Original article Strahlenther Onkol 2014 · 190:654–660 DOI 10.1007/s00066-014-0647-8 Received: 14 August 2013 Accepted: 28 November 2013 Published online: 4 March 2014 © Springer-Verlag Berlin Heidelberg 2014
A. Levy1 · P. Blanchard1 · S. Temam2 · M.-M. Maison2 · F. Janot2 · H. Mirghani2 · F. Bidault3 · J. Guigay4 · A. Lusinchi1 · J. Bourhis1,5 · N. Daly-Schveitzer1 · Y. Tao1 1Department of Radiotherapy, Gustave Roussy, Villejuif, France 2Department of Otorhinolaryngology—Head and Neck Surgery, Gustave Roussy, Villejuif, France 3Department of Diagnostic Radiology, Gustave Roussy, Villejuif, France 4Department of Medical Oncology, Gustave Roussy, Villejuif, France 5Department of Radiation Oncology, University Hospital Lausanne, Lausanne, Switzerland
Squamous cell carcinoma of the larynx with subglottic extension: is larynx preservation possible? Squamous cell carcinoma of the larynx with subglottic extension (sSCC) is rare and represents, including primary subglottic cancer, less than 7 % of all laryngeal cancers [1, 2]. Given their high propensity to lymphatic (paratracheal and recurrent lymph nodes) and systemic spread, and the risk of airway obstruction in fragile patients with cumulative toxic effects of chronic alcohol and tobacco abuse, sSCC is described to carry a poor prognosis [3]. Despite the lack of literature reporting treatment outcomes, it is generally considered that small lesions (T1–T2) can be treated successfully by radiation therapy (RT) alone [4] and that surgery may be used for larger lesions (T3–T4) or salvage treatment [5, 6]. However, the surgical management of sSCC requires the removal of the entire larynx, leading to speech disruption. Partial laryngectomy is rarely possible for subglottic cancer, and organ preservation is usually considered contraindicated in such a location. RT alone for limited tumors or combined with chemotherapy for locally advanced tumors has been used to avoid total laryngectomy (TL). Although it is accepted that concomitant chemo-RT (CRT) can achieve larynx preservation, this finding has never been explicitly been considered in sSCC [7–11]. Recently, Hata et al. [12] suggested that the use of CRT may enhance treatment efficacy and contribute to larynx preservation through improved local control for sSCC patients. Induction chemotherapy followed by defin-
654 | Strahlentherapie und Onkologie 7 · 2014
itive RT in responsive patients is another alternative for the functional organ preservation treatment of locally advanced cancer of the larynx [13]. Indeed, survival benefit has been reported for patients receiving induction chemotherapy (CT) using TPF (docetaxel, cisplatin, 5-fluorouracil [5FU]) followed by definitive RT when compared to cisplatin and 5-FU (PF) followed by the same RT [14, 15]. Currently, there are no large studies evaluating the modern therapeutic options available (RT, surgery or induction CT first) in large series of sSCC patients or larynx cancer patients with subglottic extension. The aim of this study was to analyze the outcomes and feasibility of laryngeal preservation in sSCC patients treated at our institution.
Patients and methods Patients The medical records of 251 patients who presented with laryngeal cancer involving the subglottis region, obtained from more than 1700 patients with laryngeal cancer treated at Institut Gustave Roussy between 1996 and 2012, were retrospectively analyzed. Clinical subglottis invasion was defined as the presence of the tumor 5 mm below the free edge of the true vocal folds. Patients who initiated their treatments other than RT or TL outside of the institution and were subsequently referred for curative treatment at our institution for
their primary tumor (n = 1) or a local relapse after partial surgery (n = 6) were included in the analysis. Patients with primary subglottic cancer (n = 21) were also included in the analysis. Patients 60 years and positive N stage were the only predictors for OS, with HRs of 2 (95 % CI 1.2–3.6) and 1.9 (95 % CI 1–3.5), respectively (. Tables 3 and 4). There was no survival difference in this series according to the front-line treatments or whether patients had primary subglottic cancer or not.
