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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
original article
Annals of Oncology 21: 2284–2289, 2010 doi:10.1093/annonc/mdq216 Published online 28 April 2010
Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionatedaccelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck T. Kuhnt1*, A. Sandner2, T. Wendt3, R. Engenhart-Cabillic4, G. Lammering5,6, M. Flentje7, G. Grabenbauer8, A. Schreiber9, A. Pirnasch1 & J. Dunst10
Received 4 August 2009; revised 30 November 2009; accepted 9 March 2010
original article
Background: Cetuximab is active in the treatment of squamous cell carcinoma of the head and neck (SCCHN), enhancing both radiotherapy and chemotherapy effects. This phase I study was designed to investigate the safety and tolerability of combining weekly cisplatin treatment with cetuximab and hyperfractionated-accelerated radiotherapy (HART) for locally advanced SCCHN. Patients and methods: Patients with unresectable stage III or IVA/B SCCHN were treated with cetuximab, 400 mg/ m2 initial dose on day 27 of HART, followed by 250 mg/m2 weekly during the administration of HART, which started with 2.0 Gy/day (5 days/week) for 3 weeks followed by 1.4 Gy/twice-daily (Monday to Friday) for another 3 weeks, resulting in a total dose of 70.6 Gy. Cisplatin was administered weekly starting on the first day of radiotherapy until week 6. Cisplatin was dose escalated of four dose levels from 20 to 40 mg/m2 using a classical 3 + 3 dose escalation algorithm. Results: Eighteen patients were enrolled. Sixteen patients were eligible for toxicity, and 15 for response. No maximum tolerated dose was reached for cisplatin. One of six patients of dose level 4 had grade 4 neutropenia. This patient died 1 week after the end of the study treatment. The most common types of grade 3+ adverse events were mucositis (9 of 16 patients), in-field dermatitis (6 of 16 patients) and neutropenia (4 of 16 patients). Cetuximab-related hypersensitivity was observed in 1 out of 18 patients. Six weeks after the end of the study treatment, 5 complete responses, 8 partial responses and 1 progressive disease (at distant sites) were documented in a total of 15 patients (objective response rate 87%). Conclusions: 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. Key words: cetuximab, cisplatin, hyperfractionated-accelerated, locally advanced SCCHN, radiotherapy
introduction Cancers of the head and neck, particularly those of the oral cavity, pharynx and larynx account for >5% of all malignancies worldwide with >500 000 new cases and >300 000 attributable deaths recorded in 2002 [1]. Approximately 90% of head and neck tumors are squamous cell carcinomas. For resectable early disease (stage I and II), standard treatment options include surgery or external radiation therapy. For unresectable locally advanced disease (stage *Correspondence to: Dr T. Kuhnt, Department of Radiation Oncology, University of Rostock, Suedring 75, D-18059 Rostock, Germany. Tel: +49-381-494-9030; Fax: +49-381-494-9002; E-mail: [email protected]
III and IVA/B) the addition of chemotherapy to radiotherapy (chemoradiotherapy), administered as a concomitant treatment, has been shown to improve outcomes in medically fit patients compared with radiotherapy alone, albeit at the cost of an increased toxicity [2–8]. A recent meta-analysis of 32 randomized studies including 10 225 patients evaluated the benefit of chemoradiotherapy versus radiotherapy alone in patients with unresected locally advanced squamous cell carcinoma of the head and neck (SCCHN) [9]. This meta-analysis confirmed an overall survival benefit of 12.0 months for the addition of simultaneous chemotherapy to conventionally fractionated,
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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1 Department of Radiation Oncology, University of Rostock, Rostock; 2Department of Head and Neck Surgery, Martin-Luther-University, Halle-Wittenberg; 3Department of Radiation Oncology, Friedrich-Schiller-University, Jena; 4Department of Radiation Oncology, Phillips-University, Marburg, Germany; 5Department of Radiation Oncology (Maastro Clinic), Maastricht, The Netherlands; 6Department of Radiation Therapy and Radiation Oncology, University of Du¨sseldorf, Du¨sseldorf; 7Department of Radiation Oncology, University of Wu¨rzburg, Wu¨rzburg; 8Department of Radiation Oncology, Hospital Coburg, Coburg; 9Department of Radiation Oncology, Hospital Dresden-Friedrichstadt, Friedrichstadt; 10Department of Radiation Oncology, University of Schleswig-Holstein, Campus Lu¨beck, Germany
original article
Annals of Oncology
Volume 21 | No. 11 | November 2010
cisplatin with cetuximab and hyperfractionated-accelerated radiotherapy (HART) in the treatment of patients with unresectable locally advanced SCCHN. The primary objective of the trial was to determine the maximum tolerated dose (MTD) of cisplatin as part of a three-modality regimen.
patients and methods patient eligibility Patients aged ‡18 and £70 years were eligible for inclusion if they had been diagnosed with histologically confirmed unresectable squamous cell carcinoma of the oral cavity (excluding the lip), oropharynx, hypopharynx or larynx measurable in one dimension and classified as stage III or IVA/B (International Union Against Cancer). In the phase I protocol no human papillomavirus status or p16 was determined in oropharynx carcinoma. Furthermore, inclusion required a Karnofsky Index (KI) ‡70% and adequate pulmonary, cardiac, bone marrow, hepatic and renal functions. Study treatment was given in curative intent. Before the initiation of radiotherapy, all patients had to undergo a dental examination and received a percutaneous endoscopic gastrostomy. Exclusion criteria were metastatic disease; a life expectancy of <3 months; pregnancy; cancers of an unknown primary site, the nasopharynx or the salivary gland; or a previous cancer disease within 5 years of study entry. Furthermore, patients were not entered in case of serious concomitant diseases or serious medical conditions; previous treatment with chemotherapy, radiotherapy or surgery for head and neck cancer; or any social situations that would have limited the compliance with study requirements. Concurrent treatments with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days before study screening were also not allowed. Patients were also not enrolled in case of any contraindications against cisplatin or cetuximab or in case of any prior exposure to monoclonal antibodies and/or EGFR-targeted therapy. The contraindications for cisplatin were as follows: known hypersensitivity for cisplatin or other platinum connections, existing distinctive bone marrow depression, severe nephritic damages, exsiccation, herpes zoster, fresh infections or a peripheral neuropathy. Cetuximab was contraindicated in patients with any known severe hypersensitivity reaction to medication, pregnancy or lactation.
