OC-009: Update of the randomised phase III trial DAHANCA 19: Primary C-RT or RT and zalutumumab for squamous cell carcinomas of head and neck

Eriksen, Jesper Grau; Maare, C.; Johansen, Jørgen; Primdahl, Hanne; Evensen, Jan F.; Kristensen, Claus Andrup; Andersen, Lisbeth Juhler; Overgaard, Jens

doi:10.1016/s0167-8140(15)34769-1

Cited by 7 publications

(7 citation statements)

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“…In this context a subgroup analysis of the Bonner trial showed that p16-positive OPSCC had a higher benefit from the addition of cetuximab to irradiation as compared to p16-negative OPSCC [26]. Other trials and data, however, heavily question the use of EGFR inhibition in combination with irradiation and especially chemoirradiation in both HPV(−) and HPV(+) HNSCC [27–31]. Using five of the six HPV(+) cell lines also used here we previously did not find any radiosensitizing effect of cetuximab [32].…”

Section: Discussionmentioning

confidence: 99%

Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines

et al. 2016

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Patients with HPV-positive head and neck squamous cell carcinoma (HNSCC) show better survival rates than those with HPV-negative HNSCC. While an enhanced radiosensitivity of HPV-positive tumors is clearly evident from single modality treatment, cisplatin is never administered as monotherapy and therefore its contribution to the enhanced cure rates of HPV-positive HNSCC is not known. Both cisplatin and radiotherapy can cause severe irreversible side effects and therefore various clinical studies are currently testing deintensified regimes for patients with HPV-positive HNSCC. One strategy is to omit cisplatin-based chemotherapy or replace it by less toxic treatments but the risk assessment of these approaches remains difficult. In this study we have compared the cytotoxic effects of cisplatin in a panel of HPV-positive and -negative HNSCC cell lines alone and when combined with radiation.While cisplatin-treated HPV-positive strains showed a slightly stronger inhibition of proliferation, there was no difference regarding colony formation. Cellular responses to the drug, namely cell cycle distribution, apoptosis and γH2AX-induction did not differ between the two entities but assessment of cisplatin-DNA-adducts suggests differences regarding the mechanisms that determine cisplatin sensitivity. Combining cisplatin with radiation, we generally observed an additive but only in a minority of strains from both entities a clear synergistic effect on colony formation. In summary, HPV-positive and -negative HNSCC cells were equally sensitive to cisplatin. Therefore replacing cisplatin may be feasible but the substituting agent should be of similar efficacy in order not to jeopardize the high cure rates for HPV-positive HNSCC.

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Section: Discussionmentioning

confidence: 99%

Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines

et al. 2016

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“…Focusing on prospective trials with mostly HPV-negative tumors, cetuximab failed to enhance survival when added to chemoradiation in RTOG-0522 and when added to induction chemotherapy and subsequent RT in DeLOS-II [16] , [17] . Furthermore, the alternative anti-EGFR antibodies panitumumab (CONCERT-1&2) and zalutumumab (DAHANCA 19) also failed to compete with cisplatin when added to RT or to enhance survival when added to chemoradiation, as well as the EGFR-inhibitor erlotinib [18] , [19] , [20] , [21] . Collectively, these data show that the addition of EGFR-inhibiting agents to RT-based treatment is also not effective in HPV-negative HNSCC in otherwise unselected patient cohorts.…”

Section: Egfr-targeting In Hnscc In the Curative Settingmentioning

confidence: 99%

The failure of cetuximab-based de-intensified regimes for HPV-positive OPSCC: A radiobiologists perspective

Rieckmann

Kriegs

2019

Clinical and Translational Radiation Oncology

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“…In total, 310 patients with biopsy-proven HNSCC from the zalutumumab-arm of the DAHANCA 19 study were included from November 2007 to June 2012 [10]. The inclusion criteria were age above 18 years, no prior cancer treatment, eligibility for curatively intended radiation treatment, histologically verified squamous cell carcinoma of the pharynx, larynx (except stage I larynx and stage I-II glottic larynx cancer), WHO performance status 0-2, ability to go through the treatment and follow-up, and use of contraceptives for fertile women.…”

Section: Patients and Study Designmentioning

confidence: 99%

“…In HNSCC, monoclonal antibodies against the EGFR have been reported to improve tumor control and survival in locally advanced HNSCC in combination with radiation treatment (RT) as well as increasing survival in patients with recurrent or metastatic HNSCC receiving combination chemotherapy [7][8][9]. A recent study in 619 HNSCC patients randomized to addition of zalutumumab, a fully human immunoglobulin G (IgG1k) antibody against the EGFR, to primary RT or chemoradiation (CRT) did not increase locoregional control (LRC) or overall survival (OS) [10]. Thus, tools for selecting patients for treatment are warranted.…”

Section: Introductionmentioning

confidence: 99%

Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial

et al. 2018

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Purpose: To study the associations between development of moderate to severe skin rash, clinical outcome, and single nucleotide polymorphisms (SNPs) in candidate genes in head and neck cancer patients from the DAHANCA 19 trial receiving the EGFR-inhibitor zalutumumab concurrently with radiation treatment. Material and methods: 310 patients were included from the zalutumumab-arm of the DAHANCA 19 study. Nine SNPs in the candidate genes EGFR, EGF, AREG, FCGR2A, FCGR3A, and CCND1 were successfully determined in 294 patients. Clinical endpoints were moderate to severe skin rash within the first 3 weeks of treatment, loco-regional failure (LRF), disease-specific survival (DSS), and overall survival (OS). Results: During the first 3 weeks of treatment, 86% of the patients experienced any grade of rash and 17% experienced a moderate to severe rash. Development of moderate to severe rash was not associated with LRF or DSS but was associated with improved OS, HR 0.40 (95% CI: 0.19-0.82). The effect was similar for patients with p16-negative or p16-positive tumors (p ¼ .90). After adjustment for comorbidity and performance status, the minor alleles of SNPs rs9996584 and rs13104811 located near the AREG gene were significantly associated with increased risk of moderate to severe rash with per-allele odds ratios of 1.61 (1.01-2.54) and 1.56 (1.00-2.44). SNP rs11942466 located close to rs9996584 had a borderline significant association, and none of the other SNPS were significantly associated with risk of skin rash. Conclusions: Moderate to severe skin rash after zalutumumab during radiation treatment was associated with improved OS, independent of HPV/p16-status. Genetic variants in AREG (member of the EGF family) may be associated with increased risk of skin rash.

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OC-009: Update of the randomised phase III trial DAHANCA 19: Primary C-RT or RT and zalutumumab for squamous cell carcinomas of head and neck

Cited by 7 publications

References 0 publications

Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines

Similar cisplatin sensitivity of HPV-positive and -negative HNSCC cell lines

The failure of cetuximab-based de-intensified regimes for HPV-positive OPSCC: A radiobiologists perspective

Associations between skin rash, treatment outcome, and single nucleotide polymorphisms in head and neck cancer patients receiving the EGFR-inhibitor zalutumumab: results from the DAHANCA 19 trial

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