Tolerability and efficacy of simultaneously integrated boost radiotherapy in head and neck cancer treatment

Abstract

Background

Radiotherapy (RT) plays a crucial role in managing head and neck tumors. A key challenge is balancing optimal tumor control with the preservation of healthy tissues. Our study aimed to evaluate the key benefits and complications of head and neck RT using simultaneously integrated boost (SIB) compared to conventional fractionation.

Materials and methods

This study included patients with head and neck cancers who received definitive or postoperative RT between September 2022 and October 2023 at the Department of Oncotherapy, University of Szeged. A total of 66 patients were analyzed, with 33 receiving SIB and 33 treated with sequential boost (SB). All patients underwent adaptive RT with or without concurrent cisplatin or cetuximab therapy. Demographic and pathological data were comparable between the groups. Acute toxicities, local control outcomes at three months post-RT, and tumor volume changes at two-thirds of the RT course were assessed.

Results

No significant differences were observed in dysphagia, radiomucositis, and xerostomia between the two groups. The incidence of grade 2–3 radiodermatitis was significantly higher in the SB group (42.4% vs. 15.6%; p = 0.01). and therapeutic breaks were more frequent with SB compared to SIB. There was no significant difference in local tumor response rates between the groups during and after the RT. Biological effective dose (BED) calculations suggest a slightly lower probability of late side effects with the SIB technique.

Conclusions

The SIB technique can be safely and effectively used in head and neck RT, offering reduced acute skin toxicity and maintaining proper tumor response. These early results indicate that SIB is a favorable option for managing head and neck cancers.

Introduction

Radiotherapy (RT) plays a crucial role in managing head and neck tumors, where large volumes of elective lymph nodes and tumors with high potential for local spread must be irradiated while minimizing toxicity to nearby critical structures [1–3]. A key challenge is balancing optimal tumor control with the preservation of healthy tissues. Recent technical advances, particularly spatially differentiated dose delivery, have enabled more precise treatment delivery. The simultaneously integrated boost (SIB) technique has emerged as a promising alternative to the sequential boost (SB) approach in radiation oncology [4]. SIB allows for precise dose escalation to tumors while reducing exposure to surrounding healthy tissues [5].

Numerous clinical studies have demonstrated the feasibility and effectiveness of SIB in head and neck cancer, showing improved local control and reduced toxicity [4, 6–9]. Additionally, SIB can shorten the overall RT duration compared to conventional fractionation, improving patient compliance and reducing treatment interruptions.

Our study aimed to evaluate the key benefits and complications of head and neck RT using SIB compared to conventional fractionation. The primary objective was to compare acute toxicities between these techniques, aiming to enhance patients’ quality of life. The secondary objective was to assess tumor response for investigating the therapeutic index, which considers both the therapeutic outcome and treatment-related toxicity. While we hypothesize that SIB can reduce toxicity, it is crucial to confirm that tumor response is maintained or improved. Despite the short observation period, potential late effects on both tumor and normal tissues are estimated through biological effective dose (BED) and the equivalent dose in 2 Gy fractions (EQD2) calculations. Evaluation of early clinical results in real-world settings is crucial, as it provides valuable data for understanding the nuanced differences introduced by novel techniques like SIB, aiding their integration into clinical practice.

Materials and methods

Patients

Sixty-six patients with head and neck cancers who received definitive or postoperative RT between September 2022 and October 2023 were included in our prospective study. All patients underwent RT, with or without cisplatin chemotherapy or cetuximab therapy, at the Department of Oncotherapy, University of Szeged. Patient characteristics and treatment details are summarized in Table 1. The therapeutic decisions were made by a multidisciplinary tumor board. The study was approved by the Regional Committee for Human Medical Research Council (51/2024-SZTE-IKEB).

Table 1.

