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Eur J Cardiothorac Surg 2003;24:179-186
© 2003 Elsevier Science NL

Effects of preoperative chemoradiotherapy on postsurgical morbidity and mortality in _cT3–4 +/- _cM1_lymph cancer of the oesophagus and gastro-oesophageal junction

^a Department of Thoracic Surgery, University Hospitals, U.Z. Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium
^b Department of Digestive Oncology, University Hospitals, U.Z. Gasthuisberg, 3000 Leuven, Belgium
^c Department of Radiotherapy, University Hospitals, U.Z. Gasthuisberg, 3000 Leuven, Belgium

Received 11 December 2002; received in revised form 8 April 2003; accepted 15 April 2003.

^* Corresponding author. Tel.: +32-16-346820; fax: +32-16-346821
e-mail: toni.lerut{at}uz.kuleuven.ac.be

	Abstract

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Objective: Very few studies have examined post-operative morbidity after resection of oesophageal carcinoma, especially in patients treated with induction chemo- and radiotherapy for locally advanced stages. This study assessed the effects of induction chemoradiotherapy on post-operative course after resection of locally advanced oesophageal carcinoma (_cT3–4+_cM1_lymph). Methods: Induction therapy consisted of 5-fluorouracil days 1–5 and days 21–25, cisplatin day 1+day 21 and concomitant radiotherapy 18–20 fractions of 2 Gy (total dose 36–40 Gy). Induction chemoradiotherapy was completed in 109 patients. Surgery was performed in 90 patients (operability: 90/109=83%): 85 patients underwent resection with curative intent (resectability: 85/109=78%), bypass operation was performed in five patients. Nineteen patients could not be operated on. Results were compared to a matched group of pT3M1_LYM/pT4 patients (n=86) who underwent primary surgery in the same period. Results: Resection was complete (R0) in 68 patients (68/90=76%). Mean duration of surgery was 428 min (range: 240–690). Peroperative complications were haemorrhage in three patients (3/90=3.3%), tracheobronchial perforation in three patients (3/90=3.3%). Median total hospital stay was 20.5 days (range: 8–355). Mean duration of intubation was 7 days (range: 1–190); 67 patients (67/90=74.4%) were intubated for less than 24 h. Non-tumour related hospital mortality after resection was 8.3% (7/84 patients). Mortality after two-field lymphadenectomy was 5.2 versus 11.7% after three-field lymphadenectomy. After primary surgery (n=86) overall mortality was 2.3% (P=0.015) and nil after two- and three-field lymphadenectomy (P=0.011). Medical morbidity consisted of pneumonia in 43 patients (43/90=48%), atelectasis in ten patients (10/90=11%), dysrhythmia in 21 patients (21/90=23%), sepsis in 11 patients (11/90=12%) and adult respiratory distress syndrome in ten patients (10/90=11%). Surgical morbidity included pleural effusion in 16 patients (16/90=18%), tracheal fistula in two patients (2/90=2%), chylothorax in two patients (2/90=2%) and acute pancreatitis in one patient (1/90=1%). Ten patients (10/90=11%) had a radiologically confirmed anastomotic leak; however only in four out of them with clinical manifestation; treatment was conservative in all four patients. Major morbidity occurred in 27 patients (27/90=30%). Overall rate of morbidity was significantly higher after three-field lymphadenectomy (85%) as compared to two-field lymphadenectomy (68.7%; P=0.023). Conclusions: Chemoradiotherapy followed by resection of _cT3–4 +/- _cM1_lymph oesophageal carcinoma is feasible with acceptable mortality. Mortality, however, seems to be significantly higher when compared to a group of pT3M1_LYM/pT4 patients who underwent primary surgery (8.3 versus 2.3%; P=0.015) in the same period in our department.

