Original article Strahlenther Onkol 2014 · 190:823–831 DOI 10.1007/s00066-014-0626-0 Received: 6 November 2013 Accepted: 22 January 2014 Published online: 18 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Antonin Levy1 · Pierre Blanchard1 · Sara Bellefqih1 · Nacéra Brahimi1 · Joël Guigay2 · François Janot3 · Stéphane Temam3 · Jean Bourhis1,4 · Eric Deutsch1 · Nicolas Daly-Schveitzer1 · Yungan Tao1 1 Department of Radiation Oncology, Gustave Roussy, Villejuif, France 2 Department of Medical Oncology, Gustave Roussy, Villejuif, France 3 Department of Head and Neck Surgery, Gustave Roussy, Villejuif, France 4 Department of Radiation Oncology, University Hospital Lausanne, Lausanne, Switzerland
Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas Definitive radiotherapy (RT) is a cornerstone of the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). In the MACH-NC (meta-analysis of chemotherapy in head and neck cancer), a survival benefit was demonstrated by the addition of chemotherapy (CT) to RT, especially concomitant chemoradiotherapy (CRT) [1, 2], but the optimal concurrent regimen has not yet been defined. In fact, indirect comparisons in the MACH-NC suggested a greater benefit for platinum-based as compared with other CT regimens but there is no randomized trial evaluating this question. Although it is associated with severe acute and late toxicities and poor compliance, cisplatin monotherapy (100 mg/m2 on days 1, 22, and 43 of RT) is often considered the preferred regimen [3–5]. Concomitant bioradiotherapy (BRT) with the epidermal growth factor receptor (EGFR) inhibitor cetuximab has demonstrated a significantly increased overall survival (OS) and locoregional control (LRC) compared to those receiving RT alone in one randomized controlled trial [6]. In the randomized phase II GORTEC (Groupe d’Oncologie Radiothérapie Tête Et Cou) Tremplin study that assessed the two regimens af-
ter induction CT, compliance was higher in the biotherapy arm but no difference in outcomes were reported [7]. A retrospective series suggested that patients receiving BRT had a lower LRC and OS compared with patients receiving cisplatin-based CRT [8], while another one did not find any differences in outcome between the two therapeutic modalities [9]. It is generally considered that cetuximab-based BRT is well tolerated with mild toxicity. However, one retrospective study found that BRT caused significantly more toxicity than CRT, although BRT did not increase the frequency of treatment interruptions or delay [10, 11]. On the other hand, in the RTOG (Radiation Therapy Oncology Group) 91-11 trial, CRT induced frequent severe (grade 3 and 4) adverse events (82 %) and only 120/172 patients (70 %) completed all three cycles of cisplatin [12]. In the absence of randomized trial assessing this comparison, we decided to evaluate the outcomes of LAHNSCC patients treated at our institute with definitive BRT or CRT.
Patients and methods Patients From March 2006 to October 2012, 597 consecutive patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx registered in the head and neck cancer database at Institut GustaveRoussy were treated by definitive CRT or BRT with curative intent. Postoperative patients or patients treated without concomitant treatment were not included. Patients were excluded for the following reasons: induction CT prior to RT (n = 213), treatment outside of the institution (n = 40), death before radiotherapy (n = 8), concomitant treatment not delivered due to intercurrent condition (n = 8), and other CT regimen employed (n = 63; mostly 5-fluorouracil [5FU] and carboplatin). Of the remaining 265 patients, 194 (73 %) and 71 (27 %) received concomitant CRT and BRT, respectively. Baseline patient and tumor characteristics are shown in . Table 1. Patients were selected to receive cetuximab rather than cisplatin for the following reasons: cardiac comorbidity (n = 31); clinical trial (n = 18), age > 70 years (n = 6), auditory concerns (n = 1), performance status (n = 1), physician Strahlentherapie und Onkologie 9 · 2014
| 823
Original article
Overall n (%) 265 (100) 58 (36–81)
CRT n (%) 194 (100) 58 (36–79)
BRT n (%) 71 (100) 60 (42–81)
p
before the initiation of treatment and 15 patients had another head and neck synchronous cancer.
