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Evolving Role of Stereotactic Body Radiation Therapy for Head and Neck Cancer: Where Do We Stand?

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Submitted:

29 August 2023

Posted:

30 August 2023

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Abstract
Stereotactic body radiation therapy (SBRT) is a precise and conformal radiation therapy (RT) that aims to deliver a high dose of radiation to the tumor with sparing surrounding normal tissue, making it an attractive option for head and neck cancer (HNC) patients who are not suitable for traditional long course of RT with comprehensive RT target volume. Definitive SBRT for HNC has been investigated in different settings, including early stage glottis cancer, and as alternative to brachytherapy boost after external beam RT. It also used as a primary treatment option for elderly or medically unfit patients. More recently, SBRT combination with immunotherapy in the neoadjuvant setting for HNC showed promising results. Salvage or adjuvant SBRT for HNC can be used in appropriately selected cases. Future studies are warranted to determine the optimum dose and fractionation schedules in any of these indications.
Keywords: 
head and neck cancer
;  
SBRT
;  
Hypofractionation
Subject: 
Medicine and Pharmacology  -   Oncology and Oncogenics

Introduction

Head and neck cancers (HNCs) constitute about 6% of global malignancies, with approximately 650,000 new cases and 350,000 annual deaths1. They often originate from different anatomical sub-sites in the head and neck (HN) region1, primarily being squamous cell carcinoma (SCC)2. Second primary HNC occurs at rate of 3-5%3. HNCs are increasingly prevalent, especially in men, typically diagnosed in the early 60s4–8. Treatment options generally includes surgery, radiation therapy (RT), systemic therapy, or combination of any of these according to the overall stage and type of cancer, preference and medical/general condition of the patient, and the intent of treatment 9–11. RT or chemoradiotherapy (CRT) is routinely used in the majority of advanced HNC, lasting usually for 6-7 weeks, as a primary or post-operative therapy6. However, some patients cannot tolerate prolonged RT/CRT course due to age, comorbidities, travel challenges, or lack of social support12.
Stereotactic body radiation therapy (SBRT) is a precise HN treatment targeting specific areas with high-doses of radiation delivered in 1 to 5 fractions of ≥5 Gy per fraction using image guidance12–17. It destroys tumor blood vessels, leading to endothelial cell death 18. New evidence indicates that SBRT maintains radiation-induced cellular death pathways and possibly enhances antitumor immunity with high fractional doses19.
The utilization of SBRT in real-world practice varies between 0-10%12,20–24. SBRT is increasingly being used in treating a variety of cancers. However, the SBRT indications for HNC, dose, fractionation schedules, and HN organs-at-risk (OARs) dose constraints lack uniform consensus25. The data regarding oncologic and toxicity outcomes associated with SBRT for HNC are sparse21–23. This review aims to summarize the literature for SBRT to HNC in the definitive, neoadjuvant, salvage and adjuvant settings from clinical and technical perspectives.

Definitive SBRT for primary HNC

In general, SBRT is used in the palliative setting for HNC patients who are unable to attend standard long courses of RT (e.g., social and logistic challenges), and when omission or significant reduction of elective target volume is clinically acceptable. This includes the following clinical scenarios: 1) SBRT for elderly/medically unfit patients aiming to maximize locoregional control (LRC) and decrease the disease burden for HNC, 2) SBRT for early glottis cancer, or 3) SBRT boost to gross tumor volume (GTV) after definitive external beam radiation therapy (EBRT) as an alternative option to brachytherapy boost.

Definitive SBRT in elderly or medically unfit HNC patients

The ultimate goal of SBRT in elderly or medically unfit HNC patients is to achieve an acceptable balance between LRC, cancer-associated disease burden and RT-related toxicity14,16,20–23,26,27. SBRT demonstrated acceptable local control (LC) rates with minimal side effects compared to conventional fractionation RT with standard comprehensive target volume15. The literature included single-institution studies varied in number of included patient (3-106 patients), primary tumor sites and SBRT doses and fractionation schedules (15-22 Gy in single fraction to 30-50 Gy in five or six fractions [BED10 range between 32.17 and 91.65 Gy10])24. The one-year LC and overall survival (OS) rates ranged from 69% to 87% and 60% to 85% respectively12,14,16,20–23,26–28. Acute or late grade 3 toxicities included osteoradionecrosis, pain, dermatitis, ulceration, and cataracts12,20,22,27,28 (See Table 1).
A meta-analysis evaluated SBRT for de novo HNC in elderly patients who could not undergo aggressive CRT or altered fractionation RT (median age: 76 years). SBRT dose ranged from 25 to 59.5 Gy in 3 to 17 fractions, with a median BED10 ranged from 42.63 to 82.72 Gy10 and equivalent dose in 2Gy fractions (α/β = 10) between 35.53 and 68.93 Gy. The 3-year LC rate was acceptable (73.5%), and the 3-year OS was approximately 50%, indicating that the focus might have been on optimizing the LC rather than OS due to comorbidities and old age of those patients. The late grade 5 toxicity rate was 0.1%29.

Summary and recommendation

There is limited evidence supporting the use of definitive SBRT for elderly or medically unfit HNC patients who cannot tolerate standard long course of RT. A wide SBRT dose range was used (15 to 22 Gy in 1 fraction to 30 to 50 Gy in 5-6 fractions). Further studies are warranted to establish the optimal SBRT dose, fractionation, and criteria for selecting patients with primary HNC for definitive SBRT.

