Abstract
Objectives:
To characterize factors including nodal burden, pre-treatment imaging, and other patient factors which may influence the role of ipsilateral neck radiotherapy (IRT) in tonsillar squamous cell carcinoma (SCC) with multiple involved ipsilateral nodes.
Methods:
Patients with cT1-2N0-2bM0 (AJCC 7th edition) tonsillar SCC treated with definitive radiation therapy (RT) at Duke University Medical Center from 1/1/1990-10/1/2019 were identified. Patient, tumor, and treatment characteristics were compared between those that received bilateral neck RT (BRT) versus IRT. Recurrence-free survival (RFS) was estimated with Kaplan-Meier method. A subset analysis of patients with N2b disease was performed. Patterns of recurrence were analyzed.
Results:
120 patients with cT1-2N0-2b tonsillar SCC were identified, including 71 with N2b disease (BRT: n = 30; IRT: n = 41). Median follow-up was 80 months (range: 7–209). No N2b patients who received IRT had > 1 cm of soft palate/base of tongue extension. N2b patients treated with IRT had a median of 3 (range 2–9) involved lymph nodes, with median largest nodal dimension of 2.8 cm (range 1.3–4.8 cm). 93 % of N2b patients who received IRT had staging by PET/CT, and 100 % received IMRT. For N2b patients treated with IRT, there were no contralateral neck recurrences, and 10 year RFS was 95 % (95 % CI 82 %–98 %).
Conclusions:
For patients treated with IRT for well-lateralized N2b tonsillar SCC, we observed high rates of local control with no observed contralateral neck recurrence. These data suggest that BRT is not universally necessary for patients with multiple involved ipsilateral nodes, particularly in the setting of baseline staging with PET/CT.
Keywords: Tonsil cancer, Radiation, Ipsilateral neck radiation, Multiple ipsilateral nodes, N2b
Introduction
Bilateral neck radiation therapy (BRT) has historically been utilized in the treatment of tonsillar squamous cell carcinoma (SCC). Ipsilateral neck radiation therapy (IRT) has been adopted successfully in selected patients with well-lateralized primaries, however, who are at low risk of contralateral neck recurrence (CNR) [1].
Multiple retrospective series reporting favorable outcomes with IRT in tonsillar SCC, but no consensus exists regarding the appropriateness of IRT for patients with multiple ipsilateral lymph nodes measuring <6 cm (N2b disease by AJCC 7th edition staging) [2]. Prior studies of patients with N2b disease have been limited by older radiation therapy techniques, small patient numbers, and short follow up [3–7]. Furthermore, these studies have inconsistently analyzed the nodal tumor burden (size and number of nodes), the use of pre-treatment PET imaging for staging, and other disease/patient factors (primary tumor size and local extension, smoking status, human papillomavirus [HPV] status), which may influence the decision to prescribe IRT versus BRT.
This retrospective single institution study was performed to evaluate the oncologic and toxicity outcomes for patients with cT1-2N0-2b tonsillar SCC treated with IRT or BRT, with a subset analysis of patients with N2b disease.
Materials and methods
Data collection
This retrospective study protocol was reviewed and approved by the Duke University Institutional Review Board. Patients with tonsillar squamous cell carcinoma (SCC) treated with radiation therapy (RT) at Duke University Medical Center from January 1, 1990 to October 1, 2019 were identified through a radiation oncology departmental database and an institutional EPIC query platform (Epic Systems Corporation, Verona, Wisconsin), and the Duke Enterprise Data Unified Content Explorer (DEDUCE). Patients were excluded if they had metastatic disease at diagnosis, did not receive RT, received palliative-intent RT, were treated outside of the primary institution, had missing records regarding RT, or had less than six months of follow-up. Patients were also excluded if they had had bilateral or recurrent tonsillar cancer, cT3–4 disease (AJCC 7th edition), cN2c-3 disease, or underwent definitive surgical management of the primary tumor and involved lymph nodes. Those who underwent a non-oncologic surgery (such as surgical biopsy or tonsillectomy) with residual gross disease which necessitated subsequent radiation were included. The electronic record was reviewed for demographics, tumor, RT, chemotherapy, surgery, acute and late toxicity, and dates/sites of recurrence and death variables. Oropharyngeal cancer staging was modified during the study period (AJCC 7th to 8th edition) to incorporate HPV status. As HPV testing was not available in all patients, tumor and nodal staging is reported according to AJCC 7th edition criteria to ensure consistency across the reported cohort.
