Present status and Progress of Radiotherapy for Nasopharyngeal Carcinoma
Minqiang Xie, Rizhao Liu, Xianqing Xian, Chunling Zhang, Zeyi Deng
Department of Otorhinolaryngology head and neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China
Abstract: About 90% of the nasopharyngeal carcinoma (NPC) is non-keratinizing undifferentiated carcinoma sensitive to radiotherapy and indicates a better prognosis than other types. Therefore it is important to optimize the radiation scheme and to set reasonable irradiation dose for better survival rate and life quality of the NPC patients. Herein this paper, we reviewed various radiotherapies of current practice in the clinical about the dis/advantages, applicable conditions, major complications and research prospective.
Keywords: Nasopharyngeal carcinoma; Radiotherapy prognosis; Side effect
The incidence of NPC varied widely geographically. The average incidence is less than 0.01 per 1000 people. However, NPC becomes a common head and neck tumor in South China especially in Guangdong Province. The average incidence is 0.2-0.3 per 1000 males and 0.15-0.2 per 1000 females. Therefore it is called province tumor of Guangdong’. NPC locates in the depth of the tissues surrounded by the vital tissues such as brainstem, optic nerve etc. Therefore, it is extremely hard to excise all the NPC tissues by the surgery. Moreover, about 90% of the NPC are non-keratinized undifferentiated carcinoma cells that are sensitive to radiotherapy. The anatomical and biological characteristics of NPC tumor discussed above decided that radiotherapy is the major solution for NPC.
Currently external irradiation and intra-cavity irradiation are the two major radiotherapies for NPC. External irradiation includes conventional radiotherapy, stereotactic radiotherapy, intensity modulated radiation therapy (IMRT) and tomotherapy etc. Among the classifications mentioned above, IMRT and tomotherapy have experienced a great progress in recent years, which are significantly better than the conventional radiotherapy on the local control rate. Intracavity irradiation mainly refers to intracavitary brachytherapy. All the variations will be discussed as follows.
1. External irradiation
1.1. Conventional radiotherapy
The dose of conventional radiotherapy is usually 1.8-2.0 GY per time, 5 times a week. Due to the achievements of imaging and radiotherapy, the 5-year survival rate of NPC increased to 76.1%. Although previous researches showed a positive correlation between the radiotherapy dosage and NPC control rate.The large target range, poor conformality, severe injury of normal tissues and the largest tolerances does of radiotherapy to the nasopharynx tissues limited the radiotherapy application. Moreover, due to the family income difference between Southeast and Northwest China, conventional radiotherapy still maintain an important treatment for NPC in the low income and remote area.
1.2. Stereotactic radiotherapy
In 1951, Lars Leksell, a Swedish neurosurgery doctor, put forward the concept of stereotactic radiotherapy. The stereotactic radiosurgery refers to one-fractional irradiation exposure to the intracranial benign lesions with a large does to the 3D cluster in the multiple small scales. Stereotactic radiotherapy is based on the stereotactic radiosurgery technique of fractional irradiation with high does cluster rather than the traditional evenly large does. Stereotactic radiotherapy required a fixed position and treatment with stereotaxic frame so that it may reduce the positioning error and also has the high does cluster focusing on the tumor target area. Therefore it has the advantages of high accuracy, high does for therapy and high therapeutic gain ratio, and low does in normal tissues, so it is suitable for radiotherapy boost for residual lesions and re-course radiotherapy for recurrent NPC.
