) | (n = 298; 188 events) | |||
| Cetuximab (yes vs no) | 1.02 (0.77–1.35) | .8776 | 1.04 (0.72–1.50) | .8419 | 0.96 (0.72–1.29) | .7945 |
| Age (>50 vs ≤50 y) | 1.38 (0.97–1.97) | .0752 | 0.93 (0.61–1.42) | .7279 | 1.66 (1.13–2.46) | .0103 |
| Zubrod performance status (1 vs 0) | 1.04 (0.79–1.38) | .7836 | 1.34 (0.93–1.94) | .1167 | 1.20 (0.89–1.60) | .2336 |
| Pack-years of smoking (>10 vs ≤10) | 1.43 (0.98–2.08) | .0641 | 1.36 (0.83–2.25) | .2232 | 1.60 (1.06–2.42) | .0247 |
| T category (T4 vs T2–3) | 1.17 (0.85–1.61) | .3276 | 1.47 (0.99–2.20) | .0590 | 1.09 (0.77–1.54) | .6422 |
| N category (N2c-3 vs N0-2b) | 1.41 (1.06–1.87) | .0177 | 1.63 (1.13–2.37) | .0098 | 1.40 (1.04–1.90) | .0267 |
Analysis was limited to patients with complete data for p16 status and pack-years.
Abbreviations: CI = confidence interval; HR = hazard ratio from multivariable Cox model; LRF = locoregional failure; OPC = oropharyngeal cancer; OS = overall survival; PFS = progression-free survival.
Late toxicity
Table 3 presents late treatment-related AEs that occurred in at least 5% of patients (in either arm at any time during the late period) overall and by term (grade 2–3 for dry mouth and grade 3–4 for all others). One or more grade 3 to 4 late treatment-related AEs were reported for 57.4% and 61.3% of patients on the RT and cisplatin and RT and cisplatin/cetuximab arms, respectively (P = .26). Similarly, in the p16-positive subgroup, 1 or more grade 3 to 4 late treatment-related AEs were reported for 62.4% and 66.1% of patients on the RT and cisplatin and RT and cisplatin/cetuximab arms, respectively (P = .58); these rates were 57.2% and 61.8% in the non-OPC and p16-negative OPC subgroup (P = .43) (Table E4).
Table 3.
Treatment-relatedlateadverseeventrates
| RT + cisplatin | RT + cisplatin + cetuximab | P value | |
|---|---|---|---|
| Any late (>90 d from start of RT) | (n = 432) | (n = 416) | |
| Grade 3–4 any adverse event | 57.4% | 61.3% | .26 |
| Grade 3–4 dysphagia | 39.6% | 38.2% | |
| Grade 3–4 radiation mucositis | 5.3% | 7.0% | |
| Grade 3–4 mucositis/stomatitis (clinical examination): pharynx | 4.9% | 6.0% | |
| Grade 3–4 hearing impaired | 6.0% | 5.0% | |
| Grade 3–4 weight decreased | 7.6% | 8.7% | |
| Grade 3–4 osteonecrosis | 6.0% | 4.8% | |
| Grade 2–3 dry mouth | 47.0% | 45.9% |
Grade 3 to 4 late dysphagia was reported for 39.6% and 38.2% on the RT and cisplatin and RT and cisplatin/cetuximab arms, respectively. Grade 2 to 3 dry mouth was reported for 47.0% and 45.9% on the RT and cisplatin and RT and cisplatin/cetuximab arms, respectively. The distribution of the number of grade 3 to 4 late treatment-related AEs does not differ significantly by arm (P = .46; Table E5). Reported late toxicity decreased until 2 years from the start of RT, at which point 1 or more grade 3 to 4 late treatment-related AEs were reported for 11.9% and 10.5% of patients on the RT and cisplatin and RT and cisplatin/cetuximab arms, respectively. Beyond 2 years, there was relative stability in late toxicity until 10 years (Fig. 3A). Similarly, in the p16-positive subgroup, 1 or more grade 3 to 4 late treatment-related AEs at 2 years were reported for 15.4% and 6.8% of patients on the RT and cisplatin and RT and cisplatin/cetuximab arms, respectively (P = .07). In an exploratory analysis, there was a significant difference (P = .01) in the number of grade 3 to 4 late treatment-related AEs by RT technique, with 49% of patients treated with 3D-conformal radiotherapy (3D-CRT) experiencing 1 or more events compared with 60.7% treated with IMRT (Table E6).This result must be interpreted with caution as there could be selection bias and confounding factors when comparing RT techniques. For instance, additional analyses showed that more patients with OPC were treated with IMRT (72.4%) than 3D-CRT (53.3%). Likewise, patients treated with IMRT showed higher N stages (81.6% had N2a or higher on IMRT vs 66.4% on 3D-CRT).
