Stereotactic Body Ablative Radiotherapy for Reirradiation of Small Volume Head and Neck Cancers is Associated with Prolonged Survival: A Large, Single Institution, Modern Cohort Study

Abstract

Background:

Recurrent head and neck cancer has poor prognosis. Stereotactic body radiotherapy (SBRT) may improve outcomes by delivering ablative radiation doses.

Methods:

We reviewed patients who received definitive-intent SBRT reirradiation at our institution from 2013–2020. Patterns of failure, overall survival (OS), and toxicities were analyzed.

Results:

137 patients were evaluated. The median OS was 44.3 months. The median SBRT dose was 45 Gy and median target volume 16.9 cc. The 1-year local, regional, and distant control was 78%, 66%, and 83%, respectively. Systemic therapy improved regional (p=0.004) and distant control (p=0.04) in non-metastatic patients. Grade 3+ toxicities were more common at mucosal sites (p=0.001) and with concurrent systemic therapy (p=0.02).

Conclusions:

In a large cohort of SBRT reirradiation for recurrent, small volume head and neck cancers, a median OS of 44.3 months was observed. Systemic therapy improved regional and distant control. Toxicities were modulated by anatomic site and systemic therapy.

Introduction

Locoregional recurrence of head and neck cancers occurs in up to half of all patients treated with definitive chemoradiation,^1–3 and is the most common cause of cancer-related death in this population of patients.^{4, 5} While salvage surgical resection has historically been considered the only potentially curative salvage modality for recurrence within a previously irradiated field, most patients are not suitable candidates for this approach due to patient, anatomic, and prior treatment factors.^6–9 Systemic therapies and reirradiation have been used, but in general outcomes are poor.¹⁰ Systemic therapy alone is associated with a median overall survival ranging from 5.0 – 10.1 months.^11–13 Salvage reirradiation is also associated with low survival rates; two multi-institutional clinical trials, RTOG 9610 and RTOG 9911, evaluated combined chemotherapy and reirradiation with older conventional radiation techniques and reported median overall survivals of 8.5 and 12.1 months, respectively.^{14, 15}

Combining highly conformal radiotherapy delivery techniques with precision image-guidance and patient alignment, stereotactic body radiotherapy (SBRT) can deliver ablative doses of radiation to tumor while minimizing the volume of irradiated normal tissue. These attractive features of SBRT have led to interest in its use for the reirradiation of head and neck cancers.¹⁶ Early data suggests SBRT has a favorable local control and toxicity profile compared to conventional radiotherapy techniques.¹⁷ In addition, there are numerous studies which suggest increased efficacy of SBRT when combined with systemic therapy agents such as novel immune-checkpoint inhibitors, targeted agents, and cytotoxic chemotherapy.^18–22

Despite this, the efficacy, toxicity profile, prognostic factors, and curative potential of SBRT for recurrent head and neck cancers is not well-described. Only a limited number of small retrospective series have been published with heterogeneous radiation dose regimens and reported outcomes owing to the novelty of the technique and expertise required.²³ Therefore, we conducted a review of our experience with SBRT reirradiation of head and neck cancers with a focus on clinical outcomes, patterns of relapse, side effect profile, and impact of systemic therapies.

Materials and Methods

Patients

Under institutional review board approval, we retrospectively identified patients who were treated with SBRT for (1) recurrent cancer of the head and neck with (2) definitive intent reirradiation after (3) documented prior in-field radiotherapy and with (4) at least one clinical follow up. Patients treated between September 2013 and April 2020 were included. Patients were excluded if they were treated with palliative intent SBRT doses (≤36 Gy over 6 fractions corresponding to an EQD2 of ≤48 Gy assuming an alpha/beta of 10) or did not complete the full prescribed SBRT treatment. Patients treated after 2014 were prospectively enrolled on our institutional registry protocol for head and neck reirradiation (PA14-0198).

All patients had biopsy confirmed diagnosis of head and neck carcinoma at diagnosis and at disease recurrence. Patients were evaluated by a multidisciplinary team consisting of head and neck surgery, medical oncology, radiation oncology, and radiology. Prior to SBRT, patients were presented and examined at the departmental quality assurance review. Patients were evaluated for reirradiation based on clinical factors including performance status, comorbidities, size and extent of disease, presence of metastatic disease, prior treatments received, surgical candidacy, and ability to meet critical organ radiation dose constraints. Disposition to reirradiation modality was made primarily based on gross tumor volume (GTV) with pretreatment GTV of <60 cc for a single lesion and <100 cc for all lesions typically required for SBRT.^24–26 Skin invasion was considered a contraindication²⁷ and a reirradiation interval of ≥6 months was required.