Definitive SBRT for early-stage glottis cancer

The use of SBRT is considered an attractive treatment option for early-stage glottis cancer given the shorter overall treatment time associated with SBRT that could potentially improve the LC. In addition, there is no need to treat un-involved contralateral vocal cord or elective nodal target volume which allows higher dose per fraction without possibly significant late morbidity3031–33.
A phase I trial from the University of Texas Southwestern Medical Center investigated 3 dose levels (50 Gy/15 fractions, 45 Gy/10 fractions, and 42.5 Gy in 5 fractions) for 29 patients with early (Tis-T2) glottis cancer (median follow up: 39.2 months). Two patients had dose-limiting toxicity: one with cT2 cancer received 45 Gy in 10 fractions, who developed grade 4 laryngeal edema and grade 3 dysphagia at 5 months post-RT, and another patient with cT2 disease treated with 42.5 Gy in 5 fractions developed grade 3 laryngeal necrosis and grade 3 dysphagia at 7 months post-RT34. The voice handicap index improved in all groups. Five patients developed recurrence (no recurrence was observed in the 42.5 Gy group). Although there were 2 dose-limiting toxicities; these results were the foundation of an ongoing phase II trial (NCT03548285) investigating two SBRT schedules based on risk groups: low-risk (PTV <10cc and no smoking within 1 month from registration: SBRT with 42.5Gy/5fractions) and moderate-risk (PTV >10cc, or smoking history within 1 month from the registration [≤1 pack/day]: RT with 58.08/16 fractions)35.
Another phase I trial for early glottis cancers evaluated 59.5 Gy/17 fractions and 55 Gy/11 fractions. Initial report showed satisfactory toxicity levels and favorable voice/quality of life (QoL) outcomes36. However, Kang et al.'s update led to trial closure due to toxicity in the 55 Gy group (arytenoids necrosis at 5 months post-SBRT, and vocal cord ulcer at 15 months post-SBRT), following predefined stopping rules37. Authors concluded SBRT is not feasible for early glottis cancer37.

Summary and recommendation

Two phase I trials evaluated SBRT for early glottis cancer and showed the development of pre-defined dose limiting toxicities. An ongoing phase II trial is evaluating the potential use of risk-adaptive SBRT dose selection in the setting of SBRT for early glottis cancer. SBRT twice a week for T1/T2 lesions is an interesting option, acknowledging the risk of severe late toxicity, including chondronecrosis, which may be dependent on pre-existing infiltration of the laryngeal framework.

Definitive SBRT as boost after EBRT (alternative to brachytherapy boost)

In 2008, Hara et al. updated results from Tate et al. (1999)38 and Lee et al. (2003)39 on SBRT boost for 82 patients (47 had stage IV nasopharynx cancer). SBRT boost of 7–15 Gy was given 2–6 weeks after EBRT. At 5 years, local failure, regional failure, DM rates and OS were 2%, 17%, 32% and 69% respectively. The late toxicities included radiation-induced retinopathy (n=3), carotid aneurysm (n=1) and temporal lobe necrosis (n=10)40. Chen et al. also reported outcomes and toxicity of SBRT boost (12-15 Gy in 4-5fractions) to nasopharynx cancer (n=64). The 3-year LC rate was 93.1%. Three patients had fatal nasal bleeding 6–7 months after SBRT boost41.
Uno et al. investigated the feasibility of SBRT boost (9-16 Gy in 1-3 fractions) for various HNC sites in 10 patients 42; 60% had complete response (CR), 40% had partial response (PR), with no grade ≥3 toxicities attributable to SBRT. In a Japanese series of 25 HNC patients, treated with SBRT boost (12-35 Gy in 1-5 fractions), 18 patients had CR, 6 patients had PR and one patient with disease progression (DP), resulted in 96% (24/25) overall response rate (ORR). The 2-year LC and OS rates were 89% and 70% respectively. Small SBRT planning target volume (PTV) boost (≤20 cm3) and good initial response to RT predicted favorable outcomes in terms of LC and OS43.
Lee et al. evaluated the long-term outcomes and toxicity of SBRT boost (10-25 Gy in 2-5 fractions) in 26 HNC patients. Major response rate was 100% (21 CR). Nine patients experienced grade ≥3 toxicities, of whom, 5 patients with late grade 3 (including pontine necrosis, temporal lobe necrosis (n= 2), radiation retinopathy, neovascular glaucoma, and optic neuropathy), 4 patients with late grade 4 toxicity (including soft tissue necrosis in the left base of the skull bone, mucosal ulcer and necrosis, soft tissue necrosis in the left nasopharyngeal wall, and an unhealed mucosal ulcer with bleeding), and 1 patient with grade 5 pontine necrosis. SBRT boost volume (median 47.7 cc) predicted late complications44.
Almamgani et al. prospectively evaluated SBRT boost (16.5 Gy in 3 fractions) for 51 patients with stage I-IVb oropharyngeal carcinoma (OPC), not suitable for standard brachytherapy boost45. The 2 year LC and OS were 86% and 82% respectively, with acceptable toxicity including feeding tube dependency (n=1) and grade 3 xerostomia (n=2). Subsequently, the same group adopted the above treatment for T1-2 and small T3, N0-N2 OPC. They reported the pattern of failure, outcome and long term toxicity in a cohort of 195 patients treated between 2009 and 201646,47. The 5 year LC and regional control (RC) were 90% and 93% respectively. By location of the center of the recurrent disease, 76% of failures were within the treated volume and 24% were outside the treated volume, significantly higher than what was reported in literature, attributed to highly conformal dose intensification46. At a median follow up of 4.3 years, the 5 year disease specific survival and OS were 85% and 67% respectively. Grade ≥3 toxicity was observed in 28% patients, the commonest being mucosal ulceration or soft tissue necrosis, dysphagia or weight loss and osteoradionecrosis48.
In a phase I trial of dose-escalated SBRT boost to residual gross tumor of 8 or 10 Gy in a single fraction, or 10 Gy in 2 fractions, after 60-66 Gy/30-33 fractions with concurrent cisplatin for unfavorable intermediate- or high-risk OPC. The LC rate was 85.3% at 4.3 years. Four patients with tumor necrosis had grade 3 dysphagia, and three patients had grade 4 pharyngeal hemorrhage requiring surgical intervention49. The outcome, patterns of failure and toxicity profile of various SBRT boost studies are described in Table 2.

Summary and recommendation

Despite acceptable oncologic outcome of SBRT boost after EBRT for HNC, severe treatment-related toxicities have been reported. As such, the use of SBRT boost for HNC as an alternative to brachytherapy boost is recommended only in the investigational setting.

