Clinical efficacy of intensity-modulated radiation therapy in patients with oropharyngeal carcinoma: a comparison with three-dimensional conformal radiation therapy with a focus on osteoradionecrosis

doi:10.21203/rs.3.rs-2585140/v1

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Research Article

Clinical efficacy of intensity-modulated radiation therapy in patients with oropharyngeal carcinoma: a comparison with three-dimensional conformal radiation therapy with a focus on osteoradionecrosis

https://doi.org/10.21203/rs.3.rs-2585140/v1

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published 05 Oct, 2023

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Background We explored the relative clinical efficacy of intensity-modulated radiation therapy (IMRT) in the treatment of patients with oropharyngeal cancer (OPC) compared with three-dimensional conformal radiation therapy (3D-CRT). Particular attention was paid to osteoradionecrosis (ORN).

Materials and methods Seventy-four OPC patients treated with definitive IMRT or 3D-CRT between May 2010 and December 2018 were analyzed. Of these, 42 patients were treated with IMRT and 32 with 3D-CRT. We compared clinical benefits. In particular, we focused on ORN, and evaluated the irradiated mandibular volumes.

Results Late Grade 2 xerostomia was detected in 6 (19.4%) and 15 patients (71.4%) in the IMRT and 3D-CRT groups, respectively (P = 0.003). Five patients had Grade 2–3 ORN in the 3D-CRT group. In contrast, no ORN was observed in the IMRT group. A comparison of the mandible volumes between the two groups showed that the IMRT group had lower mandibular volumes than the 3D-CRT group in the high-dose range of V40, V50, V60 and V70. In addition, a comparison of the mandibular volumes between ORN and non-ORN showed a significant difference in the V60 and V70. ORN incidence was higher in V60 ≥ 25% and V70 ≥ 15%.

Conclusion On comparing IMRT with 3D-CRT, the advantages of IMRT translated into a significant reduction of late xerostomia and ORN in patients with OPC. Reducing of the mandibular V60 and V70 values by IMRT seemed to reduce the risk of ORN.

Oropharyngeal carcinoma

Intensity-modulated radiation therapy

Three-dimensional conformal radiation therapy

Osteoradionecrosis

Japan

Oropharyngeal cancer (OPC) is one of the most common head and neck cancers (HNC) in Japan. Surgery and radiation therapy (RT) have traditionally been the standard treatments for OPC (1). Intensity-modulated radiation therapy (IMRT) was developed in the last decade of the 20th century, and is a system of radiation treatment planning and delivery that allows for more optimal radiation dose distributions (2). The advantages of IMRT in the treatment of OPC are low dose delivery to the parotid gland and minimal incidence of severe xerostomia without compromising the treatment outcome. In the PARSPORT trial (3), a randomized trial conducted in the UK that compared three-dimensional conformal radiation therapy (3D-CRT) with IMRT in HNC, xerostomia rates were significantly lower in the IMRT group than in the 3D-CRT group. Recently, with the implementation of IMRT, a reduction in the incidence of ORN has been reported in HNC treatment (4, 5). In a review of ORN and IMRT, De Felice et al. reported a decrease in the incidence of ORN compared to before the introduction of IMRT (4). However, few studies have compared the outcomes of IMRT and 3D-CRT for OPC in Japan, and even fewer reports have evaluated ORN. Given the above, we believe it is important to evaluate the clinical efficacy of OPC in Japan by comparing IMRT and 3D-CRT. We therefore compared the clinical efficacy of IMRT and 3D-CRT for OPC, with a particular focus on ORN and the irradiated mandibular volumes.

Patients

The records of 110 patients treated consecutively with definitive RT for OPC between May 2010 and December 2018 were reviewed. Eligibility criteria were as follows: biopsy-proven squamous cell carcinoma, no distant metastases, Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0–2 and written informed consent before the treatment. Thirty-six patients were excluded from the analysis because of combined treatment with both 3D-CRT and IMRT (n = 22), death from acute myocardial infarction before the end of RT (n = 1), discontinuation due to systemic disease progression during RT (n = 1), dropout from RT (n = 1), unknown human papillomavirus (HPV) status (n = 8), or other reasons (n = 3). The remaining 74 patients were included in this analysis.