Treatment and follow-up
Patients were immobilized and underwent axial CT simulation with IV contrast (unless contraindicated by poor renal function). Intensity modulated radiation therapy (IMRT) was routinely adopted starting in 2004. The gross tumor volume (GTV) included primary tumor and involved lymph nodes. The primary clinical target volume (CTV) generally included primary GTV with 5 mm margin. The boost nodal CTV generally included a 3–5 mm margin from nodal GTV. An elective low dose CTV encompassed areas at risk of microscopic involvement of the primary tumor, including levels 2–4 and retropharyngeal nodes with or without inclusion of ipsilateral IB and/or V depending on the extent of nodal involvement. The planning target volume (PTV) was usually a 3 mm expansion from CTV. Patients were generally treated 70 Gy in 2 Gy daily fractions to the high dose PTV and 44 Gy to the low dose PTV (50 Gy if concurrent chemotherapy was not utilized) using a sequential boost technique. For patients receiving cisplatin, the most common regimens were bolus cisplatin with 100 mg/m2 delivered during weeks 1, 4 and 7 (or during weeks 1 and 5) or modified bolus cisplatin with 20 mg/m2 delivered on days 1–5 in weeks 1, 4 and 7 (or during weeks 1 and 5). For patients receiving weekly cisplatin, dosing was 33–40 mg/m2 per week. For patients with poor renal function or baseline hearing loss, weekly carboplatin or weekly docetaxel was administered. Starting in 2010, patients with node-positive disease at presentation underwent PET/CT at approximately 3 months after completing RT to guide whether adjuvant/salvage neck dissection was needed [8].
After treatment, patients were followed with clinical exam and fiberoptic laryngoscopy every 2–3 months for the first year, every 3–4 months in the second year, every 6 months in years 3–5, annually in years 6–10, then every other year. Acute toxicities were defined as occurring during RT or within 3 months after the initiation of treatment. Late toxicities were defined as occurring > 3 months after initiation of radiation. All toxicities were assessed retrospectively and graded via chart review per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Analysis
Patient, tumor, and treatment characteristics of patients treated with IRT versus BRT were compared using the Kruskal Wallis, Fisher Exact or Chi-square test. The proportions of patients who developed acute and late toxicities were also compared between patients who received IRT versus BRT using the Fisher Exact test. Univariate Cox regression models were used to assess demographic, tumor, and treatment factors associated with survival and time to recurrence. Age (in years), tumor size, and nodal size were analyzed as continuous variables. The Kaplan-Meier method was used to estimate 10-year overall survival (OS) and recurrence-free survival (RFS) for all patients and compared, IRT versus BRT, using the log rank test. A subset analysis of patients with N2b disease was performed. All tests were two-tailed, and p value of < 0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (Cary, NC).
Results
All patients (cT1-2N0-2b)
376 patients were identified by the departmental database or the institutional DEDUCE query platform (Supplementary Fig. 1). Patients were excluded for the following reasons: no history of RT (n = 26), missing records/treated outside of institution (n = 97), palliative-intent RT (n = 16), cT3–4 disease (n = 100), cN2c-3 (n = 18), recurrent tonsil (n = 6), bilateral tonsil cancer (n = 3), metastatic disease (n = 3), no follow up (n = 2), did not complete RT (n = 1), follow-up<6 months (n = 4). Median follow-up for surviving patients was 80 months (range 7–209 months). Patients were diagnosed between 1990 and 2000 (n = 3), 2001–2010 (n = 55), 2011–2019 (n = 62).
120 patients with cT1-2N0-2b tonsillar SCC were treated with definitive RT, including 72 receiving IRT and 48 receiving BRT. Patient, tumor, and treatment characteristics are presented in Table 1. Median patient age was 56 years (range 33–82), and most patients were male (82.5 %). Most patients were white (89.2 %). Among patients for whom HPV testing was performed, 94.6 % of patients had HPV-related disease. Most patients were treated with definitive chemoradiation (65 %) or radiation therapy (16.7 %), although some received upfront surgery (18.3 %) followed by cisplatin-based chemoradiation or radiation therapy. Among patients receiving definitive concurrent chemoradiation, 94.8 % received cisplatin with only 16 % of these patients undergoing weekly cisplatin dosing. Median radiation dose to gross disease was 70 Gy, and most patients received IMRT (94.9 %). A higher proportion of patients who received BRT had T2 disease (79.2 % vs 48.6 %) and had >1 cm of soft palate/base of tongue extension (14.6 % vs 2.8 %). There were no significant differences by side of neck in the number of involved lymph nodes, size of largest lymph node, or clinical nodal stage. More patients treated with BRT received a 3D conformal technique (13.0 % vs 0 %, p = 0.003) and adjuvant/salvage neck dissection (37.5 % vs 11.1 %, p = 0.001).
