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Enhanced Staging and All Chemotherapy Preoperatively in Patients with Potentially Resectable Gastric Carcinoma

From the Departments of Gastrointestinal Medical Oncology and Digestive Diseases and Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX.

Address reprint requests to Jaffer A. Ajani, MD, Department of Gastrointestinal Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 78, Houston, TX 77030-4095; email jajani{at}mdanderson.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Patients with local-regional gastric carcinoma have a low rate of curative resection (R0) because of the advanced stage at diagnosis and suboptimal clinical staging. This study was designed to improve clinical staging with the use of laparoscopy and endoscopic ultrasonography (EUS) and to improve R0 resection rates and tolerance by delivering all chemotherapy preoperatively in patients with potentially resectable gastric carcinoma.

PATIENTS AND METHODS: All patients with histologic proof of localized adenocarcinoma of the stomach underwent a staging laparoscopy before registration. EUS was performed when feasible. The intention was to administer up to five courses of preoperative chemotherapy consisting of fluorouracil (500 mg/m²/d as a continuous infusion on days 1 through 5 and as a bolus on days 12 and 19), interferon alfa-2b (3 million units subcutaneously three times a week for 3 weeks), and cisplatin (15 mg/m²/d as a bolus on days 1 through 5). After chemotherapy, surgery was attempted to remove the primary and regional lymph nodes. Clinical response and EUS staging were correlated with surgical pathology. The feasibility of this approach, resection rates, patient survival, and patterns of failure also were assessed.

RESULTS: All 30 patients enrolled were assessed for toxicity, response, and survival. Nineteen men and 11 women were enrolled. The median number of courses delivered per patient was three (range, one to five courses). Fourteen patients (47%) received all five preoperative courses of chemotherapy. The overall clinical response rate was 34%. Twenty-nine patients (97%) underwent attempted resection. Twenty-five (83%) had an R0 resection. Two patients (7%) had no evidence of carcinoma in the surgical specimen, and three had only microscopic carcinoma ( 90% necrosis). Posttreatment EUS findings did not correlate well with surgical pathology. The median duration of follow-up was 30 months (range, 5 months to 65+ months). The median survival time for 30 patients, calculated by the Kaplan-Meier method, was 30 months (range, 5 months to 65+ months). There were no cases of grade 4 toxicity.

CONCLUSION: It is feasible to administer prolonged preoperative therapy in patients with potentially resectable gastric carcinoma. Enhanced staging with laparoscopy and EUS helped in proper selection of patients and better characterization of the stage.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
CARCINOMA OF THE STOMACH continues to be a significant health problem around the world, despite the fact that it has continued to decline in incidence since World War II. More than 22,600 new cases of gastric cancer and 13,700 resulting deaths were expected to occur in the United States in 1998.¹ The incidence of proximal gastric carcinoma has increased in the past 15 years.² In Western countries, routine screening is not performed and early detection is not feasible; thus in approximately 50% of newly diagnosed cases, the carcinoma is beyond its local-regional origins.¹

The goal of surgery for carcinoma of the stomach is to achieve a curative resection that involves removal of all gross cancer and regional lymph node groups and leaves no cancer cells at the resection margins as determined by histopathologic examination. This is an R0 resection, which is the predominant curative approach. However, R0 resection is possible for fewer than 50% of patients whose cancers are judged to be potentially resectable after clinical staging.^3,4 Patients who have undergone an R0 resection constitute the best prognostic group, with a median survival duration of 25 months and an estimated 5-year survival rate of 30%.^5-7 Unfortunately, postoperative adjuvant therapy has had no impact on these statistics.^8-11

Preoperative staging is of paramount importance in patients with local-regional gastric carcinoma. Improved staging techniques could, however, facilitate better selection of operable patients, thus eliminating unnecessary surgery. Laparoscopy combined with endoscopic ultrasonography (EUS) complements traditional staging methods and can even provide clinical information that is not otherwise obtainable.¹² Unsuspected peritoneal, liver, and even nodal metastases are detected at a basic frequency of 20% using laparoscopy and EUS.^13,14 Our own experience with staging laparoscopy¹⁵ in 71 consecutive patients with potentially resectable gastric carcinoma demonstrated a 23% incidence of unsuspected disease (liver or peritoneal spread) precluding resection.