Demographic and surgical data of the patients

	SB	SIB	p-value
n = 66 (%)	n = 33 (%)	n = 33 (%)
T			0.902
1	10 (30.3)	8 (24.2)
2	10 (30.3)	12 (36.4)
3	8 (24.2)	9 (27.3)
4	5 (15.2)	4 (12.1)
N			0.491
0	9 (27.3)	10 (30.3)
1	7 (21.2)	7 (21.2)
2	11 (33.3)	14 (42.4)
3	6 (18.2)	2 (6.1)
p16 status			0.842
Negative	9 (27.3)	11 (33.3)
Positive	9 (27.3)	9 (27.3)
Not examined	15 (45.5)	13 (39.4)

N — node; SB — sequential boost; SIB — simultaneously integrated boost; T — tumor

Radiotherapy

Preradiation management

The diagnostic evaluation included a complete past medical history, physical examination, blood test, panendoscopy with biopsies, histopathological analysis with human papillomavirus (HPV) definition, staging examinations by computed tomography (CT) of the head and neck, thorax and abdominal regions, and magnetic resonance imaging (MRI) of the head and neck region. Dental screening and 18 fluorodeoxyglucose-positron emission tomography/CT (18 FDG-PET/CT) were performed in all cases.

All patients underwent planning CT scanning using Advanced Immobilization and Optimization Solution^TM (AIO Solution^TM; ORFIT Industry, Belgium) for positioning and 5-points head, neck and shoulders thermoplastic mask for immobilization.

The target volume in definitive and postoperative cases encompassed the macroscopic tumor [gross tumor volume (GTV)] and the site of primary tumor [clinical target volume (CTV)], respectively. These structures were delineated based on the available imaging techniques (MRI, 18 FDG-PET/CT) using image fusion. PET/CT was performed in all of the cases in the same position as planning CT with the same mask fixation. Safety margins were applied according to internal protocol [10].

In the SIB technique, three planning target volumes (PTV) were used. PTV high risk encompassed the macroscopic tumor (the primary tumor and the metastatic lymph nodes) or tumor bed with safety margin. PTV low risk included the PTV high risk with a safety margin and, in case of lymph node metastasis, the affected lymphatic region/s. The elective PTV beside these structures involved the elective nodal regions. If SB was used, the same three PTVs were defined throughout the course of radiation sequentially, starting with the irradiation of the elective PTV. For both techniques, an adaptive approach was followed: control topometric CT scan was performed around 50 Gy to check for potential tumor size reduction and anatomical changes. The relevant structures were re-delineated, and replanning was performed. Treatment planning followed the recommendations of International Commission on Radiation Units and Measurements (ICRU) Report 83 (the median absorbed dose to the PTV was as close as possible to the prescription dose, within the range of 95% to 107%). All RapidArc plans were generated using the Eclipse treatment planning system (version 13.6; Varian Medical Systems, Palo Alto, CA). Specifically, 6 MV photon beams from a linear accelerator (TrueBeam, Varian Medical Systems) equipped with 120 multi-leaf collimators were used. Two full arcs of volumetric modulated arc therapy (VMAT) were employed for dose delivery: one arc with a gantry angle from 181 to 179 clockwise, and the other from 179 to 181 counterclockwise, with collimator angles set to 30 and 330.

We introduced the SIB technique for head and neck irradiation in March 2023. In the previous period we applied 1.8 daily fraction doses in 37–40 consecutive fractions. Different prescribed doses are summarized in Table 2. Elective regions received 50 Gy, while low risk and high-risk regions received 60 Gy and 66–70 Gy, respectively. The patient positions and radiation delivery were controlled by daily cone-beam CT.

Table 2.