The staging of OPC was based on the TNM system of the Union for International Cancer Control (UICC) 8th edition. Patients without human papillomavirus (HPV) determination were excluded from this study because HPV determination is important for staging in the UICC 8th edition. Prior to initiation of the treatment, all patients provided a comprehensive medical history and underwent a physical examination and dental evaluation. The staging evaluation included an endoscopic evaluation, palpation of the neck, a complete blood count, computed tomography (CT), positron emission tomography (PET)/CT and cervical magnetic resonance imaging (MRI).

Radiotherapy

At our institution, we traditionally used 3D-CRT for head and neck cancer. All patients were treated with a sequential-boost (SQB) method consisting of whole-neck radiotherapy to 40 Gy, followed by a boost to the primary tumor and metastatic lymph nodes to a total dose of 70 Gy. When we started performing IMRT in July 2010, whole-neck radiotherapy was irradiated with 3D-CRT, and the SQB plan was irradiated with IMRT. Since January 2015, all patients with OPC have been irradiated exclusively with IMRT, from whole-neck radiotherapy to the boost plan.

Patients were immobilized in a supine treatment position in a custom-made head-and-neck mask. CT-based simulation was performed in all patients. The XiO version 5.10 (CMS, St. Louis, MO, USA) treatment planning system was used to create an individualized radiation therapy plan for 3D-CRT patients, and Eclipse planning version 13.6 (Varian Medical Systems, Palo Alto, CA, USA) was used for treatment planning for IMRT patients. In some cases, the MRI and the PET/CT findings were used as a guide for the contours of tumor volumes on workstations.

The gross tumor volume (GTV) was defined by a clinical examination and diagnostic imaging using modalities such as CT, MRI and/or FDG-PET. The clinical target volume 1 (CTV1) included the GTV primary with an expansion of 5 mm, and the GTV node with an expansion of 5 mm. The planning target volume 1 (PTV1) was defined as CTV1 with a 5 mm margin in all dimensions. The CTV prophylactic (CTV2) was designed to include the lymph nodes at Levels II-V and VII according to nodal regions as defined by the RTOG consensus guidelines (6). In cases with base of tongue disease or lymphatic involvement on Level II, Level Ib was included in the CTV prophylactic. In patients with positive nodes, the supraclavicular region was also included. PTV2 was defined as CTV2 with a 5 mm margin in every direction. Avoidance structures, such as the spinal cord, brainstem, parotid glands, oral cavity, and larynx, were delineated at the time of treatment planning.

In 3D-CRT, the planned dose at the isocenter was prescribed as 40–41.4 Gy/20–23 fractions to the sum of the PTV1 and PTV2, followed by 30 Gy/15 fractions to PTV1 with a total dose of 70–71.4 Gy/35–38 fractions (median 71.4 Gy). 3D-CRT treatments were delivered with an ONCOR Impression plus medical accelerator (Siemens Healthineers, Erlangen, Germany). The conventional technique with parallel-opposed lateral fields and a low-anterior-neck field matched below the primary site, or lateral opposed fields with a field-in-field technique, was used. In IMRT, a planned dose of 40–41.4 Gy/20–23 fractions were prescribed for 95% of the volume of the sum of PTV1 and PTV2, and then boosted to PTV1 for a total dose of 66–70.2 Gy/33–39 fractions (median 70.2 Gy). For organs at risk, treatment planning goals include a maximum dose to the spinal cord < 50 Gy, a mean dose to the parotid dose < 26 Gy, and a maximum dose to the brainstem < 54 Gy. We decided to reduce the oral cavity and larynx doses as much as possible without compromising the irradiation of the target. At this point, we had not established dose constraints to the mandible. IMRT treatments were delivered using the VMAT (Volumetric Modulated Arc Therapy) technique with Varian accelerators (Varian Medial Systems). The X-rays beam energies used in 3D-CRT and IMRT were 6–10 MV. Boost plans were re-planned when weight loss was significant.

