| Esophageal carcinoma is a lethal disease. It was the eighth most common cancer world wide, responsible for 462,000 new cases in 2002 and sixth most common cause of death from cancer with 386,000 death. The age-standardized incidence per 100,000 was 19.7. Most patients with esophageal cancer present with locally advanced disease. Radiotherapy is crucial for tumor local control, but locoregional control rates for locally advanced esophageal cancer are less than 50%, and the 5-year overall survival rate is only about 10% when definitive radiotherapy was given. However, locoregional recurrence due to missed targets and treatment-related toxicity caused by large fields of radiation still occur in a substantial proportion of patients. The morbidity of cardiac adenocarcinoma has the tendency to increase. Some patients with cardiac adenocarcinoma need radiotherapy because of unresectable and medically inoperable reasons. More accurate radiotherapy targeting is needed to improve locoregional control and reduce toxicity. The development of new methods of image-guided radiotherapy, including three-dimensional conformal and intensity-modulated radiotherapy, has allowed radiation oncologists to target esophageal cancers more accurately and effectively while sparing surrounding normal tissue. However, target delineation for esophageal cancer still relies on previous two-dimensional treatment designs. And the definition of clinical target volume (CTV) margins is quite different among different countries. And the extent of microscopic spread of cardiac adenocarcinoma is unknown. This information is crucial for determining the CTV margin for radiotherapy for esophageal cancer and cardiac adenocarcinoma. The purpose of this study was to clarify the CTV margin needed for radiotherapy for esophageal squamous cell carcinoma and cardiac adenocarcinoma pathologically, and to evaluate the CTV for esophageal squamous cell carcinoma clinically by analyzing the patterns of failure and prognosis after radiotherapy with different radiation technique and different CTV margins.Part 1:Pathologic analysis of clinical target volume margin for radiotherapy in patients with esophageal SCC and cardiac adenocarcinoma treated by surgical resection onlyObjective: To study prospectively the extent of microscopic spread and lymph node (LN) metastasis in patients with esophageal squamous cell carcinoma (SCC) and cardiac adenocarcinoma treated by surgery only and to evaluate the clinical target volume (CTV) in radiotherapy.Methods: Sixty-six patients (34 with esophageal SCC and 32 with cardiac adenocarcinoma) treated by definitive surgical resection were included. All LNs received were labeled anatomically. The resected specimen was completely blocked for histological examination from proximal to distal at 20 mm interval in length and 3 mm in width. All H&E slides were examined by experienced pathologists for evidence of microscopic spread along the length of esophagus proximal and esophagus/stomach distal to gross tumor, and for LN metastasis.Results: The mean microscopic spread beyond gross tumor was 10.6±11.0 mm (range 0-71 mm, 32 of 34 cases <30mm) for esophageal SCC and 10.3±7.2 mm (range 0-29.0 mm, 29 of 29 cases <30mm) proximally and 18.3±16.3mm (range 0-57.0 mm, 27 of 32 cases <30mm) distally for cardiac adenocarcinoma. The length of microscopic spread within esophagus is less than 30 mm in 94.1% of esophageal squamous cell cancer cases. The proximal microscopic spread of cardiac adenocarcinoma is less than 30mm in all cases. While only in about 84.4% of cardiac adenocarcinomas, the distal microscopic spread is less than 30mm, and it is less than 50mm in 93.8% of cases in cardiac adenocarcinomas. The extent of microscopic spread of cancer was significantly associated with pathologic T stage (P=0.012). For patients with middle and lower esophageal SCC, LN metastases were observed in 35.3% (12/34 cases, subcarinal LN in 4 cases, paraesophageal LN in 3 case, paratracheal LN in 2 cases, left gastric LN in 5 cases, and paracardiac LN in 3 cases). For patients with cardiac adenocarcinoma, LN metastases were found in 46.9% (15 of 32) of cases (5 in paraesophageal LN, 14 in left gastric LN, 13 in paracardiac LN, 1 in peri-spleen LN and posterior mediastinal LN respectively).Conclusion: (1) A 3-cm longitudinal margin from gross target volume to CTV appeared to be adequate for most cases of esophageal squamous cell carcinoma within esophagus