Study Of Radiotherapy And Chemotherapy For Locally Advanced Nasopharyngeal Carcinoma And Related Radiophysics

1. A Phase I/II Study of concurrent chemoradiotherapy followed by adjuvant chemotherapy for locally advanced nasopharyngeal Carcinoma Objective: To evaluate the efficacy, compliance and toxicity of concurrent chemoradiotherapy followed by adjuvant chemotherapy in locally advanced nasopharyngeal carcinoma(NPC). Methods and Patients: From November 2003 - April 2005, sixty and seven patients with Stage III and IV locally advanced nasopharyngeal carcinoma (NPC) were treated with concurrent chemoradiotherapy followed by adjuvant chemotherapy. The dose of radiation was 70-74Gray (Gy) given in 35-37 fractions, 5 fractions per week. Two cycles of chemotherapy, consisting of Cisplatin 25 mg/m²/d and 5-fluorouracil 300mg/m²/d, were delivered simultaneously with radiotherapy on Days 1 - 3 during Weeks 1 and 5 and three cycles adjuvant chemotherapy consisting of Cisplatin 25 mg/m²/d and fluorouracil 450 mg/ m²/d were given starting in on Days 1-3 during Weeks 10, 13 and 16 after radiotherapy. Results: The median follow-up was 26 months (rang 11 to 27 months). The 2-year overall survival rate, 2-year disease-free survival rate in all 67 patients was 91.75% and 81.56% respectively. The 2-year overall survival was 96% for Stage III and 87. 65% for Stage IV (p=0. 334). The 2-year disease-free survival was 92. 16% for Stage III and 69. 35% for Stage IV respectively (p=0.2358). The compliance rates were 100% for radiotherapy , 47 cases (70. 1%) for chemotherapy, 56 cases (83.6%) for concurrent chemotherapy and 48 cases (71.6%) for adjuvant chemotherapy respectively. The main grade III/IV acute toxicity events during concurrent chemoradiotherapy were neutropenia in 15 patients (21.4%), vomitting and nausea in 2 patients(3%), mucositis in 56 patients (83.6%), and grade III skin reaction in 10(15%), respectively. The main grade III/IV acute toxicity events during adjuvant chemotherapy were neutropenia in 13 patients (19.4%), grade 3 anemia in 2 patients (1.5%) respectively. Conclusion: Concurrent chemoradiotherapy and adjuvant chemotherapy waseffective in patients with locally advanced NPC. The primary result showed prognosis of Stage III and Stage IV (MO) disease were improved, especially Stage III NPC. Longer follow-up is needed to confirm the ultimate therapeutic ratio. Phase III randomized trials comparing chemotherapy plus radiotherapy with radiotherapy alone for locally advanced nasopharyngeal carcinoma should be evaluated in future. 2. 1 Clinical study of registration between CT and MRI of nasopharyngeal carcinomaObjective: To explore and evaluate the different registration methods between CT and MRI of patients with nasopharyngeal carcinoma and evaluate the feasibility of MRI in defining appropriate target volumes and normal organs, and to compare MRI sequences with CT for nasopharyngeal carcinoma. Methods and materials: CT and MRI scans of 8 untreated patients with nasopharyngeal carcinoma were carried on in treatment position with immobilized mask. All images were transferred to and registrated at AcQSIM and Pinnacle3(?) V7.0 workstation by two physicians and one physicist respectively, according to point mark,interactive, normalize mutual information registration. Images in eight patients with nasopharyngeal carcinoma with three MRI sequences (T₁WI, T₂WI, contrast T₁WI) were compared with their corresponding CT planning scans. Segmentation ability of the following structures: eyes, brain stem , spinal cord, parapharyngeal space, prevertebral tissue, skull base and Intracranial parts were evaluated by two physicians. Six point grading scale based on the anatomical definition of the organ boundary and tissue contrast was used to assessed. Two physicians evaluated registration results with a 4 point scale based on visual evaluation and registration time was recorded and assessed as well. Results: The average scores for all structures assessed by each imaging sequence were as following: parapharyngeal space CT 2.75 ±0.37, T₁WI 4.25±0.25 , T₂WI 4.5±0.38 , contrast T₁WI 5.625±0.18; skull base CT 2.375±0.625, T₁WI 3.125±0.515, T₁WI2.75±0.59, contrast