Dhanachai et alconducted a retrospective analysis of 32 cases those were residual or recurrent nasopharyngeal carcinoma patients. These patients received fractionated stereotactic radiotherapy to evaluate its efficacy and complications. Stereotactic radiotherapy does was 17-59.4 GY (average 34.6GY), 4-25 times (average 6 times). After the mean follow-up of 25.5 months, 3-year survival rate was 71.2% and incidence of complications was up to 25%. Only one case developed complications of Grade 4 recovered after treatment and the rest cases were of Grade 2-3. Wu et al had reported 12 cases of recurrent NPC, ten cases were simple local recurrences and the other two were local recurrent NPC with metastasis. All these patients were administered by prescribed does according to the 90% isodose curve. Fractionated dose was 6-8 Gy, twice a week. After 3 months treatment, 2 patients were dead, 6 were complete remission, 3 were partial remission and 1 was stable. After a mean follow-up of 14.2 months, the 2-year survival rate and disease-free survival rate were 66.7% and 58.3% respectively, no acute or late complications occurred. Also, the report showed that stereotactic radiotherapy was effective to local recurrent NPC. Chua et al found that stereotactic radiotherapy could increase the overall survival rate of residual or recurrent NPC.
The current devices for stereotactic radiotherapy include gamma knife and cyber knife. Gamma knife is mainly used for intracranial small tumors. The cyber knife system is consist of a six-degree free manipulator, which includes 6-MV linear accelerator, real-time image tracking system, breathing-moving synchronous tracking system and spinal positioning system. Cyber knife system continuously receives the signals of the patient's position，of the tumor location and of the breathing feedback, meanwhile the system adjusts the bed position and accelerator irradiation angle in real-time. It maintains the accuracy of X-ray exposure before and under treatment so that it improves the accuracy of treatment and protects the surrounding important tissues. There are relevant literatures reported that the application of cyber knife breathing-moving tracking system reduces the positioning error that causes by breathing to 0.3 mm.
Seo et al conducted a retrospective analysis of 45 recurrent NPC patients received the cyber knife fractionated stereotactic radiotherapy to evaluate its efficacy and complications. Prescribed dose was 24-45 Gy (average 33 Gy) and fractionized 3-5 times for exposure. Among the 45 patients, 23 were complete remission. The 5-year survival rate, local progression-free survival rate and disease progression-free survival rate were 60%, 79% and 74% with only 5 cases had severe late complications of grade 4-5. Roh et al reported 44 cases of recurrent head and neck cancer that received cyber knife treatment, including 8 of NPC. The irradiation dose was 18-40 Gy (average 30 Gy), fractionized 3-5 times for exposure. The mean size of the tumor was 22.6cm3. After a mean follow-up of 17.3 months, 35 patients entered final analysis and the effective rate of treatment was 80%. Thirteen patients experienced acute phase response of Grade 3 and only three of them had late complications (1 of osteonecrosis, 2 of soft tissue necrosis).
Stereotactic radiotherapy uses the multiple non-coplanar arcs of rotation focus technology that its additional 3-level collimator is circle so that it can focus on the range of lesions less than 3 cm in diameter. Therefore it is suitable for radiotherapy boost after treating NPC by conventional external radiotherapy or for treating recurrent and residual NPC. So it limits the application. The single dose of stereotactic radiotherapy is obviously higher than that of conventional radiotherapy. The severe complications caused by irradiation include nasopharyngeal bleeding, nasopharyngeal mucosal necrosis, cranial nerve palsy, temporal lobe necrosis and radioactive basicranial osteonecrosis, etc. The most serious complication is nasopharyngeal bleeding and the incidence was reportedly ranged from 2.2% to 27.8%[11,12]. Wu et al reported 90 cases of persistent and recurrent NPC patients and the incidence of who suffered fatal nasopharyngeal bleeding after stereotactic radiotherapy was 2.2% (2/9). But Xiao et al and Cui et al reported the incidence of that was up to 16% (8/50) and 22.2% (4/18), respectively. In order to reduce the incidence of fatal nasopharyngeal bleeding, we had better to decrease the fractional-irradiation dose properly when the tumors are in or extremely close to the carotid sheath area. The incidence of radiation-induced temporal lobe necrosis was also up to 20%[11,13,14]. In conclusion, how to improve the efficacy and reduce the injury to the surrounding tissues will always be a challenge for cancer radiotherapy. Due to the short time of cyber knife in use, it remains further study for its validity and limitations.