0.001
Treatments
210 (79) 55 (21)
155 (80) 39 (20)
55 (77) 16 (23)
0.7
11 (4) 182 (69) 33 (12) 39 (15)
8 (4) 136 (70) 21 (11) 29 (15)
3 (4) 46 (65) 12 (17) 10 (14)
202 (76) 63 (24)
149 (77) 45 (23)
53 (75) 18 (25)
117 (44) 73 (28) 75 (28)
95 (49) 54 (28) 45 (23)
22 (31) 19 (27) 30 (42)
98 (37) 76 (29) 91 (34)
71 (37) 55 (28) 68 (35)
27 (38) 21 (30) 23 (32)
49 (18) 114 (43) 102 (38)
39 (20) 82 (43) 73 (38)
10 (14) 32 (45) 29 (41)
110 (42) 85 (32) 70 (26)
83 (43) 63 (32) 48 (25)
27 (38) 22 (31) 22 (31)
65 (25) 49 (19) 134 (50) 17 (9)
41 (21) 33 (17) 106 (55) 14 (7)
24 (34) 16 (23) 28 (39) 3 (4)
28 (11) 65 (25) 155 (58) 17 (9)
18 (9) 45 (23) 96 (49) 14 (7)
10 (14) 20 (28) 38 (54) 3 (4)
70 (12–75) 35 (6–36) 49 (4–70) 59 (23)
70 (12–75) 35 (6–35) 49 (4–70) 44 (23)
70 (36–75) 35 (18–36) 49 (24–60) 15 (21)
Table 1 Baseline patient clinical characteristics and treatments Patients characteristics Total Median age (years) Gender Male Female Location Buccal cavity Oropharynx Hypopharynx Larynx Performance status 0 ≥ 1 Charlson index 0 1 ≥ 2 Alcohol status Never Former Current Tobacco status Never smoker Former Current T classification 1–2 3 4 N classification 0 1 2 3 Overall stage I–II III IVa IVb Radiotherapy Median dose (Gy) Median number of fractions Median duration (days)a IMRT
0.9
0.7
0.005
0.9
0.5
0.6
0.06
Toxicities 0.6
0.1 0.2 0.2 0.8
CRT chemoradiotherapy with concurrent cisplatin, BRT bioradiotherapy with concurrent cetuximab, IMRT intensity-modulated radiotherapy a5 patients treated with accelerated fractionated RT in the CRT group were excluded from this analysis
preference (n = 5), and other coexisting conditions (n = 9). Patients receiving BRT had more pre-existing condi-
824 | Strahlentherapie und Onkologie 9 · 2014
All patients had been referred to a multidisciplinary head and neck tumor board prior to treatment initiation. Continuous-course external beam definitive RT was delivered at a median dose of 70 Gy (range 12–75 Gy) to the gross tumor volume (GTV) in 35 fractions (range 6–36 fractions) with a median overall treatment time of 49 days (range 4–70 days). A dose of 60 Gy and 50–54 Gy were delivered to the high- and low-risk clinical target volume (CTV). The CTVs were each expanded using 5 mm margins to generate their respective planned target volumes (PTV). Intensity-modulated radiation therapy (IMRT) was delivered in 59 (22 %) patients. Cisplatin was administered at a planned dose of 100 mg/m2 every 3 weeks on days 1, 22, and 43, with a maximum of three cycles. Cetuximab was administered at an initial loading dose of 400 mg/ m2 one week prior to RT (day 7), followed by weekly injection at 250 mg/m2 during RT. Patients were assessed 3 months after the completion of treatment with physical examination and imaging studies and then with physical examination every 3 months for 2 years, every 6 months until 5 years, and every year after 5 years.
tions (Charlson index > 2) than the CRT group (p = 0.005). Ten patients had a tracheostomy or laser airway clearance
Patients were evaluated by chart review using the Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4) for acute toxicity and the Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scales (LENT SOMA) for late toxicity.