Key Words: Carcinoma of the esophagus/gastroesophageal junction • Induction chemoradiotherapy • Postoperative mortality • Postoperative morbidity • Lymphadenectomy

	1. Introduction

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Primary surgery remains the standard of care for patients with localized carcinoma of the oesophagus and gastro-oesophageal junction (GEJ). In locally advanced cancer, i.e. tumour potentially involving adjacent structures (_cT4) and/or in case of distant lymph node metastasis (_cM1_lymph), results of primary surgery are dismal. A combination of induction chemoradiotherapy seems to be advantageous [1] in terms of controlling such _cT3–4 +/- _cM1_lymph tumours and improving outcome. However, little data are available in literature on the effect of these multimodality regimens on immediate surgical outcome, i.e. morbidity and mortality. The aim of this study was to evaluate the impact of induction therapy on post-operative morbidity and mortality after resection of locally advanced oesophageal carcinoma as defined above.

	2. Materials and methods

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
2.1. Patients
From 1975 through 2001, 1880 patients were treated for carcinoma of the thoracic oesophagus or cardia at our institution. In this group, 109 patients were treated with chemoradiotherapy (CRT) prior to surgical exploration because of locally advanced oesophageal carcinoma (_cT3–4 +/- _cM1_lymph). Four patients with similar stage were treated as a pilot experience with chemoradiotherapy prior to surgery before 1993. From that year on, all consecutive patients presenting with a _cT3–4 +/- _cM1_lymph oesophageal carcinoma were offered this multimodality approach.

There were 95 male patients (95/109=87%) and 14 female patients (14/109=13%) with a mean age of 57 years ranging from 34 to 78 years. Follow-up was complete with a mean of 21.9 months (range: 0.4–106) in all patients and 41.3 months (range: 2.9–106) in patients surviving at the time of this study; median follow-up being 39.8 months (range: 8–106) in this group. Fifty-two patients (52/109=48%) had no associated risk factor. Eleven patients (11/109=10%) were ASA 1, 77 patients (77/109=71%) ASA 2, and 21 patients (21/109=19%) ASA 3. Tumour characteristics were evaluated on clinical basis using oesophagogram and endoscopy with biopsy (n=109) (Table 1). Local (Table 2) and distant staging was evaluated on oesophageal endo-ultrasound (n=94), ultrasound of the neck (n=80), computed tomography (CT)-scan (n=109) and positron emission tomography (PET)-scan, the latter since October 1998 (n=47). Ninety patients (90/109=83%) underwent routine bronchoscopy. No attempt was made in our institution for routine invasive staging in patients with enlarged lymph nodes on imaging by means of laparoscopy or thoracoscopy or mediastinoscopy. Such invasive staging was only performed on elective basis. As a result, 19 patients (19/109=17%) underwent a laparoscopy for invasive staging, which contributed to the final staging in five patients. Eight patients (8/109=7%) underwent a mediastinoscopy or a thoracoscopy, which yielded additional information in six patients.

2.3. Surgery
Patients were operated on approximately 2 months following the start of induction therapy. Surgery was performed attempting at a complete R0 resection whenever possible, i.e. in all patients showing a response or with stable disease. Patients showing signs of progressive disease were excluded from further surgery. In principle a subtotal oesophagectomy was performed with wide peritumoral and perioesophageal dissection. An effort was made to perform an extensive, i.e. two- or three-field, lymphadenectomy including resection of the thoracic duct whenever the patient's condition allowed to do so.

The detailed aspects of the surgical technique have been published elsewhere [2]. All patients except patients with cervical carcinoma extending into the hypopharynx were approached through a transthoracic route, left-sided for infracarinal tumours and right-sided for supracarinal tumours.

Post-operative care was standard according to a clinical pathway approach which consisted in one overnight stay in the recovery room. If no immediate problem occurred, patients were extubated in the recovery room to return to the ward the day after their operation. Morbidity was considered as major when the patient was transferred to the intensive care unit (ICU) in case of difficulties in weaning at day 1 or, when after returning to the ward, post-operative clinical status of the patient required a return to the ICU with or without need for a re-intubation.

