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Salvage concurrent radio-chemotherapy for post-operative local recurrence of squamous-cell esophageal cancer

Salvage concurrent radio-chemotherapy for post-operative local recurrence of squamous-cell... Purpose: To evaluate the treatment outcome of salvage concurrent radio-chemotherapy for patients with loco- recurrent esophageal cancer after surgery. Methods: 50 patients with loco-recurrent squamous-cell cancer after curative esophagectomy were retrospectively analyzed. Patients were treated with radiotherapy (median 60 Gy) combined with chemotherapy consisting of either 5-fluorouracil (5-FU) plus cisplatin (DDP) (R-FP group) or paclitaxel plus DDP (R-TP group). Results: The median follow-up period was 16.0 months. The 1-year and 3-year survival rates were 56% and 14%, respectively. The median progression-free survival (PFS) and overall survival (OS) time was 9.8 and 13.3 months respectively. There was no statistical significance of the PFS of the two groups. The OS (median 16.3 months) in the R-TP group was superior to that in the R-FP group (median: 9.8 months) (p = 0.012). Among the patients who had received ≥60 Gy irradiation dose, the median PFS (10.6 months) and OS (16.3 months) were significantly superior to the PFS (8.7 months) and OS (11.3 months) among those patients did not (all p< 0.05). Grade 3 treatment-related gastritis were observed in 6 (27.3%) and 7 (25%) patients in the R-FP and R-TP group respectively. By univariate survival analysis, the age (<60 years), TP regimen and higher irradiation dose might improve the OS of such patients in present study. Conclusions: For those patients with post-operative loco-recurrent squamous-cell esophageal carcinoma, radiotherapy combined with either FP or TP regimen chemotherapy was an effective salvage treatment. Younger age, treatment with the TP regimen and an irradiation dose ≥60 Gy might improve the patients’ treatment outcome. Keywords: Squamous-cell esophageal cancer, Post-operative local recurrence, Salvage radio-chemotherapy, Treatment outcomes, Toxicity Introduction [4,5]. Depending on performance status, there are a Curative esophagectomy with radical lymph node dissec- number of patients which might tolerate the salvage treat- tion is the primary treatment for early stage esophageal ment. In these patients, a potential for cure still exists. carcinoma [1,2]. However, the 5-year survival rate remains Since 2000, radiotherapy, chemotherapy or chemo- only around 40% [3]. Loco-regional recurrence still is the radiotherapy have been demonstrated as the possible major type of failure in those patients following surgery salvage treatment for post-operative local recurrent esophageal carcinoma, with reported the median OS of 7.0-16.0 months [6-16]. In a phase II trial, Jingu et al. * Correspondence: gongyouling@gmail.com † from Japan reported that radiotherapy (60 Gy/30 frac- Equal contributors tions) combined with nedaplatin and 5-FU is a safe and Department of Thoracic Oncology and Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China effective salvage option for loco-recurrent esophageal State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, carcinoma, achieving an impressive median OS of Chengdu 610041, PR China 39 months [17]. Full list of author information is available at the end of the article © 2012 Zhang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhang et al. Radiation Oncology 2012, 7:93 Page 2 of 7 http://www.ro-journal.com/content/7/1/93 Table 1 Basic and clinical characteristics of the patients in In our experiences, the patients with loco-recurrent present study (n = 50) esophageal carcinoma and good performance status Characteristics Number of patients (%) could be considered as the potentially curative ones. Radio-chemotherapy consisting of fluorouracil (5-FU)/ Age (years) DDP (FP) or paclitaxel/DDP (TP) regimen has been used Median (range) 54 (39–64) as the salvage and definitive treatment in our practice, Gender according to the National Comprehensive Cancer Net- Male/Female 42 (84.0)/8 (16.0) work (NCCN) Guidelines [18]. ECOG performance status In this study, we retrospectively evaluated the survival 0-1 47 (94.0) of the identical patients treated with salvage concurrent 2 3 (6.0) radio-chemotherapy, in order to analyze the impacts of Pathology the chemotherapy regimen (FP or TP) and the irradiation Squamous-cell carcinoma (SCC) 50 (100.0) dose on the treatment outcome of post-operative local Tumorstage after surgery recurrences of squamous-cell esophageal carcinoma. I-II 17 (34.0) Patients and methods III-IV 33 (66.0) Patients’ data Time form surgery to recurrences (months) A loco-regional recurrence was defined as anastomotic Median (range) 13.0 (5.0-32.0) recurrence or lymph node metastasis in supraclavicular Sites of recurrence and mediastinum regions; only in patients with an initial Anastomotic 7 (14.0) diagnosis of lower thoracic carcinoma, the abdominal Supraclavicular lymph nodes 18 (36.0) lymph node metastasis was considered as local recur- Mediastinal lymph nodes 15 (30.0) rences. Between March 2005 and December 2009, a total Abdominal lymph nodes 5 (10.0) of 50 esophageal carcinoma patients received chemo- Supraclavicular/mediastinal lymph nodes 4 (8.0) radiotherapy for loco-regional recurrence at West China hospital and Second Affiliated Hospital of Anhui Med- Supraclavicular/abdominal lymph nodes 1 (2.0) a b th ical University. Each patient had undergone an R0 resec- : Eastern Cooperative Oncology Group; : Staging system, 6 edition, American Joint Committee on Cancer, 2002; : 4 patients with supraclavicular tion including extended lymph node dissection and had and mediastinal lymph nodes recurrence, 1 patients with mediastinal and histologically proven squamous-cell eaophageal carcin- abdominal lymph nodes recurrence. oma. All of the patients gave their informed consent be- fore treatment, which was in accordance with the were usually applied for treament. Intensity-modulated Declaration of Helsinki [19] and also approved by the radiotherapy (IMRT) was used if any supraclavicular Ethics Committee of our hospitals. lymph node was included as a target. The gross tumor The basic and clinical characteristics of the studied volume (GTV) included all known gross disease as deter- patients are summarized in Table 1. The median age of mined by the imaging and endoscopic findings. The clin- the patients was 54.2 years (range: 39-64 years); most of ical target volume (CTV) was defined