Preoperative therapy is appealing for patients with potentially resectable gastric carcinoma because it theoretically offers the following advantages: (1) reduction in the bulk of the primary carcinoma, which might improve the rate of R0 resection, (2) early therapy of micrometastases, and (3) a temporal presurgery window to allow for further selection of patients who may be on the verge of manifesting widely metastatic carcinoma. We previously reported the use of preoperative chemotherapy in patients with potentially resectable gastric carcinoma.^16,17 In our first study, patients received two courses of preoperative chemotherapy and three courses of the same chemotherapy postoperatively.¹⁶ In our second study, patients received three courses of preoperative chemotherapy and two courses of the same chemotherapy postoperatively.¹⁷ Tolerance to postoperative chemotherapy was poor in both studies.^16,17

In the present study, we examine the effect of delivering all five courses of chemotherapy preoperatively with the goals of improving tolerance and maximizing the benefits. No postoperative therapy was planned. All patients underwent laparoscopic staging of the peritoneal cavity, and EUS was attempted to better define the prechemotherapy stage of the carcinoma.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patient Selection and Evaluation
Patients with previously untreated, biopsy-proven, locally confined gastric adenocarcinoma were eligible. All patients were required to have a Zubrod performance status of 2, serum creatinine level less than 1.5 mg/dL, serum bilirubin level less than 1.6 mg/dL, absolute granulocyte count 1,500 cells/µL, and a platelet count of greater than 100,000/µL. Excluded were patients with T1 carcinoma as determined by EUS, patients with a tumor less than 2 cm in diameter if EUS was not performed patients with obvious T4 carcinoma, and patients with gross peritoneal carcinoma, although patients with malignant cells in the peritoneal washings (in the absence of ascites) were eligible. All patients gave written informed consent.

Tumors were considered technically unresectable if supraclavicular adenopathy, effusions, or suspected distant lesions were histologically confirmed to be malignant.

Pretreatment assessment included complete blood cell count with differential, serum multichannel chemical analysis including electrolyte and serum magnesium levels, plasma carcinoembryonic antigen titer, chest radiograph, computed tomography of the abdomen, upper gastrointestinal endoscopy and EUS to determine the tumor and node stages, and double-contrast upper-gastrointestinal radiographs. Patients were required to have laparoscopic staging performed before registration. EUS was not mandatory in this study and was performed only if other diagnostic endoscopic information was required. Before registration, a surgical oncologist, a medical oncologist, and a gastroenterologist jointly evaluated all patients to determine if the primary carcinoma was potentially resectable and if the patient was medically fit to undergo surgery. All eligible patients had the choice of proceeding with an operation if they did not wish to participate in this study.

Study Design
The objective of the study was to determine the effect of administering up to five courses of chemotherapy preoperatively without planned postoperative therapy. An attempt was made to administer five courses of chemotherapy in all patients; however, this was based on a step-wise approach. If evidence of progression of the local-regional carcinoma (but no metastatic disease) was observed at any time during preoperative chemotherapy, then chemotherapy was immediately discontinued, and a prompt attempt at surgical resection was made. After the first and third courses, if there was evidence of response, patients received two additional courses. If there was no evidence of progression after the first course, patients received two additional courses of chemotherapy; however, if there was no evidnece of response after the third course, patients underwent surgery. Response was evaluated by radiographic or endoscopic techniques.

Patients who had microscopic carcinoma present at the resection margins (R1 resection) or who had gross residual carcinoma (R2 resection) were considered eligible for radiotherapy to provide added palliation (at the discretion of the treating physician) or long-term advantage if their carcinoma was localized.¹⁸

Chemotherapy
The chemotherapy regimen consisted of a combination of fluorouracil, cisplatin, and interferon alfa-2b (Intron, Schering-Plough Corp, Kenilworth, NJ). We devised this combination based on our experience with fluorouracil and interferon in patients with colorectal carcinoma¹⁹ as well as the data suggesting that interferon alfa-2b significantly prolonged the serum half-life of fluorouracil.²⁰ We elected to add cisplatin. Fluorouracil was administered at 500 mg/m²/d as a continuous infusion administered via portable pump on days 1 through 5. This drug was repeated as a bolus infusion on days 12 and 19. Cisplatin was administered at 15 mg/m²/d as an intravenous bolus on days 1 through 5. Patients routinely received intravenous hydration and antiemetic therapy. Intron was administered subcutaneously at a total dose of 3 million units three times per week for 3 weeks. Chemotherapy courses were repeated every 28 days, provided patients had recovered from all toxic effects.

