Acta Oto-Laryngologica. 2015; 135: 96–102
ORIGINAL ARTICLE
Recurrence patterns after postoperative radiotherapy for squamous cell carcinoma of the pharynx and larynx YUSUKE IIZUKA1, MICHIO YOSHIMURA1, HARUO INOKUCHI1, YUKINORI MATSUO1, AKIRA NAKAMURA1, TAKASHI MIZOWAKI1, SHIGERU HIRANO2, MORIMASA KITAMURA2, ICHIRO TATEYA2 & MASAHIRO HIRAOKA1 1
Departments of Radiation Oncology and Image-applied Therapy, and 2Otolaryngology, Head and Neck Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
Abstract Conclusions: Distant metastasis was a major pattern of recurrence after postoperative radiotherapy (PORT) for squamous cell carcinoma (SCC) of the oropharynx, hypopharynx, and larynx. PORT provided good loco-regional control, with tolerable toxicities. Advanced pT and pN were unfavorable prognostic factors. Objective: To determine the clinical outcomes, and the patterns and risk factors for recurrence of SCCs of the oropharynx, hypopharynx, and larynx treated with surgery and PORT. Methods: We retrospectively reviewed 84 patients who received PORT after definitive surgery for SCC of the oropharynx, hypopharynx, or larynx between 2000 and 2010. The primary sites were the oropharynx in 25 patients, hypopharynx in 47 patients, and larynx in 12 patients. Results: The 3-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rates were 64.9%, 56.7%, and 92.1%, respectively. Recurrences were observed in 27 patients: 6 patients had loco-regional recurrence and 23 patients developed distant metastasis. On multivariate analysis, pT4 and pN2cN3 displayed significantly worse effects on OS (p = 0.02 and p < 0.01, respectively) and PFS (p = 0.02 and p < 0.001, respectively). In the acute phase, 12 patients experienced grade 3 or 4 toxicities. There were no grade 5 toxicities. Late grade 3 toxicity developed in six patients and no grade 4 or 5 toxicities were observed.
Keywords: Metastasis, postoperative radiotherapy, prognostic factors
Introduction The loco-regional recurrence rates of locally advanced head and neck squamous cell carcinoma (HNSCC) remain high despite the improvement in recent treatment modalities. The treatment options include surgery with or without postoperative radiotherapy (PORT), or definitive chemoradiotherapy to preserve laryngeal function (voice, swallowing, and respiration). Although deformation and loss of function of the pharynx and larynx are evident, surgery with or without PORT is widely advocated for patients with locally advanced HNSCC [1]. However, surgery without PORT is associated with a high risk of loco-regional relapse. Several predictors of recurrence
after surgery are known, including advanced stage, positive/close surgical margins, multiple positive lymph nodes (LNs), and extracapsular extension [2–5]. Two randomized trials – Radiation Therapy Oncology Group (RTOG) 95-01 and European Organization for Research and Treatment of Cancer (EORTC) 22391 – indicated that PORT plus systemic chemotherapy improves the outcomes in high-risk patients with HNSCC [6,7]. Both trials reported that cisplatin improves local control and survival. However, chemotherapy plus PORT leads to severe adverse events such as mucositis, xerostomia, dysphagia, and hematopoietic problems [8,9]. Locally advanced HNSCC shows various characteristics. For example, some good prognostic
Correspondence: Michio Yoshimura MD PhD, Departments of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan. Tel: +81 75 751 3762. Fax: +81 75 771 9749. E-mail: [email protected]
(Received 29 April 2014; accepted 8 July 2014) ISSN 0001-6489 print/ISSN 1651-2251 online 2015 Informa Healthcare DOI: 10.3109/00016489.2014.949848
Recurrence patterns after PORT for SCC Table I. Patient characteristics (n = 84). Characteristics
Value
Age (years) Median
63
Range
37–82
Sex Male
73
Female
11
Performance status 0
27
1
56
2
1
Primary site Oropharynx
25
Hypopharynx
47
Larynx
12
subgroups have been observed such as human papilloma virus (HPV)-positive oropharyngeal SCC. Thus, it is important to evaluate prognostic factors to select the optimal treatment for the individual patient and adjust the intensity of treatment according to the risk or pattern of relapse. To consider our new regimen for HNSCC, we analyzed clinical outcome, recurrence patterns, and prognostic factors in patients with SCC of the oropharynx, hypopharynx, or larynx who were treated with surgery and PORT. Material and methods Between 2000 and 2010, 84 patients with previously untreated SCC of the oropharynx, hypopharynx, or larynx were treated with definitive surgery and PORT at our hospital. The indications for PORT for HNSCC at our hospital include the following pathological findings related to the primary tumor: a T4 primary tumor; positive or close (3). The primary sites were the oropharynx in 25 patients, hypopharynx in 47, and larynx in 12. The median patient age was 63 years (range 37–82 years). There were 73 men and 11 women. The patients’ characteristics are shown in Table I. The patients were staged according to the UICC system, version 7. The older cases were restaged using the new version. The clinical stage was II, III, IVA, IVB, and IVC in 1, 11, 61, 9, and 1 patient, respectively. The T and N stages are shown in Table II. All patients underwent resection of the primary tumor with neck dissection followed by PORT. Patients who underwent excisional biopsies of the primary site for early-stage cancers instead of radical surgery were excluded from the present study. One patient with clinical stage IVC who had lung metastasis detected before surgery, underwent neck and lung surgery simultaneously. All patients were treated with megavoltage photon beams. Planned continuous-course external beam radiotherapy was used in all cases. The delivered dose to the primary tumor bed and high-risk LN regions was 50–66 Gy (median 60 Gy) in 2 Gy fractions. The LN areas of the whole neck or hemi-neck were irradiated up to 40–50 Gy in 2 Gy fractions followed by a cord-cut field or a boost field. The delivered dose to the primary tumor bed and high-risk LN regions with positive surgical margins, extracapsular extension, or multiple LN metastases was 50–66 Gy (median 60 Gy). No patient in this series was treated with intensity-modulated radiation therapy (IMRT). In total 48, 32, and 12 patients received chemotherapy before surgery, during PORT, and after PORT, respectively. We started neo-adjuvant chemotherapy (NAC) in 2006 to achieve organ preservation and reduction of distant metastases. We administered NAC aggressively if the patients’ performance status (PS) and organ function permitted. Twenty-four patients did not receive chemotherapy during the whole course of treatment. Details of the surgery, PORT, and chemotherapy are shown in Table III.