Fig. 3.
Estimated rates of (A) grade 3 to 4 late toxicity and (B) feeding tube use. Measured from the start of radiation therapy, ±6 weeks for 6-month time point and ±3 months for all other time points.
Before the start of treatment, 13.6% of patients had a feeding tube. At 1 year, feeding tube rates were 21.2% and 18.8% on the RT and cisplatin and RT and cisplatin/cetuximab arms, respectively (P = .41). Similar to overall late toxicity, feeding tube rates declined up to 2 years after treatment to 13.5% and 12.0% on the RT and cisplatin and RT and cisplatin/cetuximab arms, respectively, and remained relatively stable thereafter (Fig. 3B). Of the 26 patients with feeding tubes present at 10 years posttreatment, 8 were in place at baseline.
Discussion
Unfortunately, this updated report of RTOG/NRG Oncology 0522 confirms the addition of cetuximab to RT/cisplatin in locoregionally advanced head and neck cancer did not improve PFS or other secondary outcomes (OS, LRF, or DM), though the long-term AEs did not differ between arms.
After completion of this trial, it has become evident that the biology of head and neck cancer is heterogenous, with many cancers, primarily localized to the oropharynx, being driven by HPV. Patients with cancers associated with HPV have been shown to have a relatively good prognosis, and therefore, rather than pursuing treatment intensification, an opposite approach of deintensifying therapy in a subset of low risk cancers is being pursued. Our study confirmed a good prognosis, with our patients with p16-positive tumors treated with radiation and cisplatin having estimated 5- and 10-year OS rates of 81.4% and 67.8%, respectively. As such, rather than combining agents, as it was believed that cetuximab was less toxic than cisplatin, several trials were conducted comparing the drugs concurrently with radiation in the hopes that cetuximab would result in a noninferior survival and have less toxicity. Both RTOG/NRG Oncology 1016 and De-ESCALaTE HPV, which enrolled patients with locoregionally advanced p16-positive OPC, demonstrated that RT and cisplatin had an OS benefit over RT and cetuximab.10,11 A mirror image trial performed by the Groupe Oncologie Radiotherapie Tete et Cou (GORTEC) randomized patients to RT and cetuximab or RT, cetuximab, carboplatin, and 5-fluorouracil. GORTEC 2007–01 showed that RT, cetuximab, and carboplatin/5-fluorouracil improved 3-year PFS by 11.8% (52.3% vs 40.5%).12
Similar to cetuximab, a phase 2 randomized trial of RT and panitumumab, a fully human monoclonal antibody against EGFR, showed inferior PFS to RT and cisplatin.13 The addition of panitumumab to RT and cisplatin also did not show improvements in any measured outcome over RT and cisplatin in a randomized phase 2 trial.14 In contrast, another humanized immunoglobulin G1 isotype monoclonal antibody against EGFR, nimotuzumab, when added to RT and cisplatin (30 mg/m2 given weekly) improved LRF and PFS over RT and cisplatin alone in a phase 3 randomized trial.15 Interestingly, on subgroup analysis, the PFS benefit was only seen in p16-negative OPCs (HR, 0.54; 95% CI, 0.36–0.79).12
On subset analysis of the OPC p16-positive group, patients randomized to RT with cisplatin and cetuximab had significantly worse LRF on both univariate and multivariate analyses, and PFS and OS were not significantly different on either analysis. Although the finding of worse LRF with the addition of cetuximab to RT/cisplatin is concerning, this result should be interpreted with caution, as patients with unknown p16 status were excluded, and it represents an unplanned post hoc exploratory analysis without correction for multiple hypothesis testing.16 Reanalysis of the phase 3 cetuximab