Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival

Bonner, James A.; Harari, Paul M.; Giralt, Jordi; Cohen, Roger B.; Jones, Christopher U.; Sur, Ranjan; Raben, David; Baselga, J.; Spencer, Sharon A.; Zhu, Junming; Youssoufian, Hagop; Rowinsky, Eric K.; Ang, K. Kian

doi:10.1016/s1470-2045(09)70311-0

Cited by 1,746 publications

(1,252 citation statements)

References 28 publications

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“…In addition to DLT, this dose was associated with G3 diarrhea in another 3 patients and mandatory use of loperamide, ciprofloxacin therapy, and outpatient hydration, to minimize the severity of the diarrhea, was established through a protocol amendment. In the next dose level (11), no additional DLTs occurred. At level (12), 2 of the 4 patients developed DLTs (uncontrolled diarrhea and febrile neutropenia).…”

Section: Dose Escalation and Dltsmentioning

confidence: 88%

“…Also, in phase 3 clinical trials, adding cetuximab to first-line chemotherapy or RT improves outcomes in various types of cancers. [9][10][11] Because of encouraging results of clinical trials with cetuximab in different tumors, the need for more effective therapies, particularly in locally advanced anal canal carcinoma (LAACC), 12 and the high expression of EGFR in anal carcinoma, we set out to develop a regimen to evaluate the safety and activity of cetuximab combined with 5-fluorouracil (5-FU)/CP concurrent with radiation for LAACC.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Olivatto

Vieira

Pereira

et al. 2013

Cancer

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BACKGROUND: This study sought to determine the feasibility and recommended phase 2 dose (RP2D) of the combination of cetuximab with chemoradiotherapy based on 5-fluorouracil (5-FU) and cisplatin (CP) in locally advanced anal canal carcinoma. METHODS: Cetuximab was administered on days 1,8,15, 29, 36, 43, and 50 (400 mg/m 2 initial dose, then 250 mg/m 2 /week) concurrent with total dose radiation of 55 to 59 Gy, both starting on day 1. Escalating doses of 5-FU (96-hour infusion) and CP (2-hour infusion), both on days 1 and 29, were administered according to the following design: starting dose level (0) 5-FU/CP 5 800/60 mg/m 2 /day and up to dose level (12) 5-FU/CP 5 1000/80 mg/m 2 /day. RESULTS: Dose-limiting toxicity (DLT) events (uncontrolled diarrhea or febrile neutropenia) occurred in 3 of 14 assessable patients receiving escalated dose of 5-FU/CP, with 1 in dose level (0) and 2 in dose level (12). The RP2D was 5-FU/CP 5 800/80 mg/m 2 /day. Because of unexpected non-DLT treatment-related grade 3 (G3) adverse events (AEs) such as thrombosis/embolism, syncope, and infection occurring in 20% of patients, a safety expansion cohort with an additional 9 patients was investigated with the RP2D. The most frequent G3/G4 AEs evaluated in 23 patients were radiation dermatitis (12 patients), diarrhea (10 patients), thrombosis/embolism (6 patients), and infection (5 patients). The study was closed due to these severe AEs, although no G5 AEs occurred. Twenty of 21 patients (95%) achieved pathological complete response at primary tumor. With a median follow-up of 43.4 months, the 3-year locoregional control rate was 64.2%. CONCLUSIONS: Cetuximab could not be integrated with chemoradiotherapy-cisplatin-based therapy due to the high toxicity rate. However, efficacy is encouraging and further investigation of an epidermal growth factor receptor-targeted agent (other than cetuximab) concurrent with chemoradiation should be pursued. Cancer 2013;119:2973-80.

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Section: Dose Escalation and Dltsmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Olivatto

Vieira

Pereira

et al. 2013

Cancer

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“…EGFR was first proven as a viable oncology target in studies that used EGFR‐directed monoclonal antibodies, such as cetuximab, for the treatment of colorectal2 and head and neck3 cancers. These and other targeted EGFR therapies, including tyrosine kinase inhibitors (such as erlotinib and gefitinib) in patients with EGFR ‐activating mutations have gained widespread use in several tumor types, notably lung4 and head and neck3 cancers, leading to an increase in progression‐free and overall survival of patients.…”

Section: Introductionmentioning

confidence: 99%

“…These and other targeted EGFR therapies, including tyrosine kinase inhibitors (such as erlotinib and gefitinib) in patients with EGFR ‐activating mutations have gained widespread use in several tumor types, notably lung4 and head and neck3 cancers, leading to an increase in progression‐free and overall survival of patients.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