Statistical analysis Follow-up was estimated using the reverse Kaplan–Meier method. Overall, progression-free (PFS), cause-specific survival, locoregional control (LRC), and distant control (DC) rates were estimated using the Kaplan–Meier method. Survival rates were defined as the time between
Abstract · Zusammenfassung Strahlenther Onkol 2014 · 190:823–831 DOI 10.1007/s00066-014-0626-0 © Springer-Verlag Berlin Heidelberg 2014 A. Levy · P. Blanchard · S. Bellefqih · N. Brahimi · J. Guigay · F. Janot · S. Temam · J. Bourhis · E. Deutsch · N. Daly-Schveitzer · Y. Tao
Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas Abstract Aim. The goal of the present work was to compare outcomes of definitive concurrent cisplatin-based chemoradiotherapy (CRT) with cetuximab-based bioradiotherapy (BRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). Patients and methods. Between 2006 and 2012, 265 patients with locally advanced HNSCC were treated at our institution with CRT (n = 194; 73 %) with three cycles of cisplatin (100 mg/m2, every 3 weeks) or BRT (n = 71; 27 %) with weekly cetuximab. Patients receiving BRT had more pre-existing conditions (Charlson index ≥ 2) than the CRT group (p = 0.005). Results. Median follow-up was 29 months. In all, 56 % of patients treated with CRT received the planned three cycles (92 % at
least two cycles) and 79 % patients treated with BRT received six cycles or more. The 2-year actuarial overall survival (OS) and progression-free survival (PFS) were 72 % and 61 %, respectively. In the multivariate analysis (MVA), T4 stage, N2–3 stage, smoking status (current smoker as compared with never smoker), and non-oropharyngeal locations predicted for OS, whereas BRT association with OS was of borderline significance (p = 0.054). The 2-year actuarial locoregional control (LRC) and distant control (DC) rates were 73 and 79 %, respectively. CRT was independently associated with an improved LRC (2-year LRC: 76 % for CRT vs. 61 % for BRT) and DC (2-year LRC: 81 % for CRT vs. 68 % for BRT) in comparison with BRT (p
Antonin Levy1 · Pierre Blanchard1 · Sara Bellefqih1 · Nacéra Brahimi1 · Joël Guigay2 · François Janot3 · Stéphane Temam3 · Jean Bourhis1,4 · Eric Deutsch1 · Nicolas Daly-Schveitzer1 · Yungan Tao1 1 Department of Radiation Oncology, Gustave Roussy, Villejuif, France 2 Department of Medical Oncology, Gustave Roussy, Villejuif, France 3 Department of Head and Neck Surgery, Gustave Roussy, Villejuif, France 4 Department of Radiation Oncology, University Hospital Lausanne, Lausanne, Switzerland
Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas Definitive radiotherapy (RT) is a cornerstone of the treatment of locally advanced head and neck squamous cell carcinoma (LAHNSCC). In the MACH-NC (meta-analysis of chemotherapy in head and neck cancer), a survival benefit was demonstrated by the addition of chemotherapy (CT) to RT, especially concomitant chemoradiotherapy (CRT) [1, 2], but the optimal concurrent regimen has not yet been defined. In fact, indirect comparisons in the MACH-NC suggested a greater benefit for platinum-based as compared with other CT regimens but there is no randomized trial evaluating this question. Although it is associated with severe acute and late toxicities and poor compliance, cisplatin monotherapy (100 mg/m2 on days 1, 22, and 43 of RT) is often considered the preferred regimen [3–5]. Concomitant bioradiotherapy (BRT) with the epidermal growth factor receptor (EGFR) inhibitor cetuximab has demonstrated a significantly increased overall survival (OS) and locoregional control (LRC) compared to those receiving RT alone in one randomized controlled trial [6]. In the randomized phase II GORTEC (Groupe d’Oncologie Radiothérapie Tête Et Cou) Tremplin study that assessed the two regimens af-
ter induction CT, compliance was higher in the biotherapy arm but no difference in outcomes were reported [7]. A retrospective series suggested that patients receiving BRT had a lower LRC and OS compared with patients receiving cisplatin-based CRT [8], while another one did not find any differences in outcome between the two therapeutic modalities [9]. It is generally considered that cetuximab-based BRT is well tolerated with mild toxicity. However, one retrospective study found that BRT caused significantly more toxicity than CRT, although BRT did not increase the frequency of treatment interruptions or delay [10, 11]. On the other hand, in the RTOG (Radiation Therapy Oncology Group) 91-11 trial, CRT induced frequent severe (grade 3 and 4) adverse events (82 %) and only 120/172 patients (70 %) completed all three cycles of cisplatin [12]. In the absence of randomized trial assessing this comparison, we decided to evaluate the outcomes of LAHNSCC patients treated at our institute with definitive BRT or CRT.