Locoregional and distant control The 5-year actuarial LRC rate for the entire population was 83 % (95 % CI 77–89) and distant control rate was 88 % (95 % Strahlentherapie und Onkologie 7 · 2014
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Abstract · Zusammenfassung Strahlenther Onkol 2014 · 190:654–660 DOI 10.1007/s00066-014-0647-8 © Springer-Verlag Berlin Heidelberg 2014 A. Levy · P. Blanchard · S. Temam · M.-M. Maison · F. Janot · H. Mirghani · F. Bidault · J. Guigay · A. Lusinchi · J. Bourhis · N. Daly-Schveitzer · Y. Tao
Squamous cell carcinoma of the larynx with subglottic extension: is larynx preservation possible? Abstract Purpose. Squamous cell carcinoma of larynx with subglottic extension (sSCC) is a rare location described to carry a poor prognosis. The aim of this study was to analyze outcomes and feasibility of larynx preservation in sSCC patients. Patients and methods. Between 1996 and 2012, 197 patients with sSCC were treated at our institution and included in the analysis. Stage III–IV tumors accounted for 76 %. Patients received surgery (62 %), radiotherapy (RT) (18 %), or induction chemotherapy (CT) (20 %) as front-line therapy. Results. The 5-year actuarial overall survival (OS), locoregional control (LRC), and distant control rate were 59 % (95 % CI 51–68), 83 % (95 % CI 77–89), and 88 % (95 % CI 83–
93), respectively, with a median follow-up of 54.4 months. There was no difference in OS and LRC according to front-line treatments or between primary subglottic cancer and glottosupraglottic cancers with subglottic extension. In the multivariate analysis, age > 60 years and positive N stage were the only predictors for OS (HR 2, 95 % CI 1.2–3.6; HR1.9, 95 % CI 1–3.5, respectively). A lower LRC was observed for T3 patients receiving a larynx preservation protocol as compared with those receiving a front-line surgery (HR 14.1, 95 % CI 2.5–136.7; p = 0.02); however, no difference of ultimate LRC was observed according to the first therapy when including T3 patients who underwent salvage laryngectomy (p = 0.6). In patients receiving a larynx preservation pro-
tocol, the 5-year larynx-preservation rate was 55 % (95 % CI 43–68), with 36 % in T3 patients. The 5-year larynx preservation rate was 81 % (95 % CI 65–96) and 35 % (95 % CI 20–51) for patients who received RT or induction CT as a front-line treatment, respectively. Conclusion. Outcomes of sSCC are comparable with other laryngeal cancers when managed with modern therapeutic options. Larynx-preservation protocols could be a suitable option in T1–T2 (RT or chemo-RT) and selected T3 sSCC patients (induction CT). Keywords Squamous cell carcinoma of head and neck · Surgery · Radiotherapy · Induction chemotherapy · Larynx preservation
Plattenepithelkarzinom des Larynx mit subglottischer Ausdehnung: ist ein Larynxerhalt möglich? Zusammenfassung Ziel. Plattenepithelkarzinome des Larynx mit subglottischer Ausdehnung (PECsA) sind selten und haben eine ungünstige Prognose. Das Ziel dieser Studie war es, die Ergebnisse und Durchführbarkeit einer larynxerhaltenden Therapie bei PECsA-Patienten zu untersuchen. Patienten und Methoden. Im Zeitraum zwischen 1996 und 2012 wurden 197 Patienten mit einem PECsA des Larynx in unserer Klinik therapiert und in die Studie eingeschlossen. Davon befanden sich 76 % der Patienten im Stadium III–IV nach TNM. Als Erstlinientherapie wurden 62 % der Patienten operiert, 18 % erhielten eine Radiotherapie (RT) und 20 % eine Induktionschemotherapie (ICT). Ergebnisse. Das 5-Jahres-Gesamtüberleben, die lokoregionale Tumorkontrolle und die Kontrollrate bezüglich einer Fernmetastasierung waren 59 % (95 %-Konfidenzintervall [KI] 51–68), 83 % (95 %-KI 77–89) bzw. 88 % (95 %-KI 83–93) mit einer medianen