study design This trial was designed as a multicenter, single-arm, prospective, threemodality phase I dose escalation study. The primary objective was to determine the MTD of cisplatin in combination with cetuximab and HART, according to the incidence of dose-limiting toxic effects (DLTs). Secondary objectives included acute toxicity and objective tumor response rate (ORR). The study was conducted according to the ethical standards laid down in the Declaration of Helsinki. The study protocol was approved by the ethics committee of the Martin-Luther-University of HalleWittenberg. All patients provided written informed consent before registration. Patients had to follow the treatment plan as illustrated in Figure 1. HART started at a single dose of 2.0 Gy/day, days 1–5, during the first 3 weeks followed by 1.4-Gy b.i.d., days 1–5, during the following 3 weeks (1.4 Gy as single dose last day), resulting in a total dose of 70.6 Gy to the gross tumor volume. Patients received cetuximab, at an initial dose of 400 mg/m2 administered as a 120-min infusion, on day 27 before the start of radiotherapy, with subsequent weekly doses of 250 mg/m2, given as a 1-h infusion on day 1 during the 6 weeks of radiotherapy. Cisplatin was escalated at different levels in successive cohorts as a classic 3 + 3 dose escalation design. The doses levels were 20, 30, 35 and 40 mg/m2 on days 1, 8, 15, 22, 29 and 36.
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hyperfractionated or accelerated fractionated radiotherapy (P < 0.001). The study also reported a substantial survival gain of 14.2 months for hyperfractionated compared with conventionally fractionated radiotherapy in this setting (P < 0.001). A further meta-analysis of 15 studies, including 6515 patients with nonmetastatic SCCHN, confirmed an absolute survival benefit of 3.4% at 5 years (P = 0.003) and a locoregional control benefit of 6.4% at 5 years (P < 0.0001) for altered fractionation versus conventionally fractionated radiotherapy [10]. It is commonly accepted that the efficacy benefit achieved through the addition of chemotherapy during radiotherapy is counterbalanced by an increase in acute toxicity, which limits a broader acceptance of such treatment, especially for patients with a poor performance status. In this respect, a recently published landmark phase III study of 424 patients with locally advanced SCCHN has commenced a new era, the era of targeted agents in combination with radiotherapy [11]. This study reported for the first time that the addition of the epidermal growth factor receptor (EGFR)-targeted immunoglobulin G1 monoclonal antibody cetuximab to highdose radiotherapy significantly reduced the risk of locoregional progression and death at any given time point [hazard ratio (HR) 0.68; P = 0.005] compared with radiotherapy alone. Significant improvements in progression-free survival (HR for disease progression or death at any given time point, 0.70; P = 0.006) and overall survival (HR for death at any given time point, 0.74; P = 0.03) were also noted [11]. Importantly, this improved efficacy was achieved without an increase in the incidence or severity of toxic effects commonly associated with radiotherapy. Indeed, the addition of cetuximab to radiotherapy did not adversely affect quality of life of patients compared with radiotherapy alone [12]. Moreover, a single-institution retrospective review recently confirmed that cetuximab plus radiotherapy is at least as effective as chemoradiotherapy in the treatment of patients with locally advanced head and neck cancer [13]. Another recently published landmark phase III study subsequently demonstrated that the addition of cetuximab to first-line platinum-based chemotherapy improved survival in SCCHN patients with recurrent or metastatic SCCHN, with a median survival of 7.4 months in the chemotherapy-alone arm compared with 10.1 months in the chemotherapy plus cetuximab arm (HR for death at any given time point, 0.8; P = 0.04) [14]. Cetuximab has therefore been shown to improve the efficacy of both concurrent radiotherapy and platinum-based chemotherapy in the treatment of SCCHN, albeit in different settings. Thus, these studies formed the basis to further explore the combination of cetuximab with chemoradiotherapy in the treatment of locally advanced SCCHN. Pfister et al. [15] initiated a pilot phase II study with concurrent cetuximab (standard 400/250 mg/m2 regimen), cisplatin (100 mg/m2 i.v. during weeks 1 and 4) and concomitant boost radiotherapy (70 Gy total to gross disease) in the treatment of locally advanced SCCHN. Although promising levels of activity were noted, this study had to be closed early as a consequence of significant adverse events (AEs) of unclear attribution. The present study was therefore initiated as a phase I dose escalation trial to investigate the safety of combining weekly
original article
Annals of Oncology
Three patients were entered at each cisplatin dose level, if no DLT occurred. Before proceeding to the next higher dose level of cisplatin, all patients at the previous dose level were strictly followed up for toxic effects over a period of 6 weeks after the end of radiotherapy. In case of one DLT out of three patients at any dose level, three additional patients had to be entered at the same dose level. If no additional DLTs occurred, the dose escalation proceeded. In case of two or more DLTs in six patients at a particular dose level, the MTD was deemed to have been exceeded and the escalation was stopped. The MTD was defined as the dose level of cisplatin (below the maximal administered dose) at which none of three or not more than one of six patients experienced a DLT. If the MTD was not reached, the highest tested dose of cisplatin (40 mg/m2) was to be recommended for future studies. Acute toxicity was assessed using the National Cancer Institute’s Common Toxicity Criteria version 3.0. DLT was defined as any treatmentrelated grade ‡3 toxicity or hearing loss grade >2, excluding: grade 3 mucositis; infection with a normal absolute neutrophil count or grade 1–3 neutrophils; grade 3 hematologic or hepatic toxicity and alopecia at any grade. Within the irradiated volume, only grade 4 mucosal or skin toxic effects, xerostomia and dysphagia were considered as DLTs. Late irradiation-induced toxicity (‡90 days after the end of treatment) was graded according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria.