Neoadjuvant SBRT (with immunotherapy) for HNC

Immunotherapeutic approaches are effective in recurrent/metastatic HNC50 and enhance treatment when combined with other modalities51. SBRT can overcome immunotherapy resistance and sensitize cancer cells52. Neoadjuvant immunoradiation could potentially improve the oncologic and functional outcomes by shortening the overall treatment time, limiting radiation target volumes, and facilitating less extensive surgery through downsizing the tumor53.
A phase Ib/II trial included 19 patients (phase Ib: 6; phase II: 13) with untreated locally advanced HPV-related OPC. Patients received neoadjuvant durvalumab±tremelimumab for 2 doses (durvalumab only [n=3]; durvalumab+tremelimumab [n=16]), with concurrent SBRT of 25 Gy in 5 fractions to gross disease only, followed by transoral robotic surgery with adjuvant durvalumab for up to 4 cycles. Median follow-up was 12.7 months. No safety signals were reported. Eighteen out of 19 patients (95%) achieved a clinical/pathological downsizing, of whom 9 (47%) had pathologic complete response (pCR). Five patients (26%) developed locoregional failure (LRR), with a median time to recurrence of 3 months. Failing to achieve pCR was significantly associated with LRR (p=0.03). Caution against omitting elective volume irradiation is warranted even in favorable prognosis HPV-related OPC in the neoadjuvant setting with SBRT and immunotherapy54.
In a phase Ib trial, locally advanced p16-positive and p16-negative head and neck squamous cell carcinoma (HNSCC) patients were treated with neoadjuvant SBRT over 1 week with nivolumab (240 mg intravenous q2 week's ×3 cycles) before surgery. Cohort-I included 5 patients who received 40 Gy in 5 fractions; cohort-II included 5 patients who received 24 Gy in 3 fractions. After assessment of the toxicity, 2 expansion cohorts were added: cohort-III which included 6 patients who received SBRT alone (24 Gy in 3 fractions) for stages I-III HPV-related HNSCC and cohort-IV included 5 patients who received nivolumab + SBRT (24 Gy in 3 fractions) for stages III-IVA p16-negative HNSCC. Surgery was scheduled 5 weeks post SBRT, followed by adjuvant nivolumab 480 mg intravenous q4 weeks for 3 doses starting 4 weeks after surgery in all cohorts. All 21 patients completed neoadjuvant treatment without dose-limiting toxicity. In the entire study group, the major pathological response (mPR) and pCR rates were 86% and 67% respectively. Among the 10 HPV-related HNSCC patients who underwent treatment with nivolumab and SBRT, the pCR rate was 90% (cohort-I =5/5; cohort-II =4/5) and mPR rate was 100%. In HPV-related HNC patients treated with neoadjuvant SBRT alone (cohort-III), the pCR rate was 50% (n=3). In HPV-negative patients (cohort-IV), the pCR and mPR rates were 20% (n=1) and 60% (n=3) respectively53.
A phase I/Ib trial was conducted to evaluate the safety of administering both SBRT and a single dose of durvalumab as neoadjuvant treatment for 21 patients with HPV-unrelated locally advanced HNSCC55. Patients received neoadjuvant durvalumab (1500 mg) and SBRT approximately 3-6 weeks before surgery. The starting SBRT dose level was 6 Gy for 2 fractions (12 Gy total) every other day to gross disease. If the dose was tolerated, the dose was increased to 6 Gy for 3 fractions (18 Gy total) for the next 3 patients then 6 Gy for 4 fractions (24 Gy total). Adjuvant therapy was used based on a standard of care indications for the first enrolled 8 patients, and all patients received adjuvant durvalumab to be initiated approximately 6–12 weeks post-surgery. It was given as 1500 mg intravenously once every 4 weeks for a maximum of six doses, or until disease progression, unacceptable toxicity or withdrawal from the study. The protocol was updated after the 8th enrolled patient to omit adjuvant RT for patients with pCR or mPR, but all patients still received adjuvant durvalumab. The safety endpoint was met. With a median follow-up of 16 months, OS was 80.1%, LRC and PFS were 75.8%, and mPR was 75%. For patients treated with 24 Gy in 4 fraction, mPR rate was 89%. Radiation dose and time from SBRT to surgery correlated with mPR. One patient, treated below the maximum tolerated dose, recurred out of the SBRT volume, despite having received adjuvant RT and durvalumab. Two other patients failed in the SBRT volume, of whom one refused adjuvant RT but received adjuvant durvalumab55.
Shen et al. retrospectively studied 30 locally advanced oral cavity SCC patients treated with neoadjuvant nivolumab plus SBRT (median dose: 24 Gy, range, 14–48 Gy) with 56.6% of patients received adjuvant RT +/- chemotherapy. Treatment was well-tolerated with no serious adverse events. R0 resection was achieved in 90% of patients, with 16.7% of patients' experienced procedure-associated complications. Response rates were: CR 10%, PR 46.7%, and SD 43.3%. The mPR and pCR rates were 60.0% and 33.3% respectively. Median follow-up was 13.5 months. The 2-year disease-free survival (DFS) and OS were 70.4% and 76.4% respectively for 26 patients with surgical resection. Patients with mPR and CR showed significantly better DFS and OS (p<0.05)56.

Summary and recommendation

Neoadjuvant SBRT with immunotherapy is a safe treatment for locoregionally advanced HNSCC, potentially resulting in relatively high rates of mPR with subsequent favorable outcomes. Commonly used SBRT regimen in the neoadjuvant setting is 24Gy/3 fractions and 25-40Gy in 5 fractions. Omitting elective nodal irradiation during neoadjuvant SBRT has a higher risk of regional nodal recurrence even in favorable HPV-related OPC despite the use of immunotherapy. Futures studies are warranted to further confirm the efficacy of this stratgey53–56.

