The Laryngoscope C 2014 The American Laryngological, V
Rhinological and Otological Society, Inc.
Postoperative Radiotherapy for Patients at High Risk of Recurrence of Oral Cavity Squamous Cell Carcinoma Michael P. Herman, MD; Roi Dagan, MD; Robert J. Amdur, MD; Christopher G. Morris, MS; John W. Werning, MD; Mikhail Vaysberg, DO; William M. Mendenhall, MD Objectives: To evaluate the efficacy of postoperative radiotherapy for oral cavity squamous cell carcinoma (OCSCC) by comparing outcomes of high-risk subgroups. Study Design: Retrospective review. Methods: Outcome study of 139 patients with OCSCC treated with gross total resection and postoperative radiotherapy 6 chemotherapy and at least one high-risk pathologic finding: positive margin (52%), close (0.1–5 mm) margin (27%), or extracapsular nodal extension (ECE; 45%). Results: Median follow-up was 2.3 years. Local-regional control (LRC), freedom from distant metastases, cause-specific survival, and overall survival (OS) rates at 5 years were 64%, 85%, 51%, and 36%, respectively. Five-year LRC for negative (>5 mm), close (0.1–5 mm), and positive (carcinoma in situ or tumor at ink) margins were 73%, 83%, and 63%, respectively (P 5 not significant). Five-year neck control was 100% for node-negative patients, 88% for node-positive patients with no ECE, and 86% for node-positive patients with ECE (P 5 not significant). The combination of close/positive margin and ECE resulted in worse 5-year LRC (37% vs. 70%, P < 0.001), progression-free survival (26% vs. 60%, P < 0.001), and OS (13 vs. 43%, P < 0.001) compared with a single high-risk indication. Conclusions: Local-regional control was the predominant mode of treatment failure. Outcome in our series was not statistically different based on margin status or nodal ECE. This finding is indirect evidence of the efficacy of adjuvant radiotherapy in this setting. Key Words: Postoperative radiotherapy, outcomes, oral cavity, head and neck, surgery. Level of Evidence: 4. Laryngoscope, 125:630–635, 2015
INTRODUCTION Oral cavity squamous cell carcinoma (OCSCC) is usually treated with primary surgery followed by adjuvant radiotherapy (RT), with or without concurrent chemotherapy. The toxicity of RT in this setting is high, and data documenting the benefit from adjuvant treatment are scarce. The group where adjuvant RT is likely to be most valuable is in patients with positive or close surgical margins and/or positive nodes with extracapsular tumor extension.1–4 The primary purpose of our study is to evaluate the efficacy of adjuvant RT in OCSCC by comparing outcomes between high-risk subgroups that would be expected to have different prognoses based on findings in the surgical specimen. A secondary purpose is to report outcomes based on risk
From the Department of Radiation Oncology (M.P.H., R.D., R.J.A., and the Department Otolaryngology (J.W.W., M.V.), University of Florida College of Medicine, Gainesville, Florida, U.S.A. Editor’s Note: This Manuscript was accepted for publication August 27, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Roi Dagan, MD, 2000 SW Archer Rd., PO Box 100385, Gainesville, FL 32610-0385. E-mail: [email protected] C.G.M., W.M.M.);
DOI: 10.1002/lary.24938
Laryngoscope 125: March 2015
630
status so that clinicians and patients know what to expect in terms of cancer prognosis and to identify subgroups that are most likely to benefit from innovative treatment protocols.