study evaluations Between 7 and 30 days before the start of radiotherapy, patients had to undergo a full clinical investigation including radiological (computed tomography or magnetic resonance imaging), ultrasound, hematological and biochemical assessments. The analyses carried out at baseline, 7 days before the start of radiotherapy and every treatment week included a clinical examination and evaluations of KI and toxicity, also including hematological and biochemical parameters. At post-treatment evaluation 6 weeks after the end of study treatment, all assessments were repeated with the addition of radiological tumor assessment and neck ultrasound imaging. Disease progression, late radiation toxicity and survival were subsequently evaluated every 3 months for 2 years and at 6-month intervals until year 5, death or loss to follow-up. Tumor response was assessed according to RECIST guidelines [16], in assessable patients, comprising of those who had received at least one dose of study treatment with subsequent reevaluation of their disease. The PFS was defined as the time between the start of the treatment and the first observation of disease progression, or death from any cause. LPFS was
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defined as the time between the start of treatment and the first observation of local or regional disease recurrence or death from any cause. If a patient had not progressed and died, the PFS and LPFS were censored at the time of the last follow-up.
results patient demographics In total, 18 male patients comprising the intent to treat population were enrolled between September 2005 and April 2008. The median follow-up time reached 11 (range 2–24) months. Three patients were withdrawn from the study before the initiation of the study treatment due to the occurrence of a secondary malignancy (one patient), a cetuximab-related hypersensitivity reaction (one patient) and an accidental bone fracture (one patient). Baseline patient and tumor characteristics are summarized in Table 1. The most common primary tumor site was oropharynx and the majority of the patients had stage IVA disease. treatment compliance Four cisplatin dose levels were explored in a total of 15 patients (with total cumulated doses of 120, 180, 210 and 240 mg/m2 per patient). All 15 patients received the full scheduled course of HART. One patient suffered perforation of the stomach, which resulted in the discontinuation of the chemotherapy and the cetuximab treatment. One other patient had to receive one course of cisplatin treatment 3 days later due to a temporary increase in creatinine level. Thus, 14 and 13 patients received the planned dose of cetuximab and cisplatin, respectively, which resulted in 13 patients in total, who received the full study treatment as specified in the protocol. dose-limiting toxicity No DLTs were observed. No MTD was reached for cisplatin. safety Sixteen patients were assessable for toxicity. One grade 4 AE of neutropenia was reported in dose level 4 of six patients. This
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Figure 1. Treatment schedule. WE, weekend. W, week, d, day, Gy, gray, TD, total dose.
original article
Annals of Oncology
Table 1. Patient and disease characteristics at baseline in the safety/ efficacy population N = 18 (%)
Median age (range) years Gender Male Female UICC tumor stage III IVA IVB Nodal status N0,1 N2a,b,c N3 Primary tumor site Oral cavity Oropharynx Hypopharynx Larynx
51.2 (44–64) 18 0 3 (17) 11 (61) 4 (22) 3 (17) 14 (78) 1 (5) 2 8 3 5
(11) (44) (17) (28)
UICC, International Union Against Cancer.
patient died 1 week after completion of the treatment due to general condition deterioration. The most common grade 3 AEs observed (Table 2) were mucositis/stomatitis in 9 of 16 patients, followed by dysphagia in 6 of 16 patients, in-field dermatitis in 6 of 16 patients and neutropenia in 5 of 16 patients. Severe toxicity was more commonly observed at the highest cisplatin dose level, with 17 grade 3 AEs occurring in six patients. One grade 3 cetuximab-related hypersensitivity (6%) following the initial cetuximab infusion was observed.
efficacy Fifteen patients were assessable for tumor response at 6 weeks after the end of study treatment (Table 3). Two patients were excluded before the start of study treatment, and one patient withdrew consent during study treatment. Complete responses were achieved in 5 of 15 patients and partial responses in 8 of 15 patients, resulting in an ORR of 13/15 (87%). One patient progressed (distant metastases), and one patient died 1 week after completion of the treatment. After a median follow-up time of 11 months (range 2–24 months), three patients had developed distant metastases. At 2 years, 12/15 (80%) patients were alive and 9/15 (60%) were disease free.
discussion We demonstrated the safety and feasibility of a three-modality regimen combining cetuximab with HART and cisplatin in a dose escalation trial of cisplatin at a maximum dose of 40 mg/ m2/week. No MTD was reached and only one DLT occurred with one grade 4 neutropenia and subsequent death 1 week after end of treatment was observed in a total of 16 patients (six grade 5%). Furthermore, this regimen appeared to be active in locally advanced SCCHN and may yield promising efficacy
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Characteristic
given the objective response achieved in all tested assessable patients. Eighty percent of all patients were still alive at 2 years. Considering the demonstrated safety and activity, this trial thus provides a strong rationale for further investigating the efficacy of this regimen. The trial by Pfister et al. [15] investigating the combination of cetuximab with fixed high-dose cisplatin (100 mg/m2; weeks 1 and 4) and concomitant boost radiotherapy was halted due to serious toxicity concerns. Two patients had died while on study treatment, one of pneumonia and one of unknown cause. Three further nonfatal but significant AEs subsequently occurred, two of which were grade 4 cardiac events. These five events ultimately led to the early closure of the study. In contrast, the present study showed no evidence of significant cardiotoxicity associated with the combined treatment. One patient died 1 week after the completion of the treatment due to deterioration of the patient’s general condition associated with grade 4 neutropenia. A causal relationship with the study treatment cannot be excluded; however, all other hematological and biochemical