Endpoints and statistical analysis

Follow-up evaluations after the treatment were typically performed at intervals of one month for one year, at intervals of three months from one to three years post-treatment and at intervals of six months from three to five years post-treatment. When necessary, upper gastrointestinal fiberscopy and CT were performed at least annually during the follow-up.

Characteristics for both radiation treatment groups were compared using either a T-test or Fisher’s exact test.

Acute adverse events were defined as symptoms observed during radiotherapy and up to eight weeks after treatment. Late adverse events were defined as symptoms observed after that time. Adverse events were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Fisher’ s exact test was used for comparisons between two groups.

We compared the parotid gland dose and the mandibular doses between the two groups. Mandibular dose-volume histograms (DVHs) were extracted. T-test was used to compare the mandibular volumes that received > 10, 20, 30, 40, 50, 60 and 70Gy (V10, V25, V30, V40, V50, V60 and V70, respectively). Fisher’s exact test was used to examine the difference in ORN incidence by dosimetric parameters. In addition, for patients with ORN, we investigated the difference in the mandibular volumes produced by different irradiation methods.

All statistical analyses were performed with EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan), which is a graphical user interface for R (version 2.13.0; The R Foundation for Statistical Computing, Vienna, Austria). More precisely, it is a modified version of R commander (version 1.6-3) that was designed to add statistical functions frequently used in biostatistics (8). P < 0.05 was considered as significant.

Patient and treatment characteristics

The median follow-up period was 48 months (range, 7–86) for IMRT patients and 66 months (range, 13–120) for 3D-CRT patients. The characteristics of the 74 eligible patients are shown in Table 1. The number of HPV-positive patients was higher in the IMRT group than in the 3D-CRT group; conversely, in the 3D-CRT group, there were more patients with T3–4, and the overall stages were more advanced than in the IMRT group. CCRT was performed in 38 of 42 patients (90.5%) in the IMRT group and all patients (100%) in the 3D-CRT. Most patients (32 of 38 patients [84.2%] in the IMRT group and 29 of 32 patients [90.6%] in the 3D-CRT group) received platinum-based chemotherapy regimens. Of these, cisplatin (CDDP) was the most commonly used, (in 28 patients for IMRT and 27 patients for 3D-CRT). Three patients in the IMRT group received cetuximab. One patient for IMRT and two patients for 3D-CRT received S-1. Two patients in the IMRT group and one patient in the 3D-CRT group with esophageal double cancer received 5-fluorouracil (5-FU)/ CDDP (FP).

Table 1

Patient characteristics, n (%)
Factor	IMRT (n = 42)	3D-CRT (n = 32)	P value
Age (years)	64 (range, 22–93)	65 (range, 48–85)	0.279
Gender			0.067
Male	27 (64.3)	27(84.4)
Female	15 (35.7)	5(15.6)
Subsite			0.535
Base of the tongue	12 (28.6)	8 (25.0)
Tonsils	22 (52.4)	18 (56.3)
Soft palate	7 (16.7)	4 (12.5)
Pharyngeal wall	0	2 (6.3)
Unclassifiable	1 (2.4)	0
HPV			0.029
+	31 (73.8)	15 (46.9)
–	11 (26.2)	17 (53.1)
T-stage			0.020
1	12 (28.6)	3 (9.3)
2	20 (47.6)	11 (34.4)
3	3 (7.1)	6 (18.8)
4	6 (14.3)	9 (28.1)
4a	0	3 (9.4)
4b	1 (2.4)	0
N-stage			0.359
0	14 (33.3)	8 (25.0)
1	18 (42.9)	14 (43.8)
2	4 (9.5)	1 (3.1)
2a	0	0
2b	4 (9.5)	3 (9.3)
2c	1 (2.4)	5 (15.6)
3	1 (2.4)	1 (3.1)
Overall stage			0.005
I	23 (54.8)	6 (18.8)
II	7 (16.7)	4 (12.5)
III	7 (16.7)	13 (40.6)
IV	0	0
IVA	5 (11.9)	9 (28.1)
Concurrent CHT			0.129
+	38 (90.5)	32 (100.0)
–	4(9.5)	0
Smoking			0.913
Current	10 (23.8)	9 (28.1)
Former	18 (42.9)	13 (40.6)
Never	14 (33.3)	10 (31.3)
Double cancer			0.561
+	10 (23.8)	5 (15.6)
–	32 (76.2)	27 (84.4)
Dose (Gy)	70.2 (range, 66–70.2)	71.4 (range, 70–71.4)	–
n number of patients; IMRT intensity-modulated radiation therapy; 3D-CRT three-dimensional conventional radiation therapy; HPV human papillomavirus; CHT chemotherapy