For comparison, a group of patients that underwent primary surgery in the same period was selected. In order to make this comparison as valid as possible, all primary surgery patients were selected with a comparable tumour-load (pT3M1_LYM/pT4) in one location (intrathoracic esophagus). The group of patients that received induction therapy was adapted accordingly, excluding patients that had hypopharyngeal or GEJ/subcardiac tumours. All other variables (e.g. age, sex, cardio-pulmonary status) were comparable for both groups.

All statistical analyses were performed with the Statistical Analysis System package, version 8 (SAS Inc., Cary, NC, USA). All variables were examined by Student's t-test or Fisher's exact test. A P-value of less than 0.05 was considered significant.

	3. Results

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
3.1. Surgery
Of the 109 patients, 19 patients were not considered for operation because of progressive disease (12 patients), partial response (two patients: one patient refused surgery and one patient had a clear persistent irresectable lesion), minimal response and poor general condition (two patients), early death or persistent toxicity (three patients). Surgery was performed in 90 patients (operability: 90/109=83%) and resection was possible in 85 patients (resectability: 85/109=78%). Surgical access consisted of a right thoracotomy with laparotomy and cervicotomy in 58 patients (58/90=64%), a left thoracophrenolaparotomy and cervicotomy in 26 patients (26/90=29%) and transhiatal resection without thoracotomy in six patients (6/90=7%). Surgery consisted of a subtotal oesophagectomy with partial gastrectomy and reconstruction with a tubulated stomach and cervical anastomosis in 76 patients (76/90=84%), total oesophagectomy and laryngectomy in seven patients (7/90=8%), total gastrectomy with intra-thoracic Roux-en-Y oesophago-jejunostomy in two patients (2/90=2%), oesophageal bypass only using a retrosternal split stomach with cervical anastomosis in five patients (5/90=6%). In 34 patients (34/90=37.8%), a three-field (cervical, mediastinal and abdominal) lymph node resection was performed through a bilateral cervicotomy±partial sternotomy for the cervical compartment. In 39 patients (39/90=43.3%), a two-field (abdominal and mediastinal) lymphadenectomy was performed. Seventeen patients (17/90=18.9%) underwent no lymphadenectomy because of presence of risk factor(s) (five patients), advanced disease (eight patients) or organ metastasis (four patients) at the time of surgery. Associated procedures were performed in 18 patients (18/90=20%): lung wedge resection in 14 patients, lobectomy in one patient, parietal pleura resection in one patient, splenectomy and distal pancreatectomy in two patients, pericardial resection in one patient. These associated procedures were performed mostly because of suspicion of direct contiguity of tumour fibrosis into adjacent structures. Mean duration of surgery was 428 min (range: 240–690). Estimated blood loss was 1300 ml (range: 250–6500). Peroperative complications occurred in five patients (5/90=6%): haemorrhage in three patients (3/90=3%) (requiring splenectomy in one patient) and tracheobronchial perforation (closed primarily) in three patients (3/90=3%). No patient died during surgery.

3.2. Definitive anatomopathology
In 68 patients (68/90=76%), resection was complete (R0). No residual tumour cells were identified neither in the resected oesophagus nor in the lymph nodes (_pT0N0M0) in 22 patients (22/90=24%) (Table 3). In six patients (6/90=7%), there was still microscopic tumour in the lateral section margin (R1). In 16 patients (16/90=18%), macroscopic tumour was left behind (R2) including the five patients who received a bypass. An unexpected lung metastasis was found in three patients and removed at the time of operation; an unexpected pleural metastasis was removed at the time of operation in one patient.

Mortality was higher after three-field lymphadenectomy (4/34=11.7%) when compared to two-field lymphadenectomy (2/38=5.2%) although not statistically significant.

Comparison with a group of pT3M1_LYM/pT4 primary surgery patients (Table 8) shows a significant difference in mortality, especially overall mortality (P=0.015) and mortality after three-field lymphadenectomy (P=0.011).

