1、red1药理药效研究 动物模型Article type: Overview;Title: The Value of Elective Lymph Node Irradiation in Definitive Concurrent Chemoradiotherapy for Esophageal Cancer.AbstractEsophageal cancer remains one of the most lethal carcinomas and concurrent chemoradiotherapy has been accepted as the standard non-surgic
2、al treatment. However, no consistent conclusions have been reached whether elective lymph node irradiation (ENI) should be delivered. Therefore, we performed a systematic review of the literature on the feasibility and value of ENI during definitive concurrent chemoradiotherpay for esophageal cancer
3、. A literature search based on PubMed electronic databases was carried out to select studies including definitely concurrent chemoradiotherapy with ENI for esophageal cancer. All of the studies were evaluated carefully regarding with acute and late toxicities, treatment-related death, patterns of fa
4、ilure and overall survival. Fourteen studies were identified with a total of 975 patients included. Concurrent chemoradiotherapy with ENI was feasible with acceptable acute and late toxicities. The localregional control rate seems to be higher with ENI, comparing with studies which omitted ENI. Howe
5、ver, no obvious overall survival benefit with ENI was indicated in this review. In conclusion, the localregional control rate seems to be higher with ENI in concurrent chemoradiotherapy for esophageal cancer and no obvious better OS results were indicated in this review. Therefore, the value of ENI
6、remains controversial and further prospective phase III trials in this setting are highly warranted.Key Words: Esophageal cancer; chemoradiotherapy; elective lymph node irradiation.IntroductionEsophageal carcinoma is the eighth most common cancer and sixth cause of cancer death with approximately 48
7、0 000 new cases and 400 000 deaths annually worldwide 1-3. Esophageal cancer remains one of the most lethal carcinomas and the prognosis is dismal with surgery or radiotherapy (RT) alone. Surgery is the standard treatment for patients with resectable esophageal cancer currently. Concurrent chemoradi
8、otherapy (CCRT) has been considered as the standard non-surgical treatment for esophageal cancer based on the results of Radiation Therapy Oncology Group (RTOG) 85-01 trial 4 and 94-05 trial 5. However, there were disagreements between two trials such as elective lymph node irradiation (ENI) was use
9、d in RTOG 85-01 but was omitted in RTOG 94-05. Subsequently, the incidence of local-regional failure rate (44.3%) was apparently decreased in RTOG 8501 than the standard arm in RTOG 94-05 (55%), which suggested that ENI could improve local-regional control rate. Better local-regional control rate wi
10、th ENI was also reported in some studies 4, 6-10 but in other studies 11-16, and thus no consistent conclusions could be reached. To date, only one small sample sized prospective clinical trial 17 has been focused on the value of ENI in CCRT for cervical and upper-thoracic esophageal cancer and the
11、conclusions were inconclusive. Therefore, the role of ENI in CCRT for esophageal cancer remains controversial. Esophageal carcinomas are prone to spread axially to regional lymphatics and high incidence of occult regional lymph node metastasis was revealed by surgery 18-21. A total of 20 patients (2
12、6%) were found to have node metastasis in the dissected neck lymph nodes while the primary lesions were located at upper/middle/lower esophagus (7/42/28 patients respectively) 18. Better overall survival (OS) with prophylactic three-field lymph node dissection had been reported in esophageal cancer
13、18, 19, 22. In theory, CCRT with ENI may improve local control and thus improve OS in line with the benefit of three-field lymph node dissection in curative surgery. The purpose of this study was to review the value of ENI in CCRT for esophageal cancer regarding with toxicities， local-regional contr
14、ol rate and OS. Only articles with ENI in definitely CCRT were reviewed.Methods and materials This review was designed to investigate the feasibility and value of ENI in definitively CCRT for patients with esophageal cancer. The literature search was conducted with assistance from a research librari
15、an in the database of PubMed, to identify all clinical trials since 1980 including definitely CCRT with ENI in esophageal cancer. The following terms were explored and used for search: (esophageal OR esophagus OR oesophageal) AND (cancer OR carcinoma OR neoplasm) AND chemotherapy AND radiotherapy. S
16、tudies were excluded as following: neoadjuvant or adjuvant chemoradiotherapy combined with surgery; combined with target therapy; not published in English; not published in full text; phase study; with other site of cancers. The abstracts of articles were reviewed by the two investigators. Irrelevan