parameters assessed 3 days before remained at normal range. With the exception of infusion-related reactions, the addition of cetuximab did not increase the toxicity of the chemoradiotherapy in this phase I study. With 57%, the rate of grade 3 in-field skin-associated AEs is in the range of what is commonly observed with chemoradiotherapy alone. These data therefore counterbalance to some extent the safety concerns that caused the early closure of the trial by Pfister et al. However, data from larger randomized studies are needed in order to draw firm conclusions with regard to safety. The Eastern Cooperative Oncology Group 3303 trial (preliminary analysis presented at American Society of Clinical Oncology meeting, 2008) investigated a three-modality regimen in locally advanced SCCHN with cisplatin at 75 mg/m2 every 3 weeks, conventionally fractionated radiotherapy (total dose of 70 Gy in fractions of 2 Gy) and weekly standard dose cetuximab starting 2 weeks before chemoradiation [17]. Maintenance therapy with cetuximab monotherapy was foreseen for up to 6 months. Sixty patients were assessable for efficacy (51 males, 9 females, median age 55.4 years). Only 45 out of 59 patients (76%) received all three scheduled doses of cisplatin. Multiple grade 4 AEs were observed, including mucositis, nephrotoxicity, anemia, thrombocytopenia and neutropenia. There was one case of grade 4 skin toxicity in the irradiation field. Of 66 patients, 14 suffered grade 3 nausea and vomiting. In contrast, the present trial reported no grade 4 mucositis, no grade 4 nephrotoxicity, no grade 3 nausea and—most notably—no grade 4 skin toxicity. Thus, our regimen of weekly cisplatin at 40 mg/m2 appears to be better tolerated than the 3-weekly 75 mg/m2 of ECOG 3303. However, it should be mentioned that the incidence of severe acne-like reactions in the study presented herein is significantly lower than in all other clinical trials reported so far. It seems, as if the small number of patients included (16) might have resulted in an underrepresentation of the severe acne-like reaction. The 40-mg/m2/week dose of cisplatin has been explored previously in other SCCHN chemoradiotherapy regimens. Medina et al. [18] reported on a phase II study of concomitant boost radiation (total dose 72 Gy) plus weekly cisplatin (40 mg/ m2; first 4 weeks), which included 94 patients with locally
original article
Annals of Oncology
Table 2. All grade adverse events in the safety/efficacy population Grade adverse events
35 mg/m2, N = 3
40 mg/m2, N = 6
Total, N = 16 (%)
3 0 1 2
4 1 1 2
3 1 1 1
6 0 2 4
16 2 5 9
(100) (12) (31) (57)
3 0 2 1
4 2 1 1
3 0 2 1
6 0 3 3
16 2 8 6
(100) (12) (50) (37)
3 0 1 2
3 1 0 2
2 1 0 1
6 4 1 1
14 6 2 6
(87) (37) (12) (37)
2 1 0 1 0
2 0 1 1 0
1 0 1 0 0
6 0 2 3 1
11 1 4 5 1
(69) (6) (25) (31) (6)
1 1
0 0
0 0
2 2
3 3 0 0
1 0 1 0
2 1 1 0
5 4 0 1
2 1 1
0 0 0
0 0 0
2 2 0
2 0 2 0
2 2 0 0
1 1 0 0
6 3 2 1
11 6 4 1
(69) (37) (24) (6)
3 3 0 0
4 2 2 0
3 0 3 0
4 2 0 2
14 7 5 2
(87) (44) (31) (12)
3 3 0 0
2 1 1 0
3 2 1 0
3 2 0 1
11 8 2 1
(69) (50) (12) (6)
1 0 1
0 0 0
1 1 0
1 1 0
advanced unresectable head and neck cancers. This schedule appeared to be feasible with an acceptable level of toxicity. Grade 3 mucositis was observed in 85% of all patients in the study. In
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3 (19) 3 (19) 11 8 2 1
(69) (50) (12) (6)
4 (24) 3 (19) 1 (6)
3 (19) 2 (12) 1 (6)
line with their results, our study also noticed mucositis as the most frequent grade 2 or 3 side-effect, which was registered in four of six (67%) patients at the highest dose level.
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Mucositis/stomatitis All grades Grade 1 Grade 2 Grade 3 Dysphagia All grades Grade 1 Grade 2 Grade 3 In-field dermatitis All grades Grade 1 Grade 2 Grade 3 White blood cell count All grades Grade 1 Grade 2 Grade 3 Grade 4 Platelet count All grades Grade 1 Hemoglobin All grades Grade 1 Grade 2 Grade 3 Magnesium All grades Grade 1 Grade 2 Skin rash All grades Grade 1 Grade 2 Grade 3 Pain All grades Grade 1 Grade 2 Grade 3 Fatigue All grades Grade 1 Grade 2 Grade 3 Vomiting All grades Grade 1 Grade 2
Dose level/number of patients 30 mg/m2, N = 3 20 mg/m2, N = 3
original article
Annals of Oncology
Table 3. Efficacy N = 15
Parameter End of treatment best overall response, N (%) Complete response Partial response Stable disease Progressive disease distant Death Overall end of treatment response rate (%)
a
5 8 – 1 1 13
(33) (53) (7) (7) (87)
a
One patient withdrew informed consent. For assessable patients, 6 weeks after combined trimodality treatment.
acknowledgements This study was previously presented at the 44th Annual Meeting of the American Society of Clinical Oncology, 30 May to 3 June 2008, Chicago, IL. We would like to thank the patients and their families and the medical staff at the various centers who contributed to their care. We would like to also thank the coordinating center of the clinical studies at the Martin-Luther-University Halle-Wittenberg for data monitoring and the Merck KGaA (Darmstadt, Germany) for providing the study medication. Conflict of interest: TK, TW and AS received honoraria for speaker’s bureau and compensations for advisory boards from Merck KGaA (Darmstadt, Germany).
disclosure TK, TW and AS received honoraria for speaker’s bureau and compensations for advisory boards from Merck KGaA (Darmstadt, Germany). TK has study support by Merck KGaA (Darmstadt, Germany).
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In a retrospective comparison of cisplatin given concurrently to 51 stage IVA SCCHN patients at either 100 mg/m2 every 3 weeks or 40 mg/m2 every week, as part of a radical chemoradiotherapy regimen, Ho et al. [19] concluded that the higher cisplatin dose was less well tolerated and resulted in fewer patients achieving a cumulative dose >200 mg/m2. One important advantage of the administration of cisplatin at a weekly regimen of 40 mg/m2 as a component of chemoradiotherapy regimens for head and neck cancer, however, is the possibility of a prompt modification in case of acute toxicity [20]. In conclusion, we report here on the first dose escalation trial of cisplatin as part of a three-modality regimen. Cetuximab can be safely combined with HART and weekly cisplatin at 40 mg/ m2 in the treatment of locally advanced SCCHN. The absence of DLTs at the highest cisplatin dose and the observed activity provide a strong rationale for extending the study into a phase II trial, which is currently ongoing.