1.3. Intensity Modulated Radiation therapy (IMRT)
In 1959, Takahashi et al was the first to put forward and illuminate the concept of Intensity Modulated Radiation therapy (IMRT). In the 1970s, Bjarngard et al and Kijewski et al were the first to propose the Intensity Radiation therapy that developed rapidly in the 1990s. In order to achieve 3d Conformal Radiotherapy, the following two conditions must be met. First, the irradiation field and the cancer target field must be in the same shape. Second, the output dose in all points of each field must be modulated as requirement so as to ensure the dose equality in all fields on the surface of target areas. It is classic conformal radiotherapy if it just meet the first condition while it is IMRT if it meet both two. IMRT is not only required the irradiation field in the same shape as the target field, but also in the same ‘shape’ in the does. IMRT can not only increase the dose in target area, but also can well protect the important surrounding tissues. It also can increase the survival rate and improve the life quality. The above advantages are what conventional radiotherapy cannot achieve.
In 2009, Lin et al reported 323 cases of primary NPC patients (260 were above stage Ⅲ) received IMRT ((prescribed dose 66-69.5 Gy, 2.2-2.25 Gy per time) to evaluate its efficacy and side effect. The result showed that 3-year local control rate, regional control rate, distant metastasis-free rate, disease-free survival rate and overall survival rate were 95%, 98%, 90%, 85% and 90%. Acute toxic respond of Grade 3 includes mucositis (27.5%), desquamation of skin (4.6%) and leukopenia(5.9%), but just 1 case occurred toxic respond of Grade 4 of leukopenia. In the same year, Singaporean Tham et al also carried out a relevant report of 195 cases of metastasis-free primary NPC patients (63% were above stage Ⅲ and 26% were of stage Ⅳ) received IMRT. The prescribed dose was 70Gy, 20-2.12 Gy per time, 33-35 times. After a mean follow-up of 36.5 months, complete remission rate, 3-year local relapse-free survival rate, disease free survival rate were 96%, 93%, 82.1%. It obtained a great long-term outcome, but a heavy toxic response of at least 26% of the patients with side effects of Grade 3 or higher. Kwong et alconducted a research of 31 cases of early NPC patients who received IMRT. After a mean follow-up of 2 years, the results showed that only 1 case occurred tumor relapse in the neck. The 3-year local control rate, distant metastasis-free rate and overall survival rate were all 100%.
The inevitable xerostomia after radiotherapy is the main factor that affects the NPC patients’ life qualities. IMRT effectively reduced the dose exposed on parotid gland so that parotid gland secretion function could be preserved. Pow et al compared saliva secretory volumes and life qualities among 45 cases of early primary NPC patients (T2N0-1M0) after therapy. Among them, 24 received IMRT and 21 received conventional radiotherapy. The results showed that after 12 months of radiotherapy, among the IMRT patients, 50% stimulating saliva secretory volume recovered at least 25% of the basal volume and 83.3% of the patients’ stimulating parotid gland secretory volume recovered 25% of the basal volume while the corresponding percentage in conventional radiotherapy group were 4.8% and 9.5%, respectively. Quality of life scale analysis showed that life quality of patients received IMRT is significantly better than those received conventional radiotherapy (p<0.05). Fang et al and Hiung et al also revealed that IMRT could be more effective in protecting the function of parotid gland than the conventional therapy and then improved the patients’ life quality.Compared with traditional contouring of the entire parotid glands as organs at risk (oars) in imrt for npc, Zhang et al used a superficial parotidlobe-sparing delineation approach of contouring the superficial parotid lobes as oars.The mean dose to the parotid glands overall decreased by more than 4 Gy in the test plans. Impressively, the mean dose to thesuperficial parotid lobes in the test plans was not more than 30 Gy, regardless of clinical stage. However, for some T4 patients, the dose distributions for targets and brainstem in the test plans could not meet clinical requirements.