Radiation doses in case of simultaneously integrated boost (SIB) technique and sequential fractionation

		PTV elective		PTV low risk		PTV high risk
		Total dose [Gy]	Dose per fraction [Gy]	Total dose [Gy]	Dose per fraction [Gy]	Total dose [Gy]	Dose per fraction [Gy]
SIB	Definitive	49.9	1.47	59.8	1.76	70.04	2.06
	Postoperative	50.2	1.52	60.1	1.82	66	2
SB	Definitive	50.4	1.8	59.4	1.8	70.2	1.8
	Postoperative	50.4	1.8	61.2	1.8	66	1.8

SB — sequential boost; PTV — planning target volumes

By the time our analysis, 33 patients had finished RT with the SIB technique. We chose the same number of consecutive cases from traditional fractionation (SB) in the time period prior to the introduction of the SIB technique in order to compare the toxicity and the short-term outcome of the two methods.

During irradiation 30 mg/m² weekly cisplatin therapy was administered, if indicated. If the patient was not eligible for cisplatin therapy, cetuximab therapy was given instead, or RT alone (Tab. 3).

Table 3.

Number of administered therapies

	SB	SIB	p
n = 66 (%)	n = 33 (%)	n = 33 (%)
Only radiotherapy	8 (24.2)	7 (21.2)	1.000
Concomitant cisplatin chemotherapy	24 (72.7)	25 (75.8)	1.000
Concomitant cetuximab therapy	1 (3.0)	1 (3.0)	1.000
Induction chemotherapy	4 (12.1)	10 (30.3)	0.133

SB — sequential boost; SIB — simultaneously integrated boost

Toxicity evaluation

We calculated the BED and EQD2 values for the various structures across both treatment groups, as summarized in Table 4.

Table 4.

Biological effective dose (BED) calculation for the different structures

Structure	Daily fraction	Number of fractions	Tumor (α/β = 12, 9–14)	Oral mucosa (α/β = 8, 7–9)	Parotid gland (α/β = 3, 1.5–4)	Pharyngeal constrictor (α/β = 1.5, 1.2–2.4)	Skin (α/β = 7, 2.5–8.5)	Normal tissue (α/β = 3, 1.2–6)
PTV elective	1.47	34	BED: 56.10 (52.17–58.31)	BED: 59.16 (57.54–60.50)	BED: 74.47 (68.17–79.07)	BED: 98.96 (92.79–103.64)	BED: 60.48 (58.03–61.97)	BED: 74.47 (68.17–79.07)
			EQD2: 58.31 (55.67–59.80)	EQD2: 62.47 (60.97–63.72)	EQD2: 83.30 (76.29–86.81)	EQD2: 116.62 (107.73–121.39)	EQD2: 64.26 (61.12–65.81)	EQD2: 83.30 (74.68–86.33)
PTV elective	1.8	28	BED: 57.96 (54.08–60.12)	BED: 61.74 (60.12–63.08)	BED: 80.64 (73.78–85.80)	BED: 110.88 (103.86–115.78)	BED: 63.36 (61.01–64.79)	BED: 80.64 (73.78–85.80)
			EQD2: 58.80 (55.83–60.48)	EQD2: 63.00 (61.50–64.25)	EQD2: 84.00 (78.00–86.67)	EQD2: 117.60 (108.32–122.37)	EQD2: 64.80 (61.82–66.56)	EQD2: 84.00 (75.36–87.00)
PTV low	1.76	34	BED: 68.62 (63.71–71.24)	BED: 73.00 (71.27–74.54)	BED: 94.95 (86.91–101.01)	BED: 130.05 (121.63–135.58)	BED: 74.89 (71.93–76.80)	BED: 94.95 (86.91–101.01)
			EQD2: 69.81 (65.89–71.66)	EQD2: 74.80 (73.12–76.09)	EQD2: 99.73 (90.61–104.67)	EQD2: 139.63 (128.16–144.69)	EQD2: 76.94 (73.02–78.63)	EQD2: 99.73 (89.36–103.47)
PTV low	1.8	33	BED: 68.31 (63.43–70.46)	BED: 72.77 (71.14–74.12)	BED: 95.04 (87.17–101.20)	BED: 130.68 (122.20–136.16)	BED: 74.67 (71.73–76.58)	BED: 95.04 (87.17–101.20)
			EQD2: 69.30 (65.40–71.16)	EQD2: 74.25 (72.74–75.50)	EQD2: 99.00 (90.00–103.00)	EQD2: 138.60 (127.20–143.60)	EQD2: 76.37 (72.46–78.06)	EQD2: 99.00 (89.25–103.00)
PTV high	2.06	34	BED: 82.06 (76.09–84.94)	BED: 88.08 (86.00–89.70)	BED: 118.13 (108.03–125.21)	BED: 166.23 (155.43–172.76)	BED: 90.65 (87.10–93.45)	BED: 118.13 (108.03–125.21)
			EQD2: 81.71 (77.31–84.30)	EQD2: 87.55 (85.76–88.80)	EQD2: 116.73 (106.15–122.38)	EQD2: 163.43 (149.93–170.30)	EQD2: 90.05 (86.00–92.62)	EQD2: 116.73 (104.18–122.25)

