Abstract
Objective: To investigate the effects of three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT) on parotid gland function and quality of life in patients with nasopharyngeal carcinoma (NPC). Methods: Ninety-six patients with NPC diagnosed and treated in our hospital were divided into two groups using a random number table. The control group was treated with three-dimensional conformal radiotherapy and the research group was treated with intensity-modulated radiotherapy. Observation and comparison were conducted for differences of baseline indicators between the two groups including; short-term response rate, relevant indicators regarding parotid gland function before and after treatment, uptake index (UI) and excretion index (EI), dry mouth (xerostomia) grading and quality of life indicators after treatment, and the prognosis of patients. Results: There was no significant difference in baseline data between the two groups (all P>0.05). The short-term response rate in the research group was significantly higher than that in the control group (P<0.05). After treatment, UI and EI in both groups were significantly decreased compared to those before treatment (all P<0.05); UI and EI in the research group were significantly higher than those in control group (all P<0.05). Dry mouth grading in the research group was significantly lower than that in the control group (all P<0.05). After treatment, the levels of related indicators regarding quality of life, local recurrence-free rate, and distant metastasis-free rate in the research group were higher than those in the control group (all P<0.05). Conclusion: IMRT for patients with NPC can significantly improve short-term response rate, reduce mouth dryness and parotid gland injury after radiotherapy, enhance quality of life, and facilitate the prognosis of patients.
Keywords: Nasopharyngeal carcinoma, intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, parotid gland function, quality of life
Introduction
Nasopharyngeal carcinoma (NPC) is a common type of malignant tumor seen in clinical practice, which is distinctive for its biological characteristics, pathological type and physiological and anatomical position [1]. Presently, the preferred treatment modality for NPC in clinical practice is radiation therapy (hereafter referred to as radiotherapy) [2]. The parotid gland is highly sensitive to radiotherapy, and with high-dose irradiation will cause irreversible damage to parotid gland function, and significantly impair relevant functions of the patients, such as taste and speech [3]. Such impairment will not endanger the patient’s life and health; however, it will seriously affect the patient’s quality of life [4]. As the survival time of NPC patients is continuously prolonged and clinical radiotherapy efficacy enhanced, the patients are beginning to raise standards for quality of life. Therefore, it is of clinical significance to investigate how to minimize parotid gland dysfunction in NPC patients undergoing radiotherapy [5]. In recent years, intensity-modulated radiotherapy (IMRT) has been widely employed in clinical practice, during which the targeted lesions of the tumor are exposed to high dose irradiation, making it possible to protect parotid gland function. According to related studies, IMRT can significantly reduce the radiation dose delivered to the parotid gland, diminish subsequent adverse reactions, and restore the secretory function of the patients. Currently, most clinical studies are focused on comparison of conventional radiotherapy and intensity-modulated radiotherapy in NPC patients, and there are few studies on three-dimensional conformal radiotherapy and intensity-modulated radiotherapy. Therefore, to further investigate the changes in parotid gland function and quality of life in NPC patients after intensity-modulated radiotherapy, we selected 48 NPC patients who were diagnosed and treated in our hospital from February 2018 to April 2020 for intensity-modulated radiotherapy and compared them with those treated with three-dimensional conformal radiotherapy, with the results reported as follows.
Materials and methods
General data
Ninety-six NPC patients diagnosed and treated in our hospital from February 2018 to April 2020 were included in this study.
Inclusion criteria: Patients were eligible if they (1) all met clinical diagnosis of NPC [6]; (2) aged >20 years, and <70 years; (3) had a Karnofsky Performance Status Scale (KPS) score ≥70 points; (4) were newly diagnosed and did not receive relevant treatment before inclusion; (5) did not present distant metastasis of the lesion.
Exclusion criteria: Patients were excluded if they (1) were complicated with severe cardiac dysfunction, pulmonary dysfunction, and liver dysfunction; (2) unable to tolerate radiotherapy; (3) were at pregnant or lactating.
The patients were divided into two groups using a random number table. Patients in the control group (n=48) received three-dimensional conformal radiotherapy and those in the research group (n=48) received intensity-modulated radiotherapy.