Compared with conventional radiotherapy, IMRT possesses obvious advantages of survival, but owing to its short time of usage, some problems remain to be resolved at present. First, radiotherapy may induce potential cancer due to its multi-field non coplanar rotation irradiation that reduces the dose in surrounding tissues but irradiates more normal tissues. There are relevant literatures reporting that the incidence of IMRT-induced malignancies was twice as that of conventional radiotherapy and ranged from 1%to1.75%. Second, IMRT was required to outline the target area precisely, so the does would decrease rapidly on the area between target lesion and adjacent normal tissues. The subtle error of outlining target area may induce inadequate dose on tumor tissues or overdoes on normal tissues or both of these. Third, IMRT belongs to accurate radiotherapy and requires positioning precisely. Although it now can be positioning precisely and repeatedly by using thermoplastic mask to fix the head, certain error still exist. Forth, the radiation leakage. Multi-leaf collimator may cause a certain rate of leakage. IMRT adopts the multi-field non coplanar rotation irradiation technique so that it leads to a higher rate of radiation leakage and an irradiation dose increase throughout the body. Fifth, the expense problem. IMRT costs higher so that it increases the patients’ financial burdens to some extent.
Helical tomotherapy belongs to IMRT and developed rapidly in recent years as a new IMRT technology. The machine of helical tomotherapy resembles that of conventional CT, replacing the X-ray tube by a megavolt level linear accelerator. Compared with conventional radiotherapy, helical tomotherapy possess obvious advantages. First, it irradiates continuously in 360 degree that it could solve the ‘hot pots’ problem of connecting the irradiation fields. Second, more irradiation angles. Third, the raster moves faster, the speed of which is 100 times as that of traditional accelerator. Forth, it has its own CT scanner that it can better achieve the image-guided radiotherapy and adaptive radiotherapy. Fifth, the larger therapeutic range, and so on. The above characteristics might shorten the therapeutic time and lead to a better target conformality and dose distribution uniformity than conventional IMRT. It also avoids the critical tissues surrounding the target area being exposed through conformality and solved the problem of connecting the irradiation fields.
Ma et al conducted an analysis of 57 cases of primary NPC patients (20 were of stageⅠ-Ⅱ, 37 of stage Ⅲ-Ⅳ) received helical tomotherapy to evaluate its short-term efficacy and acute phase respond. The irradiation dose on tumor target area was 70-76 Gy/32-33 times. After a mean follow-up of 9 months, the result showed that 57 cases had a good short-term outcome and mild acute phase response. The incidence of acute phase cutaneous reaction of Grade 3 and mucosa reaction were 5.3% and 3.5%, respectively, while xerostomia above Grade 3 did not occur. Remission rate of nasopharynx was up to 86% and that of cervical lymph node was 90.7%.
Lee et alreported that helical tomotherapy had a significant dose advantage compared with conventional static IMRT. Twenty cases of NPC patients received helical tomotherapy were brought into analysis and their therapeutic regimes were designed by tomotherapy and conventional static IMRT planning system before treatment. The result showed that the consistency coefficient and homogeneity coefficient of tomotherapy treating plan a significant increasement compared with conventional static IMRT (the increasing rate were 11.9 ± 5.5% and 8.8 ± 1.5%, respectively) as well as a significant reduction in average does injury in the organs (except optic chiasma) and in the maximal therapeutic dose, the comprehensive quality index was 0.92 ± 0.08. However, the author also indicated that whether metrological advantages could be translated into clinical remained further researches.
Tomotherapy is an entirely new IMRT technology that appeared in recent years. Although some advantages have been showed in clinical, due to its short time of usage and lack of large sample randomized trials, the advantages and disadvantages of tomotherapy remain further researches.