Clinical covariates including age, sex, smoking status, performance status, initial disease site, initial radiation dose and fractionation, histology, p16/HPV status, presence of metastatic disease, SBRT site, dose, fractionation, and target volume, prior surgical salvage, reirradiation interval, and use and type of induction, concurrent, and/or adjuvant systemic therapy were obtained from electronic medical records.

Radiation planning and delivery

All patients underwent CT simulation with immobilization using a custom thermoplastic head and neck mask, cushion, and bite block.²⁸ MRI, contrast-enhanced CT, and PET-CT of the head and neck in the treatment planning position were obtained for all patients and fused to the simulation CT for target delineation. A gross tumor volume (GTV) consisting of the maximum projection of recurrent gross tumor was contoured using a combination of the imaging modalities. A clinical target volume (CTV) expansion was not used for the prescription dose region, but an optional expansion to include areas at high risk for microscopic or perineural spread could be used to generate a low-dose CTV (30–35 Gy in 5 fractions). In general, the CTV did not include elective nodal coverage. The planning target volume (PTV) was generated with a uniform expansion of 2 mm, 3 mm, and 3.5 mm, respectively, for skull base, mucosal, and neck sites.²⁴

Daily setup consisted of stereoscopic x-ray with ExacTrac (Brainlab AG, Feldkirchen, Germany) followed by cone-beam CT (CBCT), kV/MV imaging, and intrafractional ExacTrac.²⁹ Treatment was delivered using Varian TrueBeam STx (Varian Medical Systems, Palo Alto, CA) with 2.5 mm multileaf collimators and volumetric modulated arc therapy (VMAT) technique. Treatments were given every other day over 2 weeks. Treatment planning was performed using Pinnacle (Philips Healthcare, Andover, MA) from 2013–2018 and RayStation (RaySearch Laboratories, Stockholm, Sweden) from 2019–2020. Strict dose constraints were only applied for critical normal structures in series (i.e. brainstem, spinal cord, brachial plexus) which follow a more conservative version of the American Association of Physicists in Medicine (AAPM) Task Group 101 5 fraction SBRT constraints, adjusting for reirradiation and normal tissue recovery.³⁰ Institutional guidelines for other normal structures were used during planning and plans were carefully evaluated for maximal dose falloff towards important normal structures. The treating physician and physicist supervised all SBRT treatments.

Systemic therapy administration

Cetuximab dosing was 400 mg/m² loading dose one week prior to radiation start followed by 250 mg/m² weekly during radiation. Adjuvant cetuximab was given weekly up to 15 cycles. Pembrolizumab dosing was 200 mg every 3 weeks and nivolumab 480 mg every 4 weeks. Concurrent cisplatin dosing was 60–80 mg/m2 every 3 weeks or 15–25 mg/m2 given weekly. Carboplatin and paclitaxel dosing was weekly carboplatin AUC 1.5 and paclitaxel 20 mg/m². Systemic therapy use and selection was per physician preference based on clinical factors suggesting need for radiosensitization and/or high risk for out of field recurrence.

Follow up

After SBRT, follow up evaluations were performed at regular intervals of 3 months for the first year, 4 months for the second year, 6 months for years three through five, and annually thereafter. Physical exam included flexible nasopharyngolaryngoscopy where appropriate. Imaging including MRI, PET-CT, and/or contrast-enhanced CT were typically ordered with each follow up at the discretion of the treating physician. Follow up clinical exams, imaging, and pathology were comprehensively reviewed to determine local, regional, and distant control. Local failure was defined as occurring within 2 cm of the SBRT prescription isodose line. A regional failure was defined as occurring ≥2 cm outside of the prescription isodose line or in a regional lymph node. Distant failure was defined as development of any new metastatic disease or frank progression of existing metastatic disease. Progression-free survival was defined as a composite endpoint of first local, regional, distant failure, or death. Treatment-related toxicities were coded using the Common Terminology Criteria for Adverse Events (CTCAE, version 4.03).