as the GTV plus a them were male and with the Eastern Cooperative Oncol- 2-3 cm radial margin. If the target was coutoured in the ogy Group (ECOG) performance status score 0-1 (47/50, supraclavicular region, the correlated lymphatic drainage 94.0%). The initial tumor stage (Staging system, American regions was coutoured as the CTV, extending to the Joint Committee on Cancer) [20] after surgery in the cricothyroid membrane. The planning target volume present study were 17 stage I-II and 33 stage III-IV (PTV) was defined as the CTV plus a 0.5 cm margin in respectively. The median time between surgery and recur- all direction, respectively. The patients received a rence was 13.0 months (range: 5.0-32.0 months). Local conventional-fraction schedule: 1.8-2.0 Gy per fraction recurrence was diagnosed by computed tomography and 5 fractions per week with a 6-MV linear accelerator. (CT), upper gastrointestinal endoscopy and ultrasonog- As shown in Table 2, the median irradiation dose for raphy. There were 7 (12.7%), 23 (41.8%), 19 (34.5%) and the PTV was 60 Gy, with a range of 50.4-64 Gy. The 6 (10.9%) recurrences in anastomotic, supraclavicular, medi- dose constraint for the spinal cord was a maximum dose astinal and abdominal regions respectively, and 5 patients were confirmed having 2 recurrent sites respectively. Table 2 Response to treatment Complete Partial Stable Salvage radio-chemotherapy response (CR) response (PR) disease (SD) Radiotherapy R-TP group 5 (17.9%) 15 (53.6%) 8 (28.3%) All patients underwent initial CT simulation, then the R-FP group 5 (22.7%) 11 (50.0%) 6 (27.3 %) three-dimentional conformal radiotherapy (3D-CRT) and Zhang et al. Radiation Oncology 2012, 7:93 Page 3 of 7 http://www.ro-journal.com/content/7/1/93 < 45 Gy. For lungs, the mean dose and V were limited Results within 15 Gy and 30% respectively. The median follow-up time for the studied patients was 16.0 months (range: 10.0-44.0 months) and the median Chemotherapy time interval between surgery and recurrence was The chemotherapy and radiotherapy started at the same 13.0 months (range: 5.0-32.0 months). All patients com- day. The regimens consisting of either 5-FU 500 mg/m /day pleted the radiotherapy treatment. In present study, for five days plus DDP 75 mg/m on day one per 4 weeks 72.7% (16/22) and 75% (21/28) patients had received 2 2 or paclitaxel 135 mg/m and DDP 75 mg/m on day one 2 cycles of chemotherapy in the FP and TP group per 3 weeks. Only the grade 3 or higher treatment- respectively. And the remaining patients had received related esophagitis were observed and if prolonged, the at least 1 cycle of chemotherapy. chemotherapy was discontinued; otherwise the chemo- therapy was suspended until recovery and reduced the Responses to treatment regimen dose by 25% in the subsequent cycle. All patients were assessed as having had a response (details shown in Table 2). In the R-FP group, 5 (22.7%), Treatment assessment 11 (50%) and 6 (27.3%) patients showed CR, PR and SD, Evaluation of treatment response was carried out respectively. And in the R-TP group, these numbers according to Response Evaluation Criteria in Solid were 5 (17.9%), 15 (53.6%) and 8 (28.3%) respectively. Tumors (RECIST criteria) [21]. Disappearance of the all The overall responses were 72.7% (16/22) and 71.7% GTVs was designated to indicate complete response (20/28) in the R-FP and R-TP group respectively. (CR) on CT persisting for more than 4 weeks. A partial response (PR) was defined as a minimum of a 30% Follow-up decrease in the sum of the longest diameter of target Patient follow-up studies continued until December lesions. A disease was defined stable (SD) where there 2011, with no one lost to follow-up. The 1-year and 3- was neither a sufficient shrinkage to qualify for a PR nor year survival rates were 56% and 14% respectively. The a sufficient increase in the target lesions, and progressive median PFS of the whole group was 9.8 months (range: (PD), when there was at least a 20% increase in the sum 4.7-41.0 months) and the median OS of all patients was of the longest diameter of the target lesions or appear- 13.3 months (range: 5.4-44.0 months). ance of new lesions. Follow-up evaluations were per- In sub-group analysis, the median PFS and OS formed every 2 to 3 months for the first year and every were 9.8 months [95% confidential interval (CI) 9.4- 6 months thereafter by CT. 10.1 months] and 9.8 months (95% CI 9.4-10.2 months) Toxicities were evaluated according to the National in the R-FP group respectively (Figure 1). The patients Cancer Institute Common Toxicity Criteria version 3.0. receiving the TP regimen had the similar outcomes of the PFS (9.8 months, 95% CI 7.5-12.0 months) but a Statistical methods significant improvement of the OS (16.3 months, 95% CI Statistical analyses were performed using the SPSS soft- 14.5-18.1 months) (p = 0.012), compared to those patients ware (version 13.0). The progression-free survival (PFS) receiving the FP regimen. time was measured from the date the treatment began In addition, the irradiation dose had a clear impact to the date of the disease progression and the overall on the treatment outcomes in these evaluated patients survival (OS) time was considered from the start of (Figure 2). Patients receiving more than 60 Gy irradi- treatment to date of data analysis or date of loss from ation dose had significantly prolonged period in PFS follow-up for patients alive. Patients without disease (10.6 months, 95% CI 7.8-13.3 months) and OS relapse or progression who discontinued the study for (16.3 months, 95% CI 13.6-18.9 months) than those any reason were censored at the last on study tumor patients who received an irradiation dose less than assessment date. The rates of PFS and OS curves 60 Gy (for PFS: 8.7 months, 95% CI 6.5-10.8 months and depending on the different factors were calculated using for OS: 11.3 months, 95% CI 9.3-13.2 months) respect- the method of Kaplan-Meier analysis and were compared ively (p = 0.01 and 0.04, respectively). using a log-rank test. A p value< 0.05 was considered with statistical significance. Also, Cox's proportional Treatment-related toxicities hazards regression model was used for univariate survival All the patients were evaluated for tretment-related toxi- analysis. Patient age, gender, staging after surgery, time cities (Table 3). The combination of radiotherapy and interval between surgery and recurrence, irradiation dose, chemotherapy (either FP or TP regimens) were proved chemothrapy regimen, tumor