EQD2 — equivalent dose in 2 Gy fractions; PTV — planning target volumes

Side effects and complaints of the patients were recorded before RT, once every week during RT and 3 months after the completion of it. Radiomucositis, radiodermatitis, swallowing difficulty and xerostomia and necessity of additional nutrition were recorded using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [11].

The patients were followed by MRI or 18FDG PET/CT imaging 3 months after the completion of irradiation to assess the early response to RT.

Statistical analysis

Continuous data were expressed as mean ± standard deviation (SD) values if appropriate. Treatment parameters in the two groups were compared with independent sample t-test for the continuous and chi-squared test for the categorical variables. Statistical software IBM SPSS Statistics version 26.0 (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. P-values < 0.05 were regarded as statistically significant.

Results

We analyzed data from 66 cases. Thirty‐three patients were treated with SB vs. 33 patients treated with SIB. Different demographic and surgical data are summarized in Table 1. Ten female and 56 male patients were treated. Oropharyngeal (tonsilla, base of tongue) localisation was the most frequent in both groups (36.4%). Twenty-six (39.4%) patients underwent operation before RT, while in 40 cases (60.6%) only biopsy was performed. Proportion of surgical modalities were the same in both groups (p = 1.00).

Based on initial tumor parameters (Tab. 5), the majority of patients were at high risk. 71.1 % of the patients had lymph node metastasis. There was no significant difference in T and N status in the two treatment groups, however in the case of SB a higher N status could be observed (mean ± SD; conv: 2.08 ± 0.90; SIB: 1.23 ± 1.17; p = 0.22). Histologically, the tumors were of a squamous cell carcinoma type. Among those patients when p16 status was examined (n = 30, 45.5%) positive and negative results could be detected in same proportion of the patients (n = 18, 27.3%).

Table 5.

Initial parameters of the primary tumor

	SB	SIB	p-value
n = 66 (%)	n = 33 (%)	n = 33 (%)
T
1	10 (30.3)	8 (24.2)	0.902
2	10 (30.3)	12 (36.4)
3	8 (24.2)	9 (27.3)
4	5 (15.2)	4 (12.1)
N
0	9 (27.3)	10 (30.3)
1	7 (21.2)	7 (21.2)	0.491
2	11 (33.3)	14 (42.4)
3	6 (18.2)	2 (6.1)
p16 status			0.842
Negative	9 (27.3)	11 (33.3)
Positive	9 (27.3)	9 (27.3)
Not examined	15 (45.5)	13 (39.4)

N — node; SB — sequential boost; SIB — simultaneously integrated boost; T — tumor

Administered concomitant therapies are summarized in Table 3. Fifteen (22.7%) patients received RT alone. Two (3%) and 49 (74.2%) patients received concomitant cetuximab and cisplatin therapy, respectively. Regarding the administration of cetuximab therapy, the two treatment groups were similar. Mean number of cisplatin chemotherapies was 5.92 (range: 3–8). There was no difference in the presence or number of cisplatin therapy in the two groups (mean ± SD; SB: 6.24 ± 1.13; SIB: 5.6 ± 1.16; p = 0.78). Induction chemotherapy was administered in 14 (21.2%) cases. Docetaxel, cisplatin, and 5-fluorouracil (TPF) was more prevalent in the SIB group (30.3%) compared to the SB group (12.1%); however, this difference was not statistically significant (p = 0.13).