Table 1.
Patient, tumor, and treatment characteristics of all patients, cT1-2N0-2b.
| Bilateral (N = 48) | Ipsilateral (N = 72) | Total (N = 120) | p-value | |
|---|---|---|---|---|
|
| ||||
| Age at Diagnosis | 0.961 | |||
| Median (range) | 56 (35–82) | 55 (33–73) | 56 (33–82) | |
| Gender | 0.142 | |||
| Female | 5 (10.4 %) | 16 (22.2 %) | 21 (17.5 %) | |
| Male | 43 (89.6 %) | 56 (77.8 %) | 99 (82.5 %) | |
| Race | 0.912 | |||
| White | 42 (87.5 %) | 65 (90.3 %) | 107 (89.2 %) | |
| Black | 3 (6.3 %) | 4 (5.6 %) | 7 (5.8 %) | |
| Other | 3 (6.3 %) | 3 (4.2 %) | 6 (5.0 %) | |
| Smoking Status | 0.052 | |||
| Yes | 32 (68.1 %) | 36 (50.7 %) | 68 (57.6 %) | |
| No | 15 (31.9 %) | 35 (49.3 %) | 50 (42.4 %) | |
| Missing | 1 | 1 | 2 | |
| Pack Year History | 0.772 | |||
| (Among Smokers) | ||||
| ≤10 | 6 (12.8 %) | 8 (11.3 %) | 14 (11.9 %) | |
| >10 | 26 (55.3 %) | 28 (39.4 %) | 54 (45.8 %) | |
| Missing | 1 | 1 | 2 | |
| Clinical Tumor (T) | 0.0012 | |||
| Stage, AJCC 7th Ed | ||||
| 1 | 10 (20.8 %) | 37 (51.4 %) | 47 (39.2 %) | |
| 2 | 38 (79.2 %) | 35 (48.6 %) | 73 (60.8 %) | |
| Primary Size, Largest | 0.0011 | |||
| Dimension (cm) | ||||
| Median (range) | 2.5 (0.7–4.5) | 2.0 (0.6–4.0) | 2.2 (0.6–4.5) | |
| Missing | 1 | 0 | 1 | |
| Soft Palate/Base of Tongue Extension |
0.032 | |||
| None | 32 (66.7 %) | 60 (83.3 %) | 92 (76.7 %) | |
| ≤1 cm | 9 (18.8 %) | 10 (13.9 %) | 19 (15.8 %) | |
| >1 cm | 7 (14.6 %) | 2 (2.8 %) | 9 (7.5 %) | |
| Clinical Nodal (N) Stage, AJCC 7th Ed |
0.122 | |||
| 0 | 7 (14.6 %) | 5 (6.9 %) | 12 (10.0 %) | |
| 1 | 5 (10.4 %) | 19 (26.4 %) | 24 (20.0 %) | |
| 2a | 6 (12.5 %) | 7 (9.7 %) | 13 (10.8 %) | |
| 2b | 30 (62.5 %) | 41 (56.9 %) | 71 (59.2 %) | |
| Number of Involved | 0.941 | |||
| Lymph Nodes | ||||
| Median (range) | 2 (0–10) | 2 (0–9) | 2 (0–10) | |
| Missing | 1 | 0 | 1 | |
| Nodal Size | 0.151 | |||
| Median (range) | 3.0 (0.0–5.0) | 2.7 (1.3–5.0) | 2.9 (0.0–5.0) | |
| Missing | 7 | 5 | 12 | |
| Neck Staging | 0.043 | |||
| CT | 14 (29.2 %) | 10 (13.9 %) | 24 (20.0 %) | |
| PET/CT | 33 (68.8 %) | 62 (86.1 %) | 95 (79.2 %) | |
| HPV Status | 0.00031 | |||
| Negative (−) | 0 (0.0 %) | 4 (7.2 %) | 4 (5.3 %) | |
| Positive (+) | 20 (100.0%) | 51 (92.7 %) | 71 (94.6 %) | |
| Unknown | 28 | 17 | 45 | |
| Treatment Modality | 0.052 | |||
| Surgery + Radiation | 2 (4.2 %) | 14 (19.4 %) | 16 (13.3 %) | |
| Surgery + Chemoradiation | 4 (8.3 %) | 2 (2.8 %) | 6 (5.0 %) | |
| Radiation | 8 (16.7 %) | 12 (16.7 %) | 20 (16.7 %) | |
| Chemoradiation | 34 (70.8 %) | 44 (61.1 %) | 78 (65.0 %) | |
| Radiation Technique | 0.0012 | |||
| 3D | 6 (13.0 %) | 0 (0.0 %) | 6 (5.1 %) | |
| IMRT | 40 (87.0 %) | 72 (100.0 %) | 112 (94.9 %) | |
| Missing | 2 | 0 | 2 | |
| Adjuvant/Salvage Neck | 0.0012 | |||
| Dissection | ||||
| Yes | 18 (37.5 %) | 8 (11.1 %) | 26 (21.7 %) | |
| No | 30 (62.5 %) | 64 (88.9 %) | 94 (78.3 %) | |
Kruskal Wallis
Fisher Exact
Chisquare.
