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Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial

Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal... Background: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed. Methods: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Results: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log- rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms. Conclusions: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC. Background the high rates of locoregional and distant failure, there Oesophageal squamous cell carcinoma (OSCC) accounts is much interest in the combination of systemic che- for most cases of oesophageal cancer worldwide [1,2]. motherapy and local surgical treatment. Even after complete surgical dissection, the prognosis of The potential benefits of preoperative chemotherapy patients with OSCC is poor, with 5-year survival rates of include increasing the likelihood of curative resection by 20 to 30%. Factors that contribute to this dismal prog- downstaging the tumour and rapidly improving tumour- nosis include presence of locally advanced disease and related symptoms. It is also been thought that systemic undetected metastatic cancer at diagnosis. Because of chemotherapy could contribute to the eradication of micro-metastases and circulating tumour cells. More recently, the importance of systemic disease control has * Correspondence: j.j.boonstra@erasmusmc.nl been emphasized by new insights in the metastasizing Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center, Rotterdam, The Netherlands process of cancer [3]. For decades, the dissemination of Full list of author information is available at the end of the article © 2011 Boonstra 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. Boonstra et al. BMC Cancer 2011, 11:181 Page 2 of 10 http://www.biomedcentral.com/1471-2407/11/181 cancer has been considered the final stage in a deterior- malignant disease, including negative biopsies from the ating process. Now, there is accumulating evidence that former tumour area, was defined as complete response dissemination already can occur at an early stage of the (CR). Partial response (PR) was defined as >50% reduc- disease [4]. In theory, the use of preoperative che- tion of tumour bulk, without the appearance of new motherapy may therefore have a positive impact on sur- lesions. Stable disease (SD) was defined as <50% reduc- vival of patients with oesophageal cancer. Here, we tion of tumour bulk, without the appearance of new report the design and long-term results of a randomized lesions. Progressive disease (PD) was defined as >25% progression of tumour bulk or the appearance of new controlled trial in patients with resectable OSCC, com- lesions. Patients with complete or partial responses paring preoperative chemotherapy with cisplatin and etoposide followed by surgery to surgery alone. received two additional courses of chemotherapy, whereas non-responding patients (stable disease or pro- Methods gressive disease) were referred for immediate surgery. All eligible patients had histologically confirmed squa- Patients with progressive disease (T4 or M1 disease) mous cell carcinoma of the intra-thoracic ooesophagus. were treated palliative and observed for survival. Patients were deemed resectable if the disease was clini- Patients, who were randomly assigned to undergo sur- cally limited to the locoregional area (tumour stage 1, 2 gery alone, underwent the operation as soon as possible. or 3; any nodal stage and no metastases). Patients with Patients who received chemotherapy were operated 4 to carcinoma of the distal oesophagus and suspected celiac 6 weeks after the last treatment cycle. The study proto- lymph nodes involvement (M1a) were also considered col was approved by the ethics committee of all partici- eligible for surgery. Patients had to be below 80 years of pating institutions and written informed consent was age, in adequate physical condition (Karnofsky score obtained from all patients. >70) to undergo surgery and had to have adequate hepatic, renal and bone marrow function. Exclusion cri- Chemotherapy teria were synchronous cancer, tumour localization in Cisplatin, at adoseof80mg/m , was given intrave- the cervical ooesophagus (upper border, <18 cm from nously over 4 hours on day one of each cycle preceded the incisor teeth), severe cardiovascular or pulmonary and followed by adequate hydration. Etoposide, at a disease. Patients with previous malignancies were eligi- dose of 100 mg/m , was administered intravenously over ble if more than 5 years had elapsed from diagnosis 2 hours on day 1 (before cisplatin) and day 2, followed without evidence of tumour recurrence; exceptions were by etoposide 200 mg/m orally on days 3 and 5. This made for adequately treated basal cell cancer of the skin course was repeated in week 4. In case of clinical or carcinoma in situ of the cervix. Preoperative work-up response, two subsequent courses of chemotherapy were included clinical examination, oesophago-gastroscopy administered in week 8 and 11. All patients received with biopsies, chest radiography, external ultrasonogra- prophylactic anti-nausea treatment with 5-HT 3 recep- phy of the cervical and upper abdominal region and tor antagonists during chemotherapy. Treatment related computed tomography (CT) of the chest and abdomen. toxicities were measured according to the WHO recom- Radionuclide bone scans were performed if indicated. mendations [5]. Re-treatment with the next cycle was Bronchoscopy was performed when the primary tumour permitted only if the absolute neutrophil count was at was adjacent to the trachea or main stem bronchus and least 3,500/mm , and the platelet count was at least invasion was suspected. 100,000/mm . A delay of treatment of up to 2 weeks Central randomisation took place at the Erasmus Uni- was permitted. In patients with severe toxic renal or versity Medical Center in Rotterdam (by trial coordina- neurological effects (≥ WHO grade 3) chemotherapy tor TCK). Random assignment was stratified by age was stopped and patients were referred for surgery. (<50; 51-60; >60), gender (male; female), weight loss (kg) in the past four months (0-5; 6-10; >10) and length Surgery and pathological examination of the tumour (cm) as measured by oesophago-gastro- For carcinomas of the upper half of the intra-thoracic scopy (1-3; 4-6; 7-10; >10). Patients assigned to preo- ooesophagus a right-sided thoracotomy was performed. perative chemotherapy were treated with two cycles, For carcinomas of the lower half of the intra-thoracic followed by a clinical response evaluation. Response eva- ooesophagus a transhiatal oesophagectomy was done. luation was done three to four weeks after the last cycle The tumour and its adjacent lymph nodes were dis- of chemotherapy. Clinical response after chemotherapy sected en bloc. The left gastric artery was transected at was evaluated by oesophago-gastroscopy and CT of the its origin, with resection of local lymph nodes. The con- chest and abdomen. Tumour responses were assessed tinuity of the digestive tract was restored by means of according to the World Health Organisation (WHO) gastric tube reconstruction or colonic interposition with criteria [5]. Complete absence of any evidence of a cervical anastomosis. The tumour stage after resection Boonstra et al. BMC Cancer 2011, 11:181 Page 3 of 10 http://www.biomedcentral.com/1471-2407/11/181 was classified according to the TNM classification of the Results International Union Against Cancer [6]. Resections were Between January, 1989, and January, 1996, 169 patients classified as radical when microscopical examination from six Dutch University Hospitals (Rotterdam, revealed all margins to be free of tumour (R0). Resec- Amsterdam, Utrecht, Groningen, Nijmegen and Maas- tions were considered not radical, if microscopically tricht) were randomly assigned to either chemotherapy examination showed tumour-positive circumferential followed by surgery (CS group, N = 85) or surgery alone margin (R1) or presence of macroscopic disease (R2). (S group, N = 84; Figure 1). An additional number of nine patients were included to adjust for study drop- Follow-up outs. The majority of patients (N = 122) were included All patients were followed at an interval of three to four by the Erasmus Medical Center (EMC), Rotterdam. months during the first year, every six months for the From all participating centers, the EMC is the only hos- second year, and annually for up to 5 years post surgery. pital that collected outcome data (prospectively) for all After 5 years, follow-up data were obtained by telephone patients with oesophageal cancer referred in time this from the patient or his/her family practitioner. Recur- study was performed. Between January, 1989, and Janu- rence of disease was diagnosed on clinical grounds. ary, 1996, 257 patients with OSCC were referred to the However, whenever a relapse was suspected, radiologic, EMC. Of these, 183 patients were deemed eligible for endoscopic, or histologic confirmation was sought for. surgical resection, of which 122 (67%) were included in Loco-regional disease recurrence was defined as this trial. The reasons why 61 (33%) patients were not relapse at the primary site including the anastomosis or randomized for this trial are not well documented. in regional lymph nodes. Distant disease recurrence was Table 1 shows that the two groups were similar in defined as distant lymph node sites or involvement of terms of age, sex, and performance status. Distribution distant organs including lung, liver, bone, and subcuta- according to weight loss and size of the tumour was neous tissue. also balanced. One patient, allocated to preoperative chemotherapy, had a tumour located in the cervical part of the oesophagus (the reason why this patient was Statistical analysis included and randomized