胸段食管鳞癌根治术后预防性IMRT同期化疗的Ⅱ期临床研究
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摘要
目的探讨胸段食管鳞癌根治术后预防性调强放射治疗(IMRT)联合同期化疗的局部区域控制率、生存情况及安全性。方法采用前瞻性Ⅱ期临床试验设计,入组条件为根治术后病理分期为T3～T4或N+、M0的胸段食管鳞癌患者。放疗技术为IMRT,放疗范围为双侧锁骨上、上纵隔、吻合口和原食管瘤床。放疗剂量:50. 4 Gy/28次,1. 8 Gy/次,5次/周。放疗第1天开始接受紫杉醇联合顺铂(TP:紫杉醇150 mg/m~2iv d1,顺铂25 mg/m~2iv d1～d3,28天为1个周期,2个周期)方案化疗,放疗结束后再行TP方案辅助化疗2个周期。随访记录治疗后局部区域复发、远处转移时间,计算肿瘤局部控制率和总生存率并评价治疗的安全性。结果从2014年1月至2017年9月共入组74例。区域复发5例(6. 8%),其中照射野内4例,包括锁骨上1例、上纵隔2例和吻合口1例;照射野外(腹腔干淋巴结)复发1例。远处转移10例(13. 5%),包括肺转移4例、肝转移4例和胸膜转移2例。1、2年无局部复发生存率为94. 9%和92. 5%,1、2年总生存率为83. 9%和72. 9%。主要不良反应包括4级中性粒细胞减少12例(16. 2%)、血小板减少2例(2. 7%),3级中性粒细胞减少17例(23. 0%)、血红蛋白减少1例(1. 4%),经对症处理后均顺利完成预定放疗计划,无中止或延期治疗患者。结论食管鳞癌根治术后预防性IMRT(仅照射双侧锁骨上、上纵隔、吻合口和瘤床)联合同期化疗的耐受性好、局控率高且下纵隔和上腹部复发的概率较小,值得进一步开展Ⅲ期临床研究。
Objective To evaluate the loco-regional control rate and overall survival rate as well as adverse events of prophylactic intensity modulated radiotherapy( IMRT) combined with concurrent chemotherapy after radical resection for thoracic esophageal squamous cell carcinoma. Methods This was a prospective phase Ⅱ trial. Inclusion criteria were radical thoracic esophageal squamous cell carcinoma with pathological staging of T3-T4 or N positive and M0. Radiotherapy technology was IMRT. Radiotherapy range included bilateral supraclavicular region,the mediastinum area,anastomosis and the original tumor bed. The total dose was 50. 4Gy in 28 fractions( 1. 8 Gy/fraction),five fractions weekly. Patients were treated with paclitaxel+cisplatin( TP) regimen( paclitaxel150 mg/m~2 iv d1,cisplatin 25 mg/m~2 iv d1-d3,28 days was a cycle for 2 cycles). The time of local recurrence and distant metastasis after treatment was followed up and recorded. The local control rate and overall survival rate were calculated and the safety of treatment was evaluated. Results From January 2014 to September 2017,the follow-up time was 3-47 months( median 22. 8 months). The 1-,2-overall survival rates and 1-,2-loco-regional recurrence-free survival rates were 83. 9% and 72. 9%,94. 9% and 92. 5%,respectively. There were 5 cases( 6. 8%) of regional recurrence,including 4 cases of irradiation field( 1 case of supraclavicular bone,2 cases of mediastinum and 1 case of anastomotic stoma). One case recurred beyond field irradiation as celiac lymph nodes. Among 10 cases( 13. 5%) of distant metastases,there were lung metastases in 4 cases,liver metastases in 4 cases,and pleural metastases in 2 cases.The main side effects included grade 4 neutropenia in 12 cases( 16. 2%),platelet decreased in 2 cases( 2. 7%),as well as grade 3neutropenia in 17 cases( 23. 0%) and hemoglobin decreased in 1 case( 1. 4%). After symptomatic treatment,the radiotherapy plan was successfully completed without any suspend or delay in treatment. Conclusion IMRT( range including bilateral supraclavicular region,the mediastinum area,anastomosis and the original tumor bed) combined with concurrent chemotherapy after radical resection for thoracic esophageal squamous cell carcinoma is well tolerated with good local control rate. Patients have a lower probability of recurrence at the lower mediastinum and upper abdomen. It is worth to launch a phase Ⅲ clinical study.