Acute toxicity for patients receiving BRT versus IRT is presented in Supplementary Table 1. Compared to those that received IRT, a higher proportion of patients who received BRT developed acute grade 3 odynophagia (79.5 % vs 55.6 %, p = 0.01) and were hospitalized (25.0 % vs 9.7 %, p = 0.04). There was also a non-significant increased incidence of grade 3 acute mucositis among those who received BRT vs IRT (48.9 % vs 35.3 %, p = 0.18). Incidences of acute Grade 3 dysgeusia, dysphagia, dermatitis, and feeding tube placement were similar among those treated with BRT and IRT.
Ten-year recurrence-free survival (RFS) was 93 % (95 % CI 81–97 %) for patients treated with BRT and 94 % (95 % CI 86–97 %) for IRT (Fig. 1, panel A). Ten-year overall survival (OS) for patients treated with BRT was 86 % (95 % CI 70 %–94 %) and 85 % (95 % CI 71–92 %) for IRT (Fig. 1, panel B). No patient or treatment characteristics were associated with recurrence-free or overall survival on univariate analysis except smoking pack years > 10 versus 0 (Supplementary Table 2).
Fig. 1.
Recurrence-Free Survival and Overall Survival for All Patients. Caption: Recurrence-free survival (panel A) and overall survival (panel B) for all patients. Abbreviations: RT = Radiation Therapy.
Late toxicities for patients receiving BRT versus IRT are presented in Supplementary Table 3. Patients treated with BRT had a higher incidence of any late xerostomia (70.8 % vs 48.6 %, p = 0.02) and hypothyroidism (27.1 % vs 12.5 %, p = 0.05). Incidences of late dysphagia, late neck pain, late periodontal disease, carotid stenosis were similar between those treated with BRT and IRT. Detailed late toxicities by grade are presented in Supplementary Table 4.
Subset analysis (cT1–2N2b)
Among the 71 patients with N2b disease, 30 received BRT and 41 received IRT. Median follow-up among surviving patients for this patient subset was 71 months (range 7–209 months). Patient characteristics are presented in Table 2. Compared to patients who received BRT, a smaller proportion of patients who received IRT were prior/current smokers (47.5 % vs 72.4 %, p =0.03), had T2 disease (53.7 % vs 76.7 %, p = 0.08), and had > 1 cm of soft palate/base of tongue extension (0 % vs 20.0 %, p = 0.008). Patients treated with IRT had a median of 3 (range 2–9) involved lymph nodes, with median largest nodal dimension of 2.1 cm (range 1.0–4.0 cm). Similarly, patients treated with BRT had a median of 3 (range 2–10) involved lymph nodes, with median largest nodal dimension of 2.9 cm (range 0.7–4.5 cm). A higher proportion of those who received IRT had pre-treatment PET/CT staging (97.6 % vs 70.0 %, p = 0.001) and underwent IMRT (100 % vs 89.7 %, p = 0.06).
Table 2.
Patient, tumor, and treatment characteristics of patients with N2b disease.
