Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionated-accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck

Kuhnt, Thomas; Sandner, A.; Wendt, Thomas; Engenhart‐Cabillic, Rita; Lammering, Guido; Flentje, Michael; Grabenbauer, Gerhard G.; Schreiber, Allison; Pirnasch, A.; Dunst, Juergen

doi:10.1093/annonc/mdq216

Cited by 22 publications

(8 citation statements)

References 20 publications

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“…The majority of publications refer to the first mentioned option. [7][8][9][10][11][12][13][14][15] Less frequent were attempts of RT as an alone utility. [16][17][18][19][20] Some individual publications describe a combination of RT and surgery.…”

Section: Discussionmentioning

confidence: 99%

Split-course accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck cancer patients—final results of a randomized clinical trial

Miszczyk

Maciejewski²,

Tukiendorf³

et al. 2014

BJR

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Objective: Evaluation of the efficacy and toxicity of splitcourse accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck (H&N) cancer patients. Methods: We enrolled 101 patients (39 in CHA-CHA and 37 in conventional (Conv.) arm completed the treatment). The CHA-CHA arm patients were irradiated twice a day, 7 days a week, using a fraction dose (fd) of 1.6 Gy up to 64 Gy with an 8-day gap in midterm. Patients in the control (Conv.) arm group were irradiated with a fd of 2 Gy, five times a week to a total dose of 72-74 Gy in the overall treatment time of 50-53 days. Quality of life (QOL) and acute mucosal reaction were evaluated during radiotherapy (RT). After RT, we followed the effect of treatment, QOL, performance status and adverse effects of radiation. For statistical analysis mainly a hierarchical multilevel modelling was used.Results: QOL was most deteriorated in the CHA-CHA arm; the CHA-CHA scheme also caused a relatively stronger acute injury. There were no significant differences in late adverse effects. In the CHA-CHA arm in 35% and in Conv. arm in 30% of patients, disease was controlled during follow-up. Tumour regression 1 year after the treatment was significantly better in the CHA-CHA arm. However, the overall survival rate analysis did not show significant difference between both arms. Conclusion: Despite differences in treatment results, we cannot conclude that split-course accelerated hyperfractionated irradiation is superior to conventionally fractionated RT as a sole treatment for advanced H&N cancer patients. Advances in knowledge: Obtained results in the context of published data support the statement that altered fractionations alone do not give an advantage for advanced H&N cancer patients.There are, and have been, many attempts to create a clear and effective treatment modality for advanced inoperable head and neck (H&N) cancers. The most common are different combinations of chemoradiotherapy, or different schedules of altered and usually intensive radiation treatment. It is clear that intense dose delivery combined with a high total dose (TD) and short treatment time gives a higher probability of tumour destruction; unfortunately, it is also connected with a higher, usually unacceptable, risk of normal tissue damage. One of the causes of radiation toxicity in such cases is the inability of sufficient repair of healthy tissue damage.The reason for this is the intensity of dose delivery and the lack of time for repopulation of normal cells and proper repair. On the other hand, the accelerated repopulation of squamous cancer cells starts 4 weeks after radiotherapy (RT); therefore, radiation treatment should be completed in that time. Considering the aforementioned facts, we tried to construct a very intense and short RT schedule allowing for normal tissue (mainly mucosa) repair. We went back to the old concept of split-course RT and combined it with accelerated, continuous, intense hyperfractionation.Finally, we proposed twice-a-day irradiation, usi...

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Section: Discussionmentioning

confidence: 99%

Split-course accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck cancer patients—final results of a randomized clinical trial

Miszczyk

Maciejewski²,

Tukiendorf³

et al. 2014

BJR

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“…There are some concerns regarding the side effects of triple combination (cetuximab, cisplatin and radiotherapy) because one study for patients with locoregionally advanced squamous cell carcinomas of head and neck using concurrent cetuximab, cisplatin and radiotherapy was closed for significant adverse events (Pfister et al , 2006); however, in other two studies for similar lesions using cetuximab and cisplatin-based CRT, the toxicity was manageable (Kuhnt et al , 2010; Merlano et al , 2011). It needs to be mentioned that in the latter studies, cisplatin was administered weekly (lower dose), whereas in the first trial every 3 weeks (higher dose).…”

Section: Discussionmentioning

confidence: 99%

Cetuximab and platinum-based chemoradio- or chemotherapy of patients with epidermal growth factor receptor expressing adenoid cystic carcinoma: a phase II trial

et al. 2013

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Background:Epidermal growth factor receptor (EGFR) is highly expressed in adenoid cystic carcinoma (ACC). The efficacy and toxicity of cetuximab with concomitant platinum-based chemoradio- or chemotherapy in patients with locally advanced or metastatic ACC, respectively, was evaluated.Methods:Eligible patients (9 with locally advanced tumour and 12 with metastases) had positive tumour EGFR expression. The cetuximab loading dose (400 mg m−2) was followed by 250 mg m−2 per week. Locally advanced tumours were irradiated (mean dose 65 Gy) and treated with concomitant cisplatin (75 mg m−2, intravenously). Patients with metastases received concomitant cisplatin and 5-fluorouracil (4 × 1000 mg m−2).Results:For patients with locally advanced disease (median follow-up: 52 months), the median progression-free survival (PFS) was 64 months and the 2-year overall survival (OS) rate was 100%. For patients with metastases (median follow-up: 72 months), the median PFS and OS were 13 and 24 months, respectively. In both groups the objective response rate was >40%. Skin rash, in-field dermatitis, mucositis and vomiting were the most frequent grade 3/4 adverse events.Conclusion:In this single-arm study, the efficacy of cetuximab plus chemoradio- or chemotherapy appeared favourable as compared with historical controls. All side effects were manageable and did not hamper the treatment.

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“…Due to a series of serious adverse events, this study was abolished early. With these data in mind, in 2010, a feasibility study with a dose‐escalation scheme for cisplatin was published 11. Patients with unresectable HNSCC were treated with a hyperfractionated accelerated radiotherapy (2 Gy per day for 3 weeks, followed by 1.4 Gy twice daily for another 3 weeks up to 70.6 Gy), weekly cetuximab (400 mg/m 2 loading dose week 1, 250 mg/m 2 weekly), and a reduced cisplatin dose applied in a dose escalation algorithm between 20 mg/m 2 and 40 mg/m 2 .…”

Section: Reviewmentioning

confidence: 99%

“…Fifteen patients were available for assessment: 5 of 15 patients (33%) had a complete response (CR) whereas 8 of 15 patients (53%) had a partial response (PR) which adds up to an overall response rate (ORR) of 13 of 15 patients (87%). Dose‐limiting toxicities were not reported and the maximum tolerated dose was not reached 11…”

Section: Reviewmentioning

confidence: 99%

Molecular targeting agents in the context of primary chemoradiation strategies

et al. 2012

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Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionated-accelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck

Abstract: The combination of cisplatin with cetuximab and HART is active, well tolerated and merits additional investigation. The recommended weekly dose of cisplatin for phase II studies is 40 mg/m².

Cited by 22 publications

References 20 publications

Split-course accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck cancer patients—final results of a randomized clinical trial

Split-course accelerated hyperfractionated irradiation (CHA-CHA) as a sole treatment for advanced head and neck cancer patients—final results of a randomized clinical trial

Cetuximab and platinum-based chemoradio- or chemotherapy of patients with epidermal growth factor receptor expressing adenoid cystic carcinoma: a phase II trial

Molecular targeting agents in the context of primary chemoradiation strategies

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