CI 83–93). No difference was observed according to the first received therapy (p = 0.3). When including 11 patients who underwent salvage TL, ultimate LRC was 89 % (95 % CI 84–94) for the entire pop‑ ulation. There was no difference in locoregional or distant control rate according to regimen of induction CT (TPF or PF; p = 0.3), although TPF patients had
656 | Strahlentherapie und Onkologie 7 · 2014
Nachkontrolle von 54,4 Monaten. Es gab keinen Unterschied zwischen dem 5-Jahres-Gesamtüberleben und der lokoregionalen Tumorkontrolle in Anbetracht der Erstlinientherapie oder zwischen den primären subglottischen Karzinomen bzw. den glottosupraglottischen Karzinomen mit subglottischer Ausdehnung. In der multivariaten Analyse waren ein Lebensalter > 60 Jahre und ein positiver Lymphknotenstatus die einzigen Prädiktoren für das 5-Jahres-Gesamtüberleben (jeweils HR 2, 95 %-KI 1,2–3,6; HR 1,9, 95 %-KI 1–3,5). Eine schlechtere lokoregionale Tumorkontrolle wurde bei Patienten im T3-Stadium beobachtet, bei denen ein larynxerhaltendes Protokoll eingehalten wurde, im Vergleich mit denjenigen, welche eine Operation erhielten (HR 14,1; 95 %-KI 2,5–136,7; p = 0,02). Allerdings wurde in Bezug auf die Erstlinientherapie kein Unterschied bei der letzten lokoregionalen Tumorkontrolle festgestellt, wenn Patienten im Stadium T3 eingeschlossen wur-
better responses (78 % vs. 53 % for PF; p = 0.2). There was no difference of outcomes in patients receiving concurrent CRT vs. those receiving RT alone (16 vs. 19 patients). No prognostic factor of distant metastasis was identified in this population (16 distant relapses).
den, bei denen eine salvage Laryngektomie (p = 0,6) durchgeführt wurde. Bei Patienten mit einem larynxerhaltenden Protokoll war die 5-Jahres-Larynx-Erhaltungsrate 81 % (95 %-KI 65–96) bzw. 35 % (95 %-KI 20–51) für Patienten, welche eine Radiotherapie oder eine ICT als Erstlinientherapie erhielten. Schlussfolgerung. Die Ergebnisse der PECsA des Larynx sind vergleichbar mit denjenigen anderer Larynxkrebsarten, wenn mit modernen therapeutischen Methoden behandelt wird. Larynxerhaltungsprotokolle könnten eine angemessene Option sowohl bei Patientenim Stadium T1–T2 (RT oder ChemoRT) als auch bei ausgewählten T3-PECsA-Patienten sein (ICT). Schlüsselwörter Kopf-Hals-Plattenepithelkarzinom · Operation · Radiotherapie · Induktionschemotherapie · Larynxerhalt
Causes of death and late complications A total of 68 patients died, of whom 25 (37 %) died of sSCC. Other major causes of death were related to other coexisting medical conditions (n = 33) or unknown causes (n = 6). Three patients died from surgical complications.
Table 3 Univariate and multivariate analyses of prognostic factors for overall survival
Age > 60 years N stage ≥ 1 T stage = T4 PS ≥ 1 Gender Coexisting conditions Primary subglottic cancer Front-line treatment
Univariate analysis HR 95 % CI 1.8 1.1–3 1.8 1–3.1 1.8 1.1–2.9 2.1 1.1–3.9
Multivariate analysis HR 95 % CI 2 1.2–3.6 1.9 1–3.5
p 0.02 0.05 0.02 0.02 0.2 0.7 0.5 0.4
p 0.01 0.04 0.08 0.07
PS performance status, HR hazard ratio, CI confidence interval
Table 4 T stage distribution according to front-line treatment
T stage T1–2 T3 T4 N stage N0 N1 N2 N3
Surgery (n %)
RT (n %)
Induction CT total (n %)
Surgery
RT
20 (16) 30 (24) 73 (60)
23 (66) 11 (31) 1 (3)
8 (21) 23 (58) 8 (21)
2 (5) 12 (32) 4 (10)
6 (15) 11 (28) 4 (10)
98 (80) 8 (7) 16 (13) 1 (0)
33 (94) 2 (6) 0 (0) 0 (0)
30 (77) 5 (13) 2 (5) 2 (5)
13 (33) 4 (10) 0 (0) 1 (3)
17 (43) 1 (3) 2 (5) 1 (3)
p