response to treatment were to be tolerable. The most common toxicities were the put into univariate analysis. Due to the small patient treatment-related gastritis and neutropenia. Grade 3 numbers, multivariate analysis was not performed. treatment-related gastritis were observed in 6 patients Zhang et al. Radiation Oncology 2012, 7:93 Page 4 of 7 http://www.ro-journal.com/content/7/1/93 Figure 1 Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS) in the present study, according to the chemotherapy regimen the patients received. (27.3%) and 7 patients (25.0%) in the R-FP and R-TP showed the trends which could improve the overall sur- group, respectively. Grade 3 neutropenia were observed vival of the patients in present study respectively in 7 (31.8%) and 6 (26.4%) patients in the R-FP and R-TP (p = 0.048, 0.025 and 0.041, respectively). group, respectively. The other major grade 2 toxicities included the neutropenia, anemia and nausea/vomiting/ Discussion diarrhea. One patient receiving R-TP treatment had the Loco-regional recurrences after intial surgery in patients grade 3 vomiting (3.6%). No grade 4 or 5 toxicity was with esophageal cancer remain a serious challenge to recorded among all the patients. clinical oncologists. The NCCN Guidelines pointed out that a highly selected group of patients with local- Univariate survival analysis regional tumor recurrence after initial surgery may be Due to the small number of the evaluated, only the uni- considered fit and able to tolerate concurrent radio- variate analysis was performed according to the basic chemotherapy with a potential for cure [18]. In a line and clinical characteristics of the patients. The details with the previous studies, our data indicated that salvage were shown in Table 4. The gender, disease stage after concurrent radio-chemotherapy was an active and prom- surgery, the responses to the treatment and irradiation ising treatment strategy for such patients, reaching a dose did not significantly affected the survival time. median OS of 13.3 months with tolerable side-effects. While the patients’ age (<60 years), the chemotherapy The present protocol of concurrent radio-chemotherapy regimen (TP) and irradiation dose more than 60 Gy was completed in 74% (37/50) of the patients, and no Figure 2 Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS) in the present study, according to the irradiation dose the patients received. Zhang et al. Radiation Oncology 2012, 7:93 Page 5 of 7 http://www.ro-journal.com/content/7/1/93 Table 3 Treatment-related toxicities (number = 22 and 28 in R-FP and R-TP group respectively) Toxicities Toxicity grades, n (%) Grade 1 Grade 2 Grade 3 Hematological Neutropenia 3 (13.6)/5 (17.9) 12 (54.5)/17 (60.7) 7 (31.8)/6 (21.4) Anemia 8 (36.4)/10 (35.7) 14 (63.6)/18 (64.3) 0/0 Thrombocytopenia 17 (77.3)/18 (64.3) 5 (22.7)/10 (35.7) 0/0 Non-hematological Digestive tract side-effects 3 (13.6)/7 (25) 19 (86.4)/20 (71.4) 0/1 (3.6) Treatment-related esophagitis 2 (9.1)/3 (10.7) 14 (63.6)/18 (64.3) 6 (27.3)/7 (25.0) a b : Data presented as number in the R-FP group (%)/number in the R-TP group (%); : Including nausea, vomiting and diarrhea. serious treatment related toxicities were observed. The By sub-group analysis in the present study, the median tumor response rate was nearly 72% in R-TP and R-FP OS of the 28 patients received R-TP regimen group respectively, with a 3-year survival rate of 14%. (16.3 months) was significantly superior than that of These results are very similar to those reported in previ- other patients who received R-FP regimen (9.8 months) ous studies [13,15]. Yamashita et al. [13] reported the (p< 0.05). According to our knowledge, there was no results of radiotherapy with or without chemotherapy at direct comparison between FP and TP regimen when an average total dose of 56.6 Gy. The median survival time combined with radiotehrapy in the definitive treatment was 13.8 months and 1-year survival rate was 56% in for esophageal cancer. Recently, Ajani et al. reported patients with patients with loco-regional recurrence of that the regimen including 5-FU/DDP/paclitaxel with esophageal cancer after curative surgery. Recently, Baxi 50.4 Gy of radiation was associated with high morbidity, et al. from Princess Alexandra Hospital reported their although it reached a 1-year survival rate of 75.7% in treatment outcomes using DDP and 5-FU plus radiother- RTOG 0113 trial [22]. So far, FP regimen still was the apy (range: 45–60 Gy) for recurrent esophageal cancer first choice in definitive radio-chemotherapy for esopha- [15]. The 2-year survival rate of all patients was 21% and geal cancer in the NCCN guidelines [18]. The possible the median OS was 16 months. While the very impressive reason that the poorer treatment outcomes using R-FP results of salvage radio-chemotherapy for such patients regimen in present study was the relative lower dosage were reported by Jingu et al. [17] and the 3-year survival of 5-FU (500 mg/m /D, D1-5 per 4 weeks). In the trial rate was 56.3% using radiotherapy combined with nedapla- INT 0123, Minsky et al. established the standard dos- tin and 5-FU. But it was a small phase II study (patients’ age of 5-FU (1000 mg/m /D, D1-4 per 4 weeks) in the number = 30), and these data had not been confirmed by definitive radio-chemotherapy for esophageal cancer further clinical investigations. [23]. However, considering the relative smaller body size Table 4 Prognostic factors by log-rank test and univariate survival analysis in present study Factors Group Number Median OS Log-rank test Univariate analysis (months) p value p value Age < 60 years 16 14.3 0.042 0.048 ≧60 years 34 11.9 Gender Male 42 15.0 0.365 0.334 Female 8 10.6 Staging after surgery I/II 17 17.2 0.355 0.359 III/IV 33 13.8 Chemotherapy regimen TP 28 16.3 0.012 0.025 FP 22 9.8 Response to treatment CR/PR 40 15.0 0.071 0.072 SD 10 12.8 Irradiation dose ≧60 Gy 29 16.3 0.040 0.041 < 60 Gy 21 11.5 a b : Cox's proportional hazards regression model; : Overall survival. Zhang et al. Radiation Oncology 2012, 7:93 Page 6 of 7 http://www.ro-journal.com/content/7/1/93 of the Chinese population, the dosage of 5-FU was con- side-effects (neutropenia and anemia) and digestive tract sequently decreased, similar in methodology with other toxicities in present study. Compared to the previous Asian studies [12,17]. studies of patients with the locally-advanced esophageal In addition, our data indicates that an irradiation dose cancer [22,23,25-27], the treatment-related toxicities of of more than 60 Gy could improve not only the PFS but the concurrent radio-chemotherapy in present study the OS among those patients with recurrent esophageal were similar to or less than the studies mentioned above cancer after surgery (both p< 0.05). In our opinion, [8,12-15,17]. 