This study was reviewed and approved by the Ethics Committee of our hospital. Informed consent form was obtained from all included patients.
Methods
Control group
Patients in the control group received three-dimensional conformal radiotherapy. The patient was instructed to lie in a supine position with the head and neck fully fixed. Computer tomography (CT) scans were uploaded to a post-processing system, and the target area was determined and delineated accordingly. Three-dimensional conformal radiotherapy was performed for the patients according to the range of lesions revealed on the images, with a total radiation dose to the primary lesion ranging from 68 Gy to 72 Gy. The patients’ lower neck was treated with conventional irradiation combined with anterior tangential field irradiation, with a dose ranging from 56 Gy to 66 Gy, once a day, 5 times per week.
Research group
Patients in the research group underwent intensity-modulated radiotherapy. The patient was instructed to lie in a supine position with adequate fixation of the head and neck. Computer tomography (CT) scans were uploaded to a post-processing system. Then the target area was determined and delineated based on International Commission on Radiation Units and Measurements (ICRU) report No.50 and No.62. The tumor volume was determined in accordance with the scans. Clinical target volume 1 (CTV1) is defined as cervical lymph nodes and retropharyngeal metastatic lymph nodes plus a 0.5 to 1 cm margin to allow for microscopic spread, including the entire nasopharyngeal mucosa and 0.5 cm beneath submucosa. The IMRT system was adopted to locate nine different coplanar surfaces of the fixed field. The irradiation dose of gross tumor volume of nasopharynx (GTVnx) was set at a range from 68 Gy to 70 Gy, and CTV1 from 60 Gy to 66 Gy, once a day, 5 times per week.
Outcome measures
Primary outcome measures
Short-term response rate in the two groups
The short-term response rate of patients in both groups was assessed based on the following criteria [7]. Complete response (CR): The patient’s symptoms were relieved and the lesions disappeared; Partial response (PR): The patient’s symptoms were improved compared with those before treatment, and lesion size was reduced by about 30%-50%; Stable disease (SD): The patient’s symptoms were not aggravated nor improved, and the lesions showed no sign of expansion or reduction compared with those before treatment; Progressive disease (PD): The patient’s symptoms deteriorated, and new metastatic lesion tissue was noted in the body. Response rate = (CR cases + PR cases)/total number of cases *100%.
Parotid gland function indicators before and after treatment
Uptake index (UI) and excretion index (EI) were compared between the two groups. Radionuclide imaging was utilized to determine relevant parotid gland function indicators in the two groups before and after treatment. UI= (peak value-base value)/base value; EI = (apparent diffusion coefficient (ADC) value on acid stimulation-ADC value 6min after acid stimulation)/(ADC value on acid stimulation-base value) [8].
Dry mouth grading after treatment in both groups
Mouth dryness (xerostomia) of the patients was evaluated according to the following standards [9]. Grade 0: No change was found compared with that before treatment; Grade I: There was a mild change in taste to stimulation, such as metal taste, and the saliva was slightly thick, with mild dryness of the mouth; Grade II: There was marked change in taste to stimulation, and the saliva was viscous and thick, with moderate dryness of the mouth; Grade III: There was no change in taste to stimulation, with significant dryness of the mouth; Grade IV: Oral mucosal fibrosis was noted.
Prognosis of the two groups
The prognosis was mainly assessed by calculating the local recurrence-free rate, distant metastasis-free rate, and tumor-free survival rate during 1 year of follow-up in both groups [10].
Secondary outcome measures
Differences in relevant baseline data between the two groups
Differences in related indicators regarding quality of life after treatment between the two groups
Quality of life, which consists of four separate aspects including function, emotion, family/society and physiology, was evaluated using the Chinese version of the QLQ-H&N65 scale, with a total score of 100 points and a lower score denoting worse quality of life in the corresponding aspect [11].
Statistical methods
SPSS 22.0 statistical software was adopted for data analysis. Measurement data were described as mean ± standard deviation (x̅ ± sd), with the comparison between two groups performed by independent sample t-test and comparison within groups conducted using paired t-test. Enumeration data were presented as percentage, with chi-square test used for comparison between groups. A P value of less than 0.05 was defined as statistically significant.
