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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 5  |  Page : 1219-1224

Clinicopathological factors affecting the prognosis of massive hemorrhage after radiotherapy for patients having nasopharyngeal carcinoma


1 Department of Otorhinolaryngology, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzong Clinical College of Fujian Medical University, Fujian, China
2 Department of Otorhinolaryngology, The 900th Hospital of Joint Logistic Support Force, PLA, Fuzhou, Fujian, China

Date of Submission09-Apr-2021
Date of Acceptance07-Oct-2021
Date of Web Publication27-Nov-2021

Correspondence Address:
Maoxin Wang
No. 156 xihuanbei Road, Fuzhou, Fujian
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_586_21

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 > Abstract 


Aims: The aim of the study is to investigate the clinicopathological factors that determine prognosis of nasopharyngeal hemorrhage after radiotherapy in patients with nasopharyngeal carcinoma (NPC).
Patients and Methods: The clinicopathological data of 539 patients with NPC, who received radiotherapy, were analyzed retrospectively. Parameters included gender; age; T-stage; N-stage; pathological type; type of radiotherapy; synchronous chemotherapy; secondary-course radiotherapy; radiation-induced skull base osteonecrosis; diabetes, hypertension, or other systemic diseases; results of nasopharyngeal bacterial culture; and nasopharyngeal tumor recurrence. Univariate and multivariate analyses were performed using the Chi-square test and logistic regression. Afterward, the Kaplan–Meier's method was applied to analyze the survival of patients with nasopharyngeal hemorrhage.
Results: Among all patients examined, 64 (11.9%) had nasopharyngeal hemorrhage after radiotherapy. The univariate analysis showed that T-stage (P < 0.01), secondary-course radiotherapy (P < 0.01), radiation-induced skull base osteonecrosis (P < 0.01), nasopharyngeal bacterial culture results (P < 0.01), and nasopharyngeal tumor recurrence (P < 0.01) were associated with nasopharyngeal hemorrhage. Multivariate analysis showed that only radiation-induced skull base osteonecrosis was significantly associated with nasopharyngeal hemorrhage after radiotherapy (odds ratio = 41.83, P = 0.0001). Nevertheless, in patients with internal carotid artery hemorrhage, the survival rate was much lower than that in patients with external carotid artery bleeding. The main cause of death during follow-up was rebleeding.
Conclusion: The rate of mortality in patients with nasopharyngeal hemorrhage after radiotherapy was high. The presence of radiation-induced skull base osteonecrosis was a decisive factor in these patients. However, after successful rescue, arterial embolization or stent implantation is proposed to prolong survival.

Keywords: Arterial embolization, nasopharyngeal carcinoma, nasopharyngeal hemorrhage, radiation-induced skull base osteonecrosis, radiotherapy


How to cite this article:
Huang Y, Yan D, Wang M, Chen S, Yang F. Clinicopathological factors affecting the prognosis of massive hemorrhage after radiotherapy for patients having nasopharyngeal carcinoma. J Can Res Ther 2021;17:1219-24

How to cite this URL:
Huang Y, Yan D, Wang M, Chen S, Yang F. Clinicopathological factors affecting the prognosis of massive hemorrhage after radiotherapy for patients having nasopharyngeal carcinoma. J Can Res Ther [serial online] 2021 [cited 2022 Jan 22];17:1219-24. Available from: https://www.cancerjournal.net/text.asp?2021/17/5/1219/331310




 > Introduction Top


Nasopharyngeal carcinoma (NPC) is among the most common malignancy in Southeast China. Radiotherapy is the preferred treatment for the disease. Recently, with the continuous improvement in local radiotherapy technology and comprehensive treatment methods, the overall survival rate of NPC patients has increased greatly.[1],[2],[3],[4]

However, the complications of NPC patients after radiotherapy are still an urgent problem for clinicians. Among them, nasopharyngeal massive bleeding is the most dangerous situation associated with a high mortality rate.[5],[6],[7],[8] Hence, to explore the possible risk factors favoring nasopharyngeal massive hemorrhage, we retrospectively analyzed the clinicopathological data of 539 patients with NPC after radiotherapy.


 > Patients and methods Top


Inclusion and exclusion criteria

Patients with (1) nonkeratinized undifferentiated and differentiated carcinoma of the nasopharynx confirmed by pathology; (2) patients who had received radiotherapy for NPC; and (3) patients who had received initial treatment without distant metastasis were included in this study.