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Annals of Oncology 21: 2284–2289, 2010 doi:10.1093/annonc/mdq216 Published online 28 April 2010
Phase I trial of dose-escalated cisplatin with concomitant cetuximab and hyperfractionatedaccelerated radiotherapy in locally advanced squamous cell carcinoma of the head and neck T. Kuhnt1*, A. Sandner2, T. Wendt3, R. Engenhart-Cabillic4, G. Lammering5,6, M. Flentje7, G. Grabenbauer8, A. Schreiber9, A. Pirnasch1 & J. Dunst10
Received 4 August 2009; revised 30 November 2009; accepted 9 March 2010
original article
Background: Cetuximab is active in the treatment of squamous cell carcinoma of the head and neck (SCCHN), enhancing both radiotherapy and chemotherapy effects. This phase I study was designed to investigate the safety and tolerability of combining weekly cisplatin treatment with cetuximab and hyperfractionated-accelerated radiotherapy (HART) for locally advanced SCCHN. Patients and methods: Patients with unresectable stage III or IVA/B SCCHN were treated with cetuximab, 400 mg/ m2 initial dose on day 27 of HART, followed by 250 mg/m2 weekly during the administration of HART, which started with 2.0 Gy/day (5 days/week) for 3 weeks followed by 1.4 Gy/twice-daily (Monday to Friday) for another 3 weeks, resulting in a total dose of 70.6 Gy. Cisplatin was administered weekly starting on the first day of radiotherapy until week 6. Cisplatin was dose escalated of four dose levels from 20 to 40 mg/m2 using a classical 3 + 3 dose escalation algorithm. Results: Eighteen patients were enrolled. Sixteen patients were eligible for toxicity, and 15 for response. No maximum tolerated dose was reached for cisplatin. One of six patients of dose level 4 had grade 4 neutropenia. This patient died 1 week after the end of the study treatment. The most common types of grade 3+ adverse events were mucositis (9 of 16 patients), in-field dermatitis (6 of 16 patients) and neutropenia (4 of 16 patients). Cetuximab-related hypersensitivity was observed in 1 out of 18 patients. Six weeks after the end of the study treatment, 5 complete responses, 8 partial responses and 1 progressive disease (at distant sites) were documented in a total of 15 patients (objective response rate 87%). Conclusions: 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. Key words: cetuximab, cisplatin, hyperfractionated-accelerated, locally advanced SCCHN, radiotherapy
introduction Cancers of the head and neck, particularly those of the oral cavity, pharynx and larynx account for >5% of all malignancies worldwide with >500 000 new cases and >300 000 attributable deaths recorded in 2002 [1]. Approximately 90% of head and neck tumors are squamous cell carcinomas. For resectable early disease (stage I and II), standard treatment options include surgery or external radiation therapy. For unresectable locally advanced disease (stage *Correspondence to: Dr T. Kuhnt, Department of Radiation Oncology, University of Rostock, Suedring 75, D-18059 Rostock, Germany. Tel: +49-381-494-9030; Fax: +49-381-494-9002; E-mail: [email protected]
III and IVA/B) the addition of chemotherapy to radiotherapy (chemoradiotherapy), administered as a concomitant treatment, has been shown to improve outcomes in medically fit patients compared with radiotherapy alone, albeit at the cost of an increased toxicity [2–8]. A recent meta-analysis of 32 randomized studies including 10 225 patients evaluated the benefit of chemoradiotherapy versus radiotherapy alone in patients with unresected locally advanced squamous cell carcinoma of the head and neck (SCCHN) [9]. This meta-analysis confirmed an overall survival benefit of 12.0 months for the addition of simultaneous chemotherapy to conventionally fractionated,
ª The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]
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1 Department of Radiation Oncology, University of Rostock, Rostock; 2Department of Head and Neck Surgery, Martin-Luther-University, Halle-Wittenberg; 3Department of Radiation Oncology, Friedrich-Schiller-University, Jena; 4Department of Radiation Oncology, Phillips-University, Marburg, Germany; 5Department of Radiation Oncology (Maastro Clinic), Maastricht, The Netherlands; 6Department of Radiation Therapy and Radiation Oncology, University of Du¨sseldorf, Du¨sseldorf; 7Department of Radiation Oncology, University of Wu¨rzburg, Wu¨rzburg; 8Department of Radiation Oncology, Hospital Coburg, Coburg; 9Department of Radiation Oncology, Hospital Dresden-Friedrichstadt, Friedrichstadt; 10Department of Radiation Oncology, University of Schleswig-Holstein, Campus Lu¨beck, Germany
original article
Annals of Oncology
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cisplatin with cetuximab and hyperfractionated-accelerated radiotherapy (HART) in the treatment of patients with unresectable locally advanced SCCHN. The primary objective of the trial was to determine the maximum tolerated dose (MTD) of cisplatin as part of a three-modality regimen.
patients and methods patient eligibility Patients aged ‡18 and £70 years were eligible for inclusion if they had been diagnosed with histologically confirmed unresectable squamous cell carcinoma of the oral cavity (excluding the lip), oropharynx, hypopharynx or larynx measurable in one dimension and classified as stage III or IVA/B (International Union Against Cancer). In the phase I protocol no human papillomavirus status or p16 was determined in oropharynx carcinoma. Furthermore, inclusion required a Karnofsky Index (KI) ‡70% and adequate pulmonary, cardiac, bone marrow, hepatic and renal functions. Study treatment was given in curative intent. Before the initiation of radiotherapy, all patients had to undergo a dental examination and received a percutaneous endoscopic gastrostomy. Exclusion criteria were metastatic disease; a life expectancy of <3 months; pregnancy; cancers of an unknown primary site, the nasopharynx or the salivary gland; or a previous cancer disease within 5 years of study entry. Furthermore, patients were not entered in case of serious concomitant diseases or serious medical conditions; previous treatment with chemotherapy, radiotherapy or surgery for head and neck cancer; or any social situations that would have limited the compliance with study requirements. Concurrent treatments with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days before study screening were also not allowed. Patients were also not enrolled in case of any contraindications against cisplatin or cetuximab or in case of any prior exposure to monoclonal antibodies and/or EGFR-targeted therapy. The contraindications for cisplatin were as follows: known hypersensitivity for cisplatin or other platinum connections, existing distinctive bone marrow depression, severe nephritic damages, exsiccation, herpes zoster, fresh infections or a peripheral neuropathy. Cetuximab was contraindicated in patients with any known severe hypersensitivity reaction to medication, pregnancy or lactation.
