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10.1245/s10434-006-9198-2
Annals of Surgical Oncology 14:2010-2017 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Impact of Induction Chemotherapy and Preoperative Chemoradiotherapy on Operative Morbidity and Mortality in Patients with Locoregional Adenocarcinoma of the Stomach or Gastroesophageal Junction

Kazumasa Fujitani1, Jaffer A. Ajani2, Christopher H. Crane3, Barry W. Feig1, Peter W. Pisters1, Nora Janjan3, Garrett L. Walsh4, Stephen G. Swisher4, Ara A. Vaporciyan4, David Rice4, Angela Welch2, Jackie Baker2, Josephine Faust2 and Paul F. Mansfield1

1 Departments of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
2 Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
3 Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
4 Thoracic and Cardiovascular Surgery, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Address correspondence and reprint requests to: Paul F. Mansfield, Department of Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, P.O. Box 301402, Unit 444, Houston, TX 77230-1402, USA; E-mail: pmansfie{at}mdanderson.org


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Significant tumor downstaging has been achieved in patients with localized gastric or gastroesophageal adenocarcinoma by induction chemotherapy and preoperative chemoradiotherapy (CTX-CTXRT). However, the influence of CTX-CTXRT on operative morbidity and mortality has not yet been clarified. The aim of the present study was to document the frequency and nature of morbidity and mortality after surgery combined with CTX-CTXRT, and identify factors predictive of postoperative complications in patients with localized gastric or gastroesophageal adenocarcinoma.

Methods: A prospectively collected database on 71 consecutive patients who underwent CTX-CTXRT at M.D. Anderson Cancer Center between January 1997 and August 2004 was reviewed. Postoperative morbidity and mortality were investigated, and risk factors for overall complications were identified by multivariate logistic regression analysis.

Results: Overall morbidity and mortality rates were 38.0% (27 patients) and 2.8% (2 patients), respectively. Age greater than 60 years [relative risk 11.3 (95% confidence interval 2.50–50.6)] and body mass index (BMI) of 26 kg/m2 or above [relative risk 4.08 (95% confidence interval 1.08 to 15.4)] were significant risk factors for overall complications.

Conclusions: CTX-CTXRT can be performed safely with an acceptable operative morbidity and a low operative mortality rate in patients with gastric or gastroesophageal cancer, with careful consideration of added risk associated with age and obesity.

Key Words: Morbidity • Mortality • Gastric cancer • Gastroesophageal cancer • Induction chemotherapy • Preoperative chemoradiotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Despite a declining incidence in western countries,1,2 gastric cancer is the second most common cause of cancer-related death in the world, and R0 (no residual disease) surgical resection remains the only potentially curative treatment for gastric cancer. However, in the west, R0 resection is achieved in less than 50% of patients with locoregional gastric cancer.3 Therefore, various approaches have been undertaken to facilitate an R0 resection through downstaging of the primary tumor, such as preoperative chemotherapy and preoperative chemoradiotherapy. Recently, preoperative chemotherapy combined with postoperative chemotherapy has shown an improved R0 resection rate of 79% and evidence of downstaging, resulting in a significant prolongation of survival, compared with surgery alone.4 We have demonstrated significant tumor downstaging and achieved a high R0 resection rate of 70–78%, correlating with durable overall survival (OS) in patients with localized gastric or gastroesophageal adenocarcinoma by preoperative chemoradiotherapy preceded by induction chemotherapy.5,6

However, the influence of induction chemotherapy and preoperative chemoradiotherapy (CTX-CTXRT) on operative morbidity and mortality has not yet been clarified because of the very limited experience with these treatments in localized gastric or gastroesophageal cancer. The aim of the present study was to document the frequency and nature of morbidity and mortality after surgery preceded by CTX-CTXRT, and identify factors predictive of postoperative complications.


   PATIENTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Selection
A prospectively collected database of 71 consecutive patients who underwent induction chemotherapy followed by chemoradiotherapy followed by surgery for gastric or gastroesophageal carcinoma at M.D. Anderson Cancer Center between January 1997 and August 2004 was reviewed. Patients were allocated to one of four different trials. Eligibility criteria for the trials has already been reported in detail elsewhere.5,6 In brief, patients with localized, potentially curable, and histologically poven gastric or gastroesophageal adenocarcinoma were eligible. The bulk of cancer was in the stomach, even though the gastroesophageal junction (GEJ) may have been involved. Patients with T2-3 carcinoma with any lymph node (N) involvement and patients with T1N1 carcinoma were eligible. Patients with T4, M1 (any evidence of metastatic disease), or T1N0 carcinoma, peritoneal carcinomatosis or positive peritoneal cytology, or uncontrolled medical conditions (e.g., diabetes, hypertension, cardiac disease graded as New York Heart Association class III or IV, cerebrovascular disease, or psychiatric illness) were not eligible. Patients who could not comprehend or comply with the study were also ineligible. Patients had to have a performance status of less than 2 on Zubrod scale. All patients underwent endoscopic ultrasonographic (EUS) staging of the locoregional carcinoma and laparoscopic evaluation to fully stage the peritoneal cavity, and had jejunostomy feeding tube (J-tube) placed laparoscopically before the initiation of pre-operative therapy. All patients signed an institutional review board-approved written informed consent.

Preoperative Treatment
Patients were to receive up to two cycles of induction chemotherapy and then chemoradiotherapy. Each cycle of chemotherapy lasted 28 days and the second cycle was only given in the absence of disease progression. In case of local disease progression, the second cycle was skipped and the patient went on to receive concurrent chemoradiotherapy. Patients were taken off protocol if distant metastases developed at any time before surgery. As details of CTX-CTXRT have already been reported elsewhere,5,6 a summary of each of the four trials is shown briefly.

Trial A
Patients received induction chemotherapy of 5–fluorouracil (5-FU), folinic acid, and cisplatin followed by 45 Gy of radiotherapy with concurrent 5-FU.

Trial B
Patients received induction chemotherapy of 5-FU, cisplatin, and paclitaxel followed by 45 Gy of radiotherapy with concurrent 5-FU plus paclitaxel.

Trial C
Patients received induction chemotherapy of 5-FU, folinic acid, and cisplatin followed by 45 Gy of radiotherapy with concurrent 5-FU plus paclitaxel.

Trial D
Patients received induction chemotherapy of 5-FU, folinic acid, and oxaliplatin followed by 45 Gy of radiotherapy with concurrent 5-FU and oxaliplatin.

Radiotherapy
Within 14–28 days after completion of induction chemotherapy, patients began chemoradiotherapy. Radiation fields included the entire stomach, perigastric extension if present, and draining lymph nodes (perigastric, celiac, porta hepatis, gastroduodenal, splenic-suprapancreatic, and retropancreaticoduodenal). For lesions involving the cardia or GEJ, a 5-cm margin of esophagus above the proximal extent of tumor was included, and for distal lesions at or near the gastroduodenal junction, a 5-cm margin of duodenum was recommended. Idealized fields were modified as needed to shield at least two-thirds of one kidney. For proximal lesions, cardiac shielding was also recommended. A total radiotherapy dose of 45 Gy was delivered in 25 fractions of 1.8 Gy over 5 weeks.