remains unclear, even after The planned number of patients to be entered in the retrospective analysis of the patient’s record). Preopera- study was 80 for each treatment arm. With these num- tive staging by CT of the chest and the upper abdomen bers of patients the statistical power should be sufficient was performed in 149 patients (88%); two patients (1%) (power = 0.8; significance 0.05) to detect an increase of died before the planned CT scan; six patients (4%) were the median survival from 10 to 18 months. staged by endoscopic ultrasound, external ultrasonogra- Overall survival (OS) was calculated from the date of phy of the cervical and upper abdominal region and random assignment to date of death from any cause and chest radiography. From twelve patients (7%) no addi- surviving patients were censored at the date they were tional information on preoperative staging was available. last known to be alive. Disease-free survival (DFS) was calculated from a landmark time of 6 months after date Chemotherapy of randomisation to allow for the difference in timing of Of the 85 patients assigned to preoperative chemother- surgery between the two treatment groups [7]. In this apy, 80 (94%) received chemotherapy; 75 (88%) patients analysis, events including macroscopically incomplete had two or more cycles and 5 patients (13%) received resection, local and distant recurrence, and death arising one cycle. The reasons why no chemotherapy or only within the first 6 months after random assignment were one cycle was given were patient’s refusal (N = 3), death regarded as events at this landmark time. Survival curves (N = 1), tumour bleeding (N = 3) and renal toxicity are presented by the Kaplan-Meier method and treat- grade III (N = 1). Two patients allocated to preoperative ment comparisons are by the log-rank test. chemotherapy, were directly lost to follow-up after ran- Statistical analyses were performed using the SPSS sta- domization. Tracing back the original patient’s files was tistical package (SPSS Inc.,Chicago, IL,USA).Hazard impossible; therefore, it is not clear if these two patients ratios (HR) were calculated with the use of a Cox truly received chemotherapy followed by surgery. regression model including treatment alone (primary Clinical response evaluation after two cycles of che- analysis) and after adjustment for baseline stratification motherapy showed 43 patients with stable or progressive factors. Categorical data were compared with the use of disease. Partial response to chemotherapy was observed in chi-square test or Fisher’s exact test, with a test for 32 patients. Of these, 30 patients received two additional trend over ordered categories. All statistical comparisons cycles of chemotherapy; one received one additional cycle were made with two-tailed tests and P values < 0.05 and one had three additional cycles of chemotherapy. were reported as significant. Boonstra et al. BMC Cancer 2011, 11:181 Page 4 of 10 http://www.biomedcentral.com/1471-2407/11/181 Figure 1 CONSORT Flow-diagram: random assignment, and compliance to the allocated treatment. CTX, chemotherapy Clinical response evaluation after the additional cycles of was 14 days in the S group. In the CS group, the med- chemotherapy showed six patients with complete ian time from randomization to surgery was 63 days response; 20 patients had partial response; five showed (36-123) for patients who received two cycles of che- stable disease and one had progressive disease. motherapy, and 114 days (54-165) for patients who Detailed data on chemotherapy related toxicity is not received additional treatment cycles. Four patients (5%) available. In the prior phase II trial a high rate of grade III in the CS group and three patients (4%) in S group died and IV nausea (38%) and vomiting (20%) was observed, within 30-days after surgery. probably due to the fact that 5-HT3 receptor blockers were Data on postoperative complications was available of rarely given throughout the study period [8]. All patients in 67/76 (88%) of patients in the CS group and 75/82 the current trial received prophylactic anti-nausea treat- (91%) patient in the S group. The frequency of nonfatal ment with 5-HT 3 receptor antagonists during chemother- postoperative events was closely similar in both groups apy. No grade III or IV nausea and vomiting were observed. (table 2). However, pulmonary complications were sig- The major non-hematological toxicity (grade III) was alope- nificantly more observed in the CS group (P = 0.041). cia. Hematological toxicity grade III was observed in 23 Oesophagectomy was performed in 91% (69/76) in the patients (one renal, twenty-two hematological). Eight CS-group and 85% (70/82) in the S-group. In the CS patients had grade IV hematological toxicity. group, six patients did not receive an oesphagectomy because of tumour growth in adjacent structures (aorta Outcome of surgery or bronchial tree) and one had tumour positive celiac Surgery was performed in 76 CS and 82 S patients lymph nodes at laparotomy. In the S group, seven patients did not undergo surgical resection because of (Table 2). Median time from randomization to surgery Boonstra et al. BMC Cancer 2011, 11:181 Page 5 of 10 http://www.biomedcentral.com/1471-2407/11/181 Table 1 Patient’s characteristics S group, respectively). In the CS group, the pathological complete response rate (pT0N0M0) was 7%. Total CS S group group Characteristics (N = 169) (N = 85 ) (N = 84) P-value* Pattern of failure Age, years 0,73 The outcomes of treatments were considered according <50 31 (18%) 17 (20%) 14 (17%) to findings at operation and to patterns of disease pro- 51-60 54 (32%) 25 (29%) 29 (34%) gression (first disease-free survival event; Table 3). The >60 84 (50%) 43 (51%) 41 (49%) rates of unresectable tumors or macroscopically incom- Median 60 60 60 plete resections were higher in the S group (P =0.23; P Range 35 - 79 35 - 76 37 - 79 = 0.05 respectively). The pattern of first disease progres- sion was similar between both treatment groups; in par- Sex 0,9 ticular there was no clear trend toward fewer patients Male 126 (75%) 63 (74%) 63 (75%) with distant metastases as first site of relapse in the CS Female 43 (25%) 22 (26%) 21 (25%) group. Ten patients treated with preoperative che- Weight loss (% of normal 0,24 weight) motherapy developed a second primary tumor; seven <5 56 (33%) 30 (35%) 26 (31%) squamous cell carcinomas of head and neck, one pan- 6-10 40 (24%) 16 (19%) 24 (29%) creatic, one lung and one breast carcinoma. In contrast, >10 51 (30%) 30 (35%) 21 (25%) four patients who underwent immediate surgical resec- Not recorded 22 (13%) 9 (11%) 13 (15%) tion developed a second primary tumour, all squamous Tumor length (cm) 0,17 cell carcinomas of head and neck. <3 27 (16%) 14 (17%) 13 (16%) 4-6 69 (41%) 36 (42%) 33 (39%) Overall and disease-free survival 7-10 55 (32%) 22 (26%) 33 (39%) At thetimeofanalysis, themedian follow-up was15 >10 6 (4%) 5 (6%) 1 (1%) months in the CS group and 14 months in the S group. Not recorded 12 (7%) 8 (9%) 4 (5%) In an intention-to-treat survival analysis, two patients that were directly lost to follow-up were censored one Location of the tumor 0,66 month after the date of randomization. OS on intention Cervical 1 (1%) 1 (1%) 0 to treat basis is shown in Figure 2. The median overall Upper third 7 (4%) 3 (3%) 4 (5%) survival in the CS group was 16 months, and in the S Middle third 76 (45%) 38 (45%) 38 (45%) group 12 months. OS was better in the CS group than Distal third 71 (42%) 34 (40%) 37 (44%) in the S group (P = 0.03, by the log-rank test; HR 0.71; Not recorded 14 (8%) 9 (11%) 5 (6%) 95%CI 0.51-0.98; Figure 2A). Survival at one year was Karnofsky score* 0,53 64% for those allocated to chemotherapy, 52% for those 70 - 80 125 (74%) 60 (71%) 65 (77%) allocated to surgery alone; at two years 42% and 30%; 5- 90 - 100 38 (22%) 21 (24%) 17 (20%) years, survival was 26% and 17%, respectively. Not recorded 6 (4%) 4 (5%) 2 (3%) DFS is shown in Figure 2B. For DFS, 59 patients in Abbreviations: CS, Chemotherapy followed by surgery; S, Surgery alone the CS group and 40 patients in the S group remained * Comparisons were made by the chi-square test for analysis after the landmark period of six months. In 6/59 (10%) patients in the CS group the date of disease recurrence was not documented. In these, the date of tumour encasement of the aorta or the bronchial tree disease recurrence was estimated four months earlier and five due to tumour positive celiac lymph nodes at than the date of death (in the CS group the median laparotomy. Of the 69 patients in the CS group who underwent surgical resection, 71% had R0 resections, time between date of recurrence and date of death was 25% had R1 resections, and 4% had R2 resections. Of four months). In the CS group, there is prolonged DFS the 70 patients in the S group who underwent surgical compared with the surgical resection alone group (P = resection, 57% had R0 resections, 29% had R1 resec- 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). tions, and 14% had R2 resections. Although more Overall survival according clinical response to preo- patients in the CS group had R0 resections as compared perative chemotherapy showed that patients with clinical with the S group, no significant differences was observed partial or complete response (those who received three (P = 0.09). However, there was a significant difference or more cycles of therapy) had significantly better over- between the number of R2 resections in both treatment all survival then those with stable or progressive disease arm (P = 0.04). Also the number of patients with lymph (P = <0.001, by log-rank test; HR 0.38; 95%CI 0.23-0.65). node involvement (N1 or M1a) did not differ between Figure 3 shows no clear evidence that effect of che- motherapy varied in accordance with age, sex or length of both treatment arms (43 and 46% in