Statistical analysis

Local control, regional control, distant control, progression-free survival, and overall survival were calculated from the date of SBRT treatment completion and analyzed using the Kaplan-Meier method with censoring at the time of last follow up. Univariate and multivariable analysis was performed using the Cox proportional hazards model. The multivariable model of overall survival was constructed by including all relevant clinical covariables in a saturated model and removing non-significant covariables one at a time starting with the highest p-value until all remaining covariables were at a significance level of p<0.10. Acute and late toxicities were analyzed using the Chi-squared test. All statistical analysis was performed with JMP Pro (version 15; SAS Institute, Cary, NC).

Results

Patient Characteristics

We identified 224 patients treated with SBRT for reirradiation of head and neck cancers at our institution from September 2013 through April 2020. Seventy-nine patients were excluded due to palliative SBRT dose, 7 patients were excluded due to absence of clinical follow up, and 1 patient was excluded due to leaving AMA without completing SBRT. A total of 137 patients who were treated to 150 disease sites were eligible and included in this analysis. The median follow up time among all patients was 19.3 months (range, 0.4–68.1 months).

The median age was 63 years, 100 (73%) patients were male, 124 (90%) had an ECOG performance status of 0 or 1, 98 (72%) patients had squamous histology, 26 (19%) patients were metastatic at SBRT, and the median initial radiation dose was 69 Gy (Table 1). There were significant differences in baseline characteristics between squamous and non-squamous histology patients. Patients with squamous histology were older, more likely to be p16/HPV positive, less likely to have metastatic disease at SBRT, more likely to receive SBRT to the mucosa, and more likely to receive systemic therapy as part of their salvage treatment.

Table 1.

Patient and Treatment Characteristics

Variable	All Patients (N=137)	Squamous Histology (N=98)	Non-Squamous Histology (N=39)	p-value
Age, years				<0.001
Median (range)	63 (22–89)	66 (43–89)	52 (22–76)
Sex				0.06
Male	100 (73%)	76 (78%)	24 (62%)
Female	37 (27%)	22 (22%)	15 (38%)
ECOG Performance Status				0.70
0	39 (28%)	26 (27%)	13 (33%)
1	85 (62%)	62 (63%)	23 (59%)
2	13 (10%)	10 (10%)	3 (8%)
Smoking History, pack years
Median (range)	4 (0–125)
Initial Site of Disease				<0.001
Oropharynx	37 (27%)	36 (37%)	1 (3%)
Sinonasal	19 (14%)	6 (6%)	13 (33%)
Larynx	18 (13%)	18 (18%)	0 (0%)
Oral Cavity	16 (12%)	15 (15%)	1 (3%)
Nasopharynx	12 (9%)	2 (2%)	10 (26%)
Unknown Primary	7 (5%)	7 (7%)	0 (0%)
Skin/Face	7 (5%)	6 (6%)	1 (3%)
Other	21 (15%)	10 (8%)	13 (33%)
Histology				-
Squamous cell carcinoma	98 (72%)	-	-
Adenoid cystic carcinoma	11 (8%)	-	-
Sinonasal undifferentiated carcinoma	5 (4%)	-	-
Nasopharyngeal carcinoma (WHO types I, II, and III)	6 (4%)	-	-
Other	17 (12%)	-	-
p16/HPV status				<0.001
Positive	32 (23%)	32 (33%)	0 (0%)
Negative	31 (23%)	26 (27%)	5 (13%)
Unknown	74 (54%)	40 (41%)	34 (87%)
Metastatic Disease at SBRT				<0.001
Yes	26 (19%)	11 (11%)	15 (38%)
No	111 (81%)	87 (89%)	24 (62%)
Number of Disease Sites Treated with SBRT				0.40
1	124 (91%)	88 (90%)	36 (92%)
2	13 (9%)	10 (10%)	3 (8%)
Initial Radiation Dose (Gy)				0.70
Median (range)	69 (16–72)	68 (16–72)	68.4 (27.5–72)
Initial Radiation Fractions				0.81
Median (range)	33 (1–60)	33 (8–42)	33 (1–60)
SBRT Reirradiation Site				<0.001
Mucosa	55 (40%)	47 (48%)	8 (21%)
Neck	43 (31%)	34 (35%)	9 (23%)
Skull base	39 (29%)	17 (17%)	22 (56%)
SBRT Dose (Gy)				0.54
Median (range)	45 (36–47.5)	45 (36–47.5)	45 (36–45)
SBRT Fractions				0.04
Median (range)	5 (4–5)	5 (4–5)	5 (4–5)
SBRT Target Volume (cc)				0.51
Median (range)	16.91 (1.47–108.09)	18.06 (3.63–108.09)	16.73 (1.47–60.53)
Reirradiation Interval, years				0.08
Median (range)	2.55 (0.1–51.1)	2.1 (0.5–51.1)	4.2 (0.1–23.5)
Salvage Surgery Prior to SBRT				0.96
Yes	32 (23%)	23 (23%)	9 (23%)
No	105 (77%)	75 (77%)	30 (77%)
Any Peri-SBRT Systemic Therapy				<0.001
Yes	115 (84%)	89 (91%)	26 (67%)
No	22 (16%)	9 (9%)	13 (33%)
Induction Systemic Therapy				0.12
Yes	45 (33%)	36 (37%)	9 (23%)
No	92 (67%)	62 (63%)	30 (77%)
Induction Systemic Agent				0.01
Cetuximab	15 (33%)	15 (42%)	0 (0%)
PD-1/PD-L1 Based	11 (24%)	8 (22%)	3 (33%)
Conventional	19 (42%)	13 (36%)	6 (67%)
Concurrent Systemic Therapy				<0.001
Yes	96 (70%)	78 (80%)	18 (46%)
No	41 (30%)	20 (20%)	21 (54%)
Concurrent Systemic Agent				<0.001
Cetuximab	65 (68%)	60 (77%)	5 (28%)
PD-1/PD-L1 Based	13 (13%)	9 (12%)	4 (22%)
Conventional	18 (19%)	9 (12%)	9 (50%)
Adjuvant Systemic Therapy				0.89
Yes	41 (30%)	29 (30%)	12 (31%)
No	96 (70%)	69 (70%)	27 (69%)
Adjuvant Systemic Agent				0.05
Cetuximab	15 (36%)	13 (43%)	2 (17%)
PD-1/PD-L1 Based	22 (52%)	16 (53%)	6 (50%)
Conventional	5 (12%)	1 (3%)	4 (33%)