2. Internal exposure
Internal exposure is called brachytherapy that being relative to the external radiation therapy and has a history of more than 100 years so far. In 1898, Madame Curie found radiative radium, and then the first radium needle brachytherapy was realized in 1905.The brachytherapy could make a high dose area within the effective therapeutic range and a rapid attenuation of irradiation dose out of the range. Therefore it could increase irradiation dose on the tumor area as well as reduce the dose on the sensitive organs around to the maximal degree. The appearance of installing technology after 1980s and the development of novel radiative source stimulated the rapid development of brachytherapy. The brachytherapy for NPC mainly includes intracavity radiotherapy and interstitial brachytherapy and the major radiative source of which was 192Ir.
Ren et alconducted a retrospective analysis of 141 cases of NPC patients of stage T2b to evaluate the efficacy. Forty of them were assigned to experimentalgroup received external irradiation plus high dose interstitial brachytherapy guided by 3D CT, the others were in control group of receiving simple external exposure. The patients in experimental group first received external exposure with average dose of 60Gy, and then brachytherapy with dose of 12-20Gy, while the control group received the average dose of 68 Gy. The result showed that the 5-year local relapse-free survival rate and disease-free survival rate of experimental group were higher than the control group (97.5% vs. 80.2%, P = 0.012 and 92.5% vs. 73.3%, P = 0.014), but the acute and chronic complications were similar between these two groups. Lin et al also carried out a relevant report that 352 cases of NPC patients received external radiotherapy, and then received intracavitary hyperfractionated brachytherapy when the dose reached 50-70 Gy. The dose of hyperfractionated brachytherapy was 2.5-3 Gy per time, 2 times a day with 6 hours interval, total dose was 5-32Gy and the average dose was 17 Gy. The 3-year and 5-year survival rate were 87.6% and 84.7%, respectively, but the incidence of lower cranial nerves injury was up to 9.4%. Chen et al also revealed a similar significant short-term effect of brachytherapy and no severe short-term complications occurred.
The efficacy of brachytherapy for NPC is certain. However, the dose of intracavitary afterloading irradiation for NPC decreases rapidly according to distant square invertendo and its effective treatment range is not more than 1cm under mucosa, so it is just suitable for radiotherapy boost for lesions being limited to nasopharyngeal surface[27,30]. Lin et al initiated radiotherapy boost by implanting from jaw to parapharyngeal and Chan et al operated brachytherapy by implanting a source applicator through nasopharyngeal and parapharyngeal guided by nasal endoscope expanding the therapeutic range of brachytherapy for NPC. However, the brachytherapy through nasopharynx belongs to invasive treatment that may cause nasopharyngeal bleeding and infection. Meanwhile, the radioactive source used in nasopharyngeal interstitial brachytherapythrough the jaw is close to lower cranial nerve that increased the dose on lower cranial nerve and the incidence of nerve damage. In the intracavitary afterloading irradiation, due to nasopharyngeal mucosa close to radioactive source, the dose on the mucosa is the highest that can lead to a heavier mucosa reaction. Zheng et al reported that the incidence of intracavity radiotherapy-induced soft tissue necrosis was significantly higher than that of 3D conformal radiotherapy and the incidence of conventional radiotherapy was only 3.3% in an analysis of 120 cases of NPC patients receiving conventional radiotherapy in the same period. Leung et alalso reported a higher incidence of intracavity radiotherapy-induced nasopharyngeal soft tissue necrosis (6.7%).
NPC is a common head and neck tumor in China, especially in GuangDong province and its main therapy is still radiotherapy. Although IMRT has made great progress versus conventional radiotherapy, the side effects induced by radiotherapy still seriously affecting patients' life quality. How to increase the gain ratio is always a big problem that NPC radiotherapy faces. There are several researches indicated that NPC cervical lymph node metastasis follows certain rules, so it is feasible to narrow radiation area to the cervical lymph nodes. With the development of imaging and radiotherapy technology, radiotherapy will ultimately reach to goal of biologically conformal radiotherapy, real-time tracking radiotherapy and adaptive radiotherapy. The real IMRT will come true that would increase the tumor control rate and effectively protect surrounding normal tissues as well.
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