A. Levy1 · P. Blanchard1 · S. Temam2 · M.-M. Maison2 · F. Janot2 · H. Mirghani2 · F. Bidault3 · J. Guigay4 · A. Lusinchi1 · J. Bourhis1,5 · N. Daly-Schveitzer1 · Y. Tao1 1Department of Radiotherapy, Gustave Roussy, Villejuif, France 2Department of Otorhinolaryngology—Head and Neck Surgery, Gustave Roussy, Villejuif, France 3Department of Diagnostic Radiology, Gustave Roussy, Villejuif, France 4Department of Medical Oncology, Gustave Roussy, Villejuif, France 5Department of Radiation Oncology, University Hospital Lausanne, Lausanne, Switzerland
Squamous cell carcinoma of the larynx with subglottic extension: is larynx preservation possible? Squamous cell carcinoma of the larynx with subglottic extension (sSCC) is rare and represents, including primary subglottic cancer, less than 7 % of all laryngeal cancers [1, 2]. Given their high propensity to lymphatic (paratracheal and recurrent lymph nodes) and systemic spread, and the risk of airway obstruction in fragile patients with cumulative toxic effects of chronic alcohol and tobacco abuse, sSCC is described to carry a poor prognosis [3]. Despite the lack of literature reporting treatment outcomes, it is generally considered that small lesions (T1–T2) can be treated successfully by radiation therapy (RT) alone [4] and that surgery may be used for larger lesions (T3–T4) or salvage treatment [5, 6]. However, the surgical management of sSCC requires the removal of the entire larynx, leading to speech disruption. Partial laryngectomy is rarely possible for subglottic cancer, and organ preservation is usually considered contraindicated in such a location. RT alone for limited tumors or combined with chemotherapy for locally advanced tumors has been used to avoid total laryngectomy (TL). Although it is accepted that concomitant chemo-RT (CRT) can achieve larynx preservation, this finding has never been explicitly been considered in sSCC [7–11]. Recently, Hata et al. [12] suggested that the use of CRT may enhance treatment efficacy and contribute to larynx preservation through improved local control for sSCC patients. Induction chemotherapy followed by defin-
654 | Strahlentherapie und Onkologie 7 · 2014
itive RT in responsive patients is another alternative for the functional organ preservation treatment of locally advanced cancer of the larynx [13]. Indeed, survival benefit has been reported for patients receiving induction chemotherapy (CT) using TPF (docetaxel, cisplatin, 5-fluorouracil [5FU]) followed by definitive RT when compared to cisplatin and 5-FU (PF) followed by the same RT [14, 15]. Currently, there are no large studies evaluating the modern therapeutic options available (RT, surgery or induction CT first) in large series of sSCC patients or larynx cancer patients with subglottic extension. The aim of this study was to analyze the outcomes and feasibility of laryngeal preservation in sSCC patients treated at our institution.
Patients and methods Patients The medical records of 251 patients who presented with laryngeal cancer involving the subglottis region, obtained from more than 1700 patients with laryngeal cancer treated at Institut Gustave Roussy between 1996 and 2012, were retrospectively analyzed. Clinical subglottis invasion was defined as the presence of the tumor 5 mm below the free edge of the true vocal folds. Patients who initiated their treatments other than RT or TL outside of the institution and were subsequently referred for curative treatment at our institution for
their primary tumor (n = 1) or a local relapse after partial surgery (n = 6) were included in the analysis. Patients with primary subglottic cancer (n = 21) were also included in the analysis. Patients 60 years and positive N stage were the only predictors for OS, with HRs of 2 (95 % CI 1.2–3.6) and 1.9 (95 % CI 1–3.5), respectively (. Tables 3 and 4). There was no survival difference in this series according to the front-line treatments or whether patients had primary subglottic cancer or not.