MATERIALS AND METHODS In accordance with an Institutional Review Boardapproved protocol and the Health Insurance Portability and Accountability Act, we retrospectively reviewed the medical records of 139 consecutive high-risk patients (pathology demonstrating positive or close margins or extracapsular tumor extension [ECE]) with previously untreated OCSCC. These patients received postoperative curative-intent RT at our institution between December 1989 and July 2010. Patients with tumors arising from the lip, those treated with brachytherapy, and patients previously treated with RT for a head and neck cancer were excluded. Table I summarizes patient characteristics of patients included in the analysis. We collected data on six indications for postoperative RT in this high-risk cohort: positive margin (carcinoma in situ or invasive tumor at the inked margin), close margin (0.01–5 mm), nodal ECE, lymphovascular space invasion, perineural invasion, pathologic T4 classification, and two or more positive lymph nodes. We coded the final margin as listed in the pathology report. No patient was taken back to the operative room for a re-excision of a close or positive margin. If the margins were positive or close intraoperatively and a separately submitted sample from the same operation was included in the pathology report, we used the final margin status in our analysis. Table II summarizes our
Herman et al.: Radiotherapy for High-Risk Oral Cavity SCC
TABLE I. Patient Characteristics (139 Patients). Characteristic
TABLE II. Number of Indications* and High-Risk Indication Categories for Postoperative RT (139 Patients).
Value or No. of Patients (%) Indications
Age, median (range) Sex Male Female Primary Site Alveolar ridge
Number of Indications 91 (65%) 48 (35%) 21 (15%)
Buccal mucosa
9 (6%)
Floor of mouth Hard palate
48 (35%) 4 (3%)
Oral tongue
40 (29%)
Retromolar trigone Pathologic T classification
17 (12%)
T1
19 (14%)
T2 T3
58 (41%) 26 (19%)
T4
36 (26%)
Pathologic N classification N0
43 (31%)
N1
26 (19%)
N2a or b N2 c
44 (32%) 16 (11%)
N3
10 (7%)
AJCC 7th Edition Stage I
8 (6%)
II
13 (9%)
III IVA
23 (16%) 76 (55%)
IVB
19 (14%)
Lymphovascular Involvement Yes No Not reported Perinueral Invasion
Percentage of Patients
61 (28–88) years 1–2 indications 3 indications
40% 30%
4–6 indications
30%
High-Risk Indication Categories Positive margin 1 ECE
15%
Positive margin, no ECE†
36%
Close margin 1 ECE Close margin, no ECE
9% 18%
Negative margin 1 ECE
22%
*Indications: Positive or close margin, nodal extracapsular extension (ECE), lymphovascular space invasion, perineural invasion, pathologic T4 classification, 2 positive lymph nodes. Positive margin 5 tumor at ink; close margin 5 0.01–5 mm; negative margin 5 >5 mm. † Includes two patients with unknown ECE status ECE 5 extracapsular extension.
method provided estimates of local control; regional control; freedom from distant metastases (DMFS); progression-free survival (PFS), meaning alive without progression or recurrence of disease; cause-specific survival (CSS), wherein an event was death from oral cavity cancer or a treatment complication; and overall survival (OS).7 The log-rank test statistic provided estimates of statistical significance for these estimates after stratification by selected prognostic factors.
RESULTS The median follow-up for all 139 patients was 2.3 years (range, 0.1 to 16.7 years). The minimum follow-up
51 (37%) 53 (38%) 35 (25%)
Yes
66 (47%)
No Not reported
44 (32%) 29 (21%)
Positive Margin
72 (52%)
Close Margin ECE
37 (27%) 63 (45%)
AJCC 5 American Joint Committee on Cancer; ECE 5 extracapsular extension.
study population by indications for postoperative RT. Postoperative treatment details are outlined in Table III. Patients were staged from the pathology report from the primary resection specimen according to the 2009 American Joint Committee on Cancer staging system.5 Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.03.6
Statistical Analysis
TABLE III. Postoperative Treatment Details (139 Patients). Treatment Details
Value or Percent of Patients (%)
RT Technique Conventional IMRT
120 (86%) 19 (14%)
Fractionation Once daily (1.8–2 Gy per fraction) Twice daily (1.2 Gy per fraction) Concomitant boost Median dose to high-risk PTV (range) Median time from surgery to RT Chemotherapy
50 (36%) 69 (50%) 20 (14%) 72 (60–74.8) Gy 43 days 23 (17%)
Cisplatin 30mg/m2/week Cisplatin 65mg/m2/week
11 (8%) 1 (
Rhinological and Otological Society, Inc.