the CS group and Boonstra et al. BMC Cancer 2011, 11:181 Page 6 of 10 http://www.biomedcentral.com/1471-2407/11/181 Table 2 Surgical details Total CS group S group (N = 169) (N = 85) (N = 84) P-value Surgery done 0,083 Yes 158 (93%) 76 (90%) 82 (98%) No 9 (5%) 7 (8%) 2 (2%) Not recorded 2 (2%) 2 (2%) 0 Reason no surgery undertaken Died before surgery 3 (2%) 1 (1%) 2 (2%) Progressive disease Tumor unresectable 3 (2%) 3 (4%) 0 Distant metastases 3 (2%) 3 (4%) 0 Type of resection* 0,38 Transhiatal 113 (71%) 55 (72%) 58 (71%) Transthoracic 20 (13%) 9 (12%) 11 (13%) Type not recorded 5 (3%) 4 (5%) 1 (1%) Other 1 (1%) 1 (1%) 0 No resection performed 19 (12%) 7 (10%) 12 (15%) Postoperative deaths (within 30 days)* 7 (4%) 4 (5%) 3 (4%) 0,62 Non-fatal postoperative complications* 0,64 None 68 (43%) 30 (40%) 38 (46%) Any 67 (42%) 33 (43%) 34 (41%) Not recorded 16 (10%) 9 (12%) 7 (9%) Type of non-fatal postoperative complications*, Pulmonary 25 (16%) 17 (23%) 8 (10%) 0,048 Cardiac 6 (4%) 3 (4%) 3 (4%) 1,0 Anastomotic Subclinical 10 (6%) 5 (7%) 5 (6%) 1,0 Clinical 7 (4%) 3 (4%) 4 (5%) 1,0 Chylothorax 7 (4%) 4 (5%) 3 (4%) 0,70 Bleeding 5 (3%) 3 (4%) 2 (2%) 0,67 Vocal-cord injury 22 (14%) 10 (13%) 12 (15%) 0,82 Other 10 (6%) 4 (5%) 6 (7%) 0,75 Abbreviations: CS, Chemotherapy followed by surgery; S, Surgery alone * Percentages based on total patients undergoing surgery. † Nonfatal postoperative events; comparisons were made by the Fisher’s exact test the tumour. In this subgroup analysis, it appeared that Discussion patients with substantial weight loss (>10%) treated with The long-term results of this randomized controlled preoperative chemotherapy had better overall survival as trial demonstrated a survival benefit for preoperative compared to those who received surgery alone. Possibly, chemotherapy followed by surgery in patients with patients allocated to chemotherapy and in a poor nutrition OSCC, when compared with surgery alone. This study status (eg weight loss >10%) were more likely to receive has only been reported in abstract form, which ham- nutritional support over a longer period of time as com- pers interpretation of our findings in context of other pared to patients that were allocated to surgery alone. randomized trials [9]. Why it took so long to report This could have led to a better preoperative condition of the design and results of this study is not completely patients who received chemotherapy, which could possibly understood. The main reasons are change of person- contribute to improved overall survival. Furthermore, nel (the trial coordinator [TCK] moved to another patients with a tumour located in the middle thoracic hospital) and loss of interest in the used chemothera- oesophagus who received preoperative chemotherapy had peutic regime. Nevertheless, we believe that these better overall survival then patients who received surgery results contribute to the ongoing debate about the alone. The explanation for the observed survival benefit in optimal (preoperative) therapy for patients with this subgroup of patients is unclear. OSCC. Boonstra et al. BMC Cancer 2011, 11:181 Page 7 of 10 http://www.biomedcentral.com/1471-2407/11/181 Table 3 Nature of first disease-free survival event significant survival benefit for the use of preoperative chemotherapy (P = .004) [11,12]. An other large and CS S group group well-conducted randomized controlled trial among Event (N = 85) (N = 84) P- patients with oesophageal cancer (236 OAC and 204 value* OSCC patients), by the North American Intergroup Disease free 12 (14%) 7 (8%) 0,33 (RTOG Trial 8911 or USA Intergroup 113 trial; further No surgery performed 7 (8%) 2 (3%) 0,17 called the Intergroup trial), demonstrated no significant No resection performed 7 (8%) 12 (14%) 0,23 difference in survival between patients treated with pre- Macroscopic residual disease 3 (3%) 10 (12%) 0,05 operative chemotherapy and those who received surgery 2nd Primary 10 (12%) 4 (5%) 0,16 alone [10,13]. In the light of the results of both trials, Local recurrence 16 (19%) 21 (25%) 0,36 we discuss the design and results of the present study. Distant metastases 5 (6%) 5 (6%) 1 As most randomized controlled trials performed in the Local recurrence and distant metastases 9 (11%) 10 (12%) 0,81 early ‘90, this study reflects the methods for diagnosis, Death with cancer but site of failure not 5 (6%) 7 (8%) 0,57 staging, treatment delivery and outcome measurement reported that indicate clinical practice during that period. In the Death from other or unspecified cause 11 (13%) 6 (7%) 0,31 present study, the majority of patients (88%) underwent * Comparisons were made by the Fisher’s exact test preoperative staging by oesophago-gastroscopy and CT scan of the chest and upper abdomen. The same preo- The results of this study should be interpreted in the perative staging methods were used in the Intergroup timeframe in which this study was performed. This trial. In the MRC trial, however, there was no standardi- study is one of the three largest randomized controlled zation of preoperative staging. These differences in preo- trials among patients with OSCC treated with preopera- perative staging could, by selection of different tive chemotherapy followed by surgery or surgery alone populations of OSCC patients, contribute to differences [10,11]. All these large randomized controlled trials in results between the trials. were performed in the early ‘90s. The Medical Research In the Intergroup trial as well as in the MRC trial the Council (MRC) trial included most patients with oeso- chemotherapeutic regime consists of cisplatin combined phageal cancer (533 oesophageal adenocarcinoma with fluorouracil; in the present study cisplatin was (OAC) and 247 OSCC patients) and demonstrated a combined with etoposide. The ratio for this combination Figure 2 Overall and disease free survival. A) Overall survival of all allocated patients. The distribution curves represent the results of an intention-to-treat survival analysis involving all patients. Patients who received preoperative chemotherapy had a median survival of 16 months; in comparison, patients who underwent only surgery had a median survival of 12 months (P = 0.03 by the log-rank test). B) Disease-free survival of all patients from a landmark time of 6 months after date of randomisation (P = 0.02 by the log-rank test). Boonstra et al. BMC Cancer 2011, 11:181 Page 8 of 10 http://www.biomedcentral.com/1471-2407/11/181 Figure 3 Survival by characteristics at randomisation and post-treatment. Centre of each square indicates hazard ratio, and area of square the amount of information. Lines on either side indicate 95 CI. of chemotherapeutic agents was deducted from trials toxicity profile was mild [8]. Patients without clinical among patients with non-small-cell lung cancer in response to chemotherapy received a total preoperative 2 2 which this regime had showed to be safe and effective dose of 160 mg/m cisplatin and 1000 mg/m etoposide. [14]. Furthermore, a phase II trial in patients with The dose of cisplatin is similar as compared with the advanced OSCC had shown that the response rate MRC trial (160 mg/m ). Patients with clinical response equals that of other cisplatin-based regimes and that the to chemotherapy received total doses up to cisplatin 320 Boonstra et al. BMC Cancer 2011, 11:181 Page 9 of 10 http://www.biomedcentral.com/1471-2407/11/181 2 2 mg/m and etoposide 2000 mg/m . In this subgroup of time of the S group was 12 months, compared to 16 patients, the total preoperative dose of cisplatin was and 13 months in the Intergroup and MRC trial, respec- slightly higher as compared to the Intergroup trial (300 tively. It appears that the S group in our study had the mg/m ). Thecompliancetochemotherapywas 88% worst survival outcome, but this may be due to patient (patients who received two or more of the planned selection. Both the MRC as Intergroup trial included cycles of chemotherapy). This is similar to 90% of the more OAC than OSCC patients. Subgroup analysis of the MRC trial, including only OSCC patients, showed a patients that received both treatment cycles in the MRC median survival time of 11 months for patients who trial, but differed from the Intergroup wherein 71% of underwent surgery alone [12]. Remarkably, in the sub- the patients received all of three planned cycles of che- motherapy. It has been suggested that the higher dose group analysis there is no significant survival benefit for of chemotherapy in the Intergroup trial was detrimental OSCC patients treated with preoperative chemotherapy to patients who underwent oesophagectomy. Other fac- (P = 0.1). tors related to the chemotherapeutic regimes that could In line with the results of the MRC and Intergroup contribute to the differences in outcome between the trial, there was no significant difference in pattern of three studies, are the use of chemoradiotherapy in a failure between both treatment arms in our study. The subset of patients in the MRC trial and the use of post- rate of distant metastases was equal in both treatment operative chemotherapy in a subgroup of patients in the groups. These findings provide no evidence for the gen- Intergroup trial. eral hypothesis that preoperative chemotherapy elimi- In our study the majority of patients underwent a nates systemic micro-metastases. The results of this trial transhiatal oesophagectomy. This type of resection is and the MRC trial suggest that the biologic effect of associated with lower morbidity (and mortality) than a preoperative chemotherapy seems to specifically influ- transthoracic resection ([15]). In the other trials, the ence the extent of surgery [12]. In the present study, the type of surgical resection that has been performed is not incidence of incomplete resections was greater in the S clear (MRC trial) or the exact numbers are not group, but sites of first recurrence (local or