The median total dose in the IMRT group was 70.2 Gy (range, 66–70.2 Gy) at the D95 of the PTV. Thirty-six patients (85.7%) received a total dose of 70.2 Gy, 4 (9.5%) received 70 Gy, and 2 (4.8%) received 66 Gy. The median total dose of patients treated with 3D-CRT was 71.4 Gy (range, 70–71.4 Gy) at the isocenter. Fifteen patients (46.9%) received a total dose of 71.4 Gy, 13 (40.6%) received 70.2 Gy, and 4 (12.5%) received 70 Gy.

During treatment, eight patients (two in the IMRT group and six in the 3D-CRT group) required interruption of irradiation for more than seven days.

In the IMRT group, three patients (7.1%) underwent planned neck dissection after definitive RT, but no patient had residual tumor. In contrast, planned neck dissection was performed in 16 patients (50.0%) in the 3D-CRT group, with residual tumors being confirmed histologically in nine.

Treatment outcomes

Nine out of 42 patients (21.4%) in the IMRT group, and 12 out of 32 patients (37.5%) in the 3D-CRT group had died by the time of this analysis (May 31, 2022). In the IMRT group, two patients died of OPC, one patient died of hematemesis of the internal carotid artery by mucositis, three patients died of double cancer (esophagus, tongue, and malignant lymphoma: one each), and three patients died of other factors. In the 3D-CRT group, five patients died of OPC, one patient died of aspiration pneumonia, five patients died of double cancer (one: esophagus; three: lung; one: malignant lymphoma), and one patient died of other factors.

In the IMRT group, five patients (11.9%) relapsed; these consisted of one patient with relapse at the local site, one with relapse at the regional site, two with relapse at the local and regional sites and one with relapse at the regional sites and with distant metastasis (lung). Of the four patients with locoregional recurrence alone, three underwent salvage surgery including neck dissection and/or resection of the tumor at the primary site, and one received systemic chemotherapy. One patient with distant metastasis in addition to regional sites recurrence received immunotherapy and systemic chemotherapy.

In the 3D-CRT group, 10 patients (31.3%) relapsed; these consisted of two patients with relapse at the local site, five with relapse at the local and regional sites, two with lung metastasis, and one with relapse at the regional sites in addition to distant metastasis (lung). Of the seven patients with locoregional recurrence alone, five underwent salvage surgery including neck dissection and/or resection of the tumor at the primary site, followed by systemic chemotherapy in two cases. The remaining two patients chose best supportive care. One out of the three patients with distant metastases received salvage surgery and systemic chemotherapy, and the other two received systemic chemotherapy.

Acute adverse events

We showed the acute toxicities among patients in Table 2. The incidence of acute Grade 2 xerostomia was lower in the IMRT group than in the 3D-CRT group, with Grade 2 xerostomia was detected in 25 (59.5%) and 29 patients (90.6%) in the IMRT and 3D-CRT groups, respectively (P = 0.003). However, there was no significant difference in the incidence of other acute adverse events between the two groups.