Surgery
Four to six weeks after completion of chemoradiotherapy, all patients were restaged and underwent surgery free of distant disease. The type of surgery depended on the location and extent of the primary cancer. The cancer was resected along with a luminal gastric margin of at least 5 cm when feasible. Also when feasible, a 2-cm duodenal margin was obtained for distal cancers and a 3-cm esophageal margin was obtained for proximal cancers. In both cases, frozen section confirmation of a negative margin was sought. For distal cancers, a distal-subtotal gastrectomy was considered adequate. For proximal cancers, either a total gastrectomy or Ivor-Lewis esophagogastrectomy (esophagectomy with proximal gastrectomy) was the most frequently performed surgery. Occasionally, either a proximal-subtotal gastrectomy or a left thoracoabdominal esophagogastrectomy was performed for proximal cancers. En bloc resection of adjacent organs was performed when their involvement was considered. The spleen was preserved whenever possible. An attempt was made to perform a D2-type nodal dissection, though omental bursectomy was not required. The left gastric artery was divided at its origin, and lymph nodes in perigastric region, and along the celiac axis and its major branches (the left gastric artery, the common hepatic artery, and the proximal splenic artery) were removed. Esophagogastrectomy involved an additional dissection of paraesophageal and mediastinal nodes below the level of the azygous arch. The mode of reconstruction following resection was not specified. During surgery, J-tube was placed for temporary postoperative nutritional support.

Evaluation of Operative Morbidity and Mortality
Surgical and non-surgical complications were collected prospectively. Anastomotic leakage was diagnosed radiographically based on clinical suspicion. Pancreatic leakage was diagnosed when fluid with a high amylase concentration drained from the peripancreatic area. Respiratory failure was defined as need for mechanical ventilation for more than the first 48 postoperative hours. Reoperation details and length of hospital stay were also recorded. Operative mortality was defined as postoperative death of any cause within 30 days of surgery, or during the same hospital stay.

Statistical Analysis
A univariate logistic regression analysis was used to assess the association between each clinical factor and morbidity. A multivariate logistic regression analysis was performed to identify variables independently associated with morbidity. All statistical tests were two-sided, and significance was set at P < 0.05. SAS® version 8.2 (SAS Institute, Tokyo, Japan) was used for data analysis.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics
A total of 71 patients, 44 males and 27 females with a median age of 58 (range: 28–81) years, underwent surgical resection between January 1997 and August 2004, though a couple of patients had to delay surgery for a few weeks due to a decline in performance status or health during preoperative therapy, and 69 patients (97%) had an R0 resection. One patient with linitis plastica had a positive proximal margin on permanent pathologic evaluation despite a negative frozen section, and the other patient had a positive cytology of peritoneal lavage. Patient characteristics are shown in Table 1Go. Most patients had a pretreatment EUS stage uT3 cancer (89%). Forty of the 71 patients (56%) had an uN1 cancer, and 31 patients (44%) had an uN0 cancer. Thirty-five patients had a carcinoma of GEJ or proximal stomach, and 31 had a carcinoma located in the lower half of the stomach. Five patients had a carcinoma involving the whole stomach, with linitis plastica in four patients. Median body mass index (BMI) of all patients was 25.9 kg/m2 (range: 15.7–40.9). A total radiotherapy dose of 45 Gy was delivered in 60 out of 71 patients (85%).


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  		TABLE 1. Patient characteristics
 
Operative Details
The operative details are shown in Table 2Go. Total gastrectomy was performed in 31 patients (44%), and proximal-subtotal gastrectomy was in three instead of total gastrectomy. Thirteen patients underwent esophagogastrectomy, carried out in Ivor-Lewis fashion in 11 and with a left thoraco-abdominal approach in two. The remaining 24 patients (34%) underwent distal-subtotal gastrectomy. Both the spleen and the pancreas were preserved in all but three patients (96%). Two patients underwent splenectomy for intraoperatve iatrogenic laceration of the spleen, and one patient underwent concurrent resection of the spleen and the pancreatic tail due to direct invasion of the tumor into these organs. A D2-type nodal dissection was conducted in 68 patients (96%), and the median number of retrieved lymph nodes in the 71 resected specimens was 17 (range: 2–67). Median blood loss of all patients during the operation was 350 ml (range: 50–1,400). Roux-en-Y esophagojej-unostomy and gastrojejunostomy were the main reconstruction techniques performed after total and distal-subtotal gastrectomy, respectively. A gastric pull-up was used to restore continuity after esophagogastrectomy through a thoracic approach. Gastroduodenostomy was never done after distal-subtotal gastrectomy.


