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Oncology
Stereotactic Body Radiation Therapy (SBRT) is reserved for head and neck cancer (HNC) patients who are not suitable candidates for conventional radiation therapy and should not be considered as a first line of treatment option and as a boost.
- head and neck cancer
- SBRT
- hypofractionation
1. Introduction
Head and neck cancers (HNCs) constitute about 6% of global malignancies, with approximately 650,000 new cases and 350,000 annual deaths [1]. They often originate from different anatomical sub-sites in the head and neck (HN) region [1], primarily being a 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 their early 60s [4,5,6,7,8]. Treatment options generally include surgery, radiation therapy (RT), systemic therapy, or a 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 [9,10,11]. 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 therapy [6]. However, some patients cannot tolerate a prolonged RT/CRT course due to their age, comorbidities, travel challenges, or lack of social support [12].
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 guidance [12,13,14,15,16,17]. 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 anti-tumor immunity with high fractional doses [19].
2. Radiobiological Principles of SBRT for HNC
High-dose radiation per fraction induces more necroptosis and apoptosis. Consequently, the repair of tumor cells becomes almost impossible, or occurs at an exceedingly low rate, leading to the majority of tumor cells suffering from radiation-induced damage. Moreover, a single high-dose SBRT treatment completely halts the cell cycle at all stages, thereby preventing the redistribution of tumor cells. This high-dose radiation effectively eliminates both oxygenated and hypoxic cells, efficiently eradicating the tumor. In contrast, following conventional radiation therapy, accelerated repopulation of tumor stem cells often occurs after approximately three weeks. However, SBRT treatment is typically completed within one week, effectively sparing tumor cells from accelerated repopulation. On the other hand, head and neck squamous cell carcinoma (HNSCC) has a low repair capacity where hyperfractionation can potentially result in better outcomes. In addition, incomplete repair can be a problem for some late-responding normal tissues if large doses are administered without enough interfraction time to allow for a complete repair of sublethal damage. If a significant amount of residual unrepaired damage remains after a too short interfraction time, the accumulation of residual damage to the damage produced by the subsequent SBRT fraction can result in an excess of toxicity to normal tissues. Notably, normal mucosa has a very high repopulation capacity that cannot protect mucosa during SBRT, so it is ideal to keep normal tissues/mucosa out of the high dose volume during SBRT for HNC. Moreover, if the tumor is hypoxic, reoxygenation of the hypoxic region could be possible with a more protracted course rather than a short course SBRT [12,13,14,15,16,17,18].
3. Practical and Technical Aspects of SBRT for HNC
Compared with SBRT, Intensity modulated radiation therapy (IMRT) is typically administered over a longer course of treatment, often several weeks, and is better suited for larger or more complex tumors. While both techniques aim to deliver effective radiation therapy with minimal damage to healthy tissue, SBRT’s emphasis on precision, accuracy, rapid treatment, meticulous target volume delineation, no or minimal clinical target volume (CTV), possibly tighter planning target volume (PTV) margin, steep dose gradient, and larger dose per fraction make it particularly well-suited for certain clinical scenarios [11,15].
3.1. Target Volume Definition for SBRT
The majority of institutions use a cut off size and/or volume constraint for a 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 an 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 a 0 mm margin expansion to create the 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].
3.2. SBRT Dose and Fractionation
Dose prescription varied across institutions and ranged from 12 to 22 Gy single fraction, 24 to 25 Gy/2 fractions, 24 to 27 Gy/3 fractions, 24 to 30 Gy/4 fractions, and 30 to 50 Gy/5 fractions, with BED10 range from 26.4 to 100 Gy10. The primary factors influencing the selection of fractionation schedules often encompass tumor size, site, close proximity to critical structures, previous radiation doses administered, and an indication for SBRT [24]. Treatment was often delivered either every other day or twice weekly, 2 days apart.
3.3. 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. Patients are to be planned and treated using IMRT or VMAT planning (ideally with a ≤5 mm 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. The aim is to achieve a conformality index (CI) < 1.1. A daily cone beam computed tomography (CBCT) should be performed with pre- and post-shifts, with a physician present at day 1 of SBRT treatment.
4. Definitive SBRT for Primary HNC
4.1. 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 toxicity [14,16,20,21,22,23,32,33]. SBRT demonstrated acceptable local control (LC) rates with minimal side effects compared to conventional fractionation RT with a standard comprehensive target volume [15]. 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%, respectively [12,14,16,20,21,22,23,32,34]. Acute or late grade 3 toxicities included osteoradionecrosis, pain, dermatitis, ulceration, and cataracts [12,20,22,33,34].