distant) described (Intergroup trial). The postoperative mortality were similar. Furthermore, at 6 months, the DFS advan- rate (<30 days after surgery) in the current trial was 5% tage is established for the CS group (Figure 2A) and (4/76) in the CS group and 4% (3/82) in the S group remains consistent throughout follow-up as the survival and differed not among both groups. These rates are curves remain approximately parallel. This suggests that the effect of preoperative chemotherapy is to reduce similar as those observed in the Intergroup trial, with tumour volume and increase the potential for curative 6% postoperative mortality in both treatment arms. In contrast, the MRC trial reported much higher post- resection. operative mortality rate of 10% in the CS group and This study has its limitations. At first, the preoperative 11% in the S group. staging was hampered by the absence of endoscopic In the present study surgery was performed in 89% ultrasonography at the beginning of our trial. Therefore, and 98% of patients in the CS group and S group, the clinical T- and N-stage were not used as stratifica- respectively. Similar rates have been reported by the tion parameters before randomization. Secondly, the MRC trial, with surgery rates in the CS group of 92% missing data on two patients that underwent preopera- and in the S group of 97%. In the Intergroup trial fewer tive chemotherapy and the lack of some clinical charac- patients underwent surgery, 80% of the CS group and teristics of the patients reflect the difficulty of obtaining 92% of the S group. The rate of microscopically tumour all data more than twenty years after the trial was per- free resection margins (R0) in the CS group was 71%, as formed. At third, it should be noticed that we selected compared to 60% and 62% in the CS groups of the patients who showed clinical response to chemotherapy MRC and Intergroup trial, respectively. In the S group it based on oesophago-gastroscopy and CT scan of the was 57%, as compared to 54% and 59% in the S groups chest and upper abdomen, for additional cycles of che- of the MRC and Intergroup trial, respectively. The dif- motherapy. However, we did not correlate clinical ference in R0 resection rates between the CS group and response to pathological response. Therefore, selection the S group is likely to contribute to the observed survi- of this subgroup could also reflect better prognostic val benefit for patients treated with preoperative che- characteristics of patients who respond to chemother- motherapy (as showed by the MRC trial; P < 0.001), apy, rather than an effect of chemotherapy itself. however, this difference was not statistical significant in the present study (P = 0.086). Conclusions The median survival time of the CS group was 16 In summary, this study reports a significant survival months, compared to 17 and 15 months in the MRC benefit for OSCC patients treated with preoperative che- and Intergroup trial, respectively. The median survival motherapy. The chemotherapeutic regime used in this Boonstra et al. BMC Cancer 2011, 11:181 Page 10 of 10 http://www.biomedcentral.com/1471-2407/11/181 8. Kok TC, Van der Gaast A, Dees J, Eykenboom WM, Van Overhagen H, trial (etoposide and cisplatin) is not used anymore in Stoter G, Tilanus HW, Splinter TA: Cisplatin and etoposide in esophageal treatment of patients with OSCC. Today, in our institu- cancer: a phase II study. Rotterdam Oesophageal Tumour Study Group. tion (EMC) the majority of patients with OSCC (and Br J Cancer 1996, 74(6):980-984. 9. Kok TC, van Lanschot JJB, Siersema PD, van Overhagen HV, Tilanus HW: OAC) receive preoperative chemoradiotherapy (a combi- Neoadjuvant chemotherapy in operable esophageal squamous cell nation of carboplatin and paclitaxel, and concurrent cancer: final report of a phase III multicenter randomized controlled radiotherapy). trial. Proc Am Soc Clin Oncol 1997, 17:984. 10. Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA: Chemotherapy followed by surgery compared with surgery alone for localized Abbreviations esophageal cancer. N Engl J Med 1998, 339(27):1979-1984. OSCC: oesophageal squamous cell carcinoma; S-group: patients who were 11. Medical Research Council Esophageal Cancer Working Party: Surgical randomly assigned to undergo surgery alone; CS-group: patients who were resection with or without preoperative chemotherapy in esophageal randomly assigned to preoperative chemotherapy; OS: overall survival; DFS: cancer: a randomized controlled trial. Lancet 2002, 359(9319):1727-1733. disease free survival; CT: computed tomography; WHO: world health 12. Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE: Long-term organisation; CR: complete response; PR: partial response; SD: stable disease; results of a randomized trial of surgery with or without preoperative R0: microscopical tumour free resection margins; R1: microscopical tumour- chemotherapy in esophageal cancer. J Clin Oncol 2009, 27(30):5062-5067. positive circumferential margin; R2: macroscopical residual disease; EMC: 13. Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, erasmus medical center; HR: hazard ratio; MRC: medical research council; Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG: Long-term results of OAC: oesophageal adenocarcinoma. RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with Acknowledgements surgery alone for esophageal cancer. J Clin Oncol 2007, 25(24):3719-3725. The authors would like to acknowledge C.M. Vollebregt-Uiterwijk for 14. Splinter T, Kok T, Kho S, Lameris H, ten Kate F, Dalesio O, Dolman B, assistance in collecting the data. Furthermore, we would like to thank all Palmen F, Bouvy J, Burghouts J: A multicenter phase II trial of cisplatin participating gastroenterologists, surgeons and medical oncologists, in and oral etoposide (VP-16) in inoperable non-small-cell lung cancer. particular D. J. Richel and C. H. N. Veenhof, for their contributions. Semin Oncol 1986, 13(3 Suppl 3):97-103. 15. Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Author details Fockens P, Stalmeier PF, ten Kate FJ, van Dekken H, Obertop H, Tilanus HW, Department of Pathology, Josephine Nefkens Institute, Erasmus MC, van Lanschot JJB: Extended transthoracic resection compared with University Medical Center, Rotterdam, The Netherlands. Department of limited transhiatal resection for adenocarcinoma of the esophagus. N Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Engl J Med 2002, 347(21):1662-1669. Department of Internal Medicine, Maasstad Hospital, Rotterdam, The Netherlands. Department of Surgery, Academic Medical Center, Amsterdam, Pre-publication history The Netherlands. Department of Pathology, University Medical Center The pre-publication history for this paper can be accessed here: Utrecht, Utrecht, The Netherlands. Department of Gastroenterology and http://www.biomedcentral.com/1471-2407/11/181/prepub Hepatology , University Medical Center Utrecht, Utrecht, The Netherlands. Department of Internal Medicine, Josephine Nefkens Institute, Erasmus MC, doi:10.1186/1471-2407-11-181 University Medical Center, Rotterdam, The Netherlands. Cite this article as: Boonstra et al.: Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous Authors’ contributions cell carcinoma: Long-term results of a randomized controlled trial. BMC JJB made substantial contributions to data collection, data analysis, and Cancer 2011 11:181. drafted the manuscript. TCK was responsible for conception and design of the trial and coordinated the study. MH and FJWK participated in data collection. BPLW, MIBH and WNMD were involved in revising the manuscript for important intellectual content. PDS, JJBL and HWT participated in the design of the study and revised the manuscript. AG made substantial contributions to data collection, data analysis, and revised the manuscript. All authors have read an approved the final version of the manuscript. Competing interests The authors declare that they have no competing interests. Received: 1 August 2010 Accepted: 19 May 2011 Published: 19 May 2011 References 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin 2009, 59(4):225-249. Submit your next manuscript to BioMed Central 2. Umar SB, Fleischer DE: Esophageal cancer: epidemiology, pathogenesis and take full advantage of: and prevention. Nat Clin Pract Gastroenterol Hepatol 2008, 5(9):517-526. 3. Weinberg RA: Leaving home early: reexamination of the canonical models of tumour progression. Cancer Cell 2008, 14(4):283-284. • Convenient online submission 4. Fidler IJ: The pathogenesis of cancer metastasis: the ‘seed and soil’ • Thorough peer review hypothesis revisited. Nat Rev Cancer 2003, 3(6):453-458. • No space constraints or color figure charges 5. WHO: World Health Organization handbook for reporting results of cancer treatment (publication no. 48). Geneva: WHO 1979. • Immediate publication on acceptance 6. Hermanek P, Sobin LH: TNM classification of malignant tumours. Berlin: • Inclusion in PubMed, CAS, Scopus and Google Scholar Springer 1987, 40-2. 7. Sposto R, Stablein D, Carter-Campbell S: A partially grouped logrank test. • Research which is freely available for redistribution Stat Med 1997, 16(6):695-704. Submit your manuscript at www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png BMC Cancer Springer Journals

Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous cell carcinoma: Long-term results of a randomized controlled trial

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Springer Journals
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Copyright © 2011 by Boonstra et al; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Oncology; Surgical Oncology; Health Promotion and Disease Prevention; Biomedicine general; Medicine/Public Health, general
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1471-2407
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10.1186/1471-2407-11-181