Results
Baseline data
In the control group, there were 48 patients (mean age = 48.1±9.6). Among them, there were 26 were males and 22 females, with a mean disease duration of (22.2±6.9) months; pathological types included undifferentiated carcinoma in 1 patient and poorly differentiated squamous cell carcinoma in 47 patients; 6 of the 48 patients were classified as stage I, 15 as stage II, 20 as stage III, and 7 as stage IV, based on TNM staging system. In the research group, there were 48 patients (mean age = 48.0±9.1). Among them, there were 25 males and 23 females, with a mean disease duration of (21.5±7.3) months; pathological types included undifferentiated carcinoma in 2 patients and poorly differentiated squamous cell carcinoma in 46 patients; 7 of the 48 patients were classified as stage I, 16 as stage II, 19 as stage III, and 6 as stage IV, based on TNM staging system. There were no significant differences in the baseline data containing gender, mean age, mean disease duration, pathological type, and TNM staging between the two groups (all P>0.05). See Table 1 for details.
Table 1.
Baseline data (x̅ ± sd)
| Item | Control group (n=48) | Research group (n=48) | χ2/t | P |
|---|---|---|---|---|
| Gender (cases, %) | 1.032 | >0.05 | ||
| Male | 26 (54.17) | 25 (52.08) | ||
| Female | 22 (45.83) | 23 (47.92) | ||
| Mean age (years) | 48.1±9.6 | 48.0±9.1 | 1.021 | >0.05 |
| Mean disease duration (months) | 22.2±6.9 | 21.5±7.3 | 2.635 | >0.05 |
| Pathological type (cases, %) | 2.485 | >0.05 | ||
| Undifferentiated carcinoma | 1 (2.08) | 2 (4.17) | ||
| Poorly differentiated squamous cell carcinoma | 47 (97.92) | 46 (95.83) | ||
| TNM staging | ||||
| Stage I | 6 (12.50) | 7 (14.58) | 1.485 | >0.05 |
| Stage II | 15 (31.25) | 16 (33.33) | 2.362 | >0.05 |
| Stage III | 20 (41.67) | 19 (39.58) | 1.003 | >0.05 |
| Stage IV | 7 (14.58) | 6 (12.50) | 1.844 | >0.05 |
Note: TNM: tumour node metastasis.
Short-term response rate
The short-term response rate in the research group was significantly higher than that in the control group (P<0.05). See Table 2 and Figure 1 for details.
Table 2.
Short-term response rate (case, %)
| Group | Control group (n=48) | Research group (n=48) | χ2 | P |
|---|---|---|---|---|
| CP | 19 (39.58) | 22 (45.83) | ||
| PR | 8 (16.67) | 16 (33.33) | ||
| SD | 13 (27.08) | 5 (10.42) | ||
| PD | 8 (16.67) | 5 (10.42) | ||
| Response rate | 56.25% | 79.16% | 6.325 | <0.05 |
Note: CR: complete response; PR: partial response; SD: stable disease; PD: progressive disease.
Figure 1.
Comparison of clinical efficacy before and after radiotherapy between the two groups. A: Transverse view before treatment; B: Sagittal view before treatment; C: Coronal MR image before treatment. Cervical lymph node metastasis of nasopharyngeal carcinoma and cervical lymph node invasion of right parotid gland; D-F: Complete regression of the right lymph node after treatment. The patient had non-keratinizing carcinoma of the nasopharynx. The nasopharyngeal mass was located in posterior wall, invading the clivus, with bilateral cervical lymph node metastasis (cT3N2M0, Stage III), of which the right cervical lymph node invaded the right parotid gland. Radical radiotherapy for nasopharyngeal carcinoma was performed after 2 cycles of docetaxel plus cisplatin chemotherapy, at a tumor-absorbed dose (DT) of 70 Gy/33F.
Related parotid gland function indicators
UI and EI: After treatment, UI and EI were significantly decreased in both groups compared with those before treatment (P<0.05), and were higher in the research group than in the control group (P<0.05). See Table 3 and Figure 2 for details.