Salvage SBRT for recurrent unresectable or second primary HNC

Salvage SBRT for unresectable recurrent and second primary HNC in a previously irradiated volume is challenging. While studies consistently demonstrate improved LC with re-irradiation, the accumulation of high cumulative doses may result in severe side effects, such as the potentially fatal carotid blowout syndrome. Hence, it is crucial to carefully select patients and appropriate RT techniques.17,20,57–65.
Heron et al. conducted a phase I dose-escalation trial with salvage SBRT for recurrent HNC. Twenty five participants received escalating SBRT doses, starting at 5 Gy per fraction that was escalated to 8.8 Gy per fraction for 5 fractions delivered over 2 weeks. The maximum tolerated dose was 44 Gy in 5 fractions, with no associated grade ≥3 acute toxicities, and an ORR of 17%, a median duration of response of 4 months, and a median OS of 6 months66. An updated report included 85 patients showed that SBRT doses ≥35 Gy resulted in improved LC (71% vs. 59%, p = 0.01). The 1-year and 2-year LC and OS rates were 51.2% and 30.7%, and 48.5% and 16.1% respectively65.
A retrospective-matched case-control study investigated concurrent cetuximab with SBRT (n=35) vs. SBRT alone (n=35) for unresectable recurrent HNSCC. Both study arms received a median SBRT dose of 40 Gy (range, 20–44 Gy). Concurrent cetuximab showed improved OS (median 24.5 vs. 14.8 months, p = 0.03)67. In 2014, an updated retrospective review included 132 patients who were treated with salvage SBRT for recurrent HNC, with a median dose of 44 Gy in 5 fractions (range, 35–50 Gy), and median follow-up of 6 months17. The 1-year OS and LRC rates were 38% and 48% respectively. Overall, toxicity rates were acceptable; 16 patients (12%) and 6 patients (7%) experienced grade ≥3 acute and late toxicity respectively (with the majority of toxicity related to mucosal and skin reactions)17. Treatment duration <14 days improved recurrence-free survival but increased late toxicity (p = 0.03). This study found that tumor volume >25 cc predicted inferior survival, poor tumor control, and more acute toxicity (p = 0.02) but no difference in late toxicity17.
Comet et al. performed a feasibility study of salvage SBRT with or without cetuximab for locally recurrent or new primary HNC62. In this phase I trial, 40 patients with 43 lesions were treated to a total dose of 36 Gy in 6 fractions, of whom; 15 (37.5%) were treated with concurrent cetuximab, and 1 was treated with concurrent cisplatin62. Half of the patients had HNSCC. The 1-year OS rate was 58%. Of the 34 study patients who were evaluable for response, 15 (44%) had CR, 12 (35%) had PR, and 7 (21%) had SD. For the 14 patients with concurrent cetuximab, 75% had an overall objective response62. Following these results, Lartigau et al. conducted a phase II multi-institutional trial to assess re-irradiation using salvage SBRT with concurrent cetuximab in 56 patients with recurrent or new primary HNSCC who were treated with 36 Gy in 6 fractions for 11 to 12 days63. The 1-year OS was 47.5%63. Of the 49 evaluable study participants, the ORR was 69%; CR was seen in 24 (49%), PR in 10 (20%), and SD in 11 (23%). Eighteen study patients (32%) experienced toxicities of grade ≥3 and 1 patient died from arterial rupture63. These results were comparable with those seen in the study conducted by Heron et al.67, Lartigau et al63 attributed the low rate of carotid blowout to the careful selection of patients without tumor encasement of less than one-third of the carotid artery.
Cengiz et al. retrospectively analyzed 46 patients with locally recurrent HNC (65% had HNSCC) treated with re-irradiation using SBRT (median dose: 30 Gy, range: 18-35 Gy, 1 to 5 fractions)61. The 1-year OS rate was 46%61. A total of 10 of 37 evaluable study patients (27%) had CR, 11 (30%) had PR, and 10 (27%) had SD. Despite the comparable survival outcome with other studies62,63, the late-grade ≥4 toxicity rate was higher; 8 patients (17%) experienced late carotid blowout, of whom 7 died from carotid hemorrhage61. It has been suggested that the relatively high rate of late toxicity in this study was a result of daily SBRT fractionation, rather than an every- other-day fractionation scheme, as seen in other studies17.
Unger et al. reviewed 65 patients treated with SBRT for recurrent HNC. The study included 27 patients (42%) with metastatic disease or untreated local disease, 11 (17%) with non-squamous histologies, 19 (29%) treated with surgery prior to re-irradiation, and 21 (32%) treated with CRT. The SBRT dose ranged from 21 to 35 Gy in 2 to 5 fractions68. The group reported an ORR of 80%; CR rate of 54%, and PR rate of 27%. The median OS was 12 months and the 2-year OS rate for patients with non-metastatic cancer at the time of treatment was 41%. Seven patients (11%) experienced late toxicities related to SBRT, and 1 patient died due to treatment68. Roh et al.'s reviewed 36 patients (44 lesions) who were treated for locally recurrent HNC using SBRT with 18 to 40 Gy (median, 30 Gy) in 3 to 5 fractions69. More than half of the lesions were SCC. Median OS was 16 months, with CR rate of 43%, PR rate of 37%, and SD in 9%. Grade 3 acute complications affected 36% of participants, and late complications affected 8%. The study reported a high rate of late grade ≥4 toxicities, which some attributed to daily radiation rather than every-other-day delivery17,69.
Vargo et al. studied 414 patients with unresectable recurrent or second primary HNC treated with intensity-modulated radiation therapy (IMRT, n=217 patients) or SBRT (197 patients). The OS was similar for IMRT and SBRT with dose ≥35 Gy for small tumor volumes (25 cc), however dose <35 Gy resulted in significantly worse 2-year OS of 14%15. Another study with 45 patients showed higher 1-year OS of 68% with ≥40 Gy in 5 fractions, compared to 24% with lower doses70.

Summary and recommendation

Salvage SBRT for recurrent (or 2nd primary) HNC in previously irradiated volume showed acceptable survival (Table 3)17,58–64,68. Rate of carotid blowout is relatively low with appropriate patient selection, target volume definition, and every other day treatment delivery. However, differences in patient selection criteria, tumor histology, and salvage SBRT doses make direct comparisons challenging. Therefore, a large, multi-institutional trial for re-irradiation using SBRT is warranted.