Abbreviations: cc, cubic centimeter; ECOG, Eastern Cooperative Oncology Group; Gy, gray; SBRT, stereotactic body radiotherapy; WHO, World Health Organization

The SBRT treatment site was mucosa in 59 (39%), neck in 48 (32%), and skull base in 43 (29%). The median SBRT dose and fractionation was 45 Gy in 5 fractions (range, 36–47.5 Gy) and the median SBRT target volume was 16.9 cc (range, 1.5–108.1 cc). Patients who received 36 Gy were treated in 4 fractions (n=3) and were all treated at the skull base with reduced dose due to proximity with critical normal structures. The median reirradiation interval was 2.6 years. Thirty-two (23%) patients underwent surgical resection prior to SBRT but had gross recurrent disease and 115 (84%) patients received either induction, concurrent, or adjuvant systemic therapy with SBRT. Induction systemic therapy was most commonly conventional chemotherapy (42%), concurrent systemic therapy was most commonly cetuximab (68%), and adjuvant systemic therapy was most commonly a PD-1/PD-L1 agent (52%). The median number of cycles of induction, concurrent, and adjuvant systemic therapy, respectively, was 3 cycles (range, 1–14), 2 cycles (range, 1–4) and 6 cycles (range, 1–28).

Overall Survival and Salvage Treatment

The median overall survival (OS) among all patients was 44.3 months with a 1-year OS of 78% and 2-year OS of 62% (Figure 1A). Among patients with squamous histology, the median OS was 32.2 months with a 1-year OS of 76% and 2-year OS of 56%. There was no significant difference in OS by the site of SBRT treatment (p=0.45) (Figure 1B). A total of 66 patients (48%) had disease progression following SBRT while 71 (52%) did not. Of these, 54 (82%) patients received some form of salvage therapy after progression, with 43 (65%) receiving salvage systemic therapy, 16 (24%) salvage radiotherapy, and 9 (14%) salvage surgery. Patients who had disease progression had similar OS compared to those who did not (median 41.4 months versus not reached, p=0.35) (Figure 1C). Among patients who had disease progression, those who received salvage therapy had significantly better OS compared to those who did not (median 44.3 months versus 15.3 months, p=0.03) (Figure 1D).

Figure 1.

Overall survival for (A) the entire cohort with 95% confidence interval, (B) by anatomic site of stereotactic body radiotherapy treatment, (C) by occurrence of any disease progression, and (D) by receipt of salvage therapy among patients who experienced disease progression.