50.4 Gy was the standard irradiation dose for esophageal One issue should be mentioned here. According to the cancer reported by Minsky et al. [23] in trial INT 0123 NCCN guidelines [18], also as summarized by two meta- and the higher radiation dose (64.8 Gy) did not increase analysis [28,29], the pre-operative chemoradiation fol- the survival or local/regional control. But the authors lowed by surgery is the most common strategy for also pointed out that 63.6% (7/11) the treatment-related patients with resectable esophageal cancer in Western deaths in the high-dose arm occurred in patients who countries, which could significantly improve the 3-year received 50.4 Gy or less, and the higher dose of irradi- OS and reduce the loco-reginal recurrences. The irradi- ation might not be responsible for the increased mortal- ation dose in such approach is nearly 40-45 Gy. Thus, ity. In 2001, reports from Nemoto et al. [8] indicated the patient who received the pre-operative chemoradia- that no significance between the patients’ survival tion could not be treated with such higher irradiation received more than or less than 60 Gy. But the 1-year dose similarly to the present study (around 60 Gy) for and 3-year survival rates were 45% and 20% in the loco-regional recurrence. The optimal treatment strat- higher dose arm respectively, which were superior egies for this specific group of patients need further clin- than those of the lower dose arm (15% and 7% respect- ical studies. ively). In the study by Baxi et al. [15] most patients In conclusion, combination of radiotherapy with con- (79%, 11/14) received irradiation dose of 58–60 Gy and current FP or TP chemotherapy is a safe and promis- the median OS (16 months) of all patients was encour- ing salvage treatment for loco-regional recurrence of aging. And in study by Jingu et al. [17], the irradiation esophageal cancer after surgery. The use of TP regimen dose was 60 Gy/30 fractions and the treatment out- and an irradiation dose of more than 60 Gy may comes (median OS of 39 months) were extremlly excit- improve the overall survival of these patients. However, ing. To data, one study has indicated that the survival the optimal treatment strategy (irradiation dose and was similar among the patients received an irradiation chemotherapy regimen) for loco-regional recurrent dose more or less than 60 Gy [14]. After a careful review esophageal cancer warrents further studies. of the literatures, the suitable irradiation dose for recur- Competing interests rent esophageal cancer remains unclear and requires The authors declare that they have no competing interests. further investigations. With regard to the side-effects of concurrent radio- Authors’ contributions JZ, FP and NL contributed equally in collection and analysis of data and chemotherapy for post-operative esophageal cancer, the drafting the manuscript; YL, YX, LZ, JW, JZ and MH provided the critical irradiation dose for the esophago-gastric anastomosis revision of the manuscript and the administrative support; YG provided the and the gastric tube should be of particularly concerm. conception of this study and the final approval of the version to be published. And all authors read and approved the final manuscript. In the present study, grade 3 treatment-related gastritis were recorded in 6 patients (27.3%) and 7 patients Acknowledgement (25.0%) in the R-FP and R-TP group, respectively. One We would like to thank Dr. Xin Gao at the Harvard Medical School in United patient received R-TP treatment was observed having States for the improvement of English language. Part of the material will be presented in the Digital Poster Discussion session the grade 3 vomiting. As far as we know, the prediction of the 54th Annual Meeting of American Society for Radiation Oncology, probability of the normal tissue complication at 5% Boston, US. within 5 years after radiotherapy (TD 5/5) of the stom- Author details ach is 60 Gy [24]. Furthermore, Nemato et al. [8] Department of Thoracic Oncology and Radiation Oncology, Cancer Center, reported that one patient died of necrosis of the stomach 2 West China Hospital, Sichuan University, Chengdu 610041, PR China. State 6 months after comletion of radiation therapy (66 Gy). Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China. Department of Oncology, Second Affiliated Therefore, we avoided prescribing a dose of more than Hospital of Anhui Medical University, Hefei 230601, PR China. 60 Gy to the recurrence of the anastomotic sites in present study, and only recurrences of the regional Received: 14 March 2012 Accepted: 19 June 2012 Published: 19 June 2012 lymph nodes received the irradiation dose more than 60 Gy. As a result, no serious treatment-related side- References effects (gastric fistula or necrosis) were observed in the 1. Fujita H, Kakegawa T, Yamana H, Shima I, Toh Y, Tomita Y, Fujii T, Yamasaki follow-up. Other common toxicities included hematological K, Higaki K, Noake T: Mortality and morbidity rates, post-operative course, Zhang et al. Radiation Oncology 2012, 7:93 Page 7 of 7 http://www.ro-journal.com/content/7/1/93 quality of life, and prognosis after extended radical lymphadenectomy Cancer Institute of the United States, National Cancer Institute of for esophageal cancer. 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Bull World Health Organ • Thorough peer review 2001, 79:373–374. • No space constraints or color figure charges 20. AJCC Cancer Staging Manual: American Joint Committee on Cancer. 6th edition. New York: Springer-Verlag; 2002. • Immediate publication on acceptance 21. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, • Inclusion in PubMed, CAS, Scopus and Google Scholar Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG: New guidelines to evaluate the response to treatment in solid tumors. • Research which is freely available for redistribution European Organization for Research and Treatment of Cancer, National Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

Salvage concurrent radio-chemotherapy for post-operative local recurrence of squamous-cell esophageal cancer

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Copyright © 2012 by Zhang et al.; licensee BioMed Central Ltd.