17、t citations were removed according to the criteria mentioned above, thus creating a preliminary set of potentially relevant publications. Secondly, the full text articles were distributed to the two reviewers along with an evaluation form customized for reviewing the treatment outcomes for ENI in CC
18、RT. Two reviewers independently evaluated a number of allocated articles and extracted information regarding study design, study population, methods, outcome measures, results and conclusions for each article. The evaluation results were compared and re-evaluated until consensus was reached between
19、two reviewers or decided by the corresponding author. When complete information was not available, attempts were made to contact the corresponding authors of the studies for additional information. Fourteen studies with a total of 975 patients were included and the characteristic was shown in table
20、1. Results 1. Clinical target volume (CTV) for ENI. There are some slight differences in literature regarding the CTV of ENI. At large, the CTV of ENI included the whole thoracic esophagus and periesophageal lymph nodes. For the boost field, margins were usually at least 2-5 cm in the craniocaudal d
21、irection for the primary tumor, and 1-2 cm in the lateral direction for adjacent mediastinum. For cervical esophageal cancer, supraclavicular region were included in the CTV of ENI. However, lower mediastinal lymph nodal region was excluded by some authors 23. For upper thoracic esophageal carcinoma
22、, the CTV of ENI included superior mediastinal lymph nodes alone by some authors7. Supraclavicular fossa nodes were included in the CTV for ENI in most studies 4, 6, 9, 10, 12, 13, 24. The CTV of ENI included mediastinal and perigastric lymph nodes for carcinoma of the middle thoracic esophagus7. Su
23、praclavicular fossa was also included in the CTV of ENI in many studies 4, 9, 10, 12, 24. The supraclavicular nodes were not included while lesions were located in the lower third of the esophagus 4, 6, 16, 24. Perigastric nodes were included in ENI for lower thoracic esophageal carcinoma 7, 10, 23
24、and celiac lymph nodal region were also included in many studies 6, 7, 10, 13, 23. 2. Feasibility of CCRT with ENI2.1 acute toxicities. Although acute toxicities of grade 3 or higher were frequently reported (table 2), CCRT applied with ENI was feasible. Leukopenia and esophagitis were the most comm
25、on toxicities noted in literature. The incidence of leukopenia (grade 3 or higher) varied from 24% to 82.3%, and that of esophagitis varied from 6% to 35%. Other common toxicities included nausea, vomitting, anemia, infection, stomatitis, thrombocytopenia and cardiac ischemia. 2.2 late toxicities. O
26、nly 6 papers detailed late toxicities (table 3). Cardiac related toxicities were the most common late toxicities and the incidence varied from 0 to 16%, most of patients suffered from pericardial effusion. The incidence of grade 3 or greater esophagus-related toxicities (dysphagia, stenosis, fistula
27、) varied from 0 to 13%. The incidence of pneumonitis varied from 0 to 5.9%. Pleural effusion occurred in 0 to 5% patients. One case of gastrointestinal hemorrhage was reported. 2.3 treatment-related death. A total of 25 deaths were reported to be associated with treatment and the incidence of treatm
28、ent-related death varied from 0 to 12.5% (table 4) with pooled estimates of 2.6% 4, 6, 8, 10-12, 15, 24. On the whole, eight patients died from pneumonitis, 6 died from esophagus related (mainly fistula), 4 from upper-gastrointestinal hemorrhage. Each one patient died from pericarditis, pleural effu
29、sion, myocardial infarction, renal failure and neutropenic sepsis respectively. In addition, two patients died at home without defined cause 4 and 10 weeks after treatment 24. 3. Complete response rate Complete remission (CR) rate with ENI in this review varied from 33% to 75%. It seems that CR rate
30、s were comparable between higher dose (around 60Gy) and lower dose (around 50Gy) with ENI.4. Patterns of failure with ENI In order to evaluate the patterns of failure, localregional failure was defined as the first site of failure (local persistence plus localregiongal recurrence) in this review. Di
31、stant failure was defined as failure in any site beyond the primary tumor and regional lymph nodes accordingly. Some authors defined localregional failure as localregional failure without distant failure, while other authors defined localregional failure as localregional failure both with and withou
32、t distant failure. We defined localregional failure rate 1 (LRFR1) as the incidence of localregional failure without distant failure and localregional failure rate 2 (LRFR2) as the incidence of localregional failure both with and without distant failure. Localregional failure pattern in all of the articles included in this review was shown in table 5. For all of the studies included in this review (patients in stage -), LRFR1 ranged from 26.5% to 54.68% and LRFR2 ranged from 29.4% to 61%. We analyzed these articles as a whole group, the pooled estimates of LRFR1 and LRFR2 were 45.6%
