Elsevier

Oral Oncology

Volume 50, Issue 10, October 2014, Pages 947-955
Oral Oncology

Efficacy of concurrent cetuximab vs. 5-fluorouracil/carboplatin or high-dose cisplatin with intensity-modulated radiation therapy (IMRT) for locally-advanced head and neck cancer (LAHNSCC)

Presented in part at the American Society of Clinical Oncology Annual Meeting, 2012
https://doi.org/10.1016/j.oraloncology.2014.07.001Get rights and content

Summary

Objectives

We previously reported inferior outcomes for locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients treated with concurrent cetuximab vs. high-dose cisplatin with intensity-modulated radiation therapy (IMRT). Prior to FDA approval of cetuximab for LAHNSCC, non-cisplatin eligible patients at our institution received 5-fluorouracil (5FU)/carboplatin. We sought to compare concurrent cetuximab vs. 5FU/carboplatin vs. high-dose cisplatin with IMRT for LAHNSCC.

Materials and methods

Retrospective review was performed for LAHNSCC patients treated at Memorial Sloan-Kettering Cancer Center from 11/02 to 04/08 with concurrent cetuximab (n = 49), 5FU/carboplatin (n = 52), or cisplatin (n = 259) and IMRT. Overall survival (OS), locoregional failure (LRF), distant metastasis-free survival, and late toxicity were analyzed using univariate and multivariate analyses. OS analysis was confirmed by propensity score adjustment.

Results

Treatment groups were similar with regard to primary tumor site, overall stage, and alcohol and tobacco history. Cetuximab and 5FU/carboplatin patients were older, with lower performance status, more comorbidities, higher T classification, and worse renal function. On multivariate analysis, compared with cisplatin and 5FU/carboplatin, cetuximab was associated with inferior 4-year OS (86.9% vs. 70.2% vs. 40.9%; P < .0001) and 4-year LRF (6.3% vs. 9.7% vs. 40.2%; P < .0001). Late toxicity was highest with 5FU/carboplatin (25.0%) vs. cisplatin (8.0%) vs. cetuximab (7.7%).

Conclusions

Although 5FU/carboplatin patients were sicker and experienced greater toxicity than cisplatin patients, no significant difference was found in all endpoints. In contrast, despite similar pretreatment characteristics, outcomes for cetuximab vs. 5FU/carboplatin were significantly worse. We feel that caution should be used with routine use of cetuximab in the management of LAHNSCC.

Introduction

Treatment with chemoradiation is an accepted standard for locally advanced head and neck squamous cell carcinoma (LAHNSCC). The addition of concurrent chemotherapy to radiotherapy (RT) for LAHNSCC results in an absolute survival benefit of 6.5% at 5-years, with greater benefit with platinum-based chemotherapy [1]. Among the concurrent platinum agents, single-agent cisplatin is superior to single-agent carboplatin and equivalent to carboplatin with 5-fluorouracil (5FU) in retrospective analyses [2], [3].

Although chemoradiation with high-dose cisplatin improves survival versus RT alone, it is associated with higher toxicity [4]. Therefore less toxic agents that will achieve equivalent or superior outcomes have been sought. Bonner et al. reported that cetuximab/RT resulted in improved locoregional control and survival with little increase in toxicity compared with RT alone [5]. This led to the adoption of cetuximab as one alternative to cisplatin concurrent with RT for LAHNSCC. Although cisplatin is still the most commonly used agent (51%), cetuximab is being used in approximately 20% of patients [6].

Importantly, the study by Bonner was conducted when RT alone was still an accepted standard for LAHNSCC. Only recently has cetuximab/RT been compared to concurrent platinum/RT in prospective randomized trials, although results are not yet reported. Our initial retrospective report showed that concurrent cisplatin/RT versus cetuximab/RT was associated with superior locoregional control, failure-free survival, and overall survival [7]. Nonetheless, unmeasured confounders limited this study. Prior to FDA approval of cetuximab for LAHNSCC, non-cisplatin candidates were routinely treated with alternative platinum-based regimens, namely, 5FU/carboplatin [8] at our center. We hypothesized that characteristics of these patient groups would be similar and hence we sought to compare the outcomes of concurrent IMRT with high-dose cisplatin, 5FU/carboplatin, or cetuximab.

Section snippets

Study design

In this Institutional Review Board-approved (WA0654-10) study, we retrospectively identified patients with a diagnosis of LAHNSCC of the oropharynx, hypopharynx, or larynx treated with curative intent with IMRT and concurrent cisplatin, 5FU/carboplatin, or cetuximab, from 11/02 to 4/08. Reasons for exclusion were surgery to the primary site, prior RT for a non-basal cell carcinoma of the head and neck, induction or adjuvant chemotherapy, weekly cisplatin, or prior active malignancy. Three

Study population

Characteristics of all patients are shown in Table 1. Patient selection for cetuximab or 5FU/carboplatin, respectively, was based on the following factors: audiogram/poor hearing (30.6% and 53.8%), renal insufficiency (4.1% and 9.6%), cardiac history (2.0% and 1.9%), performance status (16.3% and 3.8%), patient preference (16.3% and 5.8%), neuropathy (4.1% and 9.6%), and a combination of factors (24.5% and 15.4%). Treatment groups were balanced with regard to all factors except age, KPS,

Discussion

Concurrent treatment with cetuximab and IMRT for LAHNSCC was associated with inferior OS, LRFS, and DMFS versus concurrent high-dose cisplatin or 5FU/carboplatin and IMRT in our series. Although 5FU/carboplatin and cetuximab patients had very similar pretreatment characteristics, cetuximab was associated with a 2.6-fold increased risk of death (P = .005). Furthermore, treatment with cetuximab but not 5FU/carboplatin resulted in significantly higher rates of LRF than cisplatin. These findings were

Conflicts of interest statement

Eric J. Sherman has consulted for Bristol-Myers-Squibb.

Other conflicts of interest: None declared.

References (25)

  • Rades D, Ulbricht T, Hakim SG, et al. Cisplatin superior to carboplatin in adjuvant radiochemotherapy for locally...
  • D.J. Adelstein

    An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer

    J Clin Oncol

    (2003)
  • Cited by (50)

    • To Shy Away From Chemotherapy Is to Compromise

      2020, International Journal of Radiation Oncology Biology Physics
    • The art of suicidal molecular seduction for targeting drug resistance

      2020, Medical Hypotheses
      Citation Excerpt :

      Recent studies revealed equal potency for both of these agents and found neither of them superior to the other [73,81]. 5-fluorouracil (a suicide inhibitor [82]) of combination with carboplatin also proved to be as effective as the monoclonal antibody cetuximab in the treatment of locally-advanced head and neck cancer [83]. This example indicates that suicide inhibitors can be as effective as monoclonal antibodies (mAbs), and as a small-molecule, they are extremely more cost-effective.

    View all citing articles on Scopus
    1

    Present address: Targeted Radiation Institute at VMOC, 5725 W. Las Positas Blvd, Suite 100, Pleasanton, CA 94588, USA.

    2

    Present address: Hudson Valley Oncology Associates, 19 Baker Ave, Suite 100, Poughkeepsie, New York 12601, USA.

    View full text