Table 2

Acute adverse events grade by treatment group
	IMRT					3D-CRT
	Grade 0 n (%)	Grade 1 n (%)	Grade 2 n (%)	Grade 3 n (%)	Grade 4 n (%)	Grade 0 n (%)	Grade 1 n (%)	Grade 2 n (%)	Grade 3 n (%)	Grade 4 n (%)
Dermatitis radiation	0	25 (59.5)	14 (33.3)	3 (7.1)	0	0	20 (62.5)	9 (28.1)	3 (9.3)	0
Mucositis	0	7 (16.7)	31 (73.8)	4 (9.5)	0	0	3 (9.3)	21 (50.0)	8 (25.0)	0
Dysphagia	1 (2.3)	4 (9.5)	28 (66.7)	9 (21.4)	0	0	3 (9.3)	23 (71.9)	6 (18.8)	0
Pain	0	3 (7.1)	37 (88.1)	2 (4.8)	0	1 (3.1)	1	31 (96.9)	0	0
Xerostomia	0	17 (40.5)	25 (60.0)	0	··	2 (6.3)	1 (3.1)	29 (90.6)	0	··
Weight loss	10 (23.8)	17 (40.5)	13 (31.0)	1 (2.4)	··	8 (25.0)	16 (50.0)	8 (25.0)	0	··
Dysgeusia	3 (7.1)	11 (26.2)	28 (66.7)	0	··	0	5 (15.7)	27 (84.4)	0	··
n number of patients; IMRT intensity-modulated radiation therapy; 3D-CRT three-dimensional conventional radiation therapy

Late adverse events

There was one patient with Grade 5 mucositis in the IMRT group. The patient was a 52-year-old female with OPC cT4N3M0 (HPV +). The tumor was in full circumferential contact with the internal and external carotid arteries. She was treated with definitive RT and concurrent cetuximab. However, she refused to be hospitalized and could not receive adequate tube feeding or oral protection. F The patient continued to have prolonged mucositis and a poor oral intake, resulting in a weight loss of -20 kg and poor nutritional status. Five months after completion of RT, the patient began bleeding from the right external carotid artery and died. One patient in the 3D-CRT group died of aspiration pneumonia. Late Grade 3 dysphasia was detected in one (3.1%) and one patient (4.8%) in the IMRT and the CRT groups, respectively. No patient required a percutaneous endoscopic gastrostomy (PEG) tube.

At 2 years post-treatment, the incidence of late Grade 2 xerostomia was significantly lower in the IMRT group than the 3D-CRT group: 6 (19.4%) and 15 patients (71.4%) in the IMRT and 3D-CRT groups, respectively (P = 0.003). The dose to the parotid gland was significantly lower in the IMRT group than in the 3D-CRT, both ipsilaterally and contralaterally; the mean radiation doses to the ipsilateral and contralateral parotid glands for IMRT vs. 3D-CRT were 33.69 Gy (range, 19.25–53.08 Gy) vs. 69.09 Gy (range, 45.69–72.56 Gy) (P < 0.001) and 23.48 Gy (range, 11.68–39.99 Gy) vs. 43.8 Gy (range, 28.58–60.44 Gy) (P < 0.001), respectively.

Four patients (19.0%) developed Grade 3 ORN, one patient (4.8%) developed Grade 2 ORN, and one patient developed Grade 3 laryngeal necrosis in the 3D-CRT group, while no patients developed ORN and laryngeal necrosis in the IMRT group. There was a significant difference in the incidence of Grade 3 ORN between the two groups (P = 0.003). Figure 1 shows the results of compared the mean percentage of volumes of the mandible receiving > 10, 20, 30, 40, 50, 60 and 70Gy (V10, V25, V30, V40, V50, V60 and V70, respectively) between the IMRT and 3D-CRT groups. The low-dose range of the mandible (V10 and V20) was higher in the IMRT group, whereas the high-dose range of the mandible (V40, V50, V60 and V70) was higher in the 3D-CRT group than in the IMRT group, with both differences being statistically significant. We also compared the relative volumes of the mandible between the ORN and the non-ORN groups. The result was shown in Fig. 2, which shows significant differences between the two groups in V60 and V70 of mandible. The mandibular V60 and V70 values were significantly higher in the ORN group than in the non-ORN group.

Moreover, the ORN incidence was 16.7% for the mandibular V60 ≥ 25% and 2.1% for V60 < 25% (P = 0.040), and, 23.1% for the mandibular V70 ≥ 15% and 3.4% for V70 < 15% (P = 0.038) (Table 3).