Postoperative Radiotherapy for Patients at High Risk of Recurrence of Oral Cavity Squamous Cell Carcinoma Michael P. Herman, MD; Roi Dagan, MD; Robert J. Amdur, MD; Christopher G. Morris, MS; John W. Werning, MD; Mikhail Vaysberg, DO; William M. Mendenhall, MD Objectives: To evaluate the efficacy of postoperative radiotherapy for oral cavity squamous cell carcinoma (OCSCC) by comparing outcomes of high-risk subgroups. Study Design: Retrospective review. Methods: Outcome study of 139 patients with OCSCC treated with gross total resection and postoperative radiotherapy 6 chemotherapy and at least one high-risk pathologic finding: positive margin (52%), close (0.1–5 mm) margin (27%), or extracapsular nodal extension (ECE; 45%). Results: Median follow-up was 2.3 years. Local-regional control (LRC), freedom from distant metastases, cause-specific survival, and overall survival (OS) rates at 5 years were 64%, 85%, 51%, and 36%, respectively. Five-year LRC for negative (>5 mm), close (0.1–5 mm), and positive (carcinoma in situ or tumor at ink) margins were 73%, 83%, and 63%, respectively (P 5 not significant). Five-year neck control was 100% for node-negative patients, 88% for node-positive patients with no ECE, and 86% for node-positive patients with ECE (P 5 not significant). The combination of close/positive margin and ECE resulted in worse 5-year LRC (37% vs. 70%, P < 0.001), progression-free survival (26% vs. 60%, P < 0.001), and OS (13 vs. 43%, P < 0.001) compared with a single high-risk indication. Conclusions: Local-regional control was the predominant mode of treatment failure. Outcome in our series was not statistically different based on margin status or nodal ECE. This finding is indirect evidence of the efficacy of adjuvant radiotherapy in this setting. Key Words: Postoperative radiotherapy, outcomes, oral cavity, head and neck, surgery. Level of Evidence: 4. Laryngoscope, 125:630–635, 2015
INTRODUCTION Oral cavity squamous cell carcinoma (OCSCC) is usually treated with primary surgery followed by adjuvant radiotherapy (RT), with or without concurrent chemotherapy. The toxicity of RT in this setting is high, and data documenting the benefit from adjuvant treatment are scarce. The group where adjuvant RT is likely to be most valuable is in patients with positive or close surgical margins and/or positive nodes with extracapsular tumor extension.1–4 The primary purpose of our study is to evaluate the efficacy of adjuvant RT in OCSCC by comparing outcomes between high-risk subgroups that would be expected to have different prognoses based on findings in the surgical specimen. A secondary purpose is to report outcomes based on risk
From the Department of Radiation Oncology (M.P.H., R.D., R.J.A., and the Department Otolaryngology (J.W.W., M.V.), University of Florida College of Medicine, Gainesville, Florida, U.S.A. Editor’s Note: This Manuscript was accepted for publication August 27, 2014. The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Roi Dagan, MD, 2000 SW Archer Rd., PO Box 100385, Gainesville, FL 32610-0385. E-mail: [email protected] C.G.M., W.M.M.);
DOI: 10.1002/lary.24938
Laryngoscope 125: March 2015
630
status so that clinicians and patients know what to expect in terms of cancer prognosis and to identify subgroups that are most likely to benefit from innovative treatment protocols.