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Medicine & Public Health; Oncology; Radiotherapy
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1748-717X
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10.1186/1748-717X-7-93
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22713587
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Abstract

Purpose: To evaluate the treatment outcome of salvage concurrent radio-chemotherapy for patients with loco- recurrent esophageal cancer after surgery. Methods: 50 patients with loco-recurrent squamous-cell cancer after curative esophagectomy were retrospectively analyzed. Patients were treated with radiotherapy (median 60 Gy) combined with chemotherapy consisting of either 5-fluorouracil (5-FU) plus cisplatin (DDP) (R-FP group) or paclitaxel plus DDP (R-TP group). Results: The median follow-up period was 16.0 months. The 1-year and 3-year survival rates were 56% and 14%, respectively. The median progression-free survival (PFS) and overall survival (OS) time was 9.8 and 13.3 months respectively. There was no statistical significance of the PFS of the two groups. The OS (median 16.3 months) in the R-TP group was superior to that in the R-FP group (median: 9.8 months) (p = 0.012). Among the patients who had received ≥60 Gy irradiation dose, the median PFS (10.6 months) and OS (16.3 months) were significantly superior to the PFS (8.7 months) and OS (11.3 months) among those patients did not (all p< 0.05). Grade 3 treatment-related gastritis were observed in 6 (27.3%) and 7 (25%) patients in the R-FP and R-TP group respectively. By univariate survival analysis, the age (<60 years), TP regimen and higher irradiation dose might improve the OS of such patients in present study. Conclusions: For those patients with post-operative loco-recurrent squamous-cell esophageal carcinoma, radiotherapy combined with either FP or TP regimen chemotherapy was an effective salvage treatment. Younger age, treatment with the TP regimen and an irradiation dose ≥60 Gy might improve the patients’ treatment outcome. Keywords: Squamous-cell esophageal cancer, Post-operative local recurrence, Salvage radio-chemotherapy, Treatment outcomes, Toxicity Introduction [4,5]. Depending on performance status, there are a Curative esophagectomy with radical lymph node dissec- number of patients which might tolerate the salvage treat- tion is the primary treatment for early stage esophageal ment. In these patients, a potential for cure still exists. carcinoma [1,2]. However, the 5-year survival rate remains Since 2000, radiotherapy, chemotherapy or chemo- only around 40% [3]. Loco-regional recurrence still is the radiotherapy have been demonstrated as the possible major type of failure in those patients following surgery salvage treatment for post-operative local recurrent esophageal carcinoma, with reported the median OS of 7.0-16.0 months [6-16]. In a phase II trial, Jingu et al. * Correspondence: gongyouling@gmail.com † from Japan reported that radiotherapy (60 Gy/30 frac- Equal contributors tions) combined with nedaplatin and 5-FU is a safe and Department of Thoracic Oncology and Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, PR China effective salvage option for loco-recurrent esophageal State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, carcinoma, achieving an impressive median OS of Chengdu 610041, PR China 39 months [17]. Full list of author information is available at the end of the article © 2012 Zhang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Zhang et al. Radiation Oncology 2012, 7:93 Page 2 of 7 http://www.ro-journal.com/content/7/1/93 Table 1 Basic and clinical characteristics of the patients in In our experiences, the patients with loco-recurrent present study (n = 50) esophageal carcinoma and good performance status Characteristics Number of patients (%) could be considered as the potentially curative ones. Radio-chemotherapy consisting of fluorouracil (5-FU)/ Age (years) DDP (FP) or paclitaxel/DDP (TP) regimen has been used Median (range) 54 (39–64) as the salvage and definitive treatment in our practice, Gender according to the National Comprehensive Cancer Net- Male/Female 42 (84.0)/8 (16.0) work (NCCN) Guidelines [18]. ECOG performance status In this study, we retrospectively evaluated the survival 0-1 47 (94.0) of the identical patients treated with salvage concurrent 2 3 (6.0) radio-chemotherapy, in order to analyze the impacts of Pathology the chemotherapy regimen (FP or TP) and the irradiation Squamous-cell carcinoma (SCC) 50 (100.0) dose on the treatment outcome of post-operative local Tumorstage after surgery recurrences of squamous-cell esophageal carcinoma. I-II 17 (34.0) Patients and methods III-IV 33 (66.0) Patients’ data Time form surgery to recurrences (months) A loco-regional recurrence was defined as anastomotic Median (range) 13.0 (5.0-32.0) recurrence or lymph node metastasis in supraclavicular Sites of recurrence and mediastinum regions; only in patients with an initial Anastomotic 7 (14.0) diagnosis of lower thoracic carcinoma, the abdominal Supraclavicular lymph nodes 18 (36.0) lymph node metastasis was considered as local recur- Mediastinal lymph nodes 15 (30.0) rences. Between March 2005 and December 2009, a total Abdominal lymph nodes 5 (10.0) of 50 esophageal carcinoma patients received chemo- Supraclavicular/mediastinal lymph nodes 4 (8.0) radiotherapy for loco-regional recurrence at West China hospital and Second Affiliated Hospital of Anhui Med- Supraclavicular/abdominal lymph nodes 1 (2.0) a b th ical University. Each patient had undergone an R0 resec- : Eastern Cooperative Oncology Group; : Staging system, 6 edition, American Joint Committee on Cancer, 2002; : 4 patients with supraclavicular tion including extended lymph node dissection and had and mediastinal lymph nodes recurrence, 1 patients with mediastinal and histologically proven squamous-cell eaophageal carcin- abdominal lymph nodes recurrence. oma. All of the patients gave their informed consent be- fore treatment, which was in accordance with the were usually applied for treament. Intensity-modulated Declaration of Helsinki [19] and also approved by the radiotherapy (IMRT) was used if any supraclavicular Ethics Committee of our hospitals. lymph node was included as a target. The gross tumor The basic and clinical