and for the proximal extent of microscopic spread of cardiac adenocarcinoma. And for distal microscopic spread in cardiac adenocarcinoma, 5cm was needed to cover about 94% of cases. (2) Accurate stage of LN is very important for radiation treatment target design. High-risk lymph node regions need to be covered by CTV.Part 2:The patterns of primary failure after radiotherapy with different radiation technique and clinical target volume margins for patients with squamous cell carcinoma of middle and lower third thoracic esophagusObjective: To evaluate the different radiation technique and clinical target volume margins by analyzing the patterns of primary failure after radiotherapy for patients with esophageal squamous cell carcinoma (SCC).Methods: From January 2004 to June 2006, 151 patients with middle or lower third thoracic esophageal SCC receiving definitive radiotherapy or chemoradiotherapy were accrued and were followed up. The patterns of the primary failure were analyzed. There were 64 patients in the conventional radiotherapy group. In this group, the portal was outlined on the skin under the conventional simulator. The target center was defined according to the presentation on barium meal, endoscopy and CT. Three to 5 cm proximal and distal margins and 1.5 cm lateral margin from the border of GTV were included in the CTV. The involved regional lymphatics were also included in the CTV when the lymph node was considered abnormal. The prescribed dose was 50 to 62 Gy in 5 to 6.5 weeks. 87 patients were given 3DCRT, of which there were 55 patients in the involved nodal irradiation group. The GTV was defined as any visible tumor on the image. The CTV was defined as the GTV plus a 3-cm margin superior and inferior to the primary tumor and a 0.8-1.0 cm radial margin. The PTV was defined as the CTV plus a 1.0- cm longitudinal margin and a 0.5-cm radial margin. The involved lymphatic region was also included in the CTV. The PTV1 was defined as GTV plus a 1.5cm margin superior and inferior to the primary tumor and a 0.8-1.0 cm radial margin, and also the involved lymphatic region. And 32 patients were included in the elective nodal irradiation group. The GTV, PTV and PTV1 were defined the same as that in the involved nodal irradiation group. Besides the same margins outside the primary tumor as that in the involved nodal irradiation group, the adjacent regional lymphatics was included in the CTV according to the different location of the primary tumor. The prescribed dose to PTV was 54 to 62Gy in 5.5 to 6.5 weeks or 50 Gy in 5 weeks followed by 10 to 12Gy to PTV1.Results: The total failure rate, locoregional failure rate, locoregional failure alone and total distant metastatic rate were 57.0% (86/151), 40.4% (61/151), 36.4%(55/151) and 20.5%(31/151) respectively for all patients in this study. The total failure rate was 59.4%(38/64), 61.8%(34/55) and 43.8%(14/32) respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group, which showed that it was higher in the former two groups than in the latter group, but no statistical difference was observed (P=0.228). Locoregional failure alone was 40.6% (26/64), 30.9% (17/55) and 37.5%(12/32) respectively for the three groups. And the total distant metastatic rate was 18.8% (12/64), 30.9% (17/55) and 6.3%(2/32) respectively for the three groups, which was higher in the former two groups than that in the latter group (P=0.021). The relapse rate of elective node outside CTV was 6.3%(4/64) and 7.3%(4/55) in the conventional radiotherapy group and the involved nodal irradiation group respectively. No relapse outside CTV was found in the elective nodal irradiation group. The total failure rate and locoregional failure alone rate were 60.5%(69/114)and 45.9%(17/37), 40.4%(46/114)and 24.3%(9/37)respectively in the radiotherapy alone group and chemoradiotherapy group, P<0.05.There was no significant difference in total distant metastatic rate between the radiotherapy group and chemoradiotherapy group, 20.2%(23/114) vs. 21.6%(8/37) with P>0.05. By analyzing the anatomical sites of regional failure, the probability of paraesophagotracheal lymph node metastasis was the highest (4.6%), with left gastric lymph node metastasis followed (4.0%). Only 2% (3/151) were found with esophageal disease outside CTV.Conclusion: (1) The main reason for the failure of esophageal SCC after radiotherapy was locoregional relapse. About 20% of esophageal SCC relapsed duo to distant