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21595951
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Abstract

Background: This is a randomized, controlled trial of preoperative chemotherapy in patients undergoing surgery for oesophageal squamous cell carcinoma (OSCC). Patients were allocated to chemotherapy, consisting of 2-4 cycles of cisplatin and etoposide, followed by surgery (CS group) or surgery alone (S group). Initial results reported only in abstract form in 1997, demonstrated an advantage for overall survival in the CS group. The results of this trial have been updated and discussed in the timeframe in which this study was performed. Methods: This trial recruited 169 patients with OSCC, 85 patients assigned to preoperative chemotherapy and 84 patients underwent immediate surgery. The primary study endpoint was overall survival (OS), secondary endpoints were disease free survival (DFS) and pattern of failure. Survival has been determined from Kaplan-Meier curves and treatment comparisons made with the log-rank test. Results: There were 148 deaths, 71 in the CS and 77 in the S group. Median OS time was 16 months in the CS group compared with 12 months in the S group; 2-year survival rates were 42% and 30%; and 5-year survival rates were 26% and 17%, respectively. Intention to treat analysis showed a significant overall survival benefit for patients in the CS group (P = 0.03, by the log-rank test; hazard ratio [HR] 0.71; 95%CI 0.51-0.98). DFS (from landmark time of 6 months after date of randomisation) was also better in the CS-group than in the S group (P = 0.02, by the log- rank test; HR 0.72; 95%CI 0.52-1.0). No difference in failure pattern was observed between both treatment arms. Conclusions: Preoperative chemotherapy with a combination of etoposide and cisplatin significantly improved overall survival in patients with OSCC. Background the high rates of locoregional and distant failure, there Oesophageal squamous cell carcinoma (OSCC) accounts is much interest in the combination of systemic che- for most cases of oesophageal cancer worldwide [1,2]. motherapy and local surgical treatment. Even after complete surgical dissection, the prognosis of The potential benefits of preoperative chemotherapy patients with OSCC is poor, with 5-year survival rates of include increasing the likelihood of curative resection by 20 to 30%. Factors that contribute to this dismal prog- downstaging the tumour and rapidly improving tumour- nosis include presence of locally advanced disease and related symptoms. It is also been thought that systemic undetected metastatic cancer at diagnosis. Because of chemotherapy could contribute to the eradication of micro-metastases and circulating tumour cells. More recently, the importance of systemic disease control has * Correspondence: j.j.boonstra@erasmusmc.nl been emphasized by new insights in the metastasizing Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center, Rotterdam, The Netherlands process of cancer [3]. For decades, the dissemination of Full list of author information is available at the end of the article © 2011 Boonstra 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. Boonstra et al. BMC Cancer 2011, 11:181 Page 2 of 10 http://www.biomedcentral.com/1471-2407/11/181 cancer has been considered the final stage in a deterior- malignant disease, including negative biopsies from the ating process. Now, there is accumulating evidence that former tumour area, was defined as complete response dissemination already can occur at an early stage of the (CR). Partial response (PR) was defined as >50% reduc- disease [4]. In theory, the use of preoperative che- tion of tumour bulk, without the appearance of new motherapy may therefore have a positive impact on sur- lesions. Stable disease (SD) was defined as <50% reduc- vival of patients with oesophageal cancer. Here, we tion of tumour bulk, without the appearance of new report the design and long-term results of a randomized lesions. Progressive disease (PD) was defined as >25% progression of tumour bulk or the appearance of new controlled trial in patients with resectable OSCC, com- lesions. Patients with complete or partial responses paring preoperative chemotherapy with cisplatin and etoposide followed by surgery to surgery alone. received two additional courses of chemotherapy, whereas non-responding patients (stable disease or pro- Methods gressive disease) were referred for immediate surgery. All eligible patients had histologically confirmed squa- Patients with progressive disease (T4 or M1 disease) mous cell carcinoma of the intra-thoracic ooesophagus. were treated palliative and observed for survival. Patients were deemed resectable if the disease was clini- Patients, who were randomly assigned to undergo sur- cally limited to the locoregional area (tumour stage 1, 2 gery alone, underwent the operation as soon as possible. or 3; any nodal stage and no metastases). Patients with Patients who received chemotherapy were operated 4 to carcinoma of the distal oesophagus and suspected celiac 6 weeks after the last treatment cycle. The study proto- lymph nodes involvement (M1a) were also considered col was approved by the ethics committee of all partici- eligible for surgery. Patients had to be below 80 years of pating institutions and written informed consent was age, in adequate physical condition (Karnofsky score obtained from all patients. >70) to undergo surgery and had to have adequate hepatic, renal and bone marrow function. Exclusion cri- Chemotherapy teria were synchronous cancer, tumour localization in Cisplatin, at adoseof80mg/m , was given intrave- the cervical ooesophagus (upper border, <18 cm from nously over 4 hours on day one of each cycle preceded the incisor teeth), severe cardiovascular or pulmonary and followed by adequate hydration. Etoposide, at a disease. Patients with previous malignancies were eligi- dose of 100 mg/m , was administered intravenously over ble if more than 5 years had elapsed from diagnosis 2 hours on day 1 (before cisplatin) and day 2, followed without evidence of tumour recurrence; exceptions were by etoposide 200 mg/m orally on days 3 and 5. This made for adequately treated basal cell cancer of the skin course was repeated in week 4. In case of clinical or carcinoma in situ of the cervix. Preoperative work-up response, two subsequent courses of chemotherapy were included clinical examination, oesophago-gastroscopy administered in week 8 and 11. All patients received with biopsies, chest radiography, external ultrasonogra- prophylactic anti-nausea treatment with 5-HT 3 recep- phy of the cervical and upper abdominal region and tor antagonists during chemotherapy. Treatment related computed tomography (CT) of the chest and abdomen. toxicities were measured according to the WHO recom- Radionuclide bone scans were performed if indicated. mendations [5]. Re-treatment with the next cycle was Bronchoscopy was performed when the primary tumour permitted only if the absolute neutrophil count was at was adjacent to the trachea or main stem bronchus and least 3,500/mm , and the platelet count was at least invasion was suspected. 100,000/mm . A delay of treatment of up to 2 weeks Central randomisation took place at the Erasmus Uni- was permitted. In patients with severe toxic renal or versity Medical Center in Rotterdam (by trial coordina- neurological effects (≥ WHO grade 3) chemotherapy tor TCK). Random assignment was stratified by age was stopped and patients were referred for surgery. (<50; 51-60; >60), gender (male; female), weight loss (kg) in the past four months (0-5; 6-10; >10) and length Surgery and pathological examination of the tumour (cm) as measured by oesophago-gastro- For carcinomas of the upper half of the intra-thoracic scopy (1-3; 4-6; 7-10; >10). Patients assigned to preo- ooesophagus a right-sided thoracotomy was performed. perative chemotherapy were treated with two cycles, For carcinomas of the lower half of the intra-thoracic followed by a clinical response evaluation. Response eva- ooesophagus a transhiatal oesophagectomy was done. luation was done three to four weeks after the last cycle The tumour and its adjacent lymph nodes were dis- of chemotherapy. Clinical response after chemotherapy sected en bloc. The left gastric artery was transected at was evaluated by oesophago-gastroscopy and CT of the its origin, with resection of local lymph nodes. The con- chest and abdomen. Tumour responses were assessed tinuity of the digestive tract was restored by means of according to the World Health Organisation (WHO) gastric tube reconstruction or colonic interposition with criteria [5]. Complete absence of any evidence of a cervical anastomosis. The tumour stage after resection Boonstra et al. BMC Cancer 2011, 11:181 Page 3 of 10 http://www.biomedcentral.com/1471-2407/11/181 was classified according to the TNM classification of the Results International Union Against Cancer [6]. Resections were Between January, 1989, and January, 1996, 169 patients classified as radical when microscopical examination from six Dutch University Hospitals (Rotterdam, revealed all margins to be free of tumour (R0). Resec- Amsterdam, Utrecht, Groningen, Nijmegen and Maas- tions were considered not radical, if microscopically tricht) were randomly assigned to either chemotherapy examination showed tumour-positive circumferential followed by surgery (CS group, N = 85) or surgery alone margin (R1) or presence of macroscopic disease (R2). (S group, N = 84; Figure 1). An additional number of nine patients were included to adjust for study drop- Follow-up outs. The majority of patients (N = 122) were included All patients were followed at an interval of three to four by the Erasmus Medical Center (EMC), Rotterdam. months during the first year, every six months for the From all participating centers, the EMC is the only hos- second year, and annually for