Multivariable Analysis of Overall Survival

In multivariable analysis, squamous histology (HR 4.20, 95% CI 1.39–12.70, p=0.01) and SBRT target volume >20 cc (HR 3.09, 95% CI 1.57–6.10, p=0.001) were both associated with significantly worse OS (Table 2). Initial site of disease of the skin or unknown primary was associated with significantly better OS compared to sinonasal or other site (HR 0.20, 95% CI 0.05–0.72, p=0.01). Absence of metastatic disease at SBRT (HR 0.53, 95% CI 0.25–1.13, p=0.10) and use of concurrent systemic therapy (HR 0.47, 95% CI 0.20–1.12, p=0.09) were retained in the model and numerically associated with better OS but did not meet statistical significance.

Table 2.

Univariable and Multivariable Analysis of Clinical Factors for Overall Survival

	Univariable		Multivariable
	HR (95% CI)	p-value	HR (95% CI)	p-value
Age >60
Yes	1.17 (0.67–2.07)	0.58	-	-
No	Ref.	Ref.	-	-
Sex
Male	0.87 (0.48–1.58)	0.65	-	-
Female	Ref.	Ref.	-	-
ECOG Performance Status
0	Ref.	Ref.	-	-
1	1.09 (0.58–2.04)	0.79	-	-
2	0.91 (0.35–2.37)	0.85	-	-
Smoking History
Per pack-year increase	1.01 (1.00–1.02)	0.14	-	-
Squamous Histology
Yes	1.54 (0.79–3.02)	0.21	4.20 (1.39–12.70)	0.01
No	Ref.	Ref.	Ref.	Ref.
p16/HPV Status
Positive	1.37 (0.56–3.36)	0.50	-	-
Negative	Ref.	Ref.	-	-
Unknown	1.39 (0.63–3.04)	0.42	-	-
Initial Site of Disease
Mucosaa	0.87 (0.48–1.59)	0.66	0.50 (0.21–1.22)	0.13
Skin/Unknown Primary	0.52 (0.18–1.56)	0.24	0.20 (0.05–0.72)	0.01
Sinonasal/Other	Ref.	Ref.	Ref.	Ref.
Metastatic Disease at SBRT
Yes	Ref.	Ref.	Ref.	Ref.
No	0.68 (0.37–1.25)	0.21	0.53 (0.25–1.13)	0.10
Number of Disease Sites Treated with SBRT
1	1.04 (0.32–3.36)	0.95	-	-
2	Ref.	Ref.	-	-
Reirradiation Interval
Per year increase	1.01 (0.54–1.04)	0.81	-	-
SBRT Site Group
Mucosa	1.51 (0.73–3.16)	0.27	-	-
Neck	1.36 (0.66–2.79)	0.40	-	-
Skull base	Ref.	Ref.	-	-
SBRT Dose >40 Gy
Yes	1.10 (0.34–3.55)	0.87	-	-
No	Ref.	Ref.	-	-
Target Volume >20 cc
Yes	2.26 (1.25–4.10)	0.01	3.09 (1.57–6.10)	0.001
No	Ref.	Ref.	Ref.	Ref.
Salvage Surgery Prior to SBRT
Yes	0.67 (0.33–1.34)	0.25	-	-
No	Ref.	Ref.	-	-
Concurrent Chemotherapy
Yes	0.93 (0.51–1.70)	0.81	0.47 (0.20–1.12)	0.09
No	Ref.	Ref.	Ref.	Ref.
Induction Chemotherapy
Yes	1.24 (0.70–2.19)	0.46	-	-
No	Ref.	Ref.	-	-

^aIncludes oral cavity,oropharynx, larynx, and nasopharynx primaries.

Abbreviations: cc, cubic centimeter; ECOG, Eastern Cooperative Oncology Group; Gy, gray; SBRT, stereotactic body radiotherapy

Patterns of Failure and Systemic Therapy

The 1-year local control (LC) among all patients was 78% and was significantly worse among patients with a target volume of >20 cc (85% vs. 61%, p=0.01) (Figure 2A). All observed local failures occurred within the first 2 years of follow up with a median time to local failure of 7.3 months. Among patients with a target volume of >20 cc the 1-year LC with and without concurrent systemic therapy was 64% and 34%, respectively (p=NS).

Figure 2.