Patients and methods Patients From March 2006 to October 2012, 597 consecutive patients with newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx registered in the head and neck cancer database at Institut GustaveRoussy were treated by definitive CRT or BRT with curative intent. Postoperative patients or patients treated without concomitant treatment were not included. Patients were excluded for the following reasons: induction CT prior to RT (n = 213), treatment outside of the institution (n = 40), death before radiotherapy (n = 8), concomitant treatment not delivered due to intercurrent condition (n = 8), and other CT regimen employed (n = 63; mostly 5-fluorouracil [5FU] and carboplatin). Of the remaining 265 patients, 194 (73 %) and 71 (27 %) received concomitant CRT and BRT, respectively. Baseline patient and tumor characteristics are shown in . Table 1. Patients were selected to receive cetuximab rather than cisplatin for the following reasons: cardiac comorbidity (n = 31); clinical trial (n = 18), age > 70 years (n = 6), auditory concerns (n = 1), performance status (n = 1), physician Strahlentherapie und Onkologie 9 · 2014
| 823
Original article
Overall n (%) 265 (100) 58 (36–81)
CRT n (%) 194 (100) 58 (36–79)
BRT n (%) 71 (100) 60 (42–81)
p
before the initiation of treatment and 15 patients had another head and neck synchronous cancer.
0.001
Treatments
210 (79) 55 (21)
155 (80) 39 (20)
55 (77) 16 (23)
0.7
11 (4) 182 (69) 33 (12) 39 (15)
8 (4) 136 (70) 21 (11) 29 (15)
3 (4) 46 (65) 12 (17) 10 (14)
202 (76) 63 (24)
149 (77) 45 (23)
53 (75) 18 (25)
117 (44) 73 (28) 75 (28)
95 (49) 54 (28) 45 (23)
22 (31) 19 (27) 30 (42)
98 (37) 76 (29) 91 (34)
71 (37) 55 (28) 68 (35)
27 (38) 21 (30) 23 (32)
49 (18) 114 (43) 102 (38)
39 (20) 82 (43) 73 (38)
10 (14) 32 (45) 29 (41)
110 (42) 85 (32) 70 (26)
83 (43) 63 (32) 48 (25)
27 (38) 22 (31) 22 (31)
65 (25) 49 (19) 134 (50) 17 (9)
41 (21) 33 (17) 106 (55) 14 (7)
24 (34) 16 (23) 28 (39) 3 (4)
28 (11) 65 (25) 155 (58) 17 (9)
18 (9) 45 (23) 96 (49) 14 (7)
10 (14) 20 (28) 38 (54) 3 (4)
70 (12–75) 35 (6–36) 49 (4–70) 59 (23)
70 (12–75) 35 (6–35) 49 (4–70) 44 (23)
70 (36–75) 35 (18–36) 49 (24–60) 15 (21)
Table 1 Baseline patient clinical characteristics and treatments Patients characteristics Total Median age (years) Gender Male Female Location Buccal cavity Oropharynx Hypopharynx Larynx Performance status 0 ≥ 1 Charlson index 0 1 ≥ 2 Alcohol status Never Former Current Tobacco status Never smoker Former Current T classification 1–2 3 4 N classification 0 1 2 3 Overall stage I–II III IVa IVb Radiotherapy Median dose (Gy) Median number of fractions Median duration (days)a IMRT
0.9
0.7
0.005
0.9
0.5
0.6
0.06
Toxicities 0.6
0.1 0.2 0.2 0.8
CRT chemoradiotherapy with concurrent cisplatin, BRT bioradiotherapy with concurrent cetuximab, IMRT intensity-modulated radiotherapy a5 patients treated with accelerated fractionated RT in the CRT group were excluded from this analysis
preference (n = 5), and other coexisting conditions (n = 9). Patients receiving BRT had more pre-existing condi-
824 | Strahlentherapie und Onkologie 9 · 2014