Adjuvant SBRT for recurrent HNC

An ongoing multi-center phase II trial (STEREO POSTOP, NCT03401840) evaluates post-operative SBRT (36 Gy in 6 fractions over 11-13 day) for pT1-2 N0-1 oral cavity SCC and OPC with compromised resection margins (with no pathologic extranodal extension) 72. The study hypothesize that postoperative SBRT's safety and efficacy will be similar to conventional RT schedule73,74.
Vargo et al.71 conducted a retrospective study on 28 patients who had high-risk features (involved resection margin[s] or pathologic extranodal extension) following salvage surgery with gross total resection (i.e. R0/R1) followed by adjuvant SBRT with (7/28 patients) or without (11/28) cetuximab. The SBRT dose was 40 to 44 Gy in 5 fractions over 1-2 weeks. All patients had previously received RT (median dose of initial RT was 70 Gy; range, 54-99 Gy), with a median time to re-irradiation (from original RT) of 25 months (range, 6-156 months). Median follow-up was 14 months (range, 2-69 months). The 1-year LRC, distant control, DFS, and OS rates were 51%, 90%, 49%, and 64% respectively. The rates of acute and late severe (grade ≥3) toxicity were 0% and 8%, respectively71. At six months follow-up, 56% of patients reported improved or stable overall QoL scores71.

Practical and technical aspects of SBRT for HNC

Target volume definition for SBRT

Majority of institutions use a cut off size and/or volume constraint for primary tumor (e.g., 3–5 cm/ 25–30 cc) and nodal disease (4–5 cm/ <50 cc)24. Contouring protocols varied across studies with different approaches taken.At the time of simulation, the use of intravenous contrast (whenever possible) and magnetic resonance imaging (MRI) diagnostic or simulation scans (whenever available) facilitate accurate gross tumor delineation. The commonly used strategy is centered on contouring the GTV with 0 mm margin expansion to create the clinical target volume (CTV). An elective dose CTV to include a concentric expansion of the GTV or to encompass a limited elective nodal volume is at the discretion of the treating radiation oncologist. The PTV is a uniform expansion of 3 to 5 mm from the GTV/CTV based on institutional practice 12.

SBRT dose and fractionation

Dose prescription varied across institutions and ranged from 12-22 Gy single fraction, 24–25 Gy/2 fractions, 24–27 Gy/3fractions, 24–30 Gy/4 fractions and 30-50 Gy/5 fractions, with BED10 range from 26.4-100Gy10. The most common variables altering the choice of fractionation regimens include tumor size/volume, location of tumor, prior dose delivery and indication for SBRT24. Treatment was often delivered either every other day or twice weekly 2 days apart.

Target objectives and OAR constraints

Plan normalization should provide coverage of ≥95% of the PTV. Planning optimization uses conformity indices, D95%, D99%, near-minimum dose (D98%) and near-maximum dose (D2%)24. Critical OARs are the spinal cord, brain, brainstem, optic chiasm, optic nerves and eyes. Table 4 summarizes dose constraints for various SBRT fractionation regimens. Patients are to be planned and treated using IMRT or VMAT planning (ideally with ≤5mm leaf width of the multi-leaf collimator). Maximum point dose up to 115% of the prescription dose is acceptable within the PTV and the prescription dose outside of the PTV should be avoided. Aim to achieve a conformality index (CI) < 1.1. Daily cone beam computed tomography (CBCT) should be performed with pre- and post-shifts, with physician present at day 1 of SBRT treatment.

Future directions

Recent advances in immunotherapeutic agents showed promising outcomes in the treatment of HNC. The combined application of these drugs alongside SBRT is currently under active research. For example, the RTOG 3507 phase II clinical trial, is exploring the use of re-irradiation with SBRT plus concurrent pembrolizumab for patients with recurrent HNSCC in a previously irradiated volume75. Furthermore, recent advances in RT technology such as magnetic resonance-guided radiation therapy (MRgRT) for HNCs allows precise treatment, facilitates tighter PTV margin/smaller irradiated volumes, evaluates tumor response with functional imaging i.e. DWI, with possibly response-adaptive RT. However, further research is required for evaluation of predictive MR imaging biomarkers, and the use of SBRT with MRgRT for patients with HNC who cannot tolerate long course RT76. Moreover, the impact of SBRT for HNC in the palliative setting aiming to improve HNC outcomes in patients who are unable to tolerate curative-intent RT is going to be investigated by the CCTG HN13 phase III randomized controlled trial (SBRT vs standard palliative RT).
Related: None declared
Unrelated: Ali Hosni: non-financial leadership (DSC) of liver TSG at ELEKTA MRL consortium