| Bilateral (N = 30) | Ipsilateral (N = 41) | Total (N = 71) | P-value | |
|---|---|---|---|---|
|
| ||||
| Age at Diagnosis | 0.471 | |||
| Median (range) | 56 (35–77) | 56 (36–73) | 56 (35–77) | |
| Gender | 0.342 | |||
| Female | 3 (10.0 %) | 8 (19.5 %) | 11 (15.5 %) | |
| Male | 27 (90.0 %) | 33 (80.5 %) | 60 (84.5 %) | |
| Race | 0.082 | |||
| White | 25 (83.3 %) | 40 (97.6 %) | 65 (91.5 %) | |
| Black | 3 (10.0 %) | 0 (0.0 %) | 3 (4.2 %) | |
| Others | 2 (6.7 %) | 1 (2.4 %) | 3 (4.2 %) | |
| Status | 0.032 | |||
| Yes | 21 (72.4 %) | 19 (47.5 %) | 40 (58.0 %) | |
| No | 8 (27.6 %) | 21 (52.5 %) | 29 (42.0 %) | |
| Missing | 1 | 1 | 2 | |
| Smoking Pack Years (Among Smokers) |
0.472 | |||
| ≤10 | 4 (13.8 %) | 6 (15.0 %) | 10 (14.5 %) | |
| >10 | 17 (58.6 %) | 13 (32.5 %) | 30 (43.5 %) | |
| Clinical Tumor (T) Stage, AJCC 7th Ed |
0.082 | |||
| 1 | 7 (23.3 %) | 19 (46.3 %) | 26 (36.6 %) | |
| 2 | 23 (76.7 %) | 22 (53.7 %) | 45 (63.4 %) | |
| Primary Size, Largest | 0.081 | |||
| Dimension (cm) | ||||
| Median (range) | 2.5 (0.7–4.5) | 2.1 (1.0–4.0) | 2.2 (0.7–4.0) | |
| Soft Palate/Base of Tongue Extension |
0.0082 | |||
| None | 20 (66.7 %) | 31 (75.6 %) | 51 (71.8 %) | |
| ≤1 cm | 4 (13.3 %) | 10 (24.4 %) | 14 (19.7 %) | |
| >1 cm | 6 (20.0 %) | 0 (0.0 %) | 6 (8.5 %) | |
| Largest Lymph Node (cm) | 0.221 | |||
| Median (range) | 3.0 (1.0–5.0) | 2.9 (1.3–4.8) | 3.0 (1.0–5.0) | |
| Neck Staging | 0.0012 | |||
| CT | 8 (26.7 %) | 1 (2.4 %) | 9 (12.7 %) | |
| PET | 21 (70.0 %) | 40 (97.6 %) | 61 (85.9 %) | |
| Number of Involved | 0.971 | |||
| Lymph Nodes | ||||
| Missing | 1 | 0 | 1 | |
| Median (range) | 3 (2–10) | 3 (2–9) | 3 (2–10) | |
| HPV Status | 0.0023 | |||
| Negative (−) | 0 (0.0 %) | 2 (4.3 %) | 2 (4.3 %) | |
| Positive (+) | 13 (100.0 %) | 32 (94.1 %) | 45 (95.7 %) | |
| Unknown | 17 | 7 | 24 | |
| Treatment Modality | 0.482 | |||
| Surgery + Radiation | 0 (0.0 %) | 1 (2.4 %) | 1 (1.4 %) | |
| Surgery + Chemoradiation | 3 (10.0 %) | 1 (2.4 %) | 4 (5.6 %) | |
| Radiation | 2 (6.7 %) | 3 (7.3 %) | 5 (7.0 %) | |
| Chemoradiation | 25 (83.3 %) | 36 (87.8 %) | 61 (85.9 %) | |
| Radiation Technique | 1.002 | |||
| IMRT | 26 (89.7 %) | 41 (100.0 %) | 67 (95.7 %) | |
| 3D | 3 (10.3 %) | 0 (0.0 %) | 3 (4.3 %) | |
| Missing | 1 (3.2 %) | 0 (0.0 %) | 1 (1.4 %) | |
| Adjuvant/Salvage Neck | 0.0022 | |||
| Dissection | ||||
| Yes | 14 (46.7 %) | 5 (12.2 %) | 19 (26.8 %) | |
| No | 16 (53.3 %) | 36 (87.8 %) | 52 (73.2 %) | |
Kruskal Wallis
Fisher Exact
Chisquare.
Three patients who received BRT developed recurrence (2 distant, 1 synchronous primary/ipsilateral neck) and two patients who received IRT developed recurrence (1 distant and 1 primary). Ten-year RFS was 89 % (95 % CI 71–96 %) for patients treated with BRT and 95 % (95 % CI 82 %–98 %) for patients treated with IRT (Fig. 2, panel A). Ten-year OS for patients treated with BRT was 89 % (95 % CI 71 %–96 %) and 82 % (95 % CI 52 %–94 %) for those treated with IRT (Fig. 2, panel B). Details regarding the patients who developed recurrent disease are presented in Table 3. All 5 of the 71 patients with N2b disease who developed a recurrence had cT2 disease at diagnosis, with median primary tumor size of 3.2 cm. These patients had no or minimal soft palate/base of tongue involvement < 1 cm. There were no contralateral neck recurrences in patients undergoing IRT. No patient or treatment characteristics were associated with recurrence-free or overall survival on univariate analysis of the N2b patient subset (Table 4).
Fig. 2.
Recurrence-Free Survival and Overall Survival for N2b Patients. Caption: Recurrence-free survival (panel A) and overall survival (panel B) in patients with N2b disease. Abbreviations: RT = Radiation Therapy.