	4. Discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

From a strictly surgical point of view one of the main reasons of these poor results is the incompleteness of the surgery, i.e. R1–R2 situations, in particular in upper-half carcinomas. This is due to the close relation between tumour and surrounding tissues with a high incidence of clinical T4 tumours. After primary surgery for such cases five year survival rates are generally quoted between 15 and 25%. Even involvement of any lymph node (N1) is considered by some authors as advanced disease.

In an attempt to improve survival, multimodality approaches to advanced oesophageal cancer have been developed that combine chemotherapy, radiotherapy and surgical resection. Preoperative combined chemo and radiotherapy has been investigated in a number of prospective or randomized studies [1,3–7]. Chemoradiotherapy (CRT) in the preoperative setting has several potential advantages. It may downstage local disease and convert these tumours into resectable and therefore potentially curable cancers. In the present study complete tumour sterilization was obtained in 19% of the whole study population and 24% of the resected patients and this subset of patients had a 5-year survival of 40.5%. Little is known, however, about the effects of preoperative chemoradiotherapy on immediate outcomes, i.e. morbidity and mortality after oesophagectomy. Specific post-operative complications and their potential relationship to the preoperative therapy have not been well described in such patients. The aim of our study was to evaluate the effects of preoperative chemoradiotherapy on post-operative morbidity and mortality in the patients with locally advanced oesophageal carcinoma.

Earlier series of such patients have reported mortality rates of 2–18% after resection and a morbidity rate of 15–57% [1,8–12]. Overall hospital mortality in patients with advanced oesophageal carcinoma and treated by surgery alone was 8.6% in an earlier published series from our centre, although in more recent years overall hospital mortality after primary surgery dropped to a level below 5% [11]. In the actual study overall post-oesophagectomy hospital mortality was comparable: 9.4% (8/85). In the case of unresectable tumours, bypass surgery reports high mortality [13] as in the present study (20%).

Overall morbidity was 74% (67/90) and major morbidity was seen in 27 patients (27/90=30%), being predominantly pulmonary complications in the latter group, similar to the results from other studies [1,12,14]. It is extremely difficult to evaluate whether or not induction chemoradiotherapy is really contributing to the morbidity [1,15,16]. Many factors indeed may influence morbidity. Duration of operation, duration of single lung ventilation, estimated blood loss and transfusion requirements may be related to induction therapy with increased fibrosis and oedema of tissues [1,5,17,18]. On the other hand, down-staging may facilitate dissection and resection. Other risk factors such as the advanced tumour stage itself, as advanced age, impaired pulmonary function, ethyl and tobacco consumption, cardio-vascular disease, use of medication (i.e. corticosteroids, theophylline, etc.) [19] may negatively influence morbidity. Only one study using multivariate analysis has looked into the correlation between induction chemoradiotherapy and post-operative morbidity, but no clear association could be found [20].

Another factor that may influence morbidity and mortality is the surgical access, i.e. transthoracic versus transhiatal resection. Initial reports showed a beneficial effect of transhiatal resection on morbidity especially on pulmonary complications because of the presumed shorter operation time and less intraoperative pulmonary trauma. However, two randomized trials did not reveal any difference between the two approaches [21]. In these series all, except patients with supraclavicular tumours, were treated by transthoracic approach and both major surgical and medical complications seemed to match with the reported morbidity rates after primary surgery. A recent publication [12] showed a very low incidence of overall complications, 36.5% in a large series of 120 patients treated by induction chemoradiotherapy.