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  		TABLE 2. Operative details
 
Operative Morbidity and Mortality
Postoperative complications were identified in 27 patients and the overall morbidity rate was 38.0%, as shown in Table 3Go. A temporary anastomotic leakage was observed in two patients after total gastrectomy and in one after esophagogastrectomy. Five patients had an abdominal abscess, with concomitant pancreatic leakage in one and anastomotic leakage in one. Paralytic ileus causing a delay of recommencement of oral feeding was observed in four patients. Wound infection was comparatively more frequent and occurred in nine patients (12.7%). Pneumonia developed in three patients after esophagogastrectomy and in two after distal-subtotal gastrectomy. Reoperation was performed in one patient (1.4%) immediately after the initial operation with a suspicion of intraperitoneal hemorrhage. There were two hospital deaths (2.8%). One patient died of respiratory failure 47 days after esophagogastrectomy, and the other died of aspiration pneumonia at 18 days after distal-subtotal gastrectomy. The death both occurred in the first trial since which there have been none. All other patients recovered from surgery and were discharged from the hospital, with a median hospital stay of 12 (range: 6–86) days.


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  		TABLE 3. Operative morbidity and mortality
 
Risk Factors for Operative Morbidity
The results of univariate and multivariate analyses of various factors, such as sex, age, BMI, type of resection, blood loss, and dose of radiotherapy, for overall operative morbidity are summarized in Table 4Go. Among these, age greater than 60 years (P = 0.002) and BMI of 26 kg/m2 or more (P = 0.038) were identified as significant independent risk factors for overall morbidity.


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  		TABLE 4. Risk factors for overall complications
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Although some attempts have been made so far to irradiate the whole stomach preoperatively,7–9 there has never been a prospective study to assess the influence of CTX-CTXRT on surgical morbidity and mortality in patients with gastric or GEJ cancer.

In this study, postoperative complications occurred in 38% of the patients. The rate of operative morbidity following gastric cancer surgery varies according to the countries and institutions. Although morbidity rates of 43% and 46% associated with D2 lymphadenectomy were demonstrated respectively in the Dutch10 and British11 D1/D2 trials, comparatively lower morbidity rates of 20.9% and 17.4% have been reported after D2 gastrectomy from Japan12 and Korea,13 respectively. Dedicated centers in Western Europe and the United States have shown morbidity rates of 13–43% after D2 lymph node dissections in selected patients.14–17 These findings suggest that CTX-CTXRT is feasible without significantly affecting the overall operative morbidity. As for the major surgical morbidity, anastomotic leakage was observed in 4.2% of the patients, pancreatic leakage in 1.4%, abdominal abscess in 7.0%, paralytic ileus in 5.6%, and wound infection/dehiscence in 12.7% in the present study. No patient developed postoperative hemorrhage. In specialized centers in western countries, the incidence of surgical complication was 1.2–8.1% for anastomotic leakage, 1.8–4.2% for abdominal abscess, 1.1–3.9% for wound infection/dehiscence, and 1.2–1.9% for postoperative intra-peritoneal hemorrhage.14–17 Asian studies have shown the rate of surgical morbidity as follows: anastomotic leakage, 0.2–2.3%, pancreatic leakage, 0.2–5.3%, abdominal abscess, 4.5–5.3%, and ileus, 1.9–2.5%.12,13 These findings indicate that CTX-CTXRT does not increase the rate of postoperative major surgical complications, though careful attention should be paid to postoperative wound care. Concerning wound care management, patients got a preoperative mechanical bowel preparation, and had intravenous cefazolin 1 g administered postoperatively every 8 h for two doses. In addition, hair was trimmed with a mechanical trimmer, and skin preparation was done with surgical solution containing 0.7% iodine and 74% isopropyl alcohol just prior to surgery. Further efforts should be made to decrease the rate of wound complications.