Table 3.
Recurrences, cT1–2N2b.
| Pt | Age | Stage | Primary (cm) | SP/BOT extension | Largest Node (cm) | Number of Lymph Nodes | Radiation Laterality | Recurrence Site | Time to Recurrence (months) | Salvage | Survival (months) |
|---|---|---|---|---|---|---|---|---|---|---|---|
|
| |||||||||||
| 1 | 60 | T2N2b | 3.2 | No | 3 | 3 | B-CRT | Distant | 31 | None | 37 |
| 2 | 56 | T2N2b | 3.4 | <1 cm | 2.7 | 2 | B-CRT | Primary/Ipsilateral Neck |
2 | Chemo | 35 |
| 3 | 65 | T2N2b | 2.2 | No | 3.3 | 5 | B-CRT | Distant | 10 | Chemo | 12 |
| 4 | 56 | T2N2b | 2.1 | <1 cm | 4.2 | 2 | I-CRT | Distant | 2 | Radiation | 23 |
| 5 | 48 | T2N2b | 3.8 | No | 3 | 6 | I-CRT | Primary | 3 | Surgery | 6 |
Abbreviations: SP, soft palate; BOT, base of tongue; B-CRT, bilateral neck chemoradiation; I-CRT, ipsilateral neck chemoradiation.
Table 4.
Univariate Analysis of Factors on Overall Survival and Recurrence, N2b patients.
| Recurrence-free Survival | Overall Survival | |
|---|---|---|
| HR (95 % CI) (n = 71, 5 events) | HR (95 % CI) (n = 71, 8 events) | |
|
| ||
| Age | 1.01 (0.91, 1.11) | 0.99 (0.91, 1.08) |
| Smoking Packs/Year | ||
| 0 | ref | ref |
| 1–10 | 2.70 (0.17, 43.27) | 5.05 (0.45, 55.72) |
| >10 | 2.89 (0.30, 27.78) | 3.96 (0.44, 35.47) |
| Clinical Tumor (T) 7th Stage | – | |
| 1 | – | ref |
| 2 | – | 3.08 (0.37–25.67) |
| Tumor Size (cm) | 0.88 (0.23, 3.29) | 1.00 (0.37, 2.75) |
| Soft Palate/Base of Tongue | ||
| Extension | ||
| Yes | ref | ref |
| No | 0.54 (0.09, 3.22) | 0.81 (0.16, 4.22) |
| Nodal Size (cm) | 0.98 (0.42, 2.25) | 1.01 (0.49, 2.05) |
| Side(s) of Neck Irradiated | ||
| Bilateral | ref | ref |
| Ipsilateral | 0.50 (0.84–3.01) | 1.22 (0.27, 5.48) |
| Adjuvant Neck Dissection | ||
| No | ref | ref |
| Yes | 0.57 (0.06, 5.15) | 0.70 (0.13, 3.68) |
Discussion
This study represents a large modern series reporting outcomes of N2b tonsil SCC patients undergoing definitive RT with ipsilateral neck irradiation. Patients with cT1–2N2b tonsillar SCC treated with ipsilateral neck RT had very high rates of locoregional control and overall survival, with no contralateral neck recurrences. Patients were all treated in a similar fashion, with long follow-up and rigorous toxicity reporting. Prior series that included patients with multiple ipsilateral nodes provided limited description of nodal burden [3–7,9–10]. By including data on the number and size of involved lymph nodes, we sought to specifically define the population for whom IRT appears to be appropriate. We also provide details on primary tumor size and locoregional soft palate/base of tongue extension, HPV status, smoking history, use of surgery, and pre-treatment PET/CT imaging to characterize factors which might have influenced the decision for IRT versus BRT. Incorporating these additional factors is key to assessing the generalizability of these results in a highly selected group of patients receiving IRT for cT1–2N2b tonsillar SCC.
The treatment volume for patients with clinical N2b disease has been controversial. The American Radium Society recently updated consensus recommendations for ipsilateral neck radiation therapy in tonsillar SCC patients [11], with a strong recommendation for IRT for patients with well lateralized tumors confined to the tonsil and minimal burden of nodal disease. However, the committee did not reach a consensus on employing this approach for perceived higher risk patients with multiple ipsilateral involved lymph nodes (N2b per AJCC 7th edition).