study design This trial was designed as a multicenter, single-arm, prospective, threemodality phase I dose escalation study. The primary objective was to determine the MTD of cisplatin in combination with cetuximab and HART, according to the incidence of dose-limiting toxic effects (DLTs). Secondary objectives included acute toxicity and objective tumor response rate (ORR). The study was conducted according to the ethical standards laid down in the Declaration of Helsinki. The study protocol was approved by the ethics committee of the Martin-Luther-University of HalleWittenberg. All patients provided written informed consent before registration. Patients had to follow the treatment plan as illustrated in Figure 1. HART started at a single dose of 2.0 Gy/day, days 1–5, during the first 3 weeks followed by 1.4-Gy b.i.d., days 1–5, during the following 3 weeks (1.4 Gy as single dose last day), resulting in a total dose of 70.6 Gy to the gross tumor volume. Patients received cetuximab, at an initial dose of 400 mg/m2 administered as a 120-min infusion, on day 27 before the start of radiotherapy, with subsequent weekly doses of 250 mg/m2, given as a 1-h infusion on day 1 during the 6 weeks of radiotherapy. Cisplatin was escalated at different levels in successive cohorts as a classic 3 + 3 dose escalation design. The doses levels were 20, 30, 35 and 40 mg/m2 on days 1, 8, 15, 22, 29 and 36.
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hyperfractionated or accelerated fractionated radiotherapy (P < 0.001). The study also reported a substantial survival gain of 14.2 months for hyperfractionated compared with conventionally fractionated radiotherapy in this setting (P < 0.001). A further meta-analysis of 15 studies, including 6515 patients with nonmetastatic SCCHN, confirmed an absolute survival benefit of 3.4% at 5 years (P = 0.003) and a locoregional control benefit of 6.4% at 5 years (P < 0.0001) for altered fractionation versus conventionally fractionated radiotherapy [10]. It is commonly accepted that the efficacy benefit achieved through the addition of chemotherapy during radiotherapy is counterbalanced by an increase in acute toxicity, which limits a broader acceptance of such treatment, especially for patients with a poor performance status. In this respect, a recently published landmark phase III study of 424 patients with locally advanced SCCHN has commenced a new era, the era of targeted agents in combination with radiotherapy [11]. This study reported for the first time that the addition of the epidermal growth factor receptor (EGFR)-targeted immunoglobulin G1 monoclonal antibody cetuximab to highdose radiotherapy significantly reduced the risk of locoregional progression and death at any given time point [hazard ratio (HR) 0.68; P = 0.005] compared with radiotherapy alone. Significant improvements in progression-free survival (HR for disease progression or death at any given time point, 0.70; P = 0.006) and overall survival (HR for death at any given time point, 0.74; P = 0.03) were also noted [11]. Importantly, this improved efficacy was achieved without an increase in the incidence or severity of toxic effects commonly associated with radiotherapy. Indeed, the addition of cetuximab to radiotherapy did not adversely affect quality of life of patients compared with radiotherapy alone [12]. Moreover, a single-institution retrospective review recently confirmed that cetuximab plus radiotherapy is at least as effective as chemoradiotherapy in the treatment of patients with locally advanced head and neck cancer [13]. Another recently published landmark phase III study subsequently demonstrated that the addition of cetuximab to first-line platinum-based chemotherapy improved survival in SCCHN patients with recurrent or metastatic SCCHN, with a median survival of 7.4 months in the chemotherapy-alone arm compared with 10.1 months in the chemotherapy plus cetuximab arm (HR for death at any given time point, 0.8; P = 0.04) [14]. Cetuximab has therefore been shown to improve the efficacy of both concurrent radiotherapy and platinum-based chemotherapy in the treatment of SCCHN, albeit in different settings. Thus, these studies formed the basis to further explore the combination of cetuximab with chemoradiotherapy in the treatment of locally advanced SCCHN. Pfister et al. [15] initiated a pilot phase II study with concurrent cetuximab (standard 400/250 mg/m2 regimen), cisplatin (100 mg/m2 i.v. during weeks 1 and 4) and concomitant boost radiotherapy (70 Gy total to gross disease) in the treatment of locally advanced SCCHN. Although promising levels of activity were noted, this study had to be closed early as a consequence of significant adverse events (AEs) of unclear attribution. The present study was therefore initiated as a phase I dose escalation trial to investigate the safety of combining weekly
original article
Annals of Oncology
Three patients were entered at each cisplatin dose level, if no DLT occurred. Before proceeding to the next higher dose level of cisplatin, all patients at the previous dose level were strictly followed up for toxic effects over a period of 6 weeks after the end of radiotherapy. In case of one DLT out of three patients at any dose level, three additional patients had to be entered at the same dose level. If no additional DLTs occurred, the dose escalation proceeded. In case of two or more DLTs in six patients at a particular dose level, the MTD was deemed to have been exceeded and the escalation was stopped. The MTD was defined as the dose level of cisplatin (below the maximal administered dose) at which none of three or not more than one of six patients experienced a DLT. If the MTD was not reached, the highest tested dose of cisplatin (40 mg/m2) was to be recommended for future studies. Acute toxicity was assessed using the National Cancer Institute’s Common Toxicity Criteria version 3.0. DLT was defined as any treatmentrelated grade ‡3 toxicity or hearing loss grade >2, excluding: grade 3 mucositis; infection with a normal absolute neutrophil count or grade 1–3 neutrophils; grade 3 hematologic or hepatic toxicity and alopecia at any grade. Within the irradiated volume, only grade 4 mucosal or skin toxic effects, xerostomia and dysphagia were considered as DLTs. Late irradiation-induced toxicity (‡90 days after the end of treatment) was graded according to the Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer criteria.