Table 3

Incidence osteoradionecrosis for the mandibular V60 ≥ 25% vs. V60 < 25% and the mandibular V70 ≥ 15% vs. V70 < 15%
Parameter	Cut off value	Incidence of ORN (%)	P value
V60Gy	≥ 25%	16.7	0.040
	< 25%	2.1
V70Gy	≥ 15%	23.1	0.038
	< 15%	3.4
ORN osteoradionecrosis

Clinical characteristics of patients with ORN

Table 4 shows the five patients in the 3D-CRT group who developed ORN, including four with Grade 3 and one with Grade 2. ORN was located on the ipsilateral side of the gross disease in all cases. The four patients had no cervical lymph node metastasis. The median time to develop ORN was 54 months (range, 32–96 months). The mandibular V70 values in patient 1 and 3 were in the high 30% range. Patient 2 continued smoking after RT and developed diabetes mellitus (DM) after RT. Patient 4 had a poor oral status and had to undergo extractions after RT. Patients 1–5 were treated with antibiotics and hyperbaric oxygen therapy (HBO). However, the discomfort continued, and the condition was not completely improved.

Table 4

Clinical characteristics of patients with osteoradionecrosis
Patients	Tumor Site	TN stage	RT technique	Location of ORN	Time to ORN (months)	Grade of ORN	Smoking after RT	Extraction after RT	DM	V40 (%)	V50 (%)	V60 (%)	V70 (%)
1	Rt. Soft palate	T1N0	3D-CRT	Rt.	54	Grade 3				56.78	45.95	39.95	31.48
2	Rt. Soft palate	T2N0	3D-CRT	Rt.	32	Grade 3	+		+	61.46	25.38	19.00	8.77
3	Rt. Tonsil	T1N0	3D-CRT	Rt.	54	Grade 3				60.92	52.70	46.73	36.66
4	Lt. Tonsil	T3N0	3D-CRT	Lt.	48	Grade 3		+		54.30	49.80	44.83	16.95
5	Lt. Base of tongue	T3N2b	3D-CRT	Lt.	96	Grade 2				47.42	38.46	28.14	5.06
ORN osteoradionecrosis; RT radiation therapy; DM diabetes mellitus

These five patients of ORN were re-planned with IMRT, and the volumes of the mandible receiving > 10, 20, 30, 40, 50, 60 and 70Gy (V10, V25, V30, V40, V50, V60 and V70, respectively) were compared. The results were shown in Fig. 3. IMRT irradiation was found to significantly decrease the mandibular V40, V50, V60, and V70 values. Figure 4 shows a patient with right soft palate carcinoma, cT1N0M0, in which the isodose line of 70 Gy was observed bilateral mandible by irradiation using 3D-CRT, which was reduced when irradiated using IMRT.

In the domain of radiation oncology, the concept of IMRT emerged during the mid-1990s. By leveraging computer-aided inverse treatment planning and dynamic modulation of radiation beam intensity during treatment, IMRT facilitated the delivery of 3D conformal radiotherapy. This state-of-the-art technology enabled the targeted attenuation of radiation dose to essential normal structures, such as the parotid glands and mandible in cases of HNC, even when these structures were contiguous or enmeshed with tumors (9).

The majority of studies comparing IMRT to CRT for patients with OPC have reported no marked difference in tumor control rates between these two techniques. In a study conducted by Al-Mamgani et al. (10), patients with OPC were administered definitive radiation with concurrent platinum-based chemotherapy. The treatment cohort consisted of 92 patients who received IMRT and an equivalent number of patients who received 3D-CRT, as determined by a matched-pair analysis. The 3-year Kaplan-Meier estimates of LRC, DFS, and OS for IMRT and 3D-CRT were 90% vs. 82% (p = 0.1), 82% vs. 76% (p = 0.3), and 72% vs. 64% (p = 0.2), respectively. Alterio et al. (11) conducted a systematic review and meta-analysis of eight studies. They showed that there was no statistical difference between IMRT and 2D/3D-RT in terms of death (SRR = 0.93, 95% CI: 0.83–1.04 with no heterogeneity I² = 0%) and relapse (SRR = 0.92, 95% CI: 0.83–1.03, with no heterogeneity I² = 0%).