Objective To evaluate the loco-regional control rate and overall survival rate as well as adverse events of prophylactic intensity modulated radiotherapy( IMRT) combined with concurrent chemotherapy after radical resection for thoracic esophageal squamous cell carcinoma. Methods This was a prospective phase Ⅱ trial. Inclusion criteria were radical thoracic esophageal squamous cell carcinoma with pathological staging of T3-T4 or N positive and M0. Radiotherapy technology was IMRT. Radiotherapy range included bilateral supraclavicular region,the mediastinum area,anastomosis and the original tumor bed. The total dose was 50. 4Gy in 28 fractions( 1. 8 Gy/fraction),five fractions weekly. Patients were treated with paclitaxel+cisplatin( TP) regimen( paclitaxel150 mg/m~2 iv d1,cisplatin 25 mg/m~2 iv d1-d3,28 days was a cycle for 2 cycles). The time of local recurrence and distant metastasis after treatment was followed up and recorded. The local control rate and overall survival rate were calculated and the safety of treatment was evaluated. Results From January 2014 to September 2017,the follow-up time was 3-47 months( median 22. 8 months). The 1-,2-overall survival rates and 1-,2-loco-regional recurrence-free survival rates were 83. 9% and 72. 9%,94. 9% and 92. 5%,respectively. There were 5 cases( 6. 8%) of regional recurrence,including 4 cases of irradiation field( 1 case of supraclavicular bone,2 cases of mediastinum and 1 case of anastomotic stoma). One case recurred beyond field irradiation as celiac lymph nodes. Among 10 cases( 13. 5%) of distant metastases,there were lung metastases in 4 cases,liver metastases in 4 cases,and pleural metastases in 2 cases.The main side effects included grade 4 neutropenia in 12 cases( 16. 2%),platelet decreased in 2 cases( 2. 7%),as well as grade 3neutropenia in 17 cases( 23. 0%) and hemoglobin decreased in 1 case( 1. 4%). After symptomatic treatment,the radiotherapy plan was successfully completed without any suspend or delay in treatment. Conclusion IMRT( range including bilateral supraclavicular region,the mediastinum area,anastomosis and the original tumor bed) combined with concurrent chemotherapy after radical resection for thoracic esophageal squamous cell carcinoma is well tolerated with good local control rate. Patients have a lower probability of recurrence at the lower mediastinum and upper abdomen. It is worth to launch a phase Ⅲ clinical study.
引文
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[21]Daiko H,Hayashi R,Sakuraba M,et al.A pilot study of postoperative radiotherapy with concurrent chemotherapy for high-risk squamous cell carcinoma of the cervical esophagus[J].Jpn J Clin Oncol,2011,41(4):508-513.
[22]康静静,惠周光,肖泽芬,等.食管癌术后放疗同步紫杉醇+奈达铂方案化疗的初探[J].中华放射肿瘤学杂志,2016,25(6):571-575.
[23]曹秀峰,吕进,朱斌,等.手术前后放化疗对食管鳞癌远期疗效的影响[J].中华放射肿瘤学杂志,2010,19(6):452-455.
[24]Lv J,Cao XF,Zhu B,et al.Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma[J].World J Gastroenterol,2010,16(13):1649-1654.
[25]Chen JQ,Liu SY,Pan JJ,et al.The pattern and prevalence of lymphatic spread in thoracic oesophageal squamous cell carcinoma[J].Eur J Cardiothorac Surg,2009,36(03):480-486.
[26]Bédard EL,Inculet RI,Malthaner RA,et al.The role of surgery and postoperative chemoradiation therapy in patients with lymph node positive esophageal carcinoma[J].Cancer,2001,91(12):2423-2430.
[27]Li CL,Zhang FL,Wang YD,et al.Characteristics of recurrence after radical esophagectomy with two-field lymph node dissection for thoracic esophageal cancer[J].Oncol Lett,2013,5(1):355-359.
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[29]Lu JC,Tao H,Zhang YQ,et al.Extent of prophylactic postoperative radiotherapy after radical surgery of thoracic esophageal squamous cell carcinoma[J].Dis Esophagus,2008,21(6):502-507.
[30]Chen JQ,Pan JJ,Zheng XW,et al.Number and location of positive nodes,postoperative radiotherapy,and survival after esophagectomy with three-field lymph node dissection for thoracic esophageal squamous cell carcinoma[J].Int J Radiat Oncol Biol Phys,2012,82(1):475-482.