metastasis. Regional relapse alone outside CTV was 5.3% and esophageal disease outside CTV was about 2%. (2) The elective nodal irradiation could decrease the total distant metastasis rate and elective node relapse rate outside the CTV. (3) Chemoradiotherapy may improve the local control. (4) The CTV defined as GTV plus a 3-cm margin superior and inferior to the primary tumor was considered as reasonable for the controlling esophageal primary tumor.Part 3: Comparison of efficacy and toxicities of different clinical target volumes in definitive radiotherapy for squamous cell carcinoma of middle and lower third thoracic esophagusObjective: To evaluate the different radiation technique and clinical target volume (CTV) margins by analyzing the prognosis and toxicities after radiotherapy for patients with esophageal squamous cell carcinoma (SCC) and to suggest a reasonable CTV for 3DCRT.Methods: From January 2004 to June 2006, 151 patients with middle or lower third thoracic esophageal SCC receiving definitive radiotherapy or chemoradiotherapy were accrued and were followed up. The overall survival rate, locoregional control rate, progression-free survival, distant metastasis-free survival and toxicities were analyzed and compared. The simulating method, delineation of target volumes for 3DCRT and the prescribed dose to the target were the same as that in Part 2. There were 64 patients in the conventional radiotherapy group, 55 patients in the involved nodal irradiation group and 32 patients in the elective nodal irradiation group.Results: The 12-month and 18-month overall survival rates were 75.1% and 62.2%, 69.2% and 51.1%, 73.4% and 73.4% respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group. The 12-month and 18-month locoregional control rates were 73.7% and 68.1%, 66.1% and 55.9%, 61.3% and 61.3% respectively in the three groups. The 12-month and 18-month progression-free survival rates were 63.2% and 55.9%, 47.6% and 29.8%, 53.4% and 26.7% respectively. The 12-month and 18-month distant metastasis-free survival rates were 87.8%% and 79.5%, 75.1% and 71.4%, 93.3% and 93.3% respectively. No statistical difference was found among the three groups, all with P>0.05. In Cox multivariate analysis, T stage and tumor response after radiotherapy were the independent factors for overall survival. T stage had the tendency to improve the local control and was the independent factor for progression-free survival rate. And chemoradiotherapy had the tendency to improve the overall survival, local control and progression-free survival. The CTV had no effect on the overall survival, local control, progression-free survival and metastasis-free survival. The radiation esophagitis was 71.9%(46/64), 69.1%(38/55) and 87.5% (28/32) respectively in the conventional radiotherapy group, the involved nodal irradiation group and the elective nodal irradiation group. The latter was higher than that of the former two groups, P<0.05.The symptomatic radiation pneumonitis was higher than that of the conventional radiotherapy group and the involved nodal irradiation group.Conclusion: (1) Conformal radiotherapy with elective nodal irradiation for middle and lower third thoracic esophageal SCC showed no significant advantage over the conformal radiotherapy with the involved nodal irradiation and the conventional radiotherapy in overall survival, local control, progression-free survival and distant metastasis-free survival. (2) Conformal radiotherapy with elective nodal irradiation conferred a higher radiation esophagitis and pneumonitis rate compared to the conventional radiotherapy and conformal radiotherapy with involved nodal irradiation. (3) Combined chemoradiotherapy showed a tendency to improve the overall survival, local control and progression-free survival. (4) CT-T stage and tumor response were the independent factors for overall survival. CT-T stage was the independent factor for the progression-free survival.Part 4: Comparison of efficacy and toxicity of regional and extensive clinical target volumes in postoperative radiotherapy for esophageal squamous cell carcinomaObjective: To compare and analyze the effect of different clinical target volumes (CTVs) on survival rate after postoperative radiotherapy (RT) for esophageal squamous cell carcinoma (SCC).Methods: We studied 102 patients who underwent postoperative RT after radical resection for esophageal SCC (T3/4 or N1). The radiation dose was at least 50 Gy. In the extensive