Table 3.
Related parotid gland function indicators: UI level and EI level (x̅ ± sd)
| Group | Control group (n=48) | Research group (n=48) | t | P |
|---|---|---|---|---|
| UI level (%) | ||||
| Before treatment | 7.35±2.12 | 7.40±2.04 | 1.216 | >0.05 |
| After treatment | 4.16±0.96 | 5.40±2.35 | 18.236 | <0.05 |
| EI level (%) | ||||
| Before treatment | 0.43±0.19 | 0.40±0.16 | 2.625 | >0.05 |
| After treatment | 0.13±0.03 | 0.30±0.13 | 17.021 | <0.05 |
| T value after treatment | 16.482 | 18.594 | ||
| P value after treatment | <0.05 | <0.05 |
Figure 2.
Related parotid gland function indicators: UI and EI. A: UI; B: EI. Compared with the group at enrollment, *P<0.05; compared with the control group, #P<0.05. UI: uptake index; EI: excretion index.
Dry mouth grading
After treatment, dry mouth grading in the research group was lower than that in the control group (all P<0.05). See Table 4 for details.
Table 4.
Dry mouth grading (case, %)
| Group | Control group (n=48) | Research group (n=48) | χ2 | P |
|---|---|---|---|---|
| Grade 0 | 0 (0.00) | 5 (10.41) | 6.152 | <0.05 |
| Grade I | 2 (4.17) | 21 (43.75) | 5.021 | <0.05 |
| Grade II | 27 (56.25) | 14 (29.17) | 6.485 | <0.05 |
| Grade III | 19 (39.58) | 8 (16.67) | 7.021 | <0.05 |
| Grade IV | 0 (0.00) | 0 (0.00) | 6.947 | <0.05 |
Quality of life indicators
After treatment, indicators related to quality of life in the research group were higher than those in the control group (all P<0.05). See Table 5 for details.
Table 5.
Related quality of life indicators (points, x̅ ± sd)
| Group | Control group (n=48) | Research group (n=48) | t | P |
|---|---|---|---|---|
| Function | 15.16±1.23 | 17.67±1.86 | 16.956 | <0.05 |
| Emotion | 15.96±2.01 | 19.39±2.56 | 18.021 | <0.05 |
| Family/society | 15.25±1.84 | 18.65±2.41 | 17.003 | <0.05 |
| Physiology | 18.58±1.92 | 22.34±2.15 | 16.548 | <0.05 |
| Total | 67.14±4.53 | 77.39±6.42 | 19.544 | <0.05 |
Prognosis
The local recurrence-free rate and distant metastasis-free rate in the research group were higher than those in the control group (all P<0.05). See Table 6 for details.
Table 6.
Prognosis (case, %)
| Group | Control group (n=48) | Research group (n=48) | χ2 | P |
|---|---|---|---|---|
| Local recurrence-free | 33 (68.75) | 43 (89.58) | 6.152 | <0.05 |
| Distant metastasis-free rate | 35 (72.92) | 39 (81.25) | 7.545 | <0.05 |
| Tumor-free survival | 34 (70.83) | 36 (75.00) | 2.031 | >0.05 |
Discussion
Intensity-modulated radiotherapy is a mainstream radiation technique developed in the early 2000s [12]. It allows radiation to match the shape of the lesions during the treatment of NPC and effectively kill tumor cells [13]. Meanwhile, by saving the neighboring tissue around the target lesion from or reducing the overall irradiation damage, intensity-modulated radiotherapy can also maximize the protection of normal tissues [14].