(A) Local control by target volume size in cubic centimeters, (B) regional control by receipt of concurrent systemic therapy, (C) regional control by type of concurrent systemic therapy, and (D) distant control by receipt of any systemic therapy among patients with non-metastatic disease at stereotactic body radiotherapy.

The 1-year regional control (RC) was 66%. All except one observed regional failure occurred within the first 2 years of follow up. The patient who experienced a regional failure after 2 years presented with a local failure within 2 years; therefore, all initial locoregional failures in our cohort were within 2 years. RC was worse in patients treated with SBRT to the neck compared to the skull base or mucosa with 1-year RC of 72% versus 58% (p=0.02). RC was significantly better in patients treated with concurrent systemic therapy with 1-year RC of 73% versus 53% (p=0.004) (Figure 2B). Concurrent systemic therapy with conventional chemotherapy was associated with the highest rates of RC compared to PD-1/PD-L1 agents, cetuximab, or no systemic therapy (p=0.01) (Figure 2C).

The 1-year distant metastasis-free survival was 83% among all patients and 89% in patients who were non-metastatic at SBRT. Any systemic therapy use was associated with significantly improved distant control with a 2-year distant control of 88% versus 50% in patients who were non-metastatic at SBRT (p=0.04) (Figure 2D).

The median progression-free survival (PFS) among all patients was 11.8 months with a 1-year PFS of 47% and 2-year PFS of 32%. Of 35 patients with at least 24 months of follow up, 16 (46%) had no evidence of disease progression following SBRT.

Toxicity Profile

The cumulative rate of grade 2+ and grade 3+ toxicities among all patients was 31% and 15%, respectively (Table 3). Clinically significant acute toxicities were relatively uncommon, with a total of 13 (9%) acute grade 2 toxicities and 2 (1%) grade 3 acute toxicities observed. Twenty-two patients (21%) required feeding tube following SBRT without other confirmed cause (i.e. surgery, frank tumor progression) with a median time to feeding tube of 7.3 months. Patients who were treated at a mucosal site with SBRT had significantly higher rates of grade 2+ and grade 3+ toxicities compared to those who were not (49% versus 18% and 29% versus 6%, respectively). They were also more likely to require a feeding tube (38% versus 8%). Similarly, patients who received concurrent systemic therapy with SBRT had higher rates of grade 2+ and grade 3+ toxicities compared to those who did not (38% versus 15% and 20% versus 5%, respectively).

Table 3.

Cumulative Acute and Late Toxicities, Feeding Tube Requirement

	All Patients (n=137)	Mucosa SBRT Site (n=55)	Non-Mucosa SBRT Site (n=82)	p-value	Concurrent Chemotherapy (n=96)	No Concurrent Chemotherapy (n=41)	p-value
Any Grade 2+ Toxicity	42 (31%)	27 (49%)	15 (18%)	0.001	36 (38%)	6 (15%)	0.01
Any Grade 3+ Toxicity	21 (15%)	16 (29%)	5 (6%)	0.001	19 (20%)	2 (5%)	0.02
Feeding Tube Requireda	22 (21%)	17 (38%)	5 (8%)	<0.001	18 (25%)	4 (11%)	0.07

^aExcludes n=23 patients who had feeding tube placed prior to SBRT and n=7 patients who had feeding tube placed for other confirmed cause (i.e. surgery, frank tumor progression)

Abbreviations: SBRT, stereotactic body radiotherapy

Grade 3+ toxicities included dysphagia (10), lingual artery bleed (6), mucosal ulcer and/or edema (4), osteoradionecrosis (3), and temporal lobe necrosis (1). All 6 patients who experienced lingual artery bleed received SBRT reirradiation to the oropharynx. Five of 6 cases were confirmed either with angiography or fiberoptic endoscopy and 4 patients underwent lingual artery embolization. The median SBRT reirradiation dose was 45 Gy (range, 40–45 Gy), the median initial radiation dose was 70 Gy (range, 66–70 Gy), the median pack-years smoking history was 22.5 years (range, 0–70 pack-years), and 5 patients received concurrent chemotherapy. There was one grade 5 toxicity due to bone and soft tissue necrosis ultimately leading to abscess and death 23.3 months after SBRT. This patient received SBRT to the oropharyngeal mucosa after prior chemoradiation for oropharynx cancer with concurrent cetuximab and adjuvant pembrolizumab.