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Table 1. Summary of retrospective SBRT studies for primary head and neck cancer.
Table 1. Summary of retrospective SBRT studies for primary head and neck cancer.
Author (Year)/design/subsite n Median age (range), y Median target volume Elective nodal irradiation RT dose (Gy)/Fraction EQD2 (Gy) (α/β = 10) BED10 (Gy) (α/β = 10) BED3 (Gy) (α/β = 3) Median follow up (months) LC (%) OS (%) Toxicity
Voruganti et al. (2021)/retrospective/skin 27 106 86 (56-102). (GTV)=31 cm3 (range: 17-56 cm3). Yes 32-50/4-6 48-76.38 57.6-91.65 117.3-188.83 8 1 yr 78% 1 yr 53% Acute: Grade 3: 31 dermatitis
Late grade ≥ 3: 7 fibrosis, 1 ORN and 1 grade 4 skin ulceration
Al-Assaf et al. (2020)/retrospective/mixed 12 48
 81 (25- 102) Median GTV volume = 33.2 cc (range, 1.9–368.6 cc) Yes 35-50 /4–6
 54.69- 76.38 65.63–91.65 137-189 10.5 85.5% - Acute: Grade 4:1 (Mucosal ulceration) Late : Grade 4:1 (ORN and skin ulceration)
Gogineni et al. (2020)/ retrospective/mixed 28 66 80 (47-99) Median PTV volume = 82 cc Yes 35–40/5 49.58–60 59.5–72 116.67-146.67 15 (3–88) 1 yr 73% 1 yr 64% Acute: Grade 3:2 Late: Grade ≥ 3:0
Khan et al. (2015)/ retrospective/mixed14 17 87 (25-103) Median Maximum Diameter = 3.7 cm (1–10 cm) Yes 35–48/5–6 49.58–72 59.5–86.4 116.67-176 8 1 yr 87% 1 yr 60% Grade 3:0
Amini et al. (2014)/ retrospective/mixed 16 3 82(72-88)
 Tumor volume cc= 15-36.7cc Yes 25–36/ 5 31.25–51.6 37.5–61.92 66.67-122.4 8 100 (crude rate) 33 Grade 3 = 0
Vargo et al. (2014)/ retrospective/mixed17 12 88(79-98) Median = 42.1 cc (15.1–247.9 cc) No 20–44/1–5 50–68.93 60–82.72 155.33-173.07 6 (0.5–29 1 yr 69% 1 yr 64% Acute: Grade 3:1 Late: Grade 3:1
Kawaguchi et al. (2012)/ retrospective/mixed22 14 73(64-93) - No 35–42/3–5 63.18–64.4 75.81–77.28 171-77.28 36 (14–40) Mean 71.4 Mean 78.6 Late: Grade 3:1 (ORN) (after 2nd SRS)
Karam et al./retrospective/ parotid26 13 80(34–99) PTV= 13.3-195.3cc Yes 25-40/5-7 31.25-52.37 37.5-62.84 66.67-116.13 14(0–59) 2 yr LRC 84% 2 yr 46% Acute: G5: 1 Sepsis secondary to aspiration pneumonia
Kodani et al. (2011)/ retrospective/mixed21 13 66(17-88) Median GTV volume = 22 cc (0.7–78 cc) No 19.5–42/ 3–8 26.81–53.38 32.17–64.05 61.75-115.5 16 (3–51) CR:38% PR:46% 85% Grade 3:0
Siddiqui et al. (2009)/ retrospective/mixed20 10 73.5(37-89) Median GTV 15.5 cc (1.7–155 cc) No 30–48/5–6 40–72 48–86.4 90-176 32 (7–53.4) 1 yr 83.3% 1 yr 70% Acute: Grade 3:1 (Pain) Late: Grade 3:1 (Cataract)
Abbreviations: RT: Radiotherapy, EQD2: Equivalent dose at 2 Gy/fraction, BED10: Biologically effective dose (α/β = 10); BED3: Biologically effective dose (α/β = 3) LC: local control, OS: Overall survival, GTV: Gross tumor volume, PTV: Planning target volume, CR: Complete response, PR: Partial response, ORN: Osteoradionecrosis.
Table 2. Summary of SBRT boost studies in head and neck cancer.
Table 2. Summary of SBRT boost studies in head and neck cancer.
Author (year)/subsite/d
esign		 Sample size (n) Median follow up(months) EBRT dose/fraction Boost dose (Gy)/ Fraction GTV (cc) or boost volume (range) EQD2 (Gy) (α/β = 10) (Total) BED10 (Gy) (α/β = 10) (Total) Margins for
stereotactic
boost (PTV)		 LC (%) OS (%) Initial site of Failure
(N)		 Toxicity (N)
Tate et al. (1999)/retrospective/nasopahrynx38 23 21 (2–64) 64.8 Gy- 70 Gy (Median 66 Gy/ 33frs) 7–15 Gy /1#frs Median 12 Gy Not reported Median 88 Median 105.6 Not reported 100% Not
reported		 Local: 0 Regional:2 Distant:7 As expected for EBRT
Le et al. (2003)/ retrospective/nasopahrynx39 45 31 66 Gy /33frs 7–15 Gy/ 1frs Not reported 88 105.6 Not reported 3 yr LC: 100% 3 yr OS: 75% Local: 0 Regional:3 Distant: 14 CN weakness:4 Retinopathy:1 Asymptomatic TLN: 3
Chen HH et al. (2006) retrospective/nasopahrynx41 64 31 (22–54) 64.8 Gy-68.4 Gy/ 36–38frs 12–15 Gy /4–5frs Mean GTV
62.6 (21.1–
145.3)		 76.72–83.51 92.06–100.2 CTV
+ 2–3 mm		 3 yr LC: 93.1% 3 yr OS: 84.9% Local:4 Regional:7 Distant:7 Late Grade 4: None
Note: 3 fatal nasal bleeding could be not related to SBRT boost
Hara et al. (2008)/ retrospective/nasopahrynx40 82 40.7 (6.5–144.2) 66 Gy/ 33frs 7–15 Gy /1frs Median GTV
34.2 (6.4–