In two European randomized controlled trials,10,11 D2 gastrectomy was associated with a high operative mortality rate exceeding 10%. In contrast, an operative mortality of less than 1% has been reported after D2 gastrectomy in Asian countries.12,13 Preoperative co-morbidity, hospital and surgeon volume of surgical procedures18–20 are known to correlate with the operative mortality rate. High-volume centers in western countries have demonstrated an acceptable hospital mortality rate of less than 5% for gastrectomy with D2 lymph node dissection.14–17 A favorable operative mortality rate of 2.8% shown in this study suggests the safety of CTX-CTXRT performed before D2 lymphadenectomy in patients with gastric or GEJ cancer.

Risk factors for postoperative complications have been investigated to date on D2 lymph node dissection for gastric cancer. Pancreatic resection was identified as the most significant independent risk factor in both western and Asian studies.11,21–23 Splenectomy was also highlighted as a major risk factor for operative morbidity in western trials,11,15,21,22 but not in a Japanese trial.23 As neither pancreatectomy nor splenectomy has ever been proved prospectively to produce a survival benefit to the patients despite the association with a high incidence of operative morbidity, both pancreas and spleen were preserved in the vast majority of patients in this study. It also should be noted that patients with uT4 tumors were excluded from the present study.

Among various factors, age greater than 60 years was significantly associated (relative risk 11.3) with a higher operative morbidity rate, as shown in Table 4Go. Age has been previously demonstrated to be a significant predictor of postoperative complications, while the definition of advanced age was variable among the studies.13,21,23 A BMI of 26 kg/m2 or greater was also identified as an independent risk factor for overall complications in the present study. This result was consistent with the finding of a Japanese trial,23 in which obesity was proved to be a significant risk of developing complications. If the definition of advanced age was changed from 60 years to 70 years in Table 4Go, age was a significant risk factor with a relative risk of 10.9 (95% confidence interval 2.04–57.7). Likewise, when the definition of obesity was changed from a BMI of 26 kg/m2 to 30 kg/m2, BMI was identified as an independent risk factor for overall complications with a relative risk of 4.24 (95% confidence interval 1.02–17.7). These findings show that there is no gradient to age and obesity on the risk of postoperative complications, and suggest that there is no contraindication to gastrectomy regarding age and BMI in patients with CTX-CTXRT. As a postoperative complication particularly associated with these risk factors, eight out of nine patients showing wound infection/dehiscence were over 60 years of age, and all the patients with postoperative cardiac failure were greater than 60. Similarly, all three patients with anastomotic leakage, and four out of five patients developing abdominal abscess showed a BMI of 26 kg/m2 or greater. Although postoperative morbidity might correlate with the patient’s weight loss or gain during preoperative therapy besides BMI, there believed to be no significant change of the patient’s body weight before surgery because all patients had a feeding tube in place to supplement them. In addition, since pre-operative medical conditions could be risk factors for postoperative complications, all the patients were ascertained to be fit for surgery with sufficient nutritional state as well as adequate bone marrow, liver, and renal functions prior to surgery. Although esophagogastrectomy was close to significance (P = 0.062), neither esophagogastrectomy nor total radiotherapy dose of 45 Gy was a significant risk.

The low mortality rate obtained in this study may well be related to the preservation of pancreas and spleen, because both splenectomy and pancreatectomy have been proved to be associated with higher operative mortality in western trials.11,21,22,24

The preoperative approach is designed to facilitate an R0 resection through the downstaging of the primary tumor. Recently, preoperative chemotherapy has been demonstrated to improve the R0 resection rate and overall survival in patients with localized gastric or GEJ cancer, with an operative morbidity rate of 46%, a mortality rate of 6%, and a median postoperative hospital stay of 13 days.25 Compared with these findings, CTX-CTXRT is considered to be quite acceptable in terms of safety, though there are limitations in comparing a single institutional experience with the result of a multi-institutional trial.

In conclusion, with careful patient selection, appropriate surgical expertise and preservation of pancreas and spleen, CTX-CTXRT can be performed safely with an acceptable operative morbidity and a low operative mortality in patients with gastric or GEJ cancer.

Received for publication March 30, 2006. Accepted for publication July 17, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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