Biological effective dose and EQD2 regarding different structures were calculated based on the two fractionation schedules (Tab. 4). Based on the BED calculations, tumor response is expected to be similar or slightly improved, while the probability of late normal tissue complications could be reduced, particularly in the elective large-volume region (Tab. 4) [12].

Tumor and target volumes and their changes are summarized in Table 6. Mean (range) initial GTV was 32.51 (2.7–96.5) and 24.42 (3.5–107.9) in the SB and SIB group, respectively. Mean GTV (range) after re-CT around 50 Gy was 25.1 (2.1–74.3) and 18.1 (2.6–79.8) in the SB and SIB group, respectively. Mean shrinkage in the GTV values was 7.48 and 6.12 in the SB and SIB group, respectively. Target volumes did not differ significantly in the two treatment groups. At 3 months after the completion of RT (n = 61, 91%), absence of any tumor activity was observed in 50 cases (81.9%). Partial response was detected in 11 patients (18.1%). There was no significant difference in the short-term therapeutic response in the two treatment groups (p = 1.00) (Tab. 6).

Table 6.

Target volume changes and 3 month tumor response

Mean (range) [cm3]	SB	SIB	p-value
GTV	32.51 (2.7–96.5)	24.42 (3.5–107.9)	0.72
GTV_reCT	25.08 (2.1–74.3)	18.07 (2.6–79.8)	0.74
PTV	482.69 (133.74–814.65)	465.12 (212.0–857.8)	0.46
Volume shrinkage	7.48 (0.62–22.19)	6.12 (0.0–28.0)	0.68
3 month tumor response (n = 61, %)			1.00
CR	22 (81.48)	28 (82.35)
PR	5 (18.52)	6 (17.65)

CR — complete response; GTV_reCT — gross tumor volume on repeat computed tomography; PR — partial response; PTV — planning target volumes; SB — sequential boost; SIB — simultaneously integrated boost

Radiomucositis, radiodermatitis, swallowing difficulty, xerostomia and additional nutrition were evaluated (Tab. 7, 8). Radiomucositis developed in all patients, with varying severity. Nineteen patients did not have any problem with swallowing. Additional nutrition was administered in 75.8% of the cases. During RT 84.8% of the patients had xerostomia. Except for radiodermatitis, adverse effects were similar between the two groups. Radiodermatitis was absent in 3% of patients in the SB group and 25% in the SIB group (p < 0.02). Grade 2–3 radiodermatitis occurred in 42.4% of the SB group and 15.6% of the SIB group (p < 0.02). Although not statistically significant, the difference shows a trend toward higher treatment interruption rates in the SB group (27.3% vs. 9.1%; p = 0.056).

Table 7.

Acute toxicities

n (%)	No		Grade 1		Grade 2		Grade 3		p-value
	SB	SIB	SB	SIB	SB	SIB	SB	SIB
Radiomucositis	–	–	22 (66.6)	25 (75.6)	9 (27.3)	6 (18.8)	2 (6.1)	1 (3.1)	0.734
Radiodermatitis	1 (3.0)	8 (25.0)	18 (54.5)	19 (59.4)	10 (30.3)	5 (16.6)	4 (12.1)	0 (0.0)	0.011
Swallowing difficulty	11 (33.3)	8 (25.0)	15 (45.5)	17 (53.1)	7 (21.2)	6 (18.8)	0 (0.0)	1 (3.1)	0.646

SB — sequential boost; SIB — simultaneously integrated boost

Table 8.