characteristics of the studied volume (GTV) included all known gross disease as deter- patients are summarized in Table 1. The median age of mined by the imaging and endoscopic findings. The clin- the patients was 54.2 years (range: 39-64 years); most of ical target volume (CTV) was defined as the GTV plus a them were male and with the Eastern Cooperative Oncol- 2-3 cm radial margin. If the target was coutoured in the ogy Group (ECOG) performance status score 0-1 (47/50, supraclavicular region, the correlated lymphatic drainage 94.0%). The initial tumor stage (Staging system, American regions was coutoured as the CTV, extending to the Joint Committee on Cancer) [20] after surgery in the cricothyroid membrane. The planning target volume present study were 17 stage I-II and 33 stage III-IV (PTV) was defined as the CTV plus a 0.5 cm margin in respectively. The median time between surgery and recur- all direction, respectively. The patients received a rence was 13.0 months (range: 5.0-32.0 months). Local conventional-fraction schedule: 1.8-2.0 Gy per fraction recurrence was diagnosed by computed tomography and 5 fractions per week with a 6-MV linear accelerator. (CT), upper gastrointestinal endoscopy and ultrasonog- As shown in Table 2, the median irradiation dose for raphy. There were 7 (12.7%), 23 (41.8%), 19 (34.5%) and the PTV was 60 Gy, with a range of 50.4-64 Gy. The 6 (10.9%) recurrences in anastomotic, supraclavicular, medi- dose constraint for the spinal cord was a maximum dose astinal and abdominal regions respectively, and 5 patients were confirmed having 2 recurrent sites respectively. Table 2 Response to treatment Complete Partial Stable Salvage radio-chemotherapy response (CR) response (PR) disease (SD) Radiotherapy R-TP group 5 (17.9%) 15 (53.6%) 8 (28.3%) All patients underwent initial CT simulation, then the R-FP group 5 (22.7%) 11 (50.0%) 6 (27.3 %) three-dimentional conformal radiotherapy (3D-CRT) and Zhang et al. Radiation Oncology 2012, 7:93 Page 3 of 7 http://www.ro-journal.com/content/7/1/93 < 45 Gy. For lungs, the mean dose and V were limited Results within 15 Gy and 30% respectively. The median follow-up time for the studied patients was 16.0 months (range: 10.0-44.0 months) and the median Chemotherapy time interval between surgery and recurrence was The chemotherapy and radiotherapy started at the same 13.0 months (range: 5.0-32.0 months). All patients com- day. The regimens consisting of either 5-FU 500 mg/m /day pleted the radiotherapy treatment. In present study, for five days plus DDP 75 mg/m on day one per 4 weeks 72.7% (16/22) and 75% (21/28) patients had received 2 2 or paclitaxel 135 mg/m and DDP 75 mg/m on day one 2 cycles of chemotherapy in the FP and TP group per 3 weeks. Only the grade 3 or higher treatment- respectively. And the remaining patients had received related esophagitis were observed and if prolonged, the at least 1 cycle of chemotherapy. chemotherapy was discontinued; otherwise the chemo- therapy was suspended until recovery and reduced the Responses to treatment regimen dose by 25% in the subsequent cycle. All patients were assessed as having had a response (details shown in Table 2). In the R-FP group, 5 (22.7%), Treatment assessment 11 (50%) and 6 (27.3%) patients showed CR, PR and SD, Evaluation of treatment response was carried out respectively. And in the R-TP group, these numbers according to Response Evaluation Criteria in Solid were 5 (17.9%), 15 (53.6%) and 8 (28.3%) respectively. Tumors (RECIST criteria) [21]. Disappearance of the all The overall responses were 72.7% (16/22) and 71.7% GTVs was designated to indicate complete response (20/28) in the R-FP and R-TP group respectively. (CR) on CT persisting for more than 4 weeks. A partial response (PR) was defined as a minimum of a 30% Follow-up decrease in the sum of the longest diameter of target Patient follow-up studies continued until December lesions. A disease was defined stable (SD) where there 2011, with no one lost to follow-up. The 1-year and 3- was neither a sufficient shrinkage to qualify for a PR nor year survival rates were 56% and 14% respectively. The a sufficient increase in the target lesions, and progressive median PFS of the whole group was 9.8 months (range: (PD), when there was at least a 20% increase in the sum 4.7-41.0 months) and the median OS of all patients was of the longest diameter of the target lesions or appear- 13.3 months (range: 5.4-44.0 months). ance of new lesions. Follow-up evaluations were per- In sub-group analysis, the median PFS and OS formed every 2 to 3 months for the first year and every were 9.8 months [95% confidential interval (CI) 9.4- 6 months thereafter by CT. 10.1 months] and 9.8 months (95% CI 9.4-10.2 months) Toxicities were evaluated according to the National in the R-FP group respectively (Figure 1). The patients Cancer Institute Common Toxicity Criteria version 3.0. receiving the TP regimen had the similar outcomes of the PFS (9.8 months, 95% CI 7.5-12.0 months) but a Statistical methods significant improvement of the OS (16.3 months, 95% CI Statistical analyses were performed using the SPSS soft- 14.5-18.1 months) (p = 0.012), compared to those patients ware (version 13.0). The progression-free survival (PFS) receiving the FP regimen. time was measured from the date the treatment began In addition, the irradiation dose had a clear impact to the date of the disease progression and the overall on the treatment outcomes in these evaluated patients survival (OS) time was considered from the start of (Figure 2). Patients receiving more than 60 Gy irradi- treatment to date of data analysis or date of loss from ation dose had significantly prolonged period in PFS follow-up for patients alive. Patients without disease (10.6 months, 95% CI 7.8-13.3 months) and OS relapse or progression who discontinued the study for (16.3 months, 95% CI 13.6-18.9 months) than those any reason were censored at the last on study tumor patients who received an irradiation dose less than assessment date. The rates of PFS and OS curves 60 Gy (for PFS: 8.7 months, 95% CI 6.5-10.8 months and depending on the different factors were calculated using for OS: 11.3 months, 95% CI 9.3-13.2 months) respect- the method of Kaplan-Meier analysis and were compared ively (p = 0.01 and 0.04, respectively). using a log-rank test. A p value< 0.05 was considered