T₁ 4.25 ±0.725; intracranial parts CT1, T₁WT 1.375 ± 0.375, T₁WI 1.875±0.58, contrast T₁WI 2.125±0.74; prevertebral tissue CT 2, T₁WI 4.125 ± 0.23,T₂WI 5±0.19, contrast T₁WI 5.375±0.375; spinal cord CT 4.125±0.23, T₁ WI 6,T₂WI 6, contrast T₁WI 6; brain stem CT 3.5±0.19, T₁WI 6, T₂WI 6, contrast T₁WI 6; eye CT 5.375 ± 0.18, T₁WI 6, T₂WI 6, contrast T₁WI 6. Compared with CT, the average MRI score for each assessed structure was improved, with a trend for all contrast T₁WI sequences to provide improved segmentation of all structure. Normalized mutual information registration was the method that result and time of registration were better than others. Results of registration were improved in physicians than in physicist, especially point mark method; Results of registration were similar between physicians and physicist with interactive, normalized mutual information registration. Conclusion: compared with CT, MRI appeared to provide improved definition of nasoparyngeal carcinoma target volumes and normal tissue, but further work is required to confirm this and to address the issues of MRI associated distortion and scan time, before MRI can be used routinely for nasopharyngeal carcinoma radiotherapy planning. Compared with other methods, normalized mutual information registration was automatically carried on by software and coefficient, more robust with less subjective effect. 2.2 Clinical study of MRI geometric distortion in nasopharyngeal carcinomaObjective:To explore error for registration methods between CT and MRI of patients with nasopharyngeal carcinoma and evaluate MRI geometric distortion in radiotherapy planning system. Materials and Methods: CT and MRI scans of 46 untreated patients with nasopharyngeal carcinoma were carried on in treatment position with immobilized mask. The images were transferred to and registrated at Pinnacle3(?) V7. 0 workstation. Physicians evaluated results of registration with visual evaluation and delineated eyeballs and maxillary sinuses. The 3-demention rending and the center of organs were made by software for bilateral eyeballs and maxillary sinuses. The distance between CT and MRI for center of eyeballs and maxillary sinuses laterally were measured. The volume of eyeball andmaxillary sinus were measured by CT and MRI, and the difference of volume was explained as MRI geometric distortion in volume; According CT and MRI, at X axial direction, the distance were measured as following: between two centers of eyeballs, between two centers of maxillary sinuses, between two intersection points of the line passing through center of bilateral eyeballs and skin, between two intersection points of the line passing through center of bilateral maxillary sinuses and skin; at Y axial direction, the distance were measured as following: between two intersection points of the vertical line passing through center of eyeballs and bone, between two intersection points of the line passing through center of maxillary sinuses and bone respectively; The difference of distance were explained as MRI geometric distortion in X-Y axial direction. Results: The errors for 41cases (89.1%) were ≤2 mm, excluding 5 cases .The errors of all sites for one case were beyond 2 mm. The mean of error for the center of left eyeball,right eyeball,left maxillary sinus and right maxillary sinus were 0.143±0.06cm, 0.143±0.06cm, 0.135 ±0.07cm, 0.120±0.08cm respectively. The error for the center of bilateral eyeballs was not statistical difference (t=0. 034, P=0. 973) and maxillary sinuses was not statistical difference too ( t=1.323 , P=0.193) .The errors for 41 cases were neglectible and colud be used for radiotherapy planning. MRI geometric distortions had two aspects including amplification and contraction, which was normal distribution at volume and X-Y axial. At aspect of volume, MRI amplification geometric distortion at site of left eyeball,right eyeball,left maxillary sinus and left maxillary sinus were 87%,91.3%, 63% and 60.9% respectively; and contraction geometric distortion were 13%, 8.7%, 37%and 39.1% respectively. Results of statistics showed that MRI geometric distortion had a trend of amplification at eyeballs (-0.190 