Acute and 3 months toxicities

	No		Yes		p-value
	SB	SIB	SB	SIB
Necessity of enteral/parenteral nutrition	6 (18.8)	8 (25.0)	26 (81.3)	24 (75.0)	0.763
Xerostomia during radiotherapy	6 (18.2)	4 (12.5)	27(81.8)	28 (87.5)	0.733
Xerostomia 3 months after radiotherapy	9 (28.1)	7 (31.8)	23 (71.9)	15 (68.2)	0.857

SB — sequential boost; SIB — simultaneously integrated boost

Discussion

We have analyzed data of 66 cases. The demographic, clinical, surgical, and pathological data were comparable between the two treatment groups, allowing us to conclude that the groups can be considered homogeneous (Tab. 1, 5). This similarity in key characteristics ensures that observed differences in toxicities and treatment outcomes can confidently be attributed to the treatment modalities rather than baseline patient differences. Mean (range) age at the time of diagnosis of the patients was 61.37 years (44.7–83.6), which is in the international range [13–14], as are the tumor related factors [location of the primary tumor, tumor–node–metastasis (TNM) status] [15].

Patients who were treated with the SIB technique were younger, although not significantly, and there is a higher prevalence of HPV infection, which is associated with a better tumor response, including TPF chemotherapy. This may lead to a slightly smaller GTV at RT [16–17].

Our local protocol includes pre-RT 18FGD PET/CT for more accurate target delineation. Even in a high proportion of the postoperative patients, PET/CT revealed residual tumor or lymph node metastasis requiring definitive treatment. Therefore, those patients received definitive treatment in the postoperative setting. In these cases we recommended concurrent systemic therapy in addition to irradiation. This explains why in our study 86.3% of the patients received RT with concomitant systemic therapy. Studies have shown that PET/CT has a high sensitivity in detecting residual tumor or lymph node metastasis, with some reports indicating sensitivities ranging from 80% to 93%. A systematic review reported a pooled sensitivity of 89% for detecting recurrence or residual disease in head and neck squamous cell carcinoma after treatment [18]. Moreover, PET/CT’s ability to provide both anatomical and metabolic information allows clinicians to differentiate between post-treatment changes (e.g., fibrosis) and active tumor tissue, which is essential for planning subsequent treatments and increase the accuracy of target definition [19–20].

During irradiation, when systemic therapy was recommended, two (3%) and 49 (74.2%) patients received concomitant cetuximab and cisplatin therapy, respectively. Regarding the administration of cetuximab therapy, the two treatment groups were similar, which also applies to the homogeneity of the two groups, with low frequency corresponding to the literature confirming the higher efficacy of cisplatin if not contraindicated [21–22]. Mean number of cisplatin chemotherapy was 5.92 (range: 3–8) resulting in cumulative dose of 180 mg/m² (90–240 mg/m²). Dubinský et al. [23] treated head and neck cancer patients with RT in 6 weeks delivered with simultaneous integrated boost technique and concomitant weekly cisplatin 40 mg/m². In their study cisplatin cumulative dose of 200 mg/m² was administered in 83% of patients, resulting in favorable local control rate and survival. There was no difference in the number of cisplatin therapy in the two groups (mean ± SD; conv: 6.24 ± 1.13; SIB: 5.6 ± 1.16; p = 0.78). Higher numbers in case of conventional fractionation can be explained by the longer time of irradiation.

The low proportion of induction chemotherapy in both treatment groups can be attributed to the patients’ comorbidities and low performance status, which were contraindications for the TPF. In case of unresectable squamous-cell carcinoma of the head and neck, induction chemotherapy may play an important role as it is associated with a survival benefit [24, 25]. Consequently, we made significant efforts to support our patients in becoming eligible for induction chemotherapy, which has recently resulted in an increased administration of TPF within the SIB group (30.3% vs. 12.1% in the SB group).