The results of this study suggest that short-term response rate in the research group is higher than that in the control group. Nasopharyngeal carcinoma (NPC) is one of the most ideal indications for intensity-modulated radiotherapy in clinical practice [15]. The reasons mainly include: (1) NPC is basically treated by radiotherapy in clinical practice [16]. (2) Compared with other tumors, NPC patients have a higher chance of longer survival after treatment [17]. Therefore, the patients will develop high-level requirements for quality of life during survival time [18]. (3) Shape of the target NPC region is relatively irregular [16,19]. (4) There are many vital tissues and organs adjacent to NPC, and their relationship is rather complicated [20,21]. (5) NPC has unique biological characteristics, which require full coverage of both the lymphatic drainage area and primary lesion in the same radiation field to avoid leakage or overlapping radiation doses of adjacent fields [22]. (6) The procedure to fix the head and neck is reliable and simple and involves no relative movement of vital organs, ensuring effective and smooth implementation of high-precision radiotherapy [23,24]. Clinically, NPC can be seen as a dose-dependent tumor, and its local control rate will be elevated with increasing irradiation doses. However, increased irradiation dosing at the target site may account for higher short-term efficacy of intensity-modulated radiotherapy.
Radiotherapy is the first choice for treating NPC in the clinic, while the irradiation dose at the target site is directly associated with the local control rate of the tumor. Due to dose limits for relevant vital organs, such as the brainstem and spinal cord, traditional use of bilateral opposed-field irradiation will increase the dose to tissues such as skin, and muscles surrounding the temporomandibular joint, and parotid gland, resulting in radiation injuries in patients including cervical fibrosis, skin injury, restriction of mouth opening and xerostomia. One of the most common complications in NPC patients during radiotherapy is dry mouth, mainly resulting from radiotherapy. With the major salivary glands of the patients exposed to the radiation field, salivary secretion will be reduced by about 50% of that at conventional fractionated tumor-absorbed dose (DT) of 10 Gy, and irreversible damage will be produced at a DT exceeding 45 Gy. Salivary flow rate is gradually decreased with increasing radiotherapy doses. Such change will exert a negative impact on the ability of saliva to kill bacteria, provide a buffer and dilution for food ingestion and cleanse the mouth, which allows some microorganisms to be more likely to multiply and grow in the mouth of NPC patients, further provoking oral diseases such as periodontal infection and dental caries, and can result in serious adverse effects on their physical health and quality of life. The results of this study suggested that dry mouth grading in the research group was lower than that in the control group. The main reason is that IMRT has adjustable irradiation volumes and dosing to the salivary glands during radiotherapy through multifield non-coplanar irradiation and dynamic multi-leaf grating, thus significantly reducing the dose to the parotid gland. Studies have pointed out that irradiated volume ≤50% at 34 Gy can well protect the parotid gland, reduce the risk of severe xerostomia, and avoid irreversible damage. It has also been found that over time, some patients with dry mouth after radiotherapy will gradually improve. This is probably because the tiny glands in the oral cavity were exposed to a small dose or not irradiated, so that the remaining cells keep their ability to function properly, enabling the partial recovery of salivary gland function through cell proliferation.
This study revealed that after treatment, indicators related to quality of life in the research group were higher than those in the control group. Possible reasons for this finding are: compared with three-dimensional conformal radiotherapy, intensity modulated radiotherapy can flexibly adjust irradiation dose, so as to provide better protection for the target tissue, and prevent reduction in the patients’ quality of life due to adverse reactions of irradiation. Also, psychologically, it may be considered that intensity-modulated radiotherapy is more advanced than 3DCRT, so patients will have greater confidence in IMRT and can better tolerate the disease treatment or side effects caused by radiotherapy, hence the quality of life in these patients will be higher.
In this study, a small number of patients were enrolled due to a limited time frame, which may affect study results to a certain extent. Therefore, further studies with an increased sample size are expected in the future. Furthermore, we only studied NPC patients in one hospital and did not collect relevant diagnosis and treatment data from other hospitals. Thus, the obtained data were relatively inadequate and may have certain bias. If permitted, large-sample size, multicenter investigations should be performed subsequently to obtain more detailed and objective data.
To sum up, intensity-modulated radiotherapy in NPC patients can significantly improve the short-term response rate, reduce mouth dryness and parotid gland injury after radiotherapy, as well as improve the quality of life and prognosis of patients.
Acknowledgements
This work was supported by the Zhejiang Medical and Health Research Project (2019KY245) and Taizhou Science and Technology Bureau Project (162yw06(2)).
Disclosure of conflict of interest
None.
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