cm³, -0.2975 cm³), however, a trend of contraction (0.681cm³,0.967cm³) for maxillary sinuses. All the difference of distance at X-Y axial was significant (p<0.05). Results of statistics showed that MRI geometric distortion had a trend of amplification at X-Y axial. Conclusion: The study showed the error of registration was normal distribution and ≤ 2mm for 41cases (89.1%) . The advancement of MRI had improved the characteristic of MRI image geometricdistortion. More distortion was found around the periphery while comparing with the central parts. The effects MRI geometric distortion from pneumatic cavity were so complicated that would increase uncertainty of delineation of target volume. The accuracy of CT/MRI registration was challenging, should be measured when CT/MRI registration was used for radiotherapy. Our data seemsto provide that CT/MRI registration could be used in radiotherapy and improve decision and consistence of target.2. 3 Visualization of foramen rotundum, ovale , spinosum,hypoglossal canal and nerve in registration of CT and MRIObjective: To study visualization and the appearance of foramen ovale. foramen rotundum, foramen spinosum, hypoglossal canal and nerve which can be identified on registration of CT and MRI for nasopharyngeal carcinoma. Materials and methods: 20 nasopharyngeal carcinoma cases without cranial nerve involved were scanned by CT and MRI during March to April 2005. The foramen,rotundum ovale,spinosum,hypoglossal canal and hypoglossal nerve on CT and MR images were analyzed, with normalized mutual information registration in Pinnacle3(?) 7.0 workstation. Results: The foramen rotundum could be identified on CT as lower dense canal, the bilateral rotundum canal were found in 7 cases (35%),unilateral rotundum canal were found in 5 cases (25%) and canal were not seen in 8 cases (40%); Bilateral foramen ovale and spinosum were seen on CT in 20 cases, among them symmetric foramen ovale in 13 cases (65%) and asymmetric foramen ovale in 7 cases(35%); rotundum in 8 sides (20%), ovale in 32 sides(80%). For the foramen spinosum, bilateral symmetry in 3 cases(15%) and asymmetry in 17 cases(85%). Rotundum canal were not seen on MRI sequence for 20 cases. The foramen ovale. and spinosum were not seen in T₁WI and T₂WI, but as high signal in contrast T₁WI due to bilateral blood vessels. For the foramen ovale in MRI, bilateral symmetry 13 cases (65%) and asymmetry 7 cases (35%) ; rotundum 8 sides (20%), ovale 32 sides (80%). No blood vessel in the foramen rotundum,ovale and spinosum were seen in contrast CT. All hypoglossalcanal could be identified on CT of nasopharyngeal carcinoma as following: Mean width of left canal was 6. 17mm ± 1.3mm (3.9-8.5mm), mean length of left canal was 6. 5mm±2.0mm (5.8-10.1mm), mean angle of axis of left canal was44.2°±0.6°(42°-58°), mean width of right canal was 5. 78mm ± 1.2mm (4.2-9.7mm), mean length of right canal was 6. 8mm±1. 9mm(5.6-10.6mm), mean angle of axis of right canal was 44.5°±1.7°(41° -66°). No statistical difference was found between all parameters above. All complete hypoglossal canal could be depicted on MRI of nasopharyngeal carcinoma as following : Mean width of left canal was 6.3mm ± 1.3mm(4.2-8.7mm), mean length of left canal was 6.6mm ± 1.8mm (5.6-10.2mm), mean angle of axis of left canal was 44.1°±0.7° (41° -59 °), mean width of right canal was 5.9mm ± 0.9mm (4.8-9.7mm), mean length of right canal was 6.9mm ± 1.7mm (5.7-10.5mm) , mean angle of axis of right canal was 44.3° ± 1.7°(41°-68°).No statistical difference was found between all parameters above on MRI. Conclusion: Our data showed the foramen rotundum were not observed in MRI, and the foramen ovale and spinosum could be identified on MRI, which could provide image anatomy basis for radiotherapy treatment planning and delineate target in nasoparyngeal carcinoma. The identification of hypoglossal canal could be improved on MRI of nasopharyngeal carcinoma in compare with CT. Especially, in nasopharyngeal carcinoma with hypoglossal nerve paralysis, MRI was strongly recommended to identify precisely the location, delineate the target volume and carry on concise and accurate radiotherapy treatment planning.