Consensus guidelines from other committees have recommended bilateral neck irradiation in the N2b setting based on retrospective series suggesting a higher risk for contralateral neck recurrence [3–4,12]. In an older study from the Royal Marsden Hospital, 10.9 % (6/55) patients with N2b disease treated with IRT developed contralateral neck recurrence (CNR) [5]. Another study of IRT reported a 14.2 % rate of CNR (4/28) among those with N2b disease [6]. Conversely, other series inclusive of patients with N2b disease reported more favorable outcomes with lower rates (3–5 %) of CNR [7,9–10,13]. In the largest of these studies, a series from MD Anderson including 181 patients treated with IRT reported a crude CNR rate of 3 % in patients with N2b disease treated with IRT [13]. The current study is consistent with these favorable findings with no contralateral neck recurrences among those treated with IRT.
Importantly, patients with N2b disease are a heterogenous group, and risk of contralateral neck recurrence likely differs for a patient with two small lymph nodes in a single station versus a patient with numerous larger lymph nodes spanning multiple stations. As prior series, including the recently published series from MD Anderson [13], have not commented on the number or size of involved lymph nodes of included N2b patients, it is unclear if and how these factors should influence the decision for ipsilateral versus bilateral neck irradiation. In the current study, N2b patients treated with IRT had a median of 3 involved nodes, with median largest node measuring 2.8 cm. The majority of N2b patients treated with IRT had pre-treatment PET/CT staging (93 %) to aid in the delineation of the primary tumor and detection of occult nodal metastases. Prior studies have not routinely reported on the use of pre-treatment staging PET in the modern era, which has likely improved nodal staging accuracy over CT alone [14]. Among the largest previously reported experience of IRT, only 59 % of patients had pre-treatment PET/CT staging [13]. Although 23.3 % of patients in the current series had minimal (≤1 cm) BOT or soft palate involvement, no patients with N2b disease treated with IRT had involvement >1 cm. This approach is consistent with our strategy of reserving IRT for well-lateralized tonsil tumors and employing bilateral neck irradiation for extensive BOT involvement or soft palate involvement approaching midline.
IRT enhances normal tissue sparing and reduces radiation-induced toxicity compared to BRT. Patients treated with IRT had significantly decreased incidence of grade 3 acute odynophagia and reduced hospitalization relative to patients treated with BRT. A significantly lower proportion of patients treated with IRT developed late xerostomia, compared to those treated with BRT. Those treated with IRT also had a lower incidence of hypothyroidism. Unlike other retrospective series including a significant number of N2b patients, most patients included in this study were treated with IMRT (BRT: 85.7 %; IRT: 100 %). Despite the receipt of highly conformal treatment, differences in acute and late toxicity persisted between patients who received IRT and BRT. These findings are consistent with prior studies reporting that IRT is associated with reduced rates of late toxicity including xerostomia, dysphagia, hoarseness, atrophy, fibrosis, and edema compared to BRT [15–17].
The retrospective nature of this study precludes direct comparisons between the efficacy of BRT and IRT due to possible physician selection bias regarding which patients received IRT. As expected, there were differences in tumor characteristics for patients who received BRT versus IRT, particularly with larger primary tumors in patients who received BRT. Differences in acute and late toxicity between BRT and IRT may be due also, in part, to observed baseline differences in primary tumor size. Nevertheless, we suspect that differences in xerostomia and hypothyroidism cannot be entirely attributed to differences in primary tumor size. Due to the low number of events, propensity score matching was not feasible.
The low rates of contralateral neck recurrence and high overall survival in this series suggest that IRT is appropriate in select patients with N2b disease and that BRT is not universally indicated for patients with tonsil SCC and multiple ipsilateral lymph nodes. In the era of increasing HPV-related tonsillar SCC, minimization of overtreatment and radiation-related toxicity is essential. Further data are needed to define the specific number of involved nodes and nodal size above which bilateral neck irradiation should be considered. Future work should also address the appropriateness of ipsilateral neck RT in the setting of extracapsular nodal extension and a single large node > 6 cm.
Supplementary Material
Funding
This research was supported by the National Institutes of Health through a Duke Cancer Center Support Grant (P30CA14236) and K08-DE029887-01 Award (YMM).
Footnotes
Appendix A. Supplementary material
Supplementary data to this article can be found online at https://doi.org/10.1016/j.oraloncology.2023.106362.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data availability
The data that support the findings of this study are not publicly available due to patient privacy and ethical restrictions. De-identified data will be made available upon request to the corresponding author.