Locoregional and distant control The 5-year actuarial LRC rate for the entire population was 83 % (95 % CI 77–89) and distant control rate was 88 % (95 % Strahlentherapie und Onkologie 7 · 2014
| 655
Abstract · Zusammenfassung Strahlenther Onkol 2014 · 190:654–660 DOI 10.1007/s00066-014-0647-8 © Springer-Verlag Berlin Heidelberg 2014 A. Levy · P. Blanchard · S. Temam · M.-M. Maison · F. Janot · H. Mirghani · F. Bidault · J. Guigay · A. Lusinchi · J. Bourhis · N. Daly-Schveitzer · Y. Tao
Squamous cell carcinoma of the larynx with subglottic extension: is larynx preservation possible? Abstract Purpose. Squamous cell carcinoma of larynx with subglottic extension (sSCC) is a rare location described to carry a poor prognosis. The aim of this study was to analyze outcomes and feasibility of larynx preservation in sSCC patients. Patients and methods. Between 1996 and 2012, 197 patients with sSCC were treated at our institution and included in the analysis. Stage III–IV tumors accounted for 76 %. Patients received surgery (62 %), radiotherapy (RT) (18 %), or induction chemotherapy (CT) (20 %) as front-line therapy. Results. The 5-year actuarial overall survival (OS), locoregional control (LRC), and distant control rate were 59 % (95 % CI 51–68), 83 % (95 % CI 77–89), and 88 % (95 % CI 83–
93), respectively, with a median follow-up of 54.4 months. There was no difference in OS and LRC according to front-line treatments or between primary subglottic cancer and glottosupraglottic cancers with subglottic extension. In the multivariate analysis, age > 60 years and positive N stage were the only predictors for OS (HR 2, 95 % CI 1.2–3.6; HR1.9, 95 % CI 1–3.5, respectively). A lower LRC was observed for T3 patients receiving a larynx preservation protocol as compared with those receiving a front-line surgery (HR 14.1, 95 % CI 2.5–136.7; p = 0.02); however, no difference of ultimate LRC was observed according to the first therapy when including T3 patients who underwent salvage laryngectomy (p = 0.6). In patients receiving a larynx preservation pro-
tocol, the 5-year larynx-preservation rate was 55 % (95 % CI 43–68), with 36 % in T3 patients. The 5-year larynx preservation rate was 81 % (95 % CI 65–96) and 35 % (95 % CI 20–51) for patients who received RT or induction CT as a front-line treatment, respectively. Conclusion. Outcomes of sSCC are comparable with other laryngeal cancers when managed with modern therapeutic options. Larynx-preservation protocols could be a suitable option in T1–T2 (RT or chemo-RT) and selected T3 sSCC patients (induction CT). Keywords Squamous cell carcinoma of head and neck · Surgery · Radiotherapy · Induction chemotherapy · Larynx preservation
Plattenepithelkarzinom des Larynx mit subglottischer Ausdehnung: ist ein Larynxerhalt möglich? Zusammenfassung Ziel. Plattenepithelkarzinome des Larynx mit subglottischer Ausdehnung (PECsA) sind selten und haben eine ungünstige Prognose. Das Ziel dieser Studie war es, die Ergebnisse und Durchführbarkeit einer larynxerhaltenden Therapie bei PECsA-Patienten zu untersuchen. Patienten und Methoden. Im Zeitraum zwischen 1996 und 2012 wurden 197 Patienten mit einem PECsA des Larynx in unserer Klinik therapiert und in die Studie eingeschlossen. Davon befanden sich 76 % der Patienten im Stadium III–IV nach TNM. Als Erstlinientherapie wurden 62 % der Patienten operiert, 18 % erhielten eine Radiotherapie (RT) und 20 % eine Induktionschemotherapie (ICT). Ergebnisse. Das 5-Jahres-Gesamtüberleben, die lokoregionale Tumorkontrolle und die Kontrollrate bezüglich einer Fernmetastasierung waren 59 % (95 %-Konfidenzintervall [KI] 51–68), 83 % (95 %-KI 77–89) bzw. 88 % (95 %-KI 83–93) mit einer medianen