study evaluations Between 7 and 30 days before the start of radiotherapy, patients had to undergo a full clinical investigation including radiological (computed tomography or magnetic resonance imaging), ultrasound, hematological and biochemical assessments. The analyses carried out at baseline, 7 days before the start of radiotherapy and every treatment week included a clinical examination and evaluations of KI and toxicity, also including hematological and biochemical parameters. At post-treatment evaluation 6 weeks after the end of study treatment, all assessments were repeated with the addition of radiological tumor assessment and neck ultrasound imaging. Disease progression, late radiation toxicity and survival were subsequently evaluated every 3 months for 2 years and at 6-month intervals until year 5, death or loss to follow-up. Tumor response was assessed according to RECIST guidelines [16], in assessable patients, comprising of those who had received at least one dose of study treatment with subsequent reevaluation of their disease. The PFS was defined as the time between the start of the treatment and the first observation of disease progression, or death from any cause. LPFS was
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defined as the time between the start of treatment and the first observation of local or regional disease recurrence or death from any cause. If a patient had not progressed and died, the PFS and LPFS were censored at the time of the last follow-up.
results patient demographics In total, 18 male patients comprising the intent to treat population were enrolled between September 2005 and April 2008. The median follow-up time reached 11 (range 2–24) months. Three patients were withdrawn from the study before the initiation of the study treatment due to the occurrence of a secondary malignancy (one patient), a cetuximab-related hypersensitivity reaction (one patient) and an accidental bone fracture (one patient). Baseline patient and tumor characteristics are summarized in Table 1. The most common primary tumor site was oropharynx and the majority of the patients had stage IVA disease. treatment compliance Four cisplatin dose levels were explored in a total of 15 patients (with total cumulated doses of 120, 180, 210 and 240 mg/m2 per patient). All 15 patients received the full scheduled course of HART. One patient suffered perforation of the stomach, which resulted in the discontinuation of the chemotherapy and the cetuximab treatment. One other patient had to receive one course of cisplatin treatment 3 days later due to a temporary increase in creatinine level. Thus, 14 and 13 patients received the planned dose of cetuximab and cisplatin, respectively, which resulted in 13 patients in total, who received the full study treatment as specified in the protocol. dose-limiting toxicity No DLTs were observed. No MTD was reached for cisplatin. safety Sixteen patients were assessable for toxicity. One grade 4 AE of neutropenia was reported in dose level 4 of six patients. This
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Figure 1. Treatment schedule. WE, weekend. W, week, d, day, Gy, gray, TD, total dose.
original article
Annals of Oncology
Table 1. Patient and disease characteristics at baseline in the safety/ efficacy population N = 18 (%)
Median age (range) years Gender Male Female UICC tumor stage III IVA IVB Nodal status N0,1 N2a,b,c N3 Primary tumor site Oral cavity Oropharynx Hypopharynx Larynx
51.2 (44–64) 18 0 3 (17) 11 (61) 4 (22) 3 (17) 14 (78) 1 (5) 2 8 3 5
(11) (44) (17) (28)
UICC, International Union Against Cancer.
patient died 1 week after completion of the treatment due to general condition deterioration. The most common grade 3 AEs observed (Table 2) were mucositis/stomatitis in 9 of 16 patients, followed by dysphagia in 6 of 16 patients, in-field dermatitis in 6 of 16 patients and neutropenia in 5 of 16 patients. Severe toxicity was more commonly observed at the highest cisplatin dose level, with 17 grade 3 AEs occurring in six patients. One grade 3 cetuximab-related hypersensitivity (6%) following the initial cetuximab infusion was observed.
efficacy Fifteen patients were assessable for tumor response at 6 weeks after the end of study treatment (Table 3). Two patients were excluded before the start of study treatment, and one patient withdrew consent during study treatment. Complete responses were achieved in 5 of 15 patients and partial responses in 8 of 15 patients, resulting in an ORR of 13/15 (87%). One patient progressed (distant metastases), and one patient died 1 week after completion of the treatment. After a median follow-up time of 11 months (range 2–24 months), three patients had developed distant metastases. At 2 years, 12/15 (80%) patients were alive and 9/15 (60%) were disease free.
discussion We demonstrated the safety and feasibility of a three-modality regimen combining cetuximab with HART and cisplatin in a dose escalation trial of cisplatin at a maximum dose of 40 mg/ m2/week. No MTD was reached and only one DLT occurred with one grade 4 neutropenia and subsequent death 1 week after end of treatment was observed in a total of 16 patients (six grade 5%). Furthermore, this regimen appeared to be active in locally advanced SCCHN and may yield promising efficacy
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Characteristic
given the objective response achieved in all tested assessable patients. Eighty percent of all patients were still alive at 2 years. Considering the demonstrated safety and activity, this trial thus provides a strong rationale for further investigating the efficacy of this regimen. The trial by Pfister et al. [15] investigating the combination of cetuximab with fixed high-dose cisplatin (100 mg/m2; weeks 1 and 4) and concomitant boost radiotherapy was halted due to serious toxicity concerns. Two patients had died while on study treatment, one of pneumonia and one of unknown cause. Three further nonfatal but significant AEs subsequently occurred, two of which were grade 4 cardiac events. These five events ultimately led to the early closure of the study. In contrast, the present study showed no evidence of significant cardiotoxicity associated with the combined treatment. One patient died 1 week after the completion of the treatment due to deterioration of the patient’s general condition associated with grade 4 neutropenia. A causal relationship with the study treatment cannot be excluded; however, all other hematological and biochemical parameters assessed 3 days before remained