Discussion

To our knowledge, this is one of the largest single institution studies of SBRT reirradiation for head and neck cancers reported to date. A previous single institution study included 291 patients but focused primarily on treatment toxicity.³¹ The median OS in our cohort was 44.3 months among all patients and 32.2 months among patients with squamous histology. This is comparable with survival among patients undergoing surgical salvage for recurrence³² and is substantially higher than prior reports of unresectable patients who received systemic therapy or salvage reirradiation.¹⁰ The 2-year PFS was 32%, demonstrating the curative potential of this treatment paradigm. Among patients with evidence of disease progression following SBRT, the use of salvage therapy was associated with improved survival.

Other series of patients undergoing SBRT reirradiation for head and neck cancers have reported median overall survivals ranging from 6.7 months to 16.2 months (Table 4). Early series from Henry Ford, Korea, Turkey, France, and Georgetown utilized median cumulative radiation doses of 30–36 Gy in 5–6 fractions, which may be inadequate for definitive treatment of gross disease based on biologically effective dose (BED) calculations.^33–37 Clinical data directly comparing outcomes for different radiation dose fractionations are lacking; however, our institutional practice is to use cumulative doses in the range of 30–36 Gy in 5–6 fractions with palliative intent for gross disease. Furthermore, in 2009, a phase I trial by Heron et al. found that dose escalation up to 44 Gy was feasible and well-tolerated, which corresponds to a BED that would be considered definitive.³⁸ Vargo et al. published their experience with SBRT reirradiation of head and neck cancers and found that among 132 patients treated with a median cumulative SBRT dose of 44 Gy between 2004 and 2011, the median OS was 7 months.³⁹

Table 4.

Comparison of Outcomes to Prior SBRT Reirradiation Literature

Study, Institution	Year	# of Patients	Median SBRT Dose	Fraction and Interval	Median OS	Median PFS	Late G3+ Toxicity
Diao et al, MDACC	2021	137	45 Gy	5 fx QOD	44.3 months	11.8 months	15%
Vargo et al, Multi-institutional17	2018	414 (197 SBRT)	40 Gy	5 fx QOD	7.8 months	-	11.6%
Kress et al, Georgetown33	2015	85	30 Gy	5 fx daily	8.6 months	8.6 months	5.9%
Vargo et al, Pittsburgh39	2014	132	44 Gy	5 fx QOD	7 months	-	7%
Lartigau et al, France34	2013	60	36 Gy	6 fx QOD	11.8 months	7.1 months	7%
Cengiz et al, Turkey35	2011	46	30 Gy	5 fx daily	11.9 months	10.5 months	24.4%
Roh et al, Korea36	2009	36	30 Gy	3–5 fx daily	16.2 months	-	8%
Siddiqui et al, Henry Ford37	2009	21 recurrent	36 Gy	6 fx QOD	6.7 months	-	24%

Abbreviations: fx, fraction; G3, grade 3; Gy, gray; MDACC, MD Anderson Cancer Center; OS, overall survival; PFS, progression-free survival; QOD, every other day; SBRT, stereotactic body radiotherapy

In our cohort, the majority of recurrences after SBRT were regional and outside of the reirradiation field. We do not routinely include elective nodal volumes due to higher risk of serious toxicity associated with larger reirradiation volumes. However, we found that patients who had disease progression and received salvage therapy had a median OS of 44.3 months, which was not significantly different from the median OS of the cohort as a whole. The majority of patients (82%) received some form of salvage therapy following disease recurrence or progression and the receipt of salvage therapy was associated with significantly better survival. In this modern cohort of patients treated from 2013–2020, multiple novel systemic therapy agents including cetuximab, nivolumab, pembrolizumab, and ipilimumab were available and a number of patients also underwent surgical salvage and additional salvage SBRT. Therefore, we hypothesize that the extended OS we observed despite cases of disease progression after SBRT can be attributed to effective and multiple lines of salvage therapy options.