However, (1) patients with other pathological types; (2) those who did not receive or complete radiotherapy for NPC; (3) patients with distant metastasis at the time of initial treatment; and (4) patients with incomplete clinical pathology and follow-up data were excluded.

Patient characteristics

From January 2005 to January 2015, 539 patients diagnosed with NPC at our hospital met the study's inclusion criteria. Among them, 147 patients had received radiotherapy alone, whereas 392 patients had received radiotherapy along with concurrent chemotherapy. The study ultimately included 428 males and 111 females having an average age of 47.4 years (range, 16–78 years). Then, the medical ethics committee in our hospital approved the study. Yet, because of the retrospective nature of this study, patient consent for inclusion was waived. The procedures followed were in accordance with the Helsinki Declaration of 1975, as revised in 2013.

Clinical and pathological factors

In this study, we mainly analyzed the following clinical and pathological factors: gender; age; T-stage; N-stage; pathological type; type of radiotherapy; synchronous chemotherapy; secondary-course radiotherapy; radiation-induced skull base osteonecrosis; diabetes, hypertension, or other systemic diseases; results of nasopharyngeal bacterial culture; and nasopharyngeal tumor recurrence. Clinical stage was determined according to the Union for International Cancer Control's standard (8th edition).[9],[10] However, pathological types were determined by h and e staining. Cervical lymph node metastasis was also determined through fine-needle aspiration cytology, whereas staging was determined based on the results of imaging examinations. In addition, the radiotherapy methods involved in this study comprised three-dimensional conformal intensity-modulated radiotherapy and conventional linear accelerator radiotherapy. The radiation dose was 65–70 Gy. Similarly, the radiation dose of the secondary-course radiotherapy remained 65–70 Gy. Cases treated with concurrent chemotherapy also received 21-d cisplatin single-drug therapies.

Therefore, 18 cases with incomplete pathological data were included in this study. Their original medical records were searched, after which paraffin samples from the pathology department were re-sectioned to supplement the data. Radiation-induced skull base osteonecrosis was then diagnosed according to its symptoms, such as headache, stench of the nose, and the result of nasal endoscopy, including computed tomography (CT) results, whereas, nasal endoscopy showed that no mucosa covered the skull base bone. Nevertheless, radiation-induced skull base osteonecrosis has characteristic CT findings; extensive and symmetrical bone destruction, exposed surface of the skull base bone in the air cavity, dead bone formation, and small air bubbles in the soft tissue.

Follow-up

Patients with NPC after treatment were followed up regularly through return visits, investigations, and telephone, or snail mail interviews. Among 539 patients, 64 patients had nasopharyngeal hemorrhage (all more than 400 ml). The occurrence of nasopharyngeal hemorrhage ranged from 4 months to 7 years after radiotherapy (average of 27.2 months after radiotherapy). Subsequently, nine of these cases died at home or on the way to the hospital. However, 46 patients were successfully rescued, 41 of whom received arterial embolization or stent implantation. Patients were followed until the end of life.

Statistical analysis

SPSS v. 20.0 software (International Business Machines Corporation, Armonk, State of New York, United States) was used to analyze the relationship between the clinicopathological factors of NPC patients and the occurrence of nasopharyngeal hemorrhage after radiotherapy. Then, logistic regression analysis (step by step) was performed for selected factors. In addition, the Kaplan–Meier's method was used to analyze the correlation between patient survival and nasopharyngeal hemorrhage after radiotherapy.


 > Results Top


Among the 539 patients diagnosed with NPC, 64 (11.8%) had nasopharyngeal hemorrhage after radiotherapy. The clinical and pathological factors analyzed within groups included their genders; ages; T-stages; N-stages; and pathological types. Types of radiotherapy; synchronous chemotherapies; secondary-course radiotherapy; and radiation-induced skull base osteonecrosis undergone were also analyzed. Likewise, those with underlying diabetes, hypertension, or other systemic diseases including results from nasopharyngeal bacterial cultures and nasopharyngeal tumor recurrence were analyzed. We found a significant correlation between nasopharyngeal hemorrhage and secondary-course radiotherapy (P < 0.01), radiation-induced skull base osteonecrosis (P < 0.01), nasopharyngeal bacterial culture results (P < 0.01), and nasopharyngeal tumor recurrences (P < 0.01). However, no significant correlation with nasopharyngeal hemorrhage after radiotherapy was found for gender, age, N-stage, pathological type, type of radiotherapy, synchronous chemotherapy, diabetes, hypertension, or other systemic diseases (P > 0.05) [Table 1].
Table 1: Clinical and pathological characteristics of patients diagnosed with nasopharyngeal hemorrhage after undergoing radiotherapy for nasopharyngeal carcinoma