References
- [1].Huang SH, Waldron J, Bratman SV, et al. Re-evaluation of ipsilateral radiation for T1–T2N0-N2b tonsil carcinoma at the princess Margaret hospital in the human papillomavirus era, 25 years later. Int J Radiat Oncol* Biol* Phys 2017;98(1): 159–69. [DOI] [PubMed] [Google Scholar]
- [2].Tsai CJ, Galloway TJ, Margalit DN, et al. Ipsilateral radiation for squamous cell carcinoma of the tonsil: American Radium Society appropriate use criteria executive summary. Head Neck 2021. Jan;43(1):392–406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [3].Biau J, Lapeyre M, Troussier I, et al. Selection of lymph node target volumes for definitive head and neck radiation therapy: a 2019 update. Radiother Oncol 2019; 134:1–9. [DOI] [PubMed] [Google Scholar]
- [4].Yeung AR, Garg MK, Lawson J, et al. ACR Appropriateness Criteria® ipsilateral radiation for squamous cell carcinoma of the tonsil. Head Neck 2012;34(5):613–6. [DOI] [PubMed] [Google Scholar]
- [5].Lynch J, Lal P, Schick U, et al. Multiple cervical lymph node involvement and extra-capsular extension predict for contralateral nodal recurrence after ipsilateral radiotherapy for squamous cell carcinoma of the tonsil. Oral Oncol 2014;50(9): 901–6. [DOI] [PubMed] [Google Scholar]
- [6].Maskell D, Buckley H, Sission K, Roques T, Geropantas K. Ipsilateral neck radiotherapy in N2b well-lateralized tonsil cancer-approach with caution. Head Neck 2019;41(9):2937–46. [DOI] [PubMed] [Google Scholar]
- [7].Hu KS, Mourad WF, Gamez M, et al. Low rates of contralateral neck failure in unilaterally treated oropharyngeal squamous cell carcinoma with prospectively defined criteria of lateralization. Head Neck 2017;39(8):1647–54. [DOI] [PubMed] [Google Scholar]
- [8].Porceddu SV, Pryor DI, Burmeister E, et al. Results of a prospective study of positron emission tomography-directed management of residual nodal abnormalities in node-positive head and neck cancer after definitive radiotherapy with or without systemic therapy. Head Neck 2011;33(12):1675–82. [DOI] [PubMed] [Google Scholar]
- [9].Kennedy WR, Herman MP, Deraniyagala RL, et al. Ipsilateral radiotherapy for squamous cell carcinoma of the tonsil. Eur Arch Otorhinolaryngol 2016;273(8): 2151–6. [DOI] [PubMed] [Google Scholar]
- [10].Al-Mamgani A, van Rooij P, Fransen D, Levendag P. Unilateral neck irradiation for well-lateralized oropharyngeal cancer. Radiother Oncol 2013;106(1):69–73. [DOI] [PubMed] [Google Scholar]
- [11].Tsai CJ, Galloway TJ, Margalit DN, et al. Ipsilateral radiation for squamous cell carcinoma of the tonsil: American Radium Society appropriate use criteria executive summary. Head Neck 2020;43(1):392–406. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [12].Quon H, Vapiwala N, Forastiere A, et al. Radiation therapy for oropharyngeal squamous cell carcinoma: American Society of Clinical Oncology endorsement of the American Society for Radiation Oncology evidence-based clinical practice guideline. J Clin Oncol 2017;35(36):4078–90. [DOI] [PubMed] [Google Scholar]
- [13].Taku N, Chronowski G, Gunn GB, et al. Unilateral radiotherapy for tonsillar cancer: treatment outcomes in the era of human papilloma virus (HPV), positron-emission tomography (PET) and intensity-modulated radiation therapy (IMRT). Int J Radiat Oncol Biol Phys. 2022. Aug 1;113(5):1054–1062. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [14].Cacicedo J, Navarro A, Del Hoyo O, et al. Role of fluorine-18 fluorodeoxyglucose PET/CT in head and neck oncology: the point of view of the radiation oncologist. Br J Radiol 2016;89(1067):20160217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [15].Jensen K, Overgaard M, Grau C. Morbidity after ipsilateral radiotherapy for oropharyngeal cancer. Radiother Oncol 2007;85(1):90–7. [DOI] [PubMed] [Google Scholar]
- [16].Kim Y, Cho KH, Moon SH, et al. Comparison of the clinical outcomes of patients with squamous cell carcinoma of the tonsil receiving postoperative ipsilateral versus bilateral neck radiotherapy: a propensity score matching analysis (KROG 11–07). Cancer Res Treat 2017. Oct;49(4):1097–105. [DOI] [PMC free article] [PubMed] [Google Scholar]
- [17].Chin RI, Rao YJ, Hwang MY, et al. Comparison of unilateral versus bilateral intensity-modulated radiotherapy for surgically treated squamous cell carcinoma of the palatine tonsil. Cancer 2017;123(23):4594–607. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study are not publicly available due to patient privacy and ethical restrictions. De-identified data will be made available upon request to the corresponding author.