[31]Zheng B,Zheng W,Zhu Y,et al.Role of adjuvant chemoradiotherapy in treatment of resectable esophageal carcinoma:a metaanalysis[J].Chin Med J(Engl),2013,126(6):1178-1182.
[32]van Heijl M,van Lanschot JJ,Koppert LB,et al.Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus(CROSS)[J].BMC Surg,2008,8:21.
[33]Lyu X,Huang J,Mao YS,et al.Adjuvant chemotherapy after esophagectomy:is there a role in the treatment of the lymph node positive thoracic esophageal squamous cell carcinoma?[J].JSurg Oncol,2014,110(7):864-868.
[34]Chen JQ,Pan JJ,Liu J,et al.Postoperative radiation therapy with or without concurrent chemotherapy for node-positive thoracic esophageal squamous cell carcinoma[J].Int J Radiat Oncol Biol Phys,2013,86(4):671-677.
[2]Pan R,Zhu M,Yu CQ,et al.China Kadoorie Biobank Collaborative Group.Cancer incidence and mortality:A cohort study in China,2008-2013[J].Int J Cancer,2017,141(7):1315-1323.
[3]Cheng J,Kong LL,Huang W,et al.Explore the radiotherapeutic clinical target volume delineation for thoracic esophageal squamous cell carcinoma from the pattern of lymphatic metastases[J].J Thorac Oncol,2013,8(3):359-365.
[4]Almhanna K,Shridhar R,Meredith KL.Neoadjuvant or adjuvant therapy for resectable esophageal cancer:is there a standard of care?[J].Cancer Control,2013,20(2):89-96.
[5]Liu Q,Cai XW,Wu B,et al.Patterns of failure after radical surgery among patients with thoracic esophageal squamous cell carcinoma:implications for the clinical target volume design of postoperative radiotherapy[J/OL].PLoS One,2014[2018-06-10].https://www.ncbi.nlm.nih.gov/pubmed/24820177.
[6]Hulscher JB,van Sandick JW,Tijssen JG,et al.The recurrence pattern of esophageal carcinoma after transhiatal resection[J].JAm Coll Surg,2000,191(02):143-148.
[7]Xiao ZF,Yang ZY,Liang J,et al.Value of radiotherapy after radical surgery for esophageal carcinoma:a report of 495 patients[J].Ann Thorac Surg,2003,75(2):331-336.
[8]Xiao ZF,Yang ZY,Miao YJ,et al.Influence of number of metastatic lymph nodes on survival of curative resected thoracic esophageal cancer patients and value of radiotherapy:report of 549 cases[J].Int J Radiat Oncol Biol Phys,2005,62(1):82-90.
[9]Schreiber D,Rineer J,Vongtama D,et al.Impact of postoperative radiation after esophagectomy for esophageal cancer[J].J Thorac Oncol,2010,5(2):244-250.
[10]Shridhar R,Weber J,Hoffe S,et al.Adjuvant radiation therapy and lymphadenectomy in esophageal cancer:a SEER database analysis[J].J Gastrointest Surg,2013,17(8):1339-1345.
[11]Lin SH,Wang L,Myles B,et al.Propensity score-based comparison of long-term outcomes with 3-dimensional conformal radiotherapy vs intensity-modulated radiotherapy for esophageal cancer[J].Int J Radiat Oncol Biol Phys,2012,84(5):1078-1085.
[12]Wu VW,Sham JS,Kwong DL.Inverse planning in three-dimensional conformal and intensity-modulated radiotherapy of mid-thoracic oesophageal cancer[J].Br J Radiol,2004,77(919):568-572.
[13]Hashiguchi T,Nasu M,Hashimoto T,et al.Docetaxel,cisplatin and 5-fluorouracil adjuvant chemotherapy following three-field lymph node dissection for stageⅡ/ⅢN1,2 esophageal cancer[J].Mol Clin Oncol,2014,2(5):719-724.
[14]Heroor A,Fujita H,Sueyoshi S,et al.Adjuvant chemotherapy after radical resection of squamous cell carcinoma in the thoracic esophagus:who benefits?A retrospective study[J].Dig Surg,2003,20(3):229-235.
[15]Welsh J,Palmer MB,Ajani JA,et al.Esophageal cancer dose escalation using a simultaneous integrated boost technique[J].Int J Radiat Oncol Biol Phys,2012,82(1):468-474.