In our centre much attention was always paid to a systematic wide peritumoural and oesophageal resection in order to obtain a R0 resection. In this group of patients with mostly _cT4 tumours, R0 resection was achieved in 76% (68/90) and in 80% (68/85) of the resections. This is a high rate given the high number of patients with clinical T4 lesion and/or distant lymph node metastasis. The efforts of complete tumour resection were combined whenever possible with an extensive lymphadenectomy at least a two-field lymphadenectomy and if the patient's condition allowed for adding a bilateral cervical three-field lymphadenectomy. This philosophy is based on the published results by many Japanese groups and some Western groups proving not only improved staging but also prolonged disease-free survival, and suggesting increased 5-year survival rates. From our own experience and others [22,23] it has been shown that in primary surgery patients both two- and three-field lymphadenectomy can be performed with a low hospital mortality and a morbidity equal to less aggressive transthoracic or transhiatal resections. In a group of 86 patients with an intrathoracic carcinoma and who were matched as closely as possible to a similar group of patients that received induction therapy, overall hospital mortality was significantly lower after primary surgery. While adding the cervical (third) field for infracarinal tumours is considered to be investigational many authors advocate routine bilateral cervical lymphadenectomy in supracarinal tumours because cervical nodes are considered as regional lymph nodes in this group of tumours. It is this subset group that constitutes the main indication for induction chemoradiotherapy. It seems, however, from the present experience that induction chemoradiotherapy is negatively influencing mortality. Although not statistically significant, mortality was four times as high in the three-field group as compared to the two-field group, and more than ten times as high as compared to the matched primary surgery group who had no mortality. There was a significant difference (P=0.023) in overall morbidity, 85% in three-field-lymphadenectomy versus 68.7% in two-field lymphadenectomy. Although specific complications, i.e. pulmonary complications, were not significantly different, it seems that the severity of complications is more important in the three-field lymphadenectomy. This is suggested by a longer duration of stay in ICU and hospital stay. The reason for this high trend in mortality and morbidity are not clear but may well be related to the surgical manipulations during the cervical lymphadenectomy, resulting in more oedema and laryngeal dysfunction and subsequent risk for aspiration and deficient clearing of tracheopulmonary secretions. These figures seriously question the feasibility after induction chemoradiotherapy what is considered in a number of centres, including ours, of three-field lymphadenectomy as the surgical standard of care, in particular in patients presenting with supracarinal tumour. A recent report by Altorki et al. [23] indicated an overall 25% 5-year survival in patients with positive cervicothoracic nodes after radical three-field lymphadenectomy and a 40% 5-year survival for squamous cell carcinoma in the presence of positive cervicothoracic lymph nodes. Our own experience indicates a 27% 5-year survival in patients with positive cervical lymph nodes after primary three-field lymphadenectomy in mid-thoracic squamous cell carcinoma. Akiyama et al. [24] reported 42.7% 5-year survival in patients with positive cervical lymph nodes after primary three-field lymphadenectomy versus 27.9% when performing two-field lymphadenectomy for similar groups of patients and tumour characteristics. These surgical results need to be balanced against the value of induction chemoradiotherapy followed by less aggressive surgery. In this present study overall 5-year survival was 23.8 and 40.5% in the subset of patients with a complete remission. Of course the results of this group, consisting mostly of _cT4 patients, are difficult to compare with results from surgical series containing different T and most likely also different N stages.

The lesson from our present experience, however, is to refrain from adding the third field when performing lymphadenectomy after chemoradiation. For this reason we restrict our indication for induction chemoradiotherapy mainly to the preferentially T factor, i.e. clinical T4, rather than on the N factor. For the latter we favour three-field lymphadenectomy in supracarinal tumours and to some extent in infracarinal tumours (the latter as a part of an investigational protocol). The recent introduction of PET-scan [25], however, may by helpful in detecting patients with gross cervical lymph node involvement and which in combination with other regional and/or distant lymph node metastasis should be treated preferentially by induction chemoradiotherapy.

	5. Conclusion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Induction chemoradiotherapy followed by surgery in clinical T3–4 +/- _cM1_lymph carcinoma of the oesophagus and GEJ is feasible with resectability of 78% and after resection an R0 status of 80%. Complete pathological response was seen in 24% of the patients with a 5-year survival in this group of 40.5%. Compared to a matched group of patients who underwent primary surgery in the same period, overall mortality was significantly higher, especially when compared with the subset who underwent three-field lymphadenectomy.