102.2)		 88 105.6 Not reported 5 yr LC: 98% 5 yr OS: 69% Local:1 Regional:5 Distant:27 Retinopathy: 3 Asymptomatic TLN:8 Symptomatic: 2
Uno T et al. (2010) )/ retrospective/mixed42 10 16 (6–24) 40 Gy-60 Gy/ 20–30frs 9–16 Gy/ 1–3frs Not reported 54.22–80.44 65.1–96.53 CTV + 0-5mm CR:60% PR:40% Not
reported		 Local:3 Distant:1 ≥ Grade 3: None
Lee DS et al. (2012) retrospective/mixed44 26 56 (27.6–80.2) 39.6 Gy- 70.2 Gy (Median 50.4 Gy/ 28frs) 10–25 Gy/ 2–5frs Median 21 Gy/5frs NPC
median
GTV 45.3
(21.3–
69.4)
Non-NPC
Median
GTV 19.4
(6.9–66.8)		 Median 74.41 Median 89.29 GTV + 1- mm 1 yr LRRFR: 91.4% 2 yr LRRFR: 86.3% 2 yr OS: 61.5% 5 yr OS: 46.2% Local:2 Regional:1 Distant:5 ≥ Grade 3: 9
Al-Mamgani et al. (2012)/retrospective/oropharynx 45 51 18 (6–65) 46 Gy/ 23frs 16.5 Gy/3frs Not reported 67.31 80.78 CTV
+ 3 mm		 2 yr LC: 86% 3 yr LC: 70% 2 yr OS: 82% 3 yr OS: 54% Local:5 Regional:1 Distant:1 ≥ Grade 3:2 1 feeding tube dependence
Yamazaki H et al. (2014) retrospective/mixed43 25 28 (7–128) 35 Gy –70 Gy (Median 50 Gy/ 25frs) 12–35 Gy/ 1–5frs Median 15 Gy/3frs Not reported Median 68.75 Median 82.5 2 yr LC: 89% 5 yr LC: 71% 2 yr OS: 83% 5 yr OS: 70% - ≥ Grade 3: None
Karam et al., (2014)/ retrospective/ salivary gland26 10 29(12-120) Median 64.8, range(50–75.6) Median17.5, range (10–
30)/3-6frs		 Not
reported		 87.82(61.11-113.1) 92.5(75.91-102.3) Definitive= GTV + 15–
20 mm
Post-op CTV + 10–
20 mm		 1-yr LC: 90%
2-yr LC: 80%		 1 yr:
100%
 Local: 1
Distant: 1		 ≥ Grade 3: None
Kataria et al.,
(2015) / retrospective/mixed77 		9 8 (6–19) 54 (50–60)/ (25–30) 15 (10–25)/2-5frs Median GTV
16.3 (7–
47)		 72.7 (62.5–91.2) 87.3 (75–109.5) GTV
+3–5 mm		 CR: 55% Not
reported		 Distant: 1 ≥ Grade 3: None
Diaz-
Martinez et al.,
(2018)/ retrospective/ Sinonasal/
nasopharynx78 		9 13.3 (4–32) 64.3 (54–70)/ (27–35) 13 (12–20)/1fr Mean GTV
4.5 (1.17–
8.2)		 89.2 (76–120) 107.1 (91.2–144) Not reported 1-yr LC: 100% Not reported Distant: 3 ≥ Grade 3: None
Baker S et al. (2018)/ retrospective/oropharynx
Baker S et al. (2019)b retrospective/oropharynx46 		195 42.8 (2.1–98.6) 46 Gy /23frs 16.5 Gy/3frs Not
reported		 67.31 80.78 CTV
+ 3 mm		 5 yr LC: 90% 5 yr OS:66.7% Local:18 Regional:12 Distant:11 ≥ Grade 3: 47
Vempati et al., (2020)/prospective/oropharynx79 34 50 60–66/30frs 8–10/1-2frs Mean GTVp
70
Mean boost
volume 54
(13–185)		 72–79.6 86.4–95.5 CTV = GTV
+ 7 mm
PTV = CTV
+ 3 mm		 Median follow up of 50 months LC: 85.3% Median follow up of 50 months OS: 85.3% Local:1
Regional:2Distant: 4		 ≥ Grade 3: 4
Dysphagia: 1
Pharyngeal hemorrhage: 3
Table 3. Salvage SBRT studies for unresectable recurrent or second primary head and neck cancer.
Table 3. Salvage SBRT studies for unresectable recurrent or second primary head and neck cancer.
Author (Year)/design/subsite Sample size (n) Treatment rRT dose (Gy)/Fraction Radiotherapy treatment duration rRT Tumor volume (cm3), median (range) Median follow up (Months) LC/LRC Median Survival
Rate, months		 Overall
Survival Rate, %		 Grade 4/5 Late
Toxicity, %
Heron et al. (2009)/phase I/Mixed66 25 SBRT 25-44Gy/5frs 2 weeks 44.8 (4.2–217) - 6 - 0
Rwigema et al. (2010)/Retrospective/Mixed65 85 SBRT 15-44Gy/1-5frs 1-38 days 25.1(2.5-162) 6 1-y LC: 51.2
2-y LC: 30.7		 11.5 1-y OS: 48.5
2-y OS: 16.1		 0
Heron et al. (2011)/Retrospective/Mixed67 70 SBRT +/- cetuximab 20-44Gy/5frs 9-14 days 29(4.8-86.8) 21.3 SBRT alone: 1-y LC: 53.8
2-y LC: 33.6.
SBRT + Cetuximab: 1-y LC: 78.6
2-y LC: 49.2
 SBRT alone: 14.8
SBRT + Cetuximab: 24.5 		SBRT alone: 1-y OS: 52.7
2-y OS: 21.1.
SBRT + Cetuximab: 1-y OS: 66
2-y OS: 53.3
 0
Comet et al. (2011)/Retrospective/Mixed62 40 SBRT +/-cetuximab 36Gy/6frs 11-12 days 29.5 (8-85) 25.6 - 13.6 1-y OS: 58
2-y OS: 24		 0
Lartigau et al. (2011)/Phase II/Mixed63 56 SBRT + cetuximab 36Gy/6frs 11-12 days - 11.4 3 months LC: 91.7 11.8 1-y OS: 47.5 Grade 5:2 patients: (hemorrhage and denutrition)
Cengiz et al. (2011)/Retrospective/Mixed61 46 SBRT 18-35Gy/1-5frs Daily 45(3-206) 7 Median PFS: 10.5 1.9 1-y OS: 47 Grade 5:8 patients, 17.8%): carotid blowout
Vargo et al. (2014)/Retrospective/Mixed17 132 SBRT + cetuximab 35-40Gy/5frs 7-14 days 30.9 (4.4–192.4) 6 1-y LRC: 48 7 1-y OS:38 0