up to 5 years post surgery. pital that collected outcome data (prospectively) for all After 5 years, follow-up data were obtained by telephone patients with oesophageal cancer referred in time this from the patient or his/her family practitioner. Recur- study was performed. Between January, 1989, and Janu- rence of disease was diagnosed on clinical grounds. ary, 1996, 257 patients with OSCC were referred to the However, whenever a relapse was suspected, radiologic, EMC. Of these, 183 patients were deemed eligible for endoscopic, or histologic confirmation was sought for. surgical resection, of which 122 (67%) were included in Loco-regional disease recurrence was defined as this trial. The reasons why 61 (33%) patients were not relapse at the primary site including the anastomosis or randomized for this trial are not well documented. in regional lymph nodes. Distant disease recurrence was Table 1 shows that the two groups were similar in defined as distant lymph node sites or involvement of terms of age, sex, and performance status. Distribution distant organs including lung, liver, bone, and subcuta- according to weight loss and size of the tumour was neous tissue. also balanced. One patient, allocated to preoperative chemotherapy, had a tumour located in the cervical part of the oesophagus (the reason why this patient was Statistical analysis included and randomized remains unclear, even after The planned number of patients to be entered in the retrospective analysis of the patient’s record). Preopera- study was 80 for each treatment arm. With these num- tive staging by CT of the chest and the upper abdomen bers of patients the statistical power should be sufficient was performed in 149 patients (88%); two patients (1%) (power = 0.8; significance 0.05) to detect an increase of died before the planned CT scan; six patients (4%) were the median survival from 10 to 18 months. staged by endoscopic ultrasound, external ultrasonogra- Overall survival (OS) was calculated from the date of phy of the cervical and upper abdominal region and random assignment to date of death from any cause and chest radiography. From twelve patients (7%) no addi- surviving patients were censored at the date they were tional information on preoperative staging was available. last known to be alive. Disease-free survival (DFS) was calculated from a landmark time of 6 months after date Chemotherapy of randomisation to allow for the difference in timing of Of the 85 patients assigned to preoperative chemother- surgery between the two treatment groups [7]. In this apy, 80 (94%) received chemotherapy; 75 (88%) patients analysis, events including macroscopically incomplete had two or more cycles and 5 patients (13%) received resection, local and distant recurrence, and death arising one cycle. The reasons why no chemotherapy or only within the first 6 months after random assignment were one cycle was given were patient’s refusal (N = 3), death regarded as events at this landmark time. Survival curves (N = 1), tumour bleeding (N = 3) and renal toxicity are presented by the Kaplan-Meier method and treat- grade III (N = 1). Two patients allocated to preoperative ment comparisons are by the log-rank test. chemotherapy, were directly lost to follow-up after ran- Statistical analyses were performed using the SPSS sta- domization. Tracing back the original patient’s files was tistical package (SPSS Inc.,Chicago, IL,USA).Hazard impossible; therefore, it is not clear if these two patients ratios (HR) were calculated with the use of a Cox truly received chemotherapy followed by surgery. regression model including treatment alone (primary Clinical response evaluation after two cycles of che- analysis) and after adjustment for baseline stratification motherapy showed 43 patients with stable or progressive factors. Categorical data were compared with the use of disease. Partial response to chemotherapy was observed in chi-square test or Fisher’s exact test, with a test for 32 patients. Of these, 30 patients received two additional trend over ordered categories. All statistical comparisons cycles of chemotherapy; one received one additional cycle were made with two-tailed tests and P values < 0.05 and one had three additional cycles of chemotherapy. were reported as significant. Boonstra et al. BMC Cancer 2011, 11:181 Page 4 of 10 http://www.biomedcentral.com/1471-2407/11/181 Figure 1 CONSORT Flow-diagram: random assignment, and compliance to the allocated treatment. CTX, chemotherapy Clinical response evaluation after the additional cycles of was 14 days in the S group. In the CS group, the med- chemotherapy showed six patients with complete ian time from randomization to surgery was 63 days response; 20 patients had partial response; five showed (36-123) for patients who received two cycles of che- stable disease and one had progressive disease. motherapy, and 114 days (54-165) for patients who Detailed data on chemotherapy related toxicity is not received additional treatment cycles. Four patients (5%) available. In the prior phase II trial a high rate of grade III in the CS group and three patients (4%) in S group died and IV nausea (38%) and vomiting (20%) was observed, within 30-days after surgery. probably due to the fact that 5-HT3 receptor blockers were Data on postoperative complications was available of rarely given throughout the study period [8]. All patients in 67/76 (88%) of patients in the CS group and 75/82 the current trial received prophylactic anti-nausea treat- (91%) patient in the S group. The frequency of nonfatal ment with 5-HT 3 receptor antagonists during chemother- postoperative events was closely similar in both groups apy. No grade III or IV nausea and vomiting were observed. (table 2). However, pulmonary complications were sig- The major non-hematological toxicity (grade III) was alope- nificantly more observed in the CS group (P = 0.041). cia. Hematological toxicity grade III was observed in 23 Oesophagectomy was performed in 91% (69/76) in the patients (one renal, twenty-two hematological). Eight CS-group and 85% (70/82) in the S-group. In the CS patients had grade IV hematological toxicity. group, six patients did not receive an oesphagectomy because of tumour growth in adjacent structures (aorta Outcome of surgery or bronchial tree) and one had tumour positive celiac Surgery was performed in 76 CS and 82 S patients lymph nodes at laparotomy. In the S group, seven patients did not undergo surgical resection because of (Table 2). Median time from randomization to surgery Boonstra et al. BMC Cancer 2011, 11:181 Page 5 of 10 http://www.biomedcentral.com/1471-2407/11/181 Table 1 Patient’s characteristics S group, respectively). In the CS group, the pathological complete response rate (pT0N0M0) was 7%. Total CS S group group Characteristics (N = 169) (N = 85 ) (N = 84) P-value* Pattern of failure Age, years 0,73 The outcomes of treatments were considered according <50 31 (18%) 17 (20%) 14 (17%) to findings at operation and to patterns of disease pro- 51-60 54 (32%) 25 (29%) 29 (34%) gression (first disease-free survival event; Table 3). The >60 84 (50%) 43 (51%) 41 (49%) rates of unresectable tumors or macroscopically incom- Median 60 60 60 plete resections were higher in the S group (P =0.23; P Range 35 - 79 35 - 76 37 - 79 = 0.05 respectively). The pattern of first disease progres- sion was similar between both treatment groups; in par- Sex 0,9 ticular there was no clear trend toward fewer patients Male 126 (75%) 63 (74%) 63 (75%) with distant metastases as first site of relapse in the CS Female 43 (25%) 22 (26%) 21 (25%) group. Ten patients treated with preoperative che- Weight loss (% of normal 0,24 weight) motherapy developed a second primary tumor; seven <5 56 (33%) 30 (35%) 26 (31%) squamous cell carcinomas of head and neck, one pan- 6-10 40 (24%) 16 (19%) 24 (29%) creatic, one lung and one breast carcinoma. In contrast, >10 51 (30%) 30 (35%) 21 (25%) four patients who underwent immediate surgical resec- Not recorded 22 (13%) 9 (11%) 13 (15%) tion developed a second primary tumour, all squamous Tumor length (cm) 0,17 cell carcinomas of head and neck. <3 27 (16%) 14 (17%) 13 (16%) 4-6 69 (41%) 36 (42%) 33 (39%) Overall and disease-free survival 7-10 55 (32%) 22 (26%) 33 (39%) At thetimeofanalysis, themedian follow-up was15 >10 6 (4%) 5 (6%) 1 (1%) months in the CS group and 14 months in the S group. Not recorded 12 (7%) 8 (9%) 4 (5%) In an intention-to-treat survival analysis, two patients that were directly lost to follow-up were censored one Location of the tumor 0,66 month after the date of randomization. OS on intention Cervical 1 (1%) 1 (1%) 0 to treat basis is shown in Figure 2. The median overall Upper third 7 (4%) 3 (3%) 4 (5%) survival in the CS group was 16 months, and in the S Middle third 76 (45%) 38 (45%) 38 (45%) group 12 months. OS was better in the CS group than Distal third 71 (42%) 34 (40%) 37 (44%) in the S group (P = 0.03, by the log-rank test; HR 0.71; Not recorded 14 (8%) 9 (11%) 5 (6%) 95%CI 0.51-0.98; Figure 2A). Survival at one year was Karnofsky score* 0,53 64% for those allocated to chemotherapy, 52% for those 70 - 80 125 (74%) 60 (71%) 65 (77%) allocated to surgery alone; at two years 42% and 30%; 5- 90 - 100 38 (22%) 21 (24%) 17 (20%) years, survival was 26% and 17%, respectively. Not recorded 6 (4%) 4 (5%) 2 (3%) DFS is shown in Figure 2B. For DFS, 59 patients in Abbreviations: CS, Chemotherapy followed by surgery; S, Surgery alone the CS group and 40 patients in the S group remained * Comparisons were made by the chi-square test for analysis after the landmark period of six months. In 6/59 (10%) patients in the CS group the date of disease recurrence was not documented. In these, the date of tumour encasement of the aorta or the bronchial tree disease recurrence was estimated four months earlier and five due to tumour positive celiac lymph nodes at than the