Table II. Distribution of clinical T and N stages. N0
N1
N2a
N2b
N2c
N3
T1
0/0/0
1/0/0
1/0/0
0/0/0
0/1/0
2/1/0
6
T2
0/1/0
1/1/0
1/0/0
2/4/0
2/2/0
1/0/0
15
T3
0/1/2
1/3/1
1/1/0
2/4/3
4/3/0
0/0/1
27
T4
1/3/1
0/5/0
0/0/0
2/9/2
2/3/2
1/5/0
36
9
13
4
28
19
11
84
Total
Each stage is based on the revised 7th edition of the TNM classification for the oropharynx/hypopharynx/larynx.
Total
98
Y. Iizuka et al.
Table III. Treatment details. Treatment details
No. of cases
Surgery 48
Partial excision + RND
36
Surgical risk factors Surgical margin positive
10
Extracapsular extension
14
No. of lymph node metastases 0–2
37
3–5
29
6+
18
Radiotherapy irradiated field 71
Hemi-neck
13
Used boost irradiation
54
Radiotherapy prescribed dose 60 vs 3)
0.44
Without chemotherapy
0.65
Prescribed dose (
ORIGINAL ARTICLE
Recurrence patterns after postoperative radiotherapy for squamous cell carcinoma of the pharynx and larynx YUSUKE IIZUKA1, MICHIO YOSHIMURA1, HARUO INOKUCHI1, YUKINORI MATSUO1, AKIRA NAKAMURA1, TAKASHI MIZOWAKI1, SHIGERU HIRANO2, MORIMASA KITAMURA2, ICHIRO TATEYA2 & MASAHIRO HIRAOKA1 1
Departments of Radiation Oncology and Image-applied Therapy, and 2Otolaryngology, Head and Neck Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
Abstract Conclusions: Distant metastasis was a major pattern of recurrence after postoperative radiotherapy (PORT) for squamous cell carcinoma (SCC) of the oropharynx, hypopharynx, and larynx. PORT provided good loco-regional control, with tolerable toxicities. Advanced pT and pN were unfavorable prognostic factors. Objective: To determine the clinical outcomes, and the patterns and risk factors for recurrence of SCCs of the oropharynx, hypopharynx, and larynx treated with surgery and PORT. Methods: We retrospectively reviewed 84 patients who received PORT after definitive surgery for SCC of the oropharynx, hypopharynx, or larynx between 2000 and 2010. The primary sites were the oropharynx in 25 patients, hypopharynx in 47 patients, and larynx in 12 patients. Results: The 3-year overall survival (OS), progression-free survival (PFS), and locoregional control (LRC) rates were 64.9%, 56.7%, and 92.1%, respectively. Recurrences were observed in 27 patients: 6 patients had loco-regional recurrence and 23 patients developed distant metastasis. On multivariate analysis, pT4 and pN2cN3 displayed significantly worse effects on OS (p = 0.02 and p < 0.01, respectively) and PFS (p = 0.02 and p < 0.001, respectively). In the acute phase, 12 patients experienced grade 3 or 4 toxicities. There were no grade 5 toxicities. Late grade 3 toxicity developed in six patients and no grade 4 or 5 toxicities were observed.