The present study revealed differences in patient characteristics between the IMRT and 3D-CRT groups, with variations noted in HPV status, T-stage, and overall stage. Notably, the number of patients who tested positive for HPV has increased in recent years. In Japan, a nationwide study by Hama et al. investigated the HPV prevalence in OPC across 21 institutes participating in the Basic Research Cooperative Group of HNC (12). The study reported a significant increase in the prevalence of HPV-positive OPC cases from 32% in the 2000s to 50.0% in the 2010s (12). Our study included patients who commenced radiotherapy after 2014 in the IMRT group, which may have contributed to the higher proportion of HPV-positive patients observed in this group compared to the 3D-CRT group. Staging was based on the UICC 8th edition, which reflects HPV determination. We suspected that the increased prevalence of HPV positivity in the IMRT group may have contributed to the relatively lower number of Stage IV cases compared to the 3D-CRT group.

Based on a review of previous reports, we concluded that the adverse events observed in our study were within an acceptable range. Specifically, when comparing the IMRT and 3D-CRT groups, we found that the mean radiation doses delivered to both the ipsilateral and contralateral parotid glands were significantly lower in the IMRT group than in the 3D-CRT group. It has been established that the highest tolerable mean dose to the parotid gland is 26 Gy (13), and based on our results, the parotid gland dose administered by IMRT was deemed tolerable. Furthermore, our findings confirmed that the use of IMRT resulted in a significant reduction in the incidence of late xerostomia.

In our research, there was a significant difference in the incidence of ORN between the two groups. Reuther et al. (14) reported on the median time to ORN onset. The authors reported that among 830 patients monitored over a 30-year period, the median time for the onset of ORN was 13 months (range, 2–122 months). The median follow-up duration in our study was shorter in the IMRT group than in the 3D-CRT group, at 48 months [range, 7–86] and 66 months [range, 13–120], respectively. However, we believe that these durations are not unreasonable for evaluating the incidence rate of ORN based on the literature by Reuther et al. (14) et al.

In reviewing the literature, it is necessary to consider when cases were treated with RT, as technological advances may have contributed to the lower incidence of ORNs. In a study by Wahl et al. (15), the incidence of ORN decreased from 11.8% before 1968 to 5.4% between 1968 and 1992, and further to approximately 3% after 1997. Tsai et al. (5) reported a trend towards a lower incidence of ORN in patients treated with IMRT compared to 3D-CRT in the 2000–2009 period, with rates of 6% and 13%, respectively. The use of IMRT enables selective dose reduction even when the mandible is adjacent to or surrounded by the tumor, which could have contributed to the observed lower incidence of ORN.

Several studies have assessed dosimetric parameters and the potential for ORN, with a majority reporting a markedly elevated risk of ORN in patients receiving substantial radiation doses to the mandible. Chang et al. found a radiation dose of 70 Gy to be significantly associated with an increased risk of ORN (16). The MD Anderson Head and Neck Cancer Symptom Working Group showed that majority of ORN cases have mandibular V44 ≥ 42% and V58 ≥ 25% in patients with OPC using RPA analysis in a matched case control study (17). Kubota et al. demonstrated that mandibular V60 > 14% was identified as a significant risk factor of ORN in HNC (18). In our study, significant differences were observed in the extent of mandibular V40, V50, V60, and V70 values between the IMRT and 3D-CRT groups, with evidence of a dose reduction in the high-dose range. Notably, when mandible volumes were compared between the ORN and non-ORN groups, significant differences were found in the mandibular V60 and V70 values, suggesting their potential importance in predicting ORN risk. Indeed, ORN incidence was observed to be higher in patients with V60 ≥ 25% and V70 ≥ 15%. When the five patients of ORN were re-planned with IMRT, and significant differences were found in the mandibular V40, V50, V60, and V70 values. Four of the five patients with ORN were T1–3N0, indicating relatively early stages disease and limited extent of cancer invasion. If multiple lymph node metastases were present, high-dose irradiation of the mandible would be deemed necessary, but the patients were not at such a stage. IMRT resulted in a significant decrease in mandibular V60 values from 35.74–10.44% and V70 values from 19.78–2.92%, particularly in the high-dose range. Consequently, the reduction in mandibular V60 and V70 values due to IMRT irradiation was thought to account for the decrease in ORN incidence.