portal group (E group, 43 patients), the CTV encompassed the bilateral supraclavicular region, all mediastinal lymph nodes, the anastomosis site, and the left gastric and paracardiac lymphatics. In the regional portal group (R group, 59 patients), the CTV was confined to the lymph nodes in the immediate region of the primary lesion. The 1-, 3-, and 5-year survival rates were compared between the groups and multivariate/univariate analysis for factors predicting survival was studied.Results: The 1-, 3- and 5- survival rates were 76.3%, 50.53% and 42.87% respectively, with a median survival of 30 months. The 1-, 3-and 5-year survival rates were 76.5%, 52.1% and 41.3% in the extensive portal group and 76.2%, 49.2%, and 44.6% in the regional portal group respectively, with no statistical difference between the two groups, P=0.884。The 1-, 3-, and 5-year survival rates were 88.1%, 63.4%, and 57.1%, respectively, for patients with T1 or T2 disease and 71.0%, 44.6 %, and 36.2%, respectively, for those with T3 or T4 disease. Patients with T1 or T2 disease had significantly better survival rates than did those with T3 or T4 disease (P=0.0383). The 1-, 3-, and 5-year survival rates were 95.6%, 72.0%, and 60.3%, respectively, for patients with N0 disease and 62.5%, 31.1%, and 28.9%, respectively, for patients with N1 disease (P=0.000). The 1-, 3-, and 5-year survival rates were 95.6%, 72.0%, and 60.3%, respectively, in patients with no metastatic lymph nodes (group 1); 67.4%, 33.3%, and 26.8%, respectively, in patients with 1-2 metastatic lymph nodes (group 2); and 20%, 20%, and 20% in patients with 3 or more metastatic lymph nodes (group 3) (P=0.000). The 1-, 3-, and 5-year survival rates were 81.5%, 62.0%, and 53.9%, respectively, for patients with tumors≤5 cm long and 67.9%, 37.5%, and 32.4%, respectively, for patients with tumors >5 cm long (P=0.0224). According to the multivariate analysis, N stage, number of metastatic lymph nodes and tumor length were the independent factors in survival.Conclusion: Using a regional CTV for postoperative RT in patients with esophageal SCC is feasible, and it does not compromise survival rates. Factors predicting survival time in patients with esophageal SCC are N stage, number of lymph nodes with metastatic disease, and tumor length.Conclusion1. The pathological analysis showed that a 3-cm longitudinal margin from gross target volume to CTV appeared to be adequate for most cases of esophageal squamous cell carcinoma within esophagus and for the proximal extent of microscopic spread of cardiac adenocarcinoma. And for distal microscopic spread in cardiac adenocarcinoma, 5cm was needed to cover about 94% of cases. Accurate stage of LN is very important for radiation treatment target design. High-risk lymph node regions need to be covered by CTV.2. The main reason for the primary failure of esophageal SCC after radiotherapy was locoregional relapse. About 20% of esophageal SCC relapsed duo to distant metastasis. Regional nodal relapse alone outside CTV was 5.3% and esophageal disease outside CTV was about 2%.3. Conformal radiotherapy with elective node portal for middle and lower third thoracic esophageal SCC could decrease total distant metastasis rate and elective nodal relapse rate outside the CTV. But it showed no significant advantage over the conformal radiotherapy with involved node portal and the conventional radiotherapy in overall survival, local control, progression-free survival and distant metastasis-free survival. And higher morbidities of radiation esophagitis and pneumonitis were observed in the elective node portal group.4. The clinical analysis showed that the CTV defined as GTV plus a 3-cm margin superior and inferior to the primary tumor was considered as reasonable for controlling the esophageal primary tumor.5. Chemoradiotherapy may reduce the local failure and showed a tendency to improve the overall survival, local control and progression-free survival.6. Using a regional CTV for postoperative RT in patients with esophageal SCC is feasible, and it does not compromise survival rates. Factors predicting survival time in patients with esophageal SCC are N stage, number of lymph nodes with metastatic disease, and tumor length.7. The clinical study was non-randomized and the follow-up time was not longer enough. A randomized study is being done about the different CTVs on the prognosis of esophageal SCC.
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