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Multivariate logistic regression analysis for the factors listed above also showed that only radiation-induced skull base osteonecrosis was significantly associated with nasopharyngeal hemorrhage after radiotherapy [odds ratio = 41.83, P = 0.0001, [Table 2]]. Thus, among the 64 cases of nasopharyngeal hemorrhage, 55 of these cases were immediately sent to the hospital, whereas 9 cases died at home or on the way to the hospital. Still, among the 55 patients who were immediately sent to the hospital, successful nasal packing was used to rescue 46 of these cases. In comparison, 41 cases were detected using digital subtraction angiography (DSA), including 10 cases with bleeding from the external carotid artery that was treated with arterial embolization. However, 31 cases with internal carotid artery hemorrhage, including 6 cases that were treated with arterial embolization, and 25 cases that were treated with a covered stent were observed.
Table 2: Logistic analysis of clinicopathological factors related to cases of nasopharyngeal hemorrhage after patients underwent radiotherapy for nasopharyngeal carcinoma

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Alternatively, Kaplan–Meier's survival analysis showed that the overall 3-year and 5-year survival rates were 26.6% and 12.2%, respectively [Figure 1]. Therefore, among the 31 patients with internal carotid artery hemorrhage, their 1-year survival rate was 60.9%; and their 3-year survival rate was 15.1%. However, no 5-year survival rate was observed. Here, 19 patients died of rebleeding. In contrast, the 5-year survival rate was 50% in patients with external carotid artery bleeding [Figure 2]. Thus, among the five patients who discontinued treatments after successful rescue, three cases died of rebleeding a few days later, and the other two cases were followed up for 3 years without any episode of rebleeding.
Figure 1: The overall survival rate of patients diagnosed with nasopharyngeal hemorrhage after radiotherapy

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Figure 2: Comparison of survival rates between patients diagnosed with massive hemorrhage, as induced by external versus internal carotid artery rupture

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 > Discussion Top


Radiotherapy is the preferred treatment for NPC. Radiation not only kills tumor cells but also damages normal tissues and cells around the tumor. Likewise, in patients with NPC patients, the main cause of nasopharyngeal hemorrhage after radiotherapy is damage to adjacent blood vessels. Previous studies have shown that radiation leads to vascular endothelial damage, resulting in elastic fiber rupture and increased vascular wall fragility.[11] In addition, tissue necrosis in areas surrounding the tumor impairs the delivery of nutrients to the vascular wall. This impairment is proposed to exacerbate any preexisting damage and increase the risk of vascular wall rupture and massive bleeding in the presence of infections.

Therefore, in a case–control study, Chen et al., found that secondary-course radiotherapy and radiation-induced skull base osteonecrosis were key factors predicting carotid artery rupture syndrome after radiotherapy.[12] Similarly, results from the univariate analysis in our study showed that T-stage, secondary-course radiotherapy, radiation-induced skull base osteonecrosis, results from nasopharyngeal bacterial cultures, and nasopharyngeal tumor recurrences were significantly correlated with nasopharyngeal hemorrhage. These results were similar to those reported by Chen et al. We also found that the T-stage of these cancers was closely related to nasopharyngeal hemorrhage after radiotherapy. One reason for this observation is proposed to be tumor invasion of bone tissues in addition to arteries after the T3 stage. In such cases, a high radiation dose during radiotherapy would cause bone necrosis, impairment of nutrition supplied to bone, or direct radiation damage to blood vessels.

Secondary-course radiotherapy is conducted to treat recurrent head-and-neck tumors after radiotherapy. It has been reported that this therapy achieves a good rate of local control. However, after applying this therapy, 32.5% patients died of carotid artery rupture syndromes or carotid hemorrhages during a previous study.[13] Similarly, we also found that the incidence of nasopharyngeal hemorrhage increased significantly after the second course of radiotherapy. Therefore, we speculated that an increase in radiation dose aggravated damage to the bone, mucosa, and blood vessels.

Wu et al. found that nasopharyngeal necrosis was closely related to infections after radiotherapy and that lesions eroded the internal carotid artery and caused massive hemorrhage.[14] In our study, patients with positive results on nasopharyngeal bacterial cultures were more expected to experience nasopharyngeal hemorrhage. This proposition was because toxins and enzymes released by bacteria can damage the arterial wall, especially in areas where necrosis affected the bone and mucosa, which aggravates tissue damage and causes bleeding.