study showed improvement in outcome for both p16-positive as well as p16-negative subsets, although the available sample size with p16 data was small and the results were based on a subset analysis.17 However, as noted previously, the combination of RT, cisplatin, and nimotuzumab did not demonstrate an improvement in PFS in the patients with p16-positive OPC, though these patients comprised a small percentage of the overall trial. In contrast, the addition of concurrent chemotherapy to RT/cetuximab improved LRF and PFS regardless of p16 status, without a significant improvement in OS.12 However, the p16-positive sample size in this study was limited, only 49 overall. Given the results of RTOG/NRG Oncology 1016, which compared RT/cisplatin and RT/cetuximab in p16-positive locoregionally advanced OPCs, RT/cisplatin remains the standard of care in these patients.10
Our study also confirmed that patients with non-HPV associated cancers have suboptimal survival rates, with 5- and 10-year OS approximately only 50% and 33%, respectively. Additional interventions are necessary to improve outcomes in patients with head and neck cancer, especially for the p16-negative OPC and non-OPC subgroups. Recent work in the first line recurrent/metastatic setting has shown that pembrolizumab with or without chemotherapy is superior to chemotherapy alone.18 An initial trial with RT and cisplatin with or without avelumab, however, was reported to be negative.19 Additional trials using a variety of immunotherapy agents in combination and/or adjuvantly to RT and cisplatin are ongoing. Alternatively, GORTEC recently reported a randomized phase 2 trial of RT and cisplatin with or without xevinapant, an orally available antagonist of inhibitor of apoptosis proteins. The addition of xevinapant met the primary endpoint of improving locoregional control at 18 months, 54% compared with 33%.20 Presentation of updated results also suggested an OS benefit to the addition of xevinapant (HR, 0.49; 95% CI, 0.26–0.92; P = .03).21 RTOG/NRG Oncology 0522 was one of the first multi-institutional phase 3 randomized trials to allow for IMRT, with 88% of patients receiving this technique.9 Therefore, it was concerning that in the entire cohort 59% of patients had 1 or more grade 3 to 4 late AEs. RTOG 0129, a prior study in a similar population that used 3D-conformal RT, reported 38% grade 3 to 5 late AEs with accelerated RT and cisplatin.22 However, it should be noted the definition of late toxicity on this trial was via RTOG/EORTC criteria rather than CTCAE version 3, which may result in difficulty comparing rates across trials. Although on exploratory analysis 3D conformal RT had lower late toxicity than IMRT, patients were not stratified by treatment technique, and there were imbalances between groups favoring 3D conformal RT.
A later study, RTOG/NRG Oncology 1016, which enrolled only p16-positive locoregionally advanced OPCs, used a definition of late toxicity of >180 days from completion of treatment, rather than 90 days from initiation of treatment on the current trial, and graded via CTCAE version 4. At 6 months from the start of RT, grade 3 to 4 AEs were 29.7% on RTOG/NRG Oncology 0522 in the p16-postive subgroup compared with 11% 6 months after the end of RT on RTOG/NRG Oncology 1016. Patients treated with accelerated RT and cisplatin on RTOG 0129 had 1- and 5-year feeding tube rates of 26% and 13%, respectively. Patients treated on the same arm of RTOG/NRG Oncology 1016 had similar feeding tube rates, 24% at 1 year and 10% at 5 years. RTOG/NRG Oncology 1016 reported feeding tube rates of 9% and 5% at 1 and 5 years in p16-positive oropharyngeal patients treated with accelerated RT and cisplatin.