date of death (in the CS group the median laparotomy. Of the 69 patients in the CS group who underwent surgical resection, 71% had R0 resections, time between date of recurrence and date of death was 25% had R1 resections, and 4% had R2 resections. Of four months). In the CS group, there is prolonged DFS the 70 patients in the S group who underwent surgical compared with the surgical resection alone group (P = resection, 57% had R0 resections, 29% had R1 resec- 0.02, by the log-rank test; HR 0.72; 95%CI 0.52-1.0). tions, and 14% had R2 resections. Although more Overall survival according clinical response to preo- patients in the CS group had R0 resections as compared perative chemotherapy showed that patients with clinical with the S group, no significant differences was observed partial or complete response (those who received three (P = 0.09). However, there was a significant difference or more cycles of therapy) had significantly better over- between the number of R2 resections in both treatment all survival then those with stable or progressive disease arm (P = 0.04). Also the number of patients with lymph (P = <0.001, by log-rank test; HR 0.38; 95%CI 0.23-0.65). node involvement (N1 or M1a) did not differ between Figure 3 shows no clear evidence that effect of che- motherapy varied in accordance with age, sex or length of both treatment arms (43 and 46% in the CS group and Boonstra et al. BMC Cancer 2011, 11:181 Page 6 of 10 http://www.biomedcentral.com/1471-2407/11/181 Table 2 Surgical details Total CS group S group (N = 169) (N = 85) (N = 84) P-value Surgery done 0,083 Yes 158 (93%) 76 (90%) 82 (98%) No 9 (5%) 7 (8%) 2 (2%) Not recorded 2 (2%) 2 (2%) 0 Reason no surgery undertaken Died before surgery 3 (2%) 1 (1%) 2 (2%) Progressive disease Tumor unresectable 3 (2%) 3 (4%) 0 Distant metastases 3 (2%) 3 (4%) 0 Type of resection* 0,38 Transhiatal 113 (71%) 55 (72%) 58 (71%) Transthoracic 20 (13%) 9 (12%) 11 (13%) Type not recorded 5 (3%) 4 (5%) 1 (1%) Other 1 (1%) 1 (1%) 0 No resection performed 19 (12%) 7 (10%) 12 (15%) Postoperative deaths (within 30 days)* 7 (4%) 4 (5%) 3 (4%) 0,62 Non-fatal postoperative complications* 0,64 None 68 (43%) 30 (40%) 38 (46%) Any 67 (42%) 33 (43%) 34 (41%) Not recorded 16 (10%) 9 (12%) 7 (9%) Type of non-fatal postoperative complications*, Pulmonary 25 (16%) 17 (23%) 8 (10%) 0,048 Cardiac 6 (4%) 3 (4%) 3 (4%) 1,0 Anastomotic Subclinical 10 (6%) 5 (7%) 5 (6%) 1,0 Clinical 7 (4%) 3 (4%) 4 (5%) 1,0 Chylothorax 7 (4%) 4 (5%) 3 (4%) 0,70 Bleeding 5 (3%) 3 (4%) 2 (2%) 0,67 Vocal-cord injury 22 (14%) 10 (13%) 12 (15%) 0,82 Other 10 (6%) 4 (5%) 6 (7%) 0,75 Abbreviations: CS, Chemotherapy followed by surgery; S, Surgery alone * Percentages based on total patients undergoing surgery. † Nonfatal postoperative events; comparisons were made by the Fisher’s exact test the tumour. In this subgroup analysis, it appeared that Discussion patients with substantial weight loss (>10%) treated with The long-term results of this randomized controlled preoperative chemotherapy had better overall survival as trial demonstrated a survival benefit for preoperative compared to those who received surgery alone. Possibly, chemotherapy followed by surgery in patients with patients allocated to chemotherapy and in a poor nutrition OSCC, when compared with surgery alone. This study status (eg weight loss >10%) were more likely to receive has only been reported in abstract form, which ham- nutritional support over a longer period of time as com- pers interpretation of our findings in context of other pared to patients that were allocated to surgery alone. randomized trials [9]. Why it took so long to report This could have led to a better preoperative condition of the design and results of this study is not completely patients who received chemotherapy, which could possibly understood. The main reasons are change of person- contribute to improved overall survival. Furthermore, nel (the trial coordinator [TCK] moved to another patients with a tumour located in the middle thoracic hospital) and loss of interest in the used chemothera- oesophagus who received preoperative chemotherapy had peutic regime. Nevertheless, we believe that these better overall survival then patients who received surgery results contribute to the ongoing debate about the alone. The explanation for the observed survival benefit in optimal (preoperative) therapy for patients with this subgroup of patients is unclear. OSCC. Boonstra et al. BMC Cancer 2011, 11:181 Page 7 of 10 http://www.biomedcentral.com/1471-2407/11/181 Table 3 Nature of first disease-free survival event significant survival benefit for the use of preoperative chemotherapy (P = .004) [11,12]. An other large and CS S group group well-conducted randomized controlled trial among Event (N = 85) (N = 84) P- patients with oesophageal cancer (236 OAC and 204 value* OSCC patients), by the North American Intergroup Disease free 12 (14%) 7 (8%) 0,33 (RTOG Trial 8911 or USA Intergroup 113 trial; further No surgery performed 7 (8%) 2 (3%) 0,17 called the Intergroup trial), demonstrated no significant No resection performed 7 (8%) 12 (14%) 0,23 difference in survival between patients treated with pre- Macroscopic residual disease 3 (3%) 10 (12%) 0,05 operative chemotherapy and those who received surgery 2nd Primary 10 (12%) 4 (5%) 0,16 alone [10,13]. In the light of the results of both trials, Local recurrence 16 (19%) 21 (25%) 0,36 we discuss the design and results of the present study. Distant metastases 5 (6%) 5 (6%) 1 As most randomized controlled trials performed in the Local recurrence and distant metastases 9 (11%) 10 (12%) 0,81 early ‘90, this study reflects the methods for diagnosis, Death with cancer but site of failure not 5 (6%) 7 (8%) 0,57 staging, treatment delivery and outcome measurement reported that indicate clinical practice during that period. In the Death from other or unspecified cause 11 (13%) 6 (7%) 0,31 present study, the majority of patients (88%) underwent * Comparisons were made by the Fisher’s exact test preoperative staging by oesophago-gastroscopy and CT scan of the chest and upper abdomen. The same preo- The results of this study should be interpreted in the perative staging methods were used in the Intergroup timeframe in which this study was performed. This trial. In the MRC trial, however, there was no standardi- study is one of the three largest randomized controlled zation of preoperative staging. These differences in preo- trials among patients with OSCC treated with preopera- perative staging could, by selection of different tive chemotherapy followed by surgery or surgery alone populations of OSCC patients, contribute to differences [10,11]. All these large randomized controlled trials in results between the trials. were performed in the early ‘90s. The Medical Research In the Intergroup trial as well as in the MRC trial the Council (MRC) trial included most patients with oeso- chemotherapeutic regime consists of cisplatin combined phageal cancer (533 oesophageal adenocarcinoma with fluorouracil; in the present study cisplatin was (OAC) and 247 OSCC patients) and demonstrated a combined with etoposide. The ratio for this combination Figure 2 Overall and disease free survival. A) Overall survival of all allocated patients. The distribution curves represent the results of an intention-to-treat survival analysis involving all patients. Patients who received preoperative chemotherapy had a median survival of 16 months; in comparison, patients who underwent only surgery had a median survival of 12 months (P = 0.03 by the log-rank test). B) Disease-free survival of all patients from a landmark time of 6 months after date of randomisation (P = 0.02 by the log-rank test). Boonstra et al. BMC Cancer 2011, 11:181 Page 8 of 10 http://www.biomedcentral.com/1471-2407/11/181 Figure 3 Survival by characteristics at randomisation and post-treatment. Centre of each square indicates hazard ratio, and area of square the amount of information. Lines on either side indicate 95 CI. of chemotherapeutic agents was deducted from trials toxicity profile was mild [8]. Patients without clinical among patients with non-small-cell lung cancer in response to chemotherapy received a total preoperative 2 2 which this regime had showed to be safe and effective dose of 160 mg/m cisplatin and 1000 mg/m etoposide. [14]. Furthermore, a phase II trial in patients with The dose of cisplatin is similar as compared with the advanced OSCC had shown that the response rate MRC trial (160 mg/m ). Patients with clinical response equals that of other cisplatin-based regimes and that the to chemotherapy received total doses up to cisplatin 320 Boonstra et al. BMC Cancer 2011, 11:181 Page 9 of 10 http://www.biomedcentral.com/1471-2407/11/181 2 2 mg/m and etoposide 2000 mg/m . In this subgroup of time of the S group was 12 months, compared to 16 patients, the total preoperative dose of cisplatin was and 13 months in the Intergroup and MRC trial, respec- slightly higher as compared to the Intergroup trial (300 tively. It appears that the S group in our study had the mg/m ). Thecompliancetochemotherapywas 88% worst survival outcome, but this may be due to patient (patients who received two or more of the planned selection. Both the MRC as Intergroup trial included cycles of chemotherapy). This is similar to 90% of the more OAC than OSCC patients. Subgroup analysis of the MRC trial, including only OSCC patients, showed a patients that received both treatment cycles in the MRC median survival time of 11 months for patients who trial, but differed from the Intergroup wherein 71% of underwent surgery alone [12]. Remarkably, in the sub- the patients received all of three planned cycles of che- motherapy. It has been suggested that the higher dose group analysis there is no significant survival benefit for of chemotherapy in the Intergroup trial was detrimental OSCC