with statistical significance. Also, Cox's proportional Treatment-related toxicities hazards regression model was used for univariate survival All the patients were evaluated for tretment-related toxi- analysis. Patient age, gender, staging after surgery, time cities (Table 3). The combination of radiotherapy and interval between surgery and recurrence, irradiation dose, chemotherapy (either FP or TP regimens) were proved chemothrapy regimen, tumor response to treatment were to be tolerable. The most common toxicities were the put into univariate analysis. Due to the small patient treatment-related gastritis and neutropenia. Grade 3 numbers, multivariate analysis was not performed. treatment-related gastritis were observed in 6 patients Zhang et al. Radiation Oncology 2012, 7:93 Page 4 of 7 http://www.ro-journal.com/content/7/1/93 Figure 1 Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS) in the present study, according to the chemotherapy regimen the patients received. (27.3%) and 7 patients (25.0%) in the R-FP and R-TP showed the trends which could improve the overall sur- group, respectively. Grade 3 neutropenia were observed vival of the patients in present study respectively in 7 (31.8%) and 6 (26.4%) patients in the R-FP and R-TP (p = 0.048, 0.025 and 0.041, respectively). group, respectively. The other major grade 2 toxicities included the neutropenia, anemia and nausea/vomiting/ Discussion diarrhea. One patient receiving R-TP treatment had the Loco-regional recurrences after intial surgery in patients grade 3 vomiting (3.6%). No grade 4 or 5 toxicity was with esophageal cancer remain a serious challenge to recorded among all the patients. clinical oncologists. The NCCN Guidelines pointed out that a highly selected group of patients with local- Univariate survival analysis regional tumor recurrence after initial surgery may be Due to the small number of the evaluated, only the uni- considered fit and able to tolerate concurrent radio- variate analysis was performed according to the basic chemotherapy with a potential for cure [18]. In a line and clinical characteristics of the patients. The details with the previous studies, our data indicated that salvage were shown in Table 4. The gender, disease stage after concurrent radio-chemotherapy was an active and prom- surgery, the responses to the treatment and irradiation ising treatment strategy for such patients, reaching a dose did not significantly affected the survival time. median OS of 13.3 months with tolerable side-effects. While the patients’ age (<60 years), the chemotherapy The present protocol of concurrent radio-chemotherapy regimen (TP) and irradiation dose more than 60 Gy was completed in 74% (37/50) of the patients, and no Figure 2 Kaplan-Meier analysis of progression-free survival (PFS) and overall survival (OS) in the present study, according to the irradiation dose the patients received. Zhang et al. Radiation Oncology 2012, 7:93 Page 5 of 7 http://www.ro-journal.com/content/7/1/93 Table 3 Treatment-related toxicities (number = 22 and 28 in R-FP and R-TP group respectively) Toxicities Toxicity grades, n (%) Grade 1 Grade 2 Grade 3 Hematological Neutropenia 3 (13.6)/5 (17.9) 12 (54.5)/17 (60.7) 7 (31.8)/6 (21.4) Anemia 8 (36.4)/10 (35.7) 14 (63.6)/18 (64.3) 0/0 Thrombocytopenia 17 (77.3)/18 (64.3) 5 (22.7)/10 (35.7) 0/0 Non-hematological Digestive tract side-effects 3 (13.6)/7 (25) 19 (86.4)/20 (71.4) 0/1 (3.6) Treatment-related esophagitis 2 (9.1)/3 (10.7) 14 (63.6)/18 (64.3) 6 (27.3)/7 (25.0) a b : Data presented as number in the R-FP group (%)/number in the R-TP group (%); : Including nausea, vomiting and diarrhea. serious treatment related toxicities were observed. The By sub-group analysis in the present study, the median tumor response rate was nearly 72% in R-TP and R-FP OS of the 28 patients received R-TP regimen group respectively, with a 3-year survival rate of 14%. (16.3 months) was significantly superior than that of These results are very similar to those reported in previ- other patients who received R-FP regimen (9.8 months) ous studies [13,15]. Yamashita et al. [13] reported the (p< 0.05). According to our knowledge, there was no results of radiotherapy with or without chemotherapy at direct comparison between FP and TP regimen when an average total dose of 56.6 Gy. The median survival time combined with radiotehrapy in the definitive treatment was 13.8 months and 1-year survival rate was 56% in for esophageal cancer. Recently, Ajani et al. reported patients with patients with loco-regional recurrence of that the regimen including 5-FU/DDP/paclitaxel with esophageal cancer after curative surgery. Recently, Baxi 50.4 Gy of radiation was associated with high morbidity, et al. from Princess Alexandra Hospital reported their although it reached a 1-year survival rate of 75.7% in treatment outcomes using DDP and 5-FU plus radiother- RTOG 0113 trial [22]. So far, FP regimen still was the apy (range: 45–60 Gy) for recurrent esophageal cancer first choice in definitive radio-chemotherapy for esopha- [15]. The 2-year survival rate of all patients was 21% and geal cancer in the NCCN guidelines [18]. The possible the median OS was 16 months. While the very impressive reason that the poorer treatment outcomes using R-FP results of salvage radio-chemotherapy for such patients regimen in present study was the relative lower dosage were reported by Jingu et al. [17] and the 3-year survival of 5-FU (500 mg/m /D, D1-5 per 4 weeks). In the trial rate was 56.3% using radiotherapy combined with nedapla- INT 0123, Minsky et al. established the standard dos- tin and 5-FU. But it was a small phase II study (patients’ age of 5-FU (1000 mg/m /D, D1-4 per 4 weeks) in the number = 30), and these data had not been confirmed by definitive radio-chemotherapy for esophageal cancer further clinical investigations. [23]. However, considering the relative smaller body size Table 4 Prognostic factors by log-rank test and univariate survival analysis in present study Factors Group Number Median OS Log-rank test Univariate analysis (months) p value p value Age < 60 years 16 14.3 0.042 0.048 ≧60 years 34 11.9 Gender Male 42 15.0 0.365 0.334 Female 8 10.6 Staging after surgery I/II 17 17.2 0.355 0.359 III/IV 33 13.8 Chemotherapy regimen TP 28 16.3 0.012 0.025 FP 22 9.8 Response to treatment CR/PR 40 15.0 0.071 0.072 SD 10 12.8 Irradiation dose ≧60 Gy 29 16.3 0.040 0.041 < 60 Gy 21 11.5 a b : Cox's proportional hazards regression model; : Overall survival. Zhang et al. Radiation Oncology 2012, 7:93 Page 6 of 7 http://www.ro-journal.com/content/7/1/93 of the Chinese population, the dosage of 5-FU was con- side-effects (neutropenia and anemia) and digestive tract sequently decreased, similar in methodology with other toxicities in present study. Compared to the previous Asian studies [12,17]. studies of patients with the locally-advanced esophageal In addition, our data indicates that an irradiation dose cancer [22,23,25-27], the treatment-related toxicities of of more than 60 Gy could improve not only the PFS but the concurrent radio-chemotherapy in present study the OS among those patients with recurrent esophageal were similar to or less than the studies mentioned above cancer after surgery (both p< 0.05). In our opinion, [8,12-15,17]. 