In patients receiving three-field lymphadenectomy mortality was four times as high as compared to two-field lymphadenectomy after induction therapy. Overall morbidity after three-field lymphadenectomy was significantly higher as compared to two-field lymphadenectomy. These findings question the feasibility of three-field lymphadenectomy as the possible surgical standard of care after induction chemoradiotherapy, in particular for supracarinal tumours for which cervical lymph node involvement is to be considered N1 (locoregional) rather than M1_lymph (distant) metastasis. Survival obtained with multimodality treatment forms, therefore, has to be compared with other therapeutic strategies, in particular primary resection with three-field lymphadenectomy, by prospective studies and if possible by randomized trials.

	Acknowledgments

 
The authors wish to thank J. Moons for his technical assistance and statistical analysis.

	Footnotes

 
Presented at the 16th Annual Meeting of the European Association for Cardio-thoracic Surgery, Monte Carlo, Monaco, September 22–25, 2002.

	Appendix A. Conference discussion

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 
Dr S. Mattioli (Bologna, Italy): I would like to point my comment and my question to the three-field lymphadenectomy. You had really very good survival. Forty percent at 5 years with this kind of advanced disease is a very good result. It seems to me that three-field lymphadenectomy did not increase remarkably the post-operative complications, except for the recurrent nerve injury. I think this complication should be addressed.

Secondly, what is the schema of neoadjuvant chemoradiotherapy you adopted?

Dr Hagry: For the first question about the three-field lymphadenectomy and recurrent nerve damage: this remains a problem that may cause persistent hoarseness. Actually, concerning this three-field, in our institution, especially for the supracarinal carinal tumours, we prefer now to perform in clinical T4 with or without multiple node induction chemoradiotherapy (40 Gy and cisplatin 5–fluorouracil) rather than the three-field lymphadenectomy because the morbidity is higher, especially serious morbidity.

For the second question, chemotherapy consisted in two courses of 5-fluorouracil and cisplatin; standard dose of radiotherapy was 36 Gy, increased to 40 Gy more recently for 15 patients.

Dr L. Voltolini (Siena, Italy): Have you found any difference in perioperative mortality and morbidity between patients with squamous cell carcinoma and adenocarcinoma?

Dr Hagry: We found no significant difference between those two groups.

Dr Voltolini: And in long-term survival?

Dr Hagry: No significant difference also for long-term survival.

Dr E. Rendina (Rome, Italy): Not only is your survival excellent but also your conversion rate from inoperable patients to resectable patients is very positive. Can you please expand and comment on your staging procedure before induction therapy and between induction therapy and surgery, if you did any?

Dr Hagry: For the pre-induction staging we performed as standard protocol: endoscopy, CT scan, esophagogram, EUS, bronchoscopy and now, since 1998, PET scan was systematically performed for all the patients.

Dr A. End (Vienna, Austria): If I understood you correctly, there was one patient who stayed about 380 days in the hospital post-operatively. Could you just comment briefly on his course?

Dr Hagry: If I remember well, I think it was a patient who stayed in the intensive care unit all this time for a major problem of pulmonary fibrosis and could not be weaned from the respirator. This patient finally died in the intensive care unit.

Dr O. Kshivets (Siauliai, Lithuania): Did you compare the frequency of leakage after combined treatment and surgery-only treatment?

Dr Hagry: Sorry?

Dr Kshivets: Significant frequency, significant rate of leakage, the oesophagogastric anastomosis.

Dr Hagry: There was no difference, no significant difference of frequency of the leakage after combined treatment.

	References

Top Abstract 1. Introduction 2. Materials and methods 3. Results 4. Discussion 5. Conclusion Appendix A. Conference... References

 

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