patients treated with preoperative chemotherapy to patients who underwent oesophagectomy. Other fac- (P = 0.1). tors related to the chemotherapeutic regimes that could In line with the results of the MRC and Intergroup contribute to the differences in outcome between the trial, there was no significant difference in pattern of three studies, are the use of chemoradiotherapy in a failure between both treatment arms in our study. The subset of patients in the MRC trial and the use of post- rate of distant metastases was equal in both treatment operative chemotherapy in a subgroup of patients in the groups. These findings provide no evidence for the gen- Intergroup trial. eral hypothesis that preoperative chemotherapy elimi- In our study the majority of patients underwent a nates systemic micro-metastases. The results of this trial transhiatal oesophagectomy. This type of resection is and the MRC trial suggest that the biologic effect of associated with lower morbidity (and mortality) than a preoperative chemotherapy seems to specifically influ- transthoracic resection ([15]). In the other trials, the ence the extent of surgery [12]. In the present study, the type of surgical resection that has been performed is not incidence of incomplete resections was greater in the S clear (MRC trial) or the exact numbers are not group, but sites of first recurrence (local or distant) described (Intergroup trial). The postoperative mortality were similar. Furthermore, at 6 months, the DFS advan- rate (<30 days after surgery) in the current trial was 5% tage is established for the CS group (Figure 2A) and (4/76) in the CS group and 4% (3/82) in the S group remains consistent throughout follow-up as the survival and differed not among both groups. These rates are curves remain approximately parallel. This suggests that the effect of preoperative chemotherapy is to reduce similar as those observed in the Intergroup trial, with tumour volume and increase the potential for curative 6% postoperative mortality in both treatment arms. In contrast, the MRC trial reported much higher post- resection. operative mortality rate of 10% in the CS group and This study has its limitations. At first, the preoperative 11% in the S group. staging was hampered by the absence of endoscopic In the present study surgery was performed in 89% ultrasonography at the beginning of our trial. Therefore, and 98% of patients in the CS group and S group, the clinical T- and N-stage were not used as stratifica- respectively. Similar rates have been reported by the tion parameters before randomization. Secondly, the MRC trial, with surgery rates in the CS group of 92% missing data on two patients that underwent preopera- and in the S group of 97%. In the Intergroup trial fewer tive chemotherapy and the lack of some clinical charac- patients underwent surgery, 80% of the CS group and teristics of the patients reflect the difficulty of obtaining 92% of the S group. The rate of microscopically tumour all data more than twenty years after the trial was per- free resection margins (R0) in the CS group was 71%, as formed. At third, it should be noticed that we selected compared to 60% and 62% in the CS groups of the patients who showed clinical response to chemotherapy MRC and Intergroup trial, respectively. In the S group it based on oesophago-gastroscopy and CT scan of the was 57%, as compared to 54% and 59% in the S groups chest and upper abdomen, for additional cycles of che- of the MRC and Intergroup trial, respectively. The dif- motherapy. However, we did not correlate clinical ference in R0 resection rates between the CS group and response to pathological response. Therefore, selection the S group is likely to contribute to the observed survi- of this subgroup could also reflect better prognostic val benefit for patients treated with preoperative che- characteristics of patients who respond to chemother- motherapy (as showed by the MRC trial; P < 0.001), apy, rather than an effect of chemotherapy itself. however, this difference was not statistical significant in the present study (P = 0.086). Conclusions The median survival time of the CS group was 16 In summary, this study reports a significant survival months, compared to 17 and 15 months in the MRC benefit for OSCC patients treated with preoperative che- and Intergroup trial, respectively. The median survival motherapy. The chemotherapeutic regime used in this Boonstra et al. BMC Cancer 2011, 11:181 Page 10 of 10 http://www.biomedcentral.com/1471-2407/11/181 8. Kok TC, Van der Gaast A, Dees J, Eykenboom WM, Van Overhagen H, trial (etoposide and cisplatin) is not used anymore in Stoter G, Tilanus HW, Splinter TA: Cisplatin and etoposide in esophageal treatment of patients with OSCC. Today, in our institu- cancer: a phase II study. Rotterdam Oesophageal Tumour Study Group. tion (EMC) the majority of patients with OSCC (and Br J Cancer 1996, 74(6):980-984. 9. Kok TC, van Lanschot JJB, Siersema PD, van Overhagen HV, Tilanus HW: OAC) receive preoperative chemoradiotherapy (a combi- Neoadjuvant chemotherapy in operable esophageal squamous cell nation of carboplatin and paclitaxel, and concurrent cancer: final report of a phase III multicenter randomized controlled radiotherapy). trial. Proc Am Soc Clin Oncol 1997, 17:984. 10. Kelsen DP, Ginsberg R, Pajak TF, Sheahan DG, Gunderson L, Mortimer J, Estes N, Haller DG, Ajani J, Kocha W, Minsky BD, Roth JA: Chemotherapy followed by surgery compared with surgery alone for localized Abbreviations esophageal cancer. N Engl J Med 1998, 339(27):1979-1984. OSCC: oesophageal squamous cell carcinoma; S-group: patients who were 11. Medical Research Council Esophageal Cancer Working Party: Surgical randomly assigned to undergo surgery alone; CS-group: patients who were resection with or without preoperative chemotherapy in esophageal randomly assigned to preoperative chemotherapy; OS: overall survival; DFS: cancer: a randomized controlled trial. Lancet 2002, 359(9319):1727-1733. disease free survival; CT: computed tomography; WHO: world health 12. Allum WH, Stenning SP, Bancewicz J, Clark PI, Langley RE: Long-term organisation; CR: complete response; PR: partial response; SD: stable disease; results of a randomized trial of surgery with or without preoperative R0: microscopical tumour free resection margins; R1: microscopical tumour- chemotherapy in esophageal cancer. J Clin Oncol 2009, 27(30):5062-5067. positive circumferential margin; R2: macroscopical residual disease; EMC: 13. Kelsen DP, Winter KA, Gunderson LL, Mortimer J, Estes NC, Haller DG, erasmus medical center; HR: hazard ratio; MRC: medical research council; Ajani JA, Kocha W, Minsky BD, Roth JA, Willett CG: Long-term results of OAC: oesophageal adenocarcinoma. RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with Acknowledgements surgery alone for esophageal cancer. J Clin Oncol 2007, 25(24):3719-3725. The authors would like to acknowledge C.M. Vollebregt-Uiterwijk for 14. Splinter T, Kok T, Kho S, Lameris H, ten Kate F, Dalesio O, Dolman B, assistance in collecting the data. Furthermore, we would like to thank all Palmen F, Bouvy J, Burghouts J: A multicenter phase II trial of cisplatin participating gastroenterologists, surgeons and medical oncologists, in and oral etoposide (VP-16) in inoperable non-small-cell lung cancer. particular D. J. Richel and C. H. N. Veenhof, for their contributions. Semin Oncol 1986, 13(3 Suppl 3):97-103. 15. Hulscher JB, van Sandick JW, de Boer AG, Wijnhoven BP, Tijssen JG, Author details Fockens P, Stalmeier PF, ten Kate FJ, van Dekken H, Obertop H, Tilanus HW, Department of Pathology, Josephine Nefkens Institute, Erasmus MC, van Lanschot JJB: Extended transthoracic resection compared with University Medical Center, Rotterdam, The Netherlands. Department of limited transhiatal resection for adenocarcinoma of the esophagus. N Surgery, Erasmus MC, University Medical Center, Rotterdam, The Netherlands. Engl J Med 2002, 347(21):1662-1669. Department of Internal Medicine, Maasstad Hospital, Rotterdam, The Netherlands. Department of Surgery, Academic Medical Center, Amsterdam, Pre-publication history The Netherlands. Department of Pathology, University Medical Center The pre-publication history for this paper can be accessed here: Utrecht, Utrecht, The Netherlands. Department of Gastroenterology and http://www.biomedcentral.com/1471-2407/11/181/prepub Hepatology , University Medical Center Utrecht, Utrecht, The Netherlands. Department of Internal Medicine, Josephine Nefkens Institute, Erasmus MC, doi:10.1186/1471-2407-11-181 University Medical Center, Rotterdam, The Netherlands. Cite this article as: Boonstra et al.: Chemotherapy followed by surgery versus surgery alone in patients with resectable oesophageal squamous Authors’ contributions cell carcinoma: Long-term results of a randomized controlled trial. BMC JJB made substantial contributions to data collection, data analysis, and Cancer 2011 11:181. drafted the manuscript. TCK was responsible for conception and design of the trial and coordinated the study. MH and FJWK participated in data collection. BPLW, MIBH and WNMD were involved in revising the manuscript for important intellectual content. PDS, JJBL and HWT participated in the design of the study and revised the manuscript. AG made substantial contributions to data collection, data analysis, and revised the manuscript. All authors have read an approved the final version of the manuscript. Competing interests The authors declare that they have no competing interests. Received: 1 August 2010 Accepted: 19 May 2011 Published: 19 May 2011 References 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ: Cancer statistics, 2009. CA Cancer J Clin 2009, 59(4):225-249. Submit your next manuscript to BioMed Central 2. 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Published: May 19, 2011

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