Several reports have identified risk factors for ORN, including DM, smoking, stage of disease, dental health, extraction of teeth after irradiation, and excessive alcohol (5, 19–23). Therefore, the development of ORN could not be attributed solely to the irradiation dose to the mandible, although the reduction in the mandibular V60 and V70 values with the introduction of IMRT seemed to be related to a significant risk reduction. This is because in cohorts of HNC patients who underwent IMRT, Owosho et al. found that smoking and DM were not significant risk factors for ORN (24). Due to the widespread adoption of RT using IMRT, other risk factors for ORN have become less significant.

The current study is associated with several limitations that require acknowledgment. Firstly, patients were treated by a uniform group of radiation and surgical oncologists, yet they were not chosen or treated based on a prospective protocol. Unmeasured confounding variables and potential selection biases could not be accounted for in our analysis. Second, there were differences in overall stage, T stage, and HPV status between the two groups, which may have slightly biased the assessment of adverse events. We believe that the recent increase in HPV-positive OPC is also behind this patient background. However, the fact that IMRT reduced rate of xerostomia and ORN is very significant. In particular, in this study, we compared DVHs between the IMRT and 3D-CRT groups and between the ORN and non-ORN groups in OPC patients at a single institution. There is no previous paper that examine and clarify these points, and our results are very useful clinically.

In recent years, the increase in HPV-positive OPC and the combined use of immune checkpoint inhibitors (ICI) have improved the prognosis. Therefore, the future focus will be on maintaining the quality of life (QOL) of these patients; ORN is refractory and leads to a decline in QOL. Based on the present findings, we intend to establish a treatment plan to avoid the hot spots of the mandibular V60 ≥ 25% and V70 ≥ 15% without compromising target coverage in order to suppress the development of ORN and maintain the QOL of patients. We would also like to accumulate further cases.

In this study, we aimed to compare the clinical advantages of IMRT and 3D-CRT in the OPC patients, and found that IMRT is more useful for reducing the risk of xerostomia and ORN than 3D-CRT. We observed that reducing mandibular V60 and V70 through IMRT irradiation can effectively decrease the risk of ORN.

Ethics declarations
1. Funding (information that explains whether and by whom the research was supported)

The authors declare no funding.

2. Conflicts of interest/Competing interests (include appropriate disclosures)

The authors declare no competing interests.

3. Ethics approval (include appropriate approvals or waivers)

This study was approved by the institutional review board of the National Kyushu Cancer Center.

4. Consent to participate (include appropriate statements)

Informed consent was obtained in the form of opt-out on the website.

5. Written Consent for publication (include appropriate statements)

Informed consent was obtained in the form of opt-out on the website.

6. Availability of data and material (data transparency)

The data that support the findings of this study are available from the corresponding author, Keiko Hiramine, upon reasonable request.

7. Code availability (software application or custom code)

Not applicable.

8. Authors' contributions

Study concept and design: all authors; Acquisition, preparation of the dataset and statistical analysis: Keiko Hiramine; interpretation of the data: all authors; drafting of the manuscript: Keiko Hiramine and Yoshiyuki Shioyama; critical revision of the manuscript for important intellectual content: all authors. Keiko Hiramine had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. All authors saw and agreed on the final manuscript as well as the decision to submit for publication.

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published 05 Oct, 2023

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Clinical efficacy of intensity-modulated radiation therapy in patients with oropharyngeal carcinoma: a comparison with three-dimensional conformal radiation therapy with a focus on osteoradionecrosis

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Clinical characteristics of patients with ORN

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