at normal range. With the exception of infusion-related reactions, the addition of cetuximab did not increase the toxicity of the chemoradiotherapy in this phase I study. With 57%, the rate of grade 3 in-field skin-associated AEs is in the range of what is commonly observed with chemoradiotherapy alone. These data therefore counterbalance to some extent the safety concerns that caused the early closure of the trial by Pfister et al. However, data from larger randomized studies are needed in order to draw firm conclusions with regard to safety. The Eastern Cooperative Oncology Group 3303 trial (preliminary analysis presented at American Society of Clinical Oncology meeting, 2008) investigated a three-modality regimen in locally advanced SCCHN with cisplatin at 75 mg/m2 every 3 weeks, conventionally fractionated radiotherapy (total dose of 70 Gy in fractions of 2 Gy) and weekly standard dose cetuximab starting 2 weeks before chemoradiation [17]. Maintenance therapy with cetuximab monotherapy was foreseen for up to 6 months. Sixty patients were assessable for efficacy (51 males, 9 females, median age 55.4 years). Only 45 out of 59 patients (76%) received all three scheduled doses of cisplatin. Multiple grade 4 AEs were observed, including mucositis, nephrotoxicity, anemia, thrombocytopenia and neutropenia. There was one case of grade 4 skin toxicity in the irradiation field. Of 66 patients, 14 suffered grade 3 nausea and vomiting. In contrast, the present trial reported no grade 4 mucositis, no grade 4 nephrotoxicity, no grade 3 nausea and—most notably—no grade 4 skin toxicity. Thus, our regimen of weekly cisplatin at 40 mg/m2 appears to be better tolerated than the 3-weekly 75 mg/m2 of ECOG 3303. However, it should be mentioned that the incidence of severe acne-like reactions in the study presented herein is significantly lower than in all other clinical trials reported so far. It seems, as if the small number of patients included (16) might have resulted in an underrepresentation of the severe acne-like reaction. The 40-mg/m2/week dose of cisplatin has been explored previously in other SCCHN chemoradiotherapy regimens. Medina et al. [18] reported on a phase II study of concomitant boost radiation (total dose 72 Gy) plus weekly cisplatin (40 mg/ m2; first 4 weeks), which included 94 patients with locally
original article
Annals of Oncology
Table 2. All grade adverse events in the safety/efficacy population Grade adverse events
35 mg/m2, N = 3
40 mg/m2, N = 6
Total, N = 16 (%)
3 0 1 2
4 1 1 2
3 1 1 1
6 0 2 4
16 2 5 9
(100) (12) (31) (57)
3 0 2 1
4 2 1 1
3 0 2 1
6 0 3 3
16 2 8 6
(100) (12) (50) (37)
3 0 1 2
3 1 0 2
2 1 0 1
6 4 1 1
14 6 2 6
(87) (37) (12) (37)
2 1 0 1 0
2 0 1 1 0
1 0 1 0 0
6 0 2 3 1
11 1 4 5 1
(69) (6) (25) (31) (6)
1 1
0 0
0 0
2 2
3 3 0 0
1 0 1 0
2 1 1 0
5 4 0 1
2 1 1
0 0 0
0 0 0
2 2 0
2 0 2 0
2 2 0 0
1 1 0 0
6 3 2 1
11 6 4 1
(69) (37) (24) (6)
3 3 0 0
4 2 2 0
3 0 3 0
4 2 0 2
14 7 5 2
(87) (44) (31) (12)
3 3 0 0
2 1 1 0
3 2 1 0
3 2 0 1
11 8 2 1
(69) (50) (12) (6)
1 0 1
0 0 0
1 1 0
1 1 0
advanced unresectable head and neck cancers. This schedule appeared to be feasible with an acceptable level of toxicity. Grade 3 mucositis was observed in 85% of all patients in the study. In
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3 (19) 3 (19) 11 8 2 1
(69) (50) (12) (6)
4 (24) 3 (19) 1 (6)
3 (19) 2 (12) 1 (6)
line with their results, our study also noticed mucositis as the most frequent grade 2 or 3 side-effect, which was registered in four of six (67%) patients at the highest dose level.
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Mucositis/stomatitis All grades Grade 1 Grade 2 Grade 3 Dysphagia All grades Grade 1 Grade 2 Grade 3 In-field dermatitis All grades Grade 1 Grade 2 Grade 3 White blood cell count All grades Grade 1 Grade 2 Grade 3 Grade 4 Platelet count All grades Grade 1 Hemoglobin All grades Grade 1 Grade 2 Grade 3 Magnesium All grades Grade 1 Grade 2 Skin rash All grades Grade 1 Grade 2 Grade 3 Pain All grades Grade 1 Grade 2 Grade 3 Fatigue All grades Grade 1 Grade 2 Grade 3 Vomiting All grades Grade 1 Grade 2
Dose level/number of patients 30 mg/m2, N = 3 20 mg/m2, N = 3
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Annals of Oncology
Table 3. Efficacy N = 15
Parameter End of treatment best overall response, N (%) Complete response Partial response Stable disease Progressive disease distant Death Overall end of treatment response rate (%)
a
5 8 – 1 1 13
(33) (53) (7) (7) (87)
a
One patient withdrew informed consent. For assessable patients, 6 weeks after combined trimodality treatment.
acknowledgements This study was previously presented at the 44th Annual Meeting of the American Society of Clinical Oncology, 30 May to 3 June 2008, Chicago, IL. We would like to thank the patients and their families and the medical staff at the various centers who contributed to their care. We would like to also thank the coordinating center of the clinical studies at the Martin-Luther-University Halle-Wittenberg for data monitoring and the Merck KGaA (Darmstadt, Germany) for providing the study medication. Conflict of interest: TK, TW and AS received honoraria for speaker’s bureau and compensations for advisory boards from Merck KGaA (Darmstadt, Germany).
disclosure TK, TW and AS received honoraria for speaker’s bureau and compensations for advisory boards from Merck KGaA (Darmstadt, Germany). TK has study support by Merck KGaA (Darmstadt, Germany).
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In a retrospective comparison of cisplatin given concurrently to 51 stage IVA SCCHN patients at either 100 mg/m2 every 3 weeks or 40 mg/m2 every week, as part of a radical chemoradiotherapy regimen, Ho et al. [19] concluded that the higher cisplatin dose was less well tolerated and resulted in fewer patients achieving a cumulative dose >200 mg/m2. One important advantage of the administration of cisplatin at a weekly regimen of 40 mg/m2 as a component of chemoradiotherapy regimens for head and neck cancer, however, is the possibility of a prompt modification in case of acute toxicity [20]. In conclusion, we report here on the first dose escalation trial of cisplatin as part of a three-modality regimen. Cetuximab can be safely combined with HART and weekly cisplatin at 40 mg/ m2 in the treatment of locally advanced SCCHN. The absence of DLTs at the highest cisplatin dose and the observed activity provide a strong rationale for extending the study into a phase II trial, which is currently ongoing.
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