Likewise, results of our univariate analysis indicated that the recurrence of nasopharyngeal tumors was closely related to nasopharyngeal hemorrhage. One possible reason is that recurrent nasopharyngeal tumor was more expected to invade damaged bones, and even directly destroy the vulnerable artery wall after radiotherapy, resulting in massive hemorrhage.

Further logistic multivariate analysis also showed that only radiation-induced skull base osteonecrosis was related to nasopharyngeal hemorrhage after radiotherapy, which indicated that destruction or necrosis of the skull base can be the decisive factor leading to nasopharyngeal hemorrhage cases after radiotherapy. The other four factors investigated were proposed to act only as synergistic or influencing factors.

Previous studies have shown that platinum-based concurrent chemotherapy improved the survival rate of NPC patients,[15],[16] which was proposed to also cause damage to coagulation functions and blood vessels.[17] However, our study did not find a clear correlation between treatment with chemotherapy drugs and nasopharyngeal bleeding. In contrast, the presence of diabetes, hypertension, or other systemic diseases was reported to lead to peripheral vascular lesions, which increased the risk of bleeding in tissues with radiation-related damages. However, the results from our study indicated no significant correlation between such complications and nasopharyngeal bleeding after radiotherapy.

In NPC patients who have undergone radiotherapy, nasopharyngeal hemorrhage involved the internal carotid or external carotid artery branches, which was linked to a high mortality rate. Most patients died of hemorrhagic shock or asphyxia caused by aspirating blood fluids. Likewise, this study included 64 cases with massive hemorrhage, including 55 sent immediately to the hospital, and 46 successfully rescued. The successful rescue was 83.6%. After successful rescue, DSA should be conducted to identify the vessel that caused the bleed. In the case of bleeding from the external carotid artery branch, vascular interventional embolization procedures can be conducted for hemostasis, thereby avoiding tissue ischemia and necrosis due to the abundance of collateral circulation. However, in the case of internal carotid artery hemorrhage, vascular interventional embolization or a covered stent can be used, depending on the pattern of intracranial artery vascularization. Notably, Jong et al. found that the average survival time in such patients can be increased by 9 months using interventional therapy.[18]

Likewise, Mak et al.[19] analyzed 15 patients diagnosed with massive hemorrhage. The rupture of an internal carotid artery pseudoaneurysm after radiotherapy for NPC accounted for this complication. In that study, 4 patients underwent arterial embolization and 11 patients were implanted with covered stents, after which bleeding was stopped in all cases. However, during the follow-up period, pseudoaneurysm occurred again in 2 cases, with cerebral infarction in 2 of these cases, and brain abscess in 1 case. During an average follow-up period of 13 months, the stent patency rate was 67%, and no clinical symptoms in the 3 cases were observed with stent occlusion. Therefore, good results are achieved with embolization and using a covered stent. Tsang et al.[20] reached a similar conclusion. Likewise, in our study, the rate of survival after external carotid artery branch bleeding was significantly higher than the rate of survival after internal carotid artery bleeding was observed. Nevertheless, embolization of the external carotid artery branch is, therefore, the more effective treatment strategy because the embolization of internal carotid artery hemorrhage is associated with complications, such as hemiplegia and cerebral infarction. Hence, we used the covered stent to achieve an immediate hemostatic effect. However, the covered stent is short, and the portion of the vessel wall that remains uncovered can be fragile due to radiotherapy, occasionally leading to the second massive hemorrhage and a low survival rate. In this study, 19 patients died of rebleeding after receiving a covered stent.

Conclusively, massive hemorrhage after radiotherapy in NPC patients is dangerous, with a poor prognosis. Likewise, necrosis or destruction of the skull base increases the risk of nasopharyngeal hemorrhage. Therefore, we should pay sufficient attention to the patient's condition and ensure that medical treatment given is administered in an expedient fashion. Furthermore, after successful rescue, arterial embolization or stent implantation is proposed to prolong survival time. Therefore, our findings provided a more reliable theoretical basis for the clinical analysis and judgment of the probability and risk of nasopharyngeal hemorrhage in NPC patients after radiotherapy.

Financial support and sponsorship

The Natural Science Foundation of Fujian Province, China (No: 2015J01485, 2021J011260) supported this study.

Conflicts of interest

There are no conflicts of interest.



 
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