There is limited evidence supporting the use of definitive SBRT for elderly or medically unfit HNC patients who cannot tolerate a 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.
4.2. 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 the un-involved contralateral vocal cord or elective nodal target volume which allows a higher dose per fraction without possibly significant late morbidity [36,37,38,39].
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-RT [40]. The voice handicap index improved in all groups. A total of 5 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 < 10 cc and no smoking within 1 month from registration: SBRT with 42.5 Gy/5 fractions) and moderate-risk (PTV >10 cc, or smoking history within 1 month from the registration [≤1 pack/day]: RT with 58.08/16 fractions) [41].
4.3. Definitive SBRT as Boost after EBRT (Alternative to Brachytherapy Boost)
In 2008, Hara et al. updated results from Tate et al. (1999) [44] and Lee et al. (2003) [45] on SBRT boost for 82 patients (47 had stage IV nasopharynx cancer). SBRT boost of 7–15 Gy was given for 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) [46]. Chen et al. also reported outcomes and toxicity of SBRT boost (12–15 Gy in 4–5 fractions) to nasopharynx cancer (n = 64). The 3-year LC rate was 93.1%. Three patients had fatal nasal bleeding at 6–7 months after SBRT boost [47].
Uno et al. investigated the feasibility of SBRT boost (9–16 Gy in 1–3 fractions) for various HNC sites in 10 patients [48]; 60% had a complete response (CR), 40% had a 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), which resulted in a 96% (24/25) overall response rate (ORR). The 2-year LC and OS rates were 89% and 70%, respectively. The small SBRT planning target volume (PTV) boost (≤20 cm3) and the good initial response to RT predicted favorable outcomes in terms of LC and OS [49].
5. Neoadjuvant SBRT (with Immunotherapy) for HNC
Immunotherapeutic approaches are effective in recurrent/metastatic HNC [57] and enhance treatment when combined with other modalities [58]. SBRT can overcome immunotherapy resistance and sensitize cancer cells [59]. Neoadjuvant immunoradiation could potentially improve the oncologic and functional outcomes through shortening the overall treatment time, limiting radiation target volumes, and facilitating less extensive surgery through downsizing the tumor [60].
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. The median follow-up was 12.7 months. No safety signals were reported. A total of 18 out of 19 patients (95%) achieved a clinical/pathological downsizing, of whom 9 (47%) had a pathologic complete response (pCR). In total, 5 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 a favorable prognosis HPV-related OPC in the neoadjuvant setting with SBRT and immunotherapy [61].
Neoadjuvant SBRT with immunotherapy is a safe treatment for locoregionally advanced HNSCC, potentially resulting in relatively high rates of mPR with subsequent favorable outcomes. The commonly used SBRT regimen in the neoadjuvant setting is 24 Gy/3 fractions and 25–40 Gy 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 strategy [60,61,62,63].
6. 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 [17,20,64,65,66,67,68,69,70,71,72].
Heron et al. conducted a phase I dose-escalation trial with salvage SBRT for recurrent HNC. A total of 25 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 months [73]. An updated report included 85 patients and 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%, respectively [72].
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) [68]. The 1-year OS rate was 46% [68]. Out of the 37 study patients assessed for response, 10 (27%) achieved CR, 11 (30%) demonstrated PR, and 10 (27%) had SD. Despite the comparable survival outcome with other studies [69,70], the study reported a higher incidence of late-grade ≥ 4 toxicity, with 8 patients (17%) experiencing late carotid blowout, of whom 7 died from a carotid hemorrhage [68]. It has been suggested that the relatively elevated rate of late toxicity in the study might be attributed to the daily SBRT fractionation schedule, rather than an every-other-day SBRT fractionation schedule employed in other studies [17].
7. 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) [76]. The study hypothesizes that postoperative SBRT’s safety and efficacy will be similar to a conventional RT schedule [77,78].
Vargo et al. [79] 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%, respectively [79]. At six months follow-up, 56% of patients reported improved or stable overall QoL scores [79].
8. Conclusions
Head and neck SBRT represents a significant advancement in the field of radiation therapy, offering a promising treatment option for highly selected patients with HNCs who are not suitable for standard treatment options. Multidisciplinary case discussion, close monitoring, and follow-up are crucial to assess treatment response and manage any potential treatment related side effects.
This entry is adapted from the peer-reviewed paper 10.3390/cancers15205010
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