CI 83–93). No difference was observed according to the first received therapy (p = 0.3). When including 11 patients who underwent salvage TL, ultimate LRC was 89 % (95 % CI 84–94) for the entire pop‑ ulation. There was no difference in locoregional or distant control rate according to regimen of induction CT (TPF or PF; p = 0.3), although TPF patients had
656 | Strahlentherapie und Onkologie 7 · 2014
Nachkontrolle von 54,4 Monaten. Es gab keinen Unterschied zwischen dem 5-Jahres-Gesamtüberleben und der lokoregionalen Tumorkontrolle in Anbetracht der Erstlinientherapie oder zwischen den primären subglottischen Karzinomen bzw. den glottosupraglottischen Karzinomen mit subglottischer Ausdehnung. In der multivariaten Analyse waren ein Lebensalter > 60 Jahre und ein positiver Lymphknotenstatus die einzigen Prädiktoren für das 5-Jahres-Gesamtüberleben (jeweils HR 2, 95 %-KI 1,2–3,6; HR 1,9, 95 %-KI 1–3,5). Eine schlechtere lokoregionale Tumorkontrolle wurde bei Patienten im T3-Stadium beobachtet, bei denen ein larynxerhaltendes Protokoll eingehalten wurde, im Vergleich mit denjenigen, welche eine Operation erhielten (HR 14,1; 95 %-KI 2,5–136,7; p = 0,02). Allerdings wurde in Bezug auf die Erstlinientherapie kein Unterschied bei der letzten lokoregionalen Tumorkontrolle festgestellt, wenn Patienten im Stadium T3 eingeschlossen wur-
better responses (78 % vs. 53 % for PF; p = 0.2). There was no difference of outcomes in patients receiving concurrent CRT vs. those receiving RT alone (16 vs. 19 patients). No prognostic factor of distant metastasis was identified in this population (16 distant relapses).
den, bei denen eine salvage Laryngektomie (p = 0,6) durchgeführt wurde. Bei Patienten mit einem larynxerhaltenden Protokoll war die 5-Jahres-Larynx-Erhaltungsrate 81 % (95 %-KI 65–96) bzw. 35 % (95 %-KI 20–51) für Patienten, welche eine Radiotherapie oder eine ICT als Erstlinientherapie erhielten. Schlussfolgerung. Die Ergebnisse der PECsA des Larynx sind vergleichbar mit denjenigen anderer Larynxkrebsarten, wenn mit modernen therapeutischen Methoden behandelt wird. Larynxerhaltungsprotokolle könnten eine angemessene Option sowohl bei Patientenim Stadium T1–T2 (RT oder ChemoRT) als auch bei ausgewählten T3-PECsA-Patienten sein (ICT). Schlüsselwörter Kopf-Hals-Plattenepithelkarzinom · Operation · Radiotherapie · Induktionschemotherapie · Larynxerhalt
Causes of death and late complications A total of 68 patients died, of whom 25 (37 %) died of sSCC. Other major causes of death were related to other coexisting medical conditions (n = 33) or unknown causes (n = 6). Three patients died from surgical complications.
Table 3 Univariate and multivariate analyses of prognostic factors for overall survival
Age > 60 years N stage ≥ 1 T stage = T4 PS ≥ 1 Gender Coexisting conditions Primary subglottic cancer Front-line treatment
Univariate analysis HR 95 % CI 1.8 1.1–3 1.8 1–3.1 1.8 1.1–2.9 2.1 1.1–3.9
Multivariate analysis HR 95 % CI 2 1.2–3.6 1.9 1–3.5
p 0.02 0.05 0.02 0.02 0.2 0.7 0.5 0.4
p 0.01 0.04 0.08 0.07
PS performance status, HR hazard ratio, CI confidence interval
Table 4 T stage distribution according to front-line treatment
T stage T1–2 T3 T4 N stage N0 N1 N2 N3
Surgery (n %)
RT (n %)
Induction CT total (n %)
Surgery
RT
20 (16) 30 (24) 73 (60)
23 (66) 11 (31) 1 (3)
8 (21) 23 (58) 8 (21)
2 (5) 12 (32) 4 (10)
6 (15) 11 (28) 4 (10)
98 (80) 8 (7) 16 (13) 1 (0)
33 (94) 2 (6) 0 (0) 0 (0)
30 (77) 5 (13) 2 (5) 2 (5)
13 (33) 4 (10) 0 (0) 1 (3)
17 (43) 1 (3) 2 (5) 1 (3)
p