50.4 Gy was the standard irradiation dose for esophageal One issue should be mentioned here. According to the cancer reported by Minsky et al. [23] in trial INT 0123 NCCN guidelines [18], also as summarized by two meta- and the higher radiation dose (64.8 Gy) did not increase analysis [28,29], the pre-operative chemoradiation fol- the survival or local/regional control. But the authors lowed by surgery is the most common strategy for also pointed out that 63.6% (7/11) the treatment-related patients with resectable esophageal cancer in Western deaths in the high-dose arm occurred in patients who countries, which could significantly improve the 3-year received 50.4 Gy or less, and the higher dose of irradi- OS and reduce the loco-reginal recurrences. The irradi- ation might not be responsible for the increased mortal- ation dose in such approach is nearly 40-45 Gy. Thus, ity. In 2001, reports from Nemoto et al. [8] indicated the patient who received the pre-operative chemoradia- that no significance between the patients’ survival tion could not be treated with such higher irradiation received more than or less than 60 Gy. But the 1-year dose similarly to the present study (around 60 Gy) for and 3-year survival rates were 45% and 20% in the loco-regional recurrence. The optimal treatment strat- higher dose arm respectively, which were superior egies for this specific group of patients need further clin- than those of the lower dose arm (15% and 7% respect- ical studies. ively). In the study by Baxi et al. [15] most patients In conclusion, combination of radiotherapy with con- (79%, 11/14) received irradiation dose of 58–60 Gy and current FP or TP chemotherapy is a safe and promis- the median OS (16 months) of all patients was encour- ing salvage treatment for loco-regional recurrence of aging. And in study by Jingu et al. [17], the irradiation esophageal cancer after surgery. The use of TP regimen dose was 60 Gy/30 fractions and the treatment out- and an irradiation dose of more than 60 Gy may comes (median OS of 39 months) were extremlly excit- improve the overall survival of these patients. However, ing. To data, one study has indicated that the survival the optimal treatment strategy (irradiation dose and was similar among the patients received an irradiation chemotherapy regimen) for loco-regional recurrent dose more or less than 60 Gy [14]. After a careful review esophageal cancer warrents further studies. of the literatures, the suitable irradiation dose for recur- Competing interests rent esophageal cancer remains unclear and requires The authors declare that they have no competing interests. further investigations. With regard to the side-effects of concurrent radio- Authors’ contributions JZ, FP and NL contributed equally in collection and analysis of data and chemotherapy for post-operative esophageal cancer, the drafting the manuscript; YL, YX, LZ, JW, JZ and MH provided the critical irradiation dose for the esophago-gastric anastomosis revision of the manuscript and the administrative support; YG provided the and the gastric tube should be of particularly concerm. conception of this study and the final approval of the version to be published. And all authors read and approved the final manuscript. In the present study, grade 3 treatment-related gastritis were recorded in 6 patients (27.3%) and 7 patients Acknowledgement (25.0%) in the R-FP and R-TP group, respectively. One We would like to thank Dr. Xin Gao at the Harvard Medical School in United patient received R-TP treatment was observed having States for the improvement of English language. Part of the material will be presented in the Digital Poster Discussion session the grade 3 vomiting. As far as we know, the prediction of the 54th Annual Meeting of American Society for Radiation Oncology, probability of the normal tissue complication at 5% Boston, US. within 5 years after radiotherapy (TD 5/5) of the stom- Author details ach is 60 Gy [24]. Furthermore, Nemato et al. [8] Department of Thoracic Oncology and Radiation Oncology, Cancer Center, reported that one patient died of necrosis of the stomach 2 West China Hospital, Sichuan University, Chengdu 610041, PR China. State 6 months after comletion of radiation therapy (66 Gy). Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, PR China. Department of Oncology, Second Affiliated Therefore, we avoided prescribing a dose of more than Hospital of Anhui Medical University, Hefei 230601, PR China. 60 Gy to the recurrence of the anastomotic sites in present study, and only recurrences of the regional Received: 14 March 2012 Accepted: 19 June 2012 Published: 19 June 2012 lymph nodes received the irradiation dose more than 60 Gy. As a result, no serious treatment-related side- References effects (gastric fistula or necrosis) were observed in the 1. Fujita H, Kakegawa T, Yamana H, Shima I, Toh Y, Tomita Y, Fujii T, Yamasaki follow-up. Other common toxicities included hematological K, Higaki K, Noake T: Mortality and morbidity rates, post-operative course, Zhang et al. Radiation Oncology 2012, 7:93 Page 7 of 7 http://www.ro-journal.com/content/7/1/93 quality of life, and prognosis after extended radical lymphadenectomy Cancer Institute of the United States, National Cancer Institute of for esophageal cancer. 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Journal

Radiation OncologySpringer Journals

Published: Jun 19, 2012

References