Goss

Vokes

Gordon

et al. 2018

Cancer

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BACKGROUNDEpidermal growth factor receptor (EGFR) alterations are associated with multiple cancers. Current EGFR‐directed therapies have led to increased efficacy but are associated with specific side effects. The antibody‐drug conjugate depatuxizumab mafodotin (depatux‐m) targets EGFR with a monoclonal antibody linked to a cytotoxin, and is highly tumor‐specific.METHODSThis phase 1/2 study evaluated the safety, pharmacokinetics, and efficacy of depatux‐m in patients who had advanced solid tumors with known wild‐type EGFR overexpression, amplification, or mutated EGFR variant III. A 3 + 3 dose escalation was used, and 2 dosing schedules were evaluated. Depatux‐m also was manufactured under an alternate process to reduce the drug load and improve the safety profile, and it was tested at the maximum tolerated dose (MTD). In another cohort, prolonged infusion time of depatux‐m was evaluated; and a cohort with confirmed EGFR amplification also was evaluated at the MTD.RESULTSFifty‐six patients were treated. The MTD and the recommended phase 2 dose for depatux‐m was 3.0 mg/kg. Common adverse events (AEs) were blurred vision (48%) and fatigue (41%). A majority of patients (66%) experienced 1 or more ocular AEs. Grade 3 or 4 AEs were observed in 43% of patients. One patient with EGFR‐amplified, triple‐negative breast cancer had a partial response. Stable disease was observed in 23% of patients. Pharmacokinetics revealed that depatux‐m exposures were approximately dose‐proportional.CONCLUSIONSDepatux‐m resulted in infrequent nonocular AEs but increased ocular AEs. Patient follow‐up confirmed that ocular AEs were reversible. Lowering the drug‐antibody ratio did not decrease the number of ocular AEs. A partial response in 1 patient with EGFR‐amplified disease provides the opportunity to study depatux‐m in diseases with a high incidence of EGFR amplification. Cancer 2018;124:2174‐83. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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“…Toxicity and tolerability of cetuximab in treatment of patients with locoregionally advanced head and neck cancer (LAHNC) has been actively studied for years with conflicting results. Bonner et al,19, 20 in their prospective randomized trial, compared RT‐alone with RT plus cetuximab and reported improvement in locoregional control and survival with no significant increase in toxicity. Short‐term QOL between the two arms was also similar 21.…”

Section: Discussionmentioning

confidence: 99%

Feasibility of optimizing intensity‐modulated radiation therapy plans based on measured mucosal dose adjacent to dental fillings and toxicity outcomes

Seol

Aggarwal

Eyben

et al. 2018

J Applied Clin Med Phys

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We prospectively investigated the feasibility of IMRT treatment plan optimization based on dosimeter measurements of lateral tongue mucosal dose adjacent to the dental fillings and evaluated dose‐toxicity relationship and factors affecting oral mucositis (OM) in head and neck cancer patients. Twenty‐nine head and neck cancer patients with metallic dental fillings who were scheduled to undergo fractionated external beam radiation therapy (RT) ± chemotherapy were enrolled. The lateral tongue dose was measured and if the calculated dose for the entire treatment was ≥35 Gy, a re‐plan was generated to reduce the lateral tongue mucosal dose. OM was graded weekly according to Common Terminology Criteria for Adverse Events version 4.0 and the patients completed the Oral Mucositis Weekly Questionnaire‐Head and Neck Cancer. The result showed that it was not feasible to optimize the IMRT plan based on measured tongue dose in most of the patients who needed re‐plan as re‐planning compromised the target coverage in 60% of these patients. The duration of grade (Gr) 2 OM was correlated with measured lateral tongue dose (P = 0.050). Concurrent cetuximab was significantly associated with faster onset of Gr2 OM than concurrent cisplatin (P = 0.006) and with longer duration of OM (P = 0.041) compared to concurrent cisplatin or IMRT‐alone. The pattern of reported pain over time was significantly different for each treatment type (RT and cetuximab, RT and cisplatin and RT‐alone) and depending on the dose level (P = 0.006). In conclusion, optimizing the IMRT plan based on measured lateral tongue dose was not feasible. Measured lateral tongue dose was significantly correlated with longer duration of OM ≥Gr2, and concurrent cetuximab was associated with earlier onset and longer duration of OM ≥Gr2.

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Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival

Cited by 1,746 publications

References 28 publications

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Phase 1 study of cetuximab in combination with 5‐fluorouracil, cisplatin, and radiotherapy in patients with locally advanced anal canal carcinoma

Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

Feasibility of optimizing intensity‐modulated radiation therapy plans based on measured mucosal dose adjacent to dental fillings and toxicity outcomes

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