Keywords: Metastasis, postoperative radiotherapy, prognostic factors
Introduction The loco-regional recurrence rates of locally advanced head and neck squamous cell carcinoma (HNSCC) remain high despite the improvement in recent treatment modalities. The treatment options include surgery with or without postoperative radiotherapy (PORT), or definitive chemoradiotherapy to preserve laryngeal function (voice, swallowing, and respiration). Although deformation and loss of function of the pharynx and larynx are evident, surgery with or without PORT is widely advocated for patients with locally advanced HNSCC [1]. However, surgery without PORT is associated with a high risk of loco-regional relapse. Several predictors of recurrence
after surgery are known, including advanced stage, positive/close surgical margins, multiple positive lymph nodes (LNs), and extracapsular extension [2–5]. Two randomized trials – Radiation Therapy Oncology Group (RTOG) 95-01 and European Organization for Research and Treatment of Cancer (EORTC) 22391 – indicated that PORT plus systemic chemotherapy improves the outcomes in high-risk patients with HNSCC [6,7]. Both trials reported that cisplatin improves local control and survival. However, chemotherapy plus PORT leads to severe adverse events such as mucositis, xerostomia, dysphagia, and hematopoietic problems [8,9]. Locally advanced HNSCC shows various characteristics. For example, some good prognostic
Correspondence: Michio Yoshimura MD PhD, Departments of Radiation Oncology and Image-applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan. Tel: +81 75 751 3762. Fax: +81 75 771 9749. E-mail: [email protected]
(Received 29 April 2014; accepted 8 July 2014) ISSN 0001-6489 print/ISSN 1651-2251 online 2015 Informa Healthcare DOI: 10.3109/00016489.2014.949848
Recurrence patterns after PORT for SCC Table I. Patient characteristics (n = 84). Characteristics
Value
Age (years) Median
63
Range
37–82
Sex Male
73
Female
11
Performance status 0
27
1
56
2
1
Primary site Oropharynx
25
Hypopharynx
47
Larynx
12
subgroups have been observed such as human papilloma virus (HPV)-positive oropharyngeal SCC. Thus, it is important to evaluate prognostic factors to select the optimal treatment for the individual patient and adjust the intensity of treatment according to the risk or pattern of relapse. To consider our new regimen for HNSCC, we analyzed clinical outcome, recurrence patterns, and prognostic factors in patients with SCC of the oropharynx, hypopharynx, or larynx who were treated with surgery and PORT. Material and methods Between 2000 and 2010, 84 patients with previously untreated SCC of the oropharynx, hypopharynx, or larynx were treated with definitive surgery and PORT at our hospital. The indications for PORT for HNSCC at our hospital include the following pathological findings related to the primary tumor: a T4 primary tumor; positive or close (3). The primary sites were the oropharynx in 25 patients, hypopharynx in 47, and larynx in 12. The median patient age was 63 years (range 37–82 years). There were 73 men and 11 women. The patients’ characteristics are shown in Table I. The patients were staged according to the UICC system, version 7. The older cases were restaged using the new version. The clinical stage was II, III, IVA, IVB, and IVC in 1, 11, 61, 9, and 1 patient, respectively. The T and N stages are shown in Table II. All patients underwent resection of the primary tumor with neck dissection followed by PORT. Patients who underwent excisional biopsies of the primary site for early-stage cancers instead of radical surgery were excluded from the present study. One patient with clinical stage IVC who had lung metastasis detected before surgery, underwent neck and lung surgery simultaneously. All patients were treated with megavoltage photon beams. Planned continuous-course external beam radiotherapy was used in all cases. The delivered dose to the primary tumor bed and high-risk LN regions was 50–66 Gy (median 60 Gy) in 2 Gy fractions. The LN areas of the whole neck or hemi-neck were irradiated up to 40–50 Gy in 2 Gy fractions followed by a cord-cut field or a boost field. The delivered dose to the primary tumor bed and high-risk LN regions with positive surgical margins, extracapsular extension, or multiple LN metastases was 50–66 Gy (median 60 Gy). No patient in this series was treated with intensity-modulated radiation therapy (IMRT). In total 48, 32, and 12 patients received chemotherapy before surgery, during PORT, and after PORT, respectively. We started neo-adjuvant chemotherapy (NAC) in 2006 to achieve organ preservation and reduction of distant metastases. We administered NAC aggressively if the patients’ performance status (PS) and organ function permitted. Twenty-four patients did not receive chemotherapy during the whole course of treatment. Details of the surgery, PORT, and chemotherapy are shown in Table III.
Table II. Distribution of clinical T and N stages. N0
N1
N2a
N2b
N2c
N3
T1
0/0/0
1/0/0
1/0/0
0/0/0
0/1/0
2/1/0
6
T2
0/1/0
1/1/0
1/0/0
2/4/0
2/2/0
1/0/0
15
T3
0/1/2
1/3/1
1/1/0
2/4/3
4/3/0
0/0/1
27
T4
1/3/1
0/5/0
0/0/0
2/9/2
2/3/2
1/5/0
36
9
13
4
28
19
11
84
Total
Each stage is based on the revised 7th edition of the TNM classification for the oropharynx/hypopharynx/larynx.
Total
98
Y. Iizuka et al.
Table III. Treatment details. Treatment details
No. of cases
Surgery 48
Partial excision + RND
36
Surgical risk factors Surgical margin positive
10
Extracapsular extension
14
No. of lymph node metastases 0–2
37
3–5
29
6+
18
Radiotherapy irradiated field 71
Hemi-neck
13
Used boost irradiation
54
Radiotherapy prescribed dose 60 vs 3)
0.44
Without chemotherapy
0.65
Prescribed dose (