Furthermore, the volume of tumor is known to be strongly associated with OS in head and neck cancers^40–42 and it is conceivable that maximal debulking of tumor with SBRT and aggressive salvage strategies can influence subsequent disease course by preventing functional deterioration and/or a reduction in clonogenic cells.⁴³ In multivariable analysis, squamous histology, SBRT target volume >20 cc, and initial sinonasal or other site of disease were associated with worse OS. As we did not find SBRT target site to be associated with OS, this suggests that the initial site of disease is a stronger prognostic factor than recurrent site of disease, likely due to biologic differences which may influence survival even in the recurrent setting. Our finding of target volume >20 cc as a poor prognostic factor is in keeping with prior SBRT studies which demonstrated tumor volume >25 cc to be associated with worse local control and OS.³⁹

The role of systemic therapy in reirradiation SBRT is not well-defined. In the present study, the inclusion of concurrent systemic therapy did not significantly improve local control rates when analyzed across all patients. Among patients with SBRT target volume >20 cc, however, there was a numerical difference in 1-year LC of 64% vs. 34% with and without concurrent therapy. The findings suggest SBRT doses in the range of 40–45 Gy in 5 fractions are sufficient for local control of smaller tumor volumes. On the other hand, we found that regional or disease control outside the reirradiation field was significantly improved when using concurrent systemic therapy and that conventional chemotherapy was associated with the highest rates of regional control. Finally, among patients who were non-metastatic at SBRT, the use of systemic therapy was associated with a significantly higher rate of distant control. Taken together, our data provide evidence to support the use of systemic therapy with SBRT reirradiation in order to sterilize micrometastatic disease outside the reirradiation field with a decreased emphasis on radiosensitization.

The rate of grade 3+ toxicity was 15% in the entire cohort, 29% among patients treated to the mucosa with SBRT, and only 6% among patients treated to a non-mucosal (neck or skull base) site, demonstrating the considerable influence of reirradiation site on the side effect profile. Notably, despite higher SBRT doses, we did not observe any instances of carotid blowout syndrome (CBOS). However, we observed 6 cases of lingual artery bleed, which may be underreported in literature and in our experience is a particular concern with reirradiation of the oropharynx. Although the low case numbers precluded direct statistical comparison, an oropharynx site, high cumulative radiation dose, use of concurrent chemotherapy, and a significant smoking history may be risk factors for lingual artery bleed. The use of concurrent systemic therapy was a significant modifier of toxicity, with a rate of grade 3+ toxicity of 20% among those receiving concurrent systemic therapy and only 5% among those who did not. Currently, there exists some normal tissue complication probability (NTCP) data to guide radiation dose constraints for SBRT reirradiation for CBOS and laryngeal toxicity, but more organ-specific data is needed.^44–47 As additional NTCP studies are published and radiation planning techniques advance, these rates may improve. All patients, and in particular those with a mucosal recurrence and/or receiving concurrent systemic therapy, should be counseled on the side effects that can occur with SBRT reirradiation, including feeding tube requirement, lingual artery bleed, CBOS, mucosal ulceration, and osteoradionecrosis.

There are important limitations to the study. Patients in the cohort were well-selected for SBRT reirradiation with relatively small recurrent tumor volumes and adequate reserve to undergo a physically taxing therapy. Radiation dosing was relatively homogeneous based on our institutional practice and we therefore cannot establish optimal radiation dose and fractionation. Definitive conclusions regarding the impact of systemic therapies may be difficult to ascertain since clinical factors were taken into consideration when deciding whether and what type of systemic therapy to administer. While every effort was made to carefully document toxicities, there may be underreporting in actual toxicity due to absence of follow up. Reirradiation of head and neck sites with SBRT is technically difficult and may not be feasible without the required physician expertise, treatment planning capabilities, equipment, and confidence in patient setup.

In summary, in one of the largest single institution studies of SBRT reirradiation for head and neck cancers reported to date, patients with limited volume recurrent head and neck cancers undergoing definitive intent reirradiation with SBRT had an overall survival time of 44.3 months among all patients and 32.2 months among those with squamous histology. The observed survival times are comparable to patients undergoing surgical salvage and considerably better than prior reports of salvage with systemic therapy or reirradiation. A minority of patients did not experience disease progression more than 2 years after SBRT, demonstrating the curative potential of the treatment paradigm. Squamous histology, SBRT target volume >20 cc, and initial sinonasal site of disease were statistically significant prognostic factors associated with worse OS. Our data provide evidence for the use of systemic therapy to improve regional and distant control in this setting. Clinically significant toxicities were common in patients receiving SBRT to the mucosa and concurrent systemic therapy but overall were acceptable. Clinical trials, including our institution’s ongoing randomized phase II (SOAR-HN; ClinicalTrials.gov Identifier: NCT03164460) and phase I/II (TRAP; ClinicalTrials.gov Identifier: NCT04220775) trials are warranted to further explore this treatment strategy.