Different GTV volumes are shown in Table 6. Both GTVs and PTVs were similar between the two treatment groups, with only slight differences observed. However, the trend of tumor shrinkage was also similar. This was consistent with early (3 months) post-RT tumor assessments, where 91% of patients achieved complete response (CR), becoming tumor-free. Partial response was detected in 11 patients (18.1%), with no significant differences between the two treatment groups. This aligns with the literature, where a CR range of 53–76% has been reported [4, 26].

During RT of head and neck cancer the management of side effects is a big challenge [27]. So, reducing them is an important goal of radiation oncologists as it can significantly decrease patients’ quality of life [28]. Early side effects develop during the therapy and shortly after the completion of it (approximately 2–3 weeks later). Late effects can manifest any time thereafter, from weeks to years later [29]. The incidence and severity of side effects depend on a number of factors, such as the total dose of radiation delivered, the fractionation dose and what parts of the head and neck region are irradiated [30, 31].

Radiomucositis develops gradually, typically 2–3 weeks after the start of irradiation, and begins to improve around 5 weeks after the therapy concludes [32]. In our study, radiomucositis developed in all cases, though with varying severity. However, serious grade 3 radiomucositis was observed in only 3 cases. This low incidence may be attributed to the use of standard preventive and supportive management strategies (mouth hygiene, Caphosol, laser therapy) and the relatively low fraction doses (1.8–2.06 Gy). Although higher daily doses have been well tolerated in other studies, Butler et al. [33] reported a series of 20 patients treated with a boost technique that delivered a maximum daily dose of 2.4 Gy and a prophylactic dose of 2 Gy per fraction. They observed a high early CR rate in a heterogeneous patient population, with acceptable levels of acute mucosal toxicity. In contrast, the study by Montejo et al. [8] reported a much higher proportion of grade 3 radiomucositis (30.2%) compared to our patient cohort.

Radiodermatitis is one of the most common side effects of head and neck RT [34]. In our study, no radiodermatitis developed in nine patients (13.6%), with rates of 3% and 25% in the SB and SIB groups, respectively (p < 0.02). This difference is likely due to the lower fraction dose delivered to the large elective target volume. Grade 2–3 radiodermatitis was observed in 42.4% of patients in the SB group and 15.6% in the SIB group (p < 0.02). These findings support the advantage of the SIB technique, as severe dermatitis is associated with prolonged inflammation, delayed healing and skin fibrosis [8].

Most of the patients complained of swallowing difficulty, mainly due to radiomucositis. But grade 3 severity was presented only in one case. Nineteen patients did not have any problem with swallowing. Additional nutrition, usually by enteral nutrients, was administered in 75.8% of the cases. Salivary glands are directly affected by irradiation that result in radiation-induced xerostomia. It is the most common long-term complication of head and neck RT. Its early incidence among our patients was 84.8%. Follow-up of this patient cohort is ongoing, and longer-term xerostomia and swallowing function outcomes will be analyzed and reported in future work.

Except for radiodermatitis, the prevalence of adverse effects was similar between the two treatment groups, with a notably low incidence of serious events. The literature, however, is contradictory on this topic. Spiotto et al. [7] found that intensity-modulated radiotherapy (IMRT) with SIB predicted fewer cases of serious mucositis, dermatitis, and feeding tube use compared to three-dimensional conformal radiotherapy (3D-CRT), and less dermatitis compared to IMRT with SB. In contrast, other studies with similar daily fractionation doses have reported higher rates of acute dermatitis, mucositis, dysphagia, and salivary gland toxicities in the SIB arm compared to the SB arm [26].