[16]Berger B,Belka C.Evidence-based radiation oncology:oesophagus[J].Radiother Oncol,2009,92(2):276-290.
[17]Zhang WC,Liu X,Xiao ZF,et al.Postoperative intensity-modulated radiotherapy improved survival in lymph node-positive or stageⅢthoracic esophageal squamous cell carcinoma[J].Oncol Res Treat,2015,38(3):97-102.
[18]于舒飞,章文成,肖泽芬,等.胸中段淋巴结阳性食管癌术后放疗的临床意义[J].中华放射肿瘤学杂志,2016,25(4):332-338.
[19]沈文斌,高红梅,祝淑钗,等.pT3N0M0期胸段食管鳞癌患者术后失败原因分析及其术后放疗思考[J].中华放射肿瘤学杂志,2017,26(4):394-399.
[20]Adelstein DJ,Rice TW,Rybicki LA,et al.Mature results from a phaseⅡtrial of postoperative concurrent chemoradiotherapy for poor prognosis cancer of the esophagus and gastroesophageal junction[J].J Thorac Oncol,2009,4(10):1264-1269.
[21]Daiko H,Hayashi R,Sakuraba M,et al.A pilot study of postoperative radiotherapy with concurrent chemotherapy for high-risk squamous cell carcinoma of the cervical esophagus[J].Jpn J Clin Oncol,2011,41(4):508-513.
[22]康静静,惠周光,肖泽芬,等.食管癌术后放疗同步紫杉醇+奈达铂方案化疗的初探[J].中华放射肿瘤学杂志,2016,25(6):571-575.
[23]曹秀峰,吕进,朱斌,等.手术前后放化疗对食管鳞癌远期疗效的影响[J].中华放射肿瘤学杂志,2010,19(6):452-455.
[24]Lv J,Cao XF,Zhu B,et al.Long-term efficacy of perioperative chemoradiotherapy on esophageal squamous cell carcinoma[J].World J Gastroenterol,2010,16(13):1649-1654.
[25]Chen JQ,Liu SY,Pan JJ,et al.The pattern and prevalence of lymphatic spread in thoracic oesophageal squamous cell carcinoma[J].Eur J Cardiothorac Surg,2009,36(03):480-486.
[26]Bédard EL,Inculet RI,Malthaner RA,et al.The role of surgery and postoperative chemoradiation therapy in patients with lymph node positive esophageal carcinoma[J].Cancer,2001,91(12):2423-2430.
[27]Li CL,Zhang FL,Wang YD,et al.Characteristics of recurrence after radical esophagectomy with two-field lymph node dissection for thoracic esophageal cancer[J].Oncol Lett,2013,5(1):355-359.
[28]Zieren HU,Müller JM,Jacobi CA,et al.Adjuvant postoperative radiation therapy after curative resection of squamous cell carcinoma of the thoracic esophagus:a prospective randomized study[J].World J Surg,1995,19(3):444-449.
[29]Lu JC,Tao H,Zhang YQ,et al.Extent of prophylactic postoperative radiotherapy after radical surgery of thoracic esophageal squamous cell carcinoma[J].Dis Esophagus,2008,21(6):502-507.
[30]Chen JQ,Pan JJ,Zheng XW,et al.Number and location of positive nodes,postoperative radiotherapy,and survival after esophagectomy with three-field lymph node dissection for thoracic esophageal squamous cell carcinoma[J].Int J Radiat Oncol Biol Phys,2012,82(1):475-482.
[31]Zheng B,Zheng W,Zhu Y,et al.Role of adjuvant chemoradiotherapy in treatment of resectable esophageal carcinoma:a metaanalysis[J].Chin Med J(Engl),2013,126(6):1178-1182.
[32]van Heijl M,van Lanschot JJ,Koppert LB,et al.Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus(CROSS)[J].BMC Surg,2008,8:21.
[33]Lyu X,Huang J,Mao YS,et al.Adjuvant chemotherapy after esophagectomy:is there a role in the treatment of the lymph node positive thoracic esophageal squamous cell carcinoma?[J].JSurg Oncol,2014,110(7):864-868.
[34]Chen JQ,Pan JJ,Liu J,et al.Postoperative radiation therapy with or without concurrent chemotherapy for node-positive thoracic esophageal squamous cell carcinoma[J].Int J Radiat Oncol Biol Phys,2013,86(4):671-677.