MATERIALS AND METHODS In accordance with an Institutional Review Boardapproved protocol and the Health Insurance Portability and Accountability Act, we retrospectively reviewed the medical records of 139 consecutive high-risk patients (pathology demonstrating positive or close margins or extracapsular tumor extension [ECE]) with previously untreated OCSCC. These patients received postoperative curative-intent RT at our institution between December 1989 and July 2010. Patients with tumors arising from the lip, those treated with brachytherapy, and patients previously treated with RT for a head and neck cancer were excluded. Table I summarizes patient characteristics of patients included in the analysis. We collected data on six indications for postoperative RT in this high-risk cohort: positive margin (carcinoma in situ or invasive tumor at the inked margin), close margin (0.01–5 mm), nodal ECE, lymphovascular space invasion, perineural invasion, pathologic T4 classification, and two or more positive lymph nodes. We coded the final margin as listed in the pathology report. No patient was taken back to the operative room for a re-excision of a close or positive margin. If the margins were positive or close intraoperatively and a separately submitted sample from the same operation was included in the pathology report, we used the final margin status in our analysis. Table II summarizes our
Herman et al.: Radiotherapy for High-Risk Oral Cavity SCC
TABLE I. Patient Characteristics (139 Patients). Characteristic
TABLE II. Number of Indications* and High-Risk Indication Categories for Postoperative RT (139 Patients).
Value or No. of Patients (%) Indications
Age, median (range) Sex Male Female Primary Site Alveolar ridge
Number of Indications 91 (65%) 48 (35%) 21 (15%)
Buccal mucosa
9 (6%)
Floor of mouth Hard palate
48 (35%) 4 (3%)
Oral tongue
40 (29%)
Retromolar trigone Pathologic T classification
17 (12%)
T1
19 (14%)
T2 T3
58 (41%) 26 (19%)
T4
36 (26%)
Pathologic N classification N0
43 (31%)
N1
26 (19%)
N2a or b N2 c
44 (32%) 16 (11%)
N3
10 (7%)
AJCC 7th Edition Stage I
8 (6%)
II
13 (9%)
III IVA
23 (16%) 76 (55%)
IVB
19 (14%)
Lymphovascular Involvement Yes No Not reported Perinueral Invasion
Percentage of Patients
61 (28–88) years 1–2 indications 3 indications
40% 30%
4–6 indications
30%
High-Risk Indication Categories Positive margin 1 ECE
15%
Positive margin, no ECE†
36%
Close margin 1 ECE Close margin, no ECE
9% 18%
Negative margin 1 ECE
22%
*Indications: Positive or close margin, nodal extracapsular extension (ECE), lymphovascular space invasion, perineural invasion, pathologic T4 classification, 2 positive lymph nodes. Positive margin 5 tumor at ink; close margin 5 0.01–5 mm; negative margin 5 >5 mm. † Includes two patients with unknown ECE status ECE 5 extracapsular extension.
method provided estimates of local control; regional control; freedom from distant metastases (DMFS); progression-free survival (PFS), meaning alive without progression or recurrence of disease; cause-specific survival (CSS), wherein an event was death from oral cavity cancer or a treatment complication; and overall survival (OS).7 The log-rank test statistic provided estimates of statistical significance for these estimates after stratification by selected prognostic factors.
RESULTS The median follow-up for all 139 patients was 2.3 years (range, 0.1 to 16.7 years). The minimum follow-up
51 (37%) 53 (38%) 35 (25%)
Yes
66 (47%)
No Not reported
44 (32%) 29 (21%)
Positive Margin
72 (52%)
Close Margin ECE
37 (27%) 63 (45%)
AJCC 5 American Joint Committee on Cancer; ECE 5 extracapsular extension.
study population by indications for postoperative RT. Postoperative treatment details are outlined in Table III. Patients were staged from the pathology report from the primary resection specimen according to the 2009 American Joint Committee on Cancer staging system.5 Toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.03.6
Statistical Analysis
TABLE III. Postoperative Treatment Details (139 Patients). Treatment Details
Value or Percent of Patients (%)
RT Technique Conventional IMRT
120 (86%) 19 (14%)
Fractionation Once daily (1.8–2 Gy per fraction) Twice daily (1.2 Gy per fraction) Concomitant boost Median dose to high-risk PTV (range) Median time from surgery to RT Chemotherapy
50 (36%) 69 (50%) 20 (14%) 72 (60–74.8) Gy 43 days 23 (17%)
Cisplatin 30mg/m2/week Cisplatin 65mg/m2/week
11 (8%) 1 (