Treatment breaks due to side effects reduce locoregional tumor control and survival rates [35, 36]. In our study, irradiation was interrupted in 27.3% of patients in the SB group and 9.1% in the SIB group, due to toxicities and patient requests. The higher rate of interruption in the SB group may be attributed to more frequent radiodermatitis, mucositis (grade 2–3), and lower patient compliance during the longer treatment course. There is quite a high proportion of interruption despite the low incidence of grade 3 mucositis. As shown in the patient characteristics, approximately half of the patients in both the SB and SIB groups were diagnosed with laryngeal or hypopharyngeal cancers. In these tumor sites, the assessment of deep pharyngeal mucositis (hypopharynx, laryngeal inlet) is inherently challenging, as direct visualization is limited during routine clinical examinations. Consequently, the mucositis grading in our cohort primarily reflects changes in the oral cavity and mesopharyngeal mucosa.

Only two patients received cetuximab during irradiation, and while no statistical significance regarding treatment breaks can be drawn due to the small sample, both required temporary cessation. Calderon et al. [37] reported that grade 3–4 adverse effects were less frequent in patients receiving cisplatin compared to cetuximab (radiomucositis: 32.5% vs. 61%, p = 0.018; radioepithelitis: 13% vs. 61%, p < 0.0001).

When we calculated the BED and the EQD2 for both approachesFtab, the values for the tumor were comparable: BED was 84.5 for SB and 84.9 for SIB, while EQD2 was 70.4 (SB) and 70.8 (SIB). However, significant differences were observed in doses to normal tissues in the elective large volume [α/β = 3.4 (2–4 Gy)]. For SB, the BED was 110.1 compared to 71.1 for SIB, and the EQD2 was 69.3 for SB and 45.07 for SIB. These findings align with previous studies that emphasize the advantage of SIB in sparing normal tissues while maintaining effective tumor control. By delivering a higher dose to the tumor in a more targeted fashion, SIB helps reduce the radiation exposure to surrounding healthy tissues, lowering the risk of toxicity without compromising treatment efficacy [38, 39]. Mireștean et al. [38] found that the overall treatment time is a significant factor influencing both acute and late mucosal toxicity, regardless of the fractionation dose, taking different α/β values into account [21]. Jiang et al. [39] meta-analysis highlighted the advantages of SIB in increasing BED to the tumor, shortening treatment time, and delivering more conformal dose distributions compared to SB, which uses a large-field phase followed by a boost phase. Nonetheless, some studies showed that SIB-IMRT might present a risk of locoregional failure. The target delineation on the basis of PET/CT, daily CBCT control and the repeated imaging and replanning for SIB as well as assure the accuracy of dose delivery to the macroscopic tumor while minimizing the risk of locoregional failure [39].

The limitations of our study include its retrospective nature, relatively small sample size, which may limit the statistical power of our analyses, and short observation period, which may limit the generalizability of the findings and the ability to assess long-term outcomes and late toxicities. Although during the observed period no systematic changes in supportive measures were documented, we cannot fully exclude an influence of new supportive techniques (soft-laser therapy) on acute toxicity outcomes.

Despite these limitations, the study has several strengths. Consecutive patient selection led to a relatively homogeneous population in terms of tumor and patient-related factors, and the RT parameters were consistent across all cases, with the only difference being the temporal dose delivery, specifically, the simultaneous application of the boost. Furthermore, the very precise and systemic toxicity detection and assessment allowed us to reveal even subtle differences in adverse events. As a result, we can reliably attribute the observed differences in toxicity and tumor response to the treatment modalities, confirming the improved therapeutic index of the SIB technique. An additional benefit of the SIB approach is the shortened treatment time, reducing the overall duration from 40 days to 34 days, which may contribute to greater patient convenience, reduced treatment burden, and improved compliance with therapy. Nevertheless, larger prospective studies with extended follow-ups are needed to validate these results.

Conclusions

Simultaneously integrated boost technique represents a significant advancement in the field of radiation therapy for head and neck cancer patients by offering improved or similar tumor control within the observed sample size and reduced treatment duration while minimizing toxicity. Continued research and long-term follow-up studies are essential to further establish the role of SIB in the management of head and neck cancer and to refine its implementation in clinical practice.

Data availability statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.