Although differences may be a result of a different mix of primary sites, stage, p16-positivity, and time of measurement, it should also be acknowledged the techniques of RT have also changed and improved with time. For example, in RTOG/NRG Oncology 0522 the gross tumor volume was expanded by 1 cm for the high-dose target and 2 cm for the intermediate-dose target, and then an additional 5 mm for the planning target volumes (PTVs). In RTOG/NRG Oncology 1016, the gross tumor volume was expanded 0.5 to 1.5 cm to create the clinical target volume, and then an additional 3 to 5 mm for the PTV. Smaller targets will result in lower doses to organs at risk outside the PTV, and thus presumably less toxicity. In RTOG/NRG Oncology 0522, only 4 critical structures were required to be contoured—spinal cord, parotids, glottis larynx, and brachial plexus. RTOG/NRG Oncology 1016 required at least 9 critical structures to be contoured—spinal cord, brain stem, lips, oral cavity, parotid gland, pharyngeal constrictors, cervical esophagus, glottic/supraglottic larynx, and mandible. Prospective studies have suggested continued improvements in the risk of late toxicity with refinements in IMRT techniques.23–26
Conclusions
In summary, with a median follow-up of over 10 years, this updated report confirms the addition of cetuximab to RT and cisplatin did not improve any measured outcome in the entire cohort or when stratifying by p16 status. We therefore must conclude the combination of cetuximab, and perhaps any EGFR-inhibition, with the combination of RT and cisplatin is not a viable option to improve the treatment results in patients with locoregionally advanced laryngeal, hypopharyngeal, or OPC, whether p16-positive or −negative. Although late toxicity with intensive RT and cisplatin is substantial, there is evidence of resolution of reported events over the first 2 years after treatment.
Supplementary Material
Acknowledgments—
We gratefully acknowledge the late Dr Kian Ang of Anderson Cancer Center for his guidance and extensive work on the NRG/RTOG 0522 protocol design and development and his expertise in head and neck cancer research. Thank you to the investigators and their teams; the NRG protocol development, regulatory, statistical, data management, and tissue bank staff; the Imaging and Radiation Oncology Core and National Clinical Trials Network participants; and most importantly, the patients and their families.
This project was supported by grants UG1CA189867 (NRG Oncology NCORP), U10CA180868 (NRG Oncology Operations), U10CA180822 (NRG Oncology SDMC), U24CA196067 (NRG Oncology Biospecimen Bank), and U24CA180803 (Imaging and Radiation Oncology Core) from the National Cancer Institute, with additional support from Eli Lilly.
Disclosures:
J.J.C. declares during the past 36 months grants or contracts from, consulting fees, and payment or honoraria from Varian Medical Systems. D.I.R. declares during the past 36 months participation on data safety monitoring or advisory board for Merck. R.S.A. declares her institution has received NRG/Radiation Therapy Oncology Group (RTOG) support for the study in the past. E.J.S. declares during the past 36 months grants or contracts from Roche, Eli Lilly, and Regeneron (institution); consulting fees from BMS, Regeneron, Novartis, Eisai, BluePrint, Lilly, and Novartis; and manuscript writing from Roche. A.A. K. declares during the past 36 months participation on the board of chancellors at ACR. N.E.D. declares during the past 36 months speaker fees from AstraZeneca. J.A.B. declares during the past 36 months royalties or licenses from Bristol Meyers, Eli Lilly, and Merck Serono; consulting fees from Cel-Sci and Merck Serono; payment or honoraria from Bristol Meyers, Eli Lilly, Merck Serono, and Cel-Sci; and support for attending meetings and/or travel from Bristol Meyers, Eli Lilly, and Merck Serono. Q.-T.L. declares during the past 36 months an honorarium from and advisory board participation at CWTS Spore; the position of head and neck chair at NRG Oncology; and stock or stock options from Aldea.
Footnotes
The abstract was presented at the 2020 Annual Multidisciplinary H&N Meeting as an oral presentation.
This protocol is registered with ClinicalTrials.gov and may be viewed online at https://clinicaltrials.gov/ct2/show/NCT00265941.
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.ijrobp.2022.12.015.
Data sharing statement:
All data will be made available per the National Clinical Trials Network Data Archive rules. The link for the archive is: https://nctn-data-archive.nci.nih.gov/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
All data will be made available per the National Clinical Trials Network Data Archive rules. The link for the archive is: https://nctn-data-archive.nci.nih.gov/.