Unger et al. (2010)/Retrospective/Mixed57 65 SBRT 21-35Gy/2-5frs Daily - 16 2-y LRC: 30 12 2-y OS: 41 Grade 4/5 late
Toxicity: (6 patients, 9%) arterial bleeding, soft tissue necrosis, fistula formation, and dysphagia requiring hospitalization.
Roh et al. (2009)/Retrospective/Mixed69 36 SBRT 18-40Gy/3-5frs Daily 22.6(.2-114.9) 17.3 1-y LRFS: 61
2-y LRFS: 52.2		 16.2 1-y OS: 52.1
2-y OS: 30.9
 Grade 4/5 late
Toxicity: (3 patients, 6.8%) (1 bone necrosis, 2 soft tissue necrosis )
15 et al. (2018)/Retrospective/Mixed 197 SBRT 16-50Gy/1-8frs Every other day 30 (1-427) 24 2-y cumulative LRF: 57 7.8 2-y OS: 16.3
 Grade 4/5 late
Toxicity: (5% of patients developed carotid blowout syndrome, fistula, and intensive care unit admission)
Ansinelli et al. (2018)/Retrospective/Mixed70 45 SBRT 20-42.5Gy/5frs Every other day 34.09 (1.00 - 258.12) 8.78 1-y LC: 49.6 9.23 1-y OS: 37.7 0
Abbreviations: rRT = re-irradiation, LC= local control, LRC= locoregional control, SBRT = stereotactic body radiotherapy, PFS: Progression free survival, Fr = fraction.
Table 4. Oragns-at-risk constaints among different different head and neck SBRT regimen.
Table 4. Oragns-at-risk constaints among different different head and neck SBRT regimen.
OAR constraint Constraint for 1 fx Constraint for 2 fx Constraint for 3 fx Constraint for 4 fx Constraint for 5 fx Endpoint ≥ grade 3
Primary disease Re-RT Primary disease Re-RT Primary disease Re-RT Primary disease Re-RT Primary disease Re-RT Primary disease Re-RT
Spinal cord and medulla_ PRV Dmax 14 Gy (D0.035cc), V10 (<0.35cc) 80–83 Dmax 9 Gy80,84 Dmax 17- 19.3 Gy (D0.035cc), V13 (<0.35cc)84,84 Dmax 12.2 Gy80,84 Dmax 20.3-22.5 Gy (D0.035cc), V15.9 (<0.35 cc)80,81,83 Dmax 14.5 Gy80,84 Dmax 23-25.6 Gy (D0.035cc), V19.2(<0.35 cc)80,83 Dmax 16.2 Gy80,84 Dmax 25.3-30 Gy (D0.035cc), V22 (<0.35 cc)80,81,83 Dmax 18 Gy80,84 Myelitis83 Sahgal et al. 80: Radiation myelopathy (1-5% risk for 1-5 fractions) Myelitis84
Optic pathway Dmax 10 Gy, V8(<0.2 cc)83 Dmax 8 Gy24 Dmax 17.3 Gy, V11.7 (<0.2 cc)83 - Dmax 17.4 Gy, V15.3(<0.2cc)83 Dmax Gy, V15 < 0.2cc (Optic nerves)24 Dmax 21.2 Gy, V19.2(<0.2cc)83 - Dmax 25 Gy, V23 (<0.2 cc)83 Dmax 10 Gy24 Neuritis83 -
Cochlea Dmax 10 Gy 83, Dmax 4-12 Gy24 Dmax 12 Gy24 Dmax 13.7 Gy 83 - Dmax 17.4 Gy 83, Dmax 20 Gy24 Dmax 24 Gy24 Dmax 21.2 Gy 83 - Dmax 22 Gy 83, Dmax 25-30 Gy24 Dmax 20-27.5 Gy24 Hearing loss83 -
Brain stem (not medulla) Dmax 15 Gy, V10(<0.5 cc)83 Dmax 10-15 Gy, V10<1cc24 Dmax 17.3, V13 Gy (<0.5 cc)83 - Dmax 23.1 Gy, V15.9 (<0.5 cc)83 Dmax 23 Gy, V18<1cc24 Dmax 27.2 Gy, V20.8 (<0.5 cc)83 - Dmax 31 Gy, V23(<0.5 cc)83 Dmax 9-15 Gy24 Cranial neuropathy83 -
Esophagus Dmax 24 Gy, V20 (< 5 cc)83, Dmax 19 Gy24 Dmax 10 Gy24 Dmax 28.3 Gy, V24.3 (<5 cc) 83 - Dmax 32.4 Gy, V27.9(<5 cc) 83 - Dmax 35.6 Gy, V30.4(<30.4 cc)83 - Dmax 38 Gy, V32.5(5 cc) 83, Dmax 27-35 Gy24 Dmax 20-25 Gy24 Esophagitis83 -
Brachial plexus Dmax 16.4 Gy, V 13.6 (<3 cc)83 Dmax 10-16 Gy, V14.4 <3cc24 Dmax 20.8 Gy, V17.8 (<3 cc)83 - Dmax 26 Gy, V22 (<3 cc)83 Dmax 23 Gy, V22.5 <3cc24 Dmax 29.6 Gy, V24.8 (24.8(3 cc)83 - Dmax 32.5 Gy, V27 (3 cc)83 Dmax 20-32 Gy V30<3cc24 Neuropathy83
-
Trachea Dmax 30 Gy, V27.5(<4 cc)83 - Dmax 38 Gy, V 34.5(<4 cc)83 - Dmax 43 Gy, V39<(5 cc)83 - Dmax 47 Gy, V42.4(5 cc)83 - Dmax 50Gy, V45(<5 cc)83 - Stenosis83 -
Skin Dmax 27.5 Gy, V25.5(10 cc)83 - Dmax 30.3Gy. V28.3 (10cc)83 - Dmax 33Gy, V31(10 cc)83 - Dmax 54Gy, V33.6(10cc)83 - Dmax 38.5Gy, V36.5(10 cc)83 Dmax 20 Gy24 Ulceration83 -
Brain V12 Gy (10-15 cc)85, Dmax 15-20 Gy
V10<1cc24 		Dmax 10 Gy24 - - 20Gy (D20cc)85, Dmax23 Gy
V18<1cc24 		- - - 24Gy (D20cc)85, Dmax 10-25 Gy24 Dmax 20-23 Gy24 Milano et al. 85: Symptomatic radiation necrosis (one fraction), oedema/necrosis (three and five fractions) -
Carotid artery - Dmax 10 Gy24 - - - - - - Dmax 25–47 Gy24 Dmax 15–34 Gy < 50% gets PTV dose24 - -
Parotid - - - - - - - - - Dmax 20–25 Gy24 - -
Lens - - - - - - - - - Dmax 6 Gy24 - -
Larynx - - - - - - - - Dmax 20 Gy24 Dmax 20 Gy24 - -
Abbreviations: Dmax: Maximal dose; Fx: Fraction; OAR: Organ-at-risk; Re-RT: Re-irradiation.
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