All patients had been referred to a multidisciplinary head and neck tumor board prior to treatment initiation. Continuous-course external beam definitive RT was delivered at a median dose of 70 Gy (range 12–75 Gy) to the gross tumor volume (GTV) in 35 fractions (range 6–36 fractions) with a median overall treatment time of 49 days (range 4–70 days). A dose of 60 Gy and 50–54 Gy were delivered to the high- and low-risk clinical target volume (CTV). The CTVs were each expanded using 5 mm margins to generate their respective planned target volumes (PTV). Intensity-modulated radiation therapy (IMRT) was delivered in 59 (22 %) patients. Cisplatin was administered at a planned dose of 100 mg/m2 every 3 weeks on days 1, 22, and 43, with a maximum of three cycles. Cetuximab was administered at an initial loading dose of 400 mg/ m2 one week prior to RT (day 7), followed by weekly injection at 250 mg/m2 during RT. Patients were assessed 3 months after the completion of treatment with physical examination and imaging studies and then with physical examination every 3 months for 2 years, every 6 months until 5 years, and every year after 5 years.
tions (Charlson index > 2) than the CRT group (p = 0.005). Ten patients had a tracheostomy or laser airway clearance
Patients were evaluated by chart review using the Common Terminology Criteria for Adverse Events v4.0 (CTCAE v4) for acute toxicity and the Late Effects in Normal Tissues Subjective, Objective, Management and Analytic scales (LENT SOMA) for late toxicity.
Statistical analysis Follow-up was estimated using the reverse Kaplan–Meier method. Overall, progression-free (PFS), cause-specific survival, locoregional control (LRC), and distant control (DC) rates were estimated using the Kaplan–Meier method. Survival rates were defined as the time between
Abstract · Zusammenfassung Strahlenther Onkol 2014 · 190:823–831 DOI 10.1007/s00066-014-0626-0 © Springer-Verlag Berlin Heidelberg 2014 A. Levy · P. Blanchard · S. Bellefqih · N. Brahimi · J. Guigay · F. Janot · S. Temam · J. Bourhis · E. Deutsch · N. Daly-Schveitzer · Y. Tao
Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas Abstract Aim. The goal of the present work was to compare outcomes of definitive concurrent cisplatin-based chemoradiotherapy (CRT) with cetuximab-based bioradiotherapy (BRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). Patients and methods. Between 2006 and 2012, 265 patients with locally advanced HNSCC were treated at our institution with CRT (n = 194; 73 %) with three cycles of cisplatin (100 mg/m2, every 3 weeks) or BRT (n = 71; 27 %) with weekly cetuximab. Patients receiving BRT had more pre-existing conditions (Charlson index ≥ 2) than the CRT group (p = 0.005). Results. Median follow-up was 29 months. In all, 56 % of patients treated with CRT received the planned three cycles (92 % at
least two cycles) and 79 % patients treated with BRT received six cycles or more. The 2-year actuarial overall survival (OS) and progression-free survival (PFS) were 72 % and 61 %, respectively. In the multivariate analysis (MVA), T4 stage, N2–3 stage, smoking status (current smoker as compared with never smoker), and non-oropharyngeal locations predicted for OS, whereas BRT association with OS was of borderline significance (p = 0.054). The 2-year actuarial locoregional control (LRC) and distant control (DC) rates were 73 and 79 %, respectively. CRT was independently associated with an improved LRC (2-year LRC: 76 % for CRT vs. 61 % for BRT) and DC (2-year LRC: 81 % for CRT vs. 68 % for BRT) in comparison with BRT (p