Based on the predetermined criteria of toxicity grades, the doses of chemotherapy drugs were decreased by 25% if necessary.²¹ Criteria for dose reduction included development of grade 3 nonhematologic toxicity or grade 4 hematologic toxicity. Complete blood cell counts were evaluated at least once per week and often more frequently when patients experienced chemotherapy-induced myelosuppression. Serum creatinine, blood urea nitrogen, electrolyte, and magnesium levels were monitored regularly during each course.

Surgery
Subtotal or total gastrectomy with regional lymphadenectomy was performed on each patient in whom metastatic carcinoma did not develop. During surgery, a feeding jejunostomy tube was placed for temporary postoperative nutritional support.

Response, Toxicity Criteria, and Data Management
Upper gastrointestinal barium radiographs were repeated after the first, third, and fifth courses of chemotherapy, and esophagogastroscopy, barium radiographs, computed tomography of the abdomen, chest radiograph, and all blood tests were repeated before surgery.

Previously described criteria for response evaluation were used.^16,17 Briefly, criteria for response included: (1) pathologic complete response (pathCR) was defined as the absence of carcinoma cells in the resected specimen, (2) pathologic partial response was defined as 90% necrosis in the resected specimen, (3) clinical complete response (CCR) was defined as the absence of carcinoma cells in the endoscopic biopsy and cytology specimens with no radiographic evidence of carcinoma, (4) major response was defined as marked reduction in the tumor bulk as evidenced by radiographs, and (5) minor response was defined as objective but less dramatic regression of carcinoma as documented by barium radiographs. The purpose for defining clinical responses by the above criteria was to identify those patients who should continue to receive up to five courses of preoperative chemotherapy.

Follow-Up
Patients were assessed every 3 months for the first year after completion of all therapy. They were then assessed every 6 months for 4 years.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Thirty-four patients considered for this study underwent laparoscopy, however, four patients had gross peritoneal carcinoma and were not eligible. Thus 30 patients were entered onto this study from February 1993 to May 1995. All patients were considered assessable for toxicity, response, and survival. Patient characteristics are listed in Table 1. The primary tumor was present in the proximal stomach in 21 (70%) of 30 cases. Although the gastroesophageal junction was involved in some patients, the bulk of the tumor was in the stomach. The majority of patients were men (19; 63%), and all patients had a performance status of either 0 or 1.

Response to Preoperative Chemotherapy
A total of 108 courses of chemotherapy were delivered to 30 assessable patients, for a median of three courses per patient (range, one to five courses per patient). Fourteen patients (47%) received five courses of chemotherapy before surgery, 10 (33%) received three courses of chemotherapy before surgery, and the remaining six patients received fewer than three courses of chemotherapy (two courses in two patients and one course in four patients). Dose reduction by 25% was required in only six (5.5%) of the 108 courses delivered. The best response to preoperative therapy is listed in Table 2. Five (17%) of 30 patients were determined to have achieved a CCR, and five (17%) achieved a partial (major) response. Thus the overall major clinical response rate was 34%. Nine patients (30%) also achieved a minor response and four patients (13%) had progressive disease after one course. The location of the primary tumor (proximal or distal) seemed to have a bearing on the response to this chemotherapy: 11 patients (53%) with proximal carcinoma responded, but only one patient (11%) with distal carcinoma responded. Six (43%) of 14 tumors with moderate pathologic differentiation responded, compared with eight (30%) of 27 with poor pathologic differentiation (not significant).

EUS Results
Our intention was to obtain EUS before therapy (baseline) and before surgery (preoperative) in as many patients as possible.

Baseline EUS. Before registration, EUS was attempted in 16 patients and was technically feasible in 14 patients. The results of the EUS are listed in Tables 2 and 3. Seven (50%) of 14 EUS demonstrated a T3N1 lesion, four (29%) demonstrated a T3N0 lesion; two (14%) demonstrated a T2N1 lesion, and two (14%) demonstrated a T2N0 lesion. Thus more than 85% of patients had at least a T3 or N1 lesion.

Preoperative EUS. Before surgery, EUS was attempted in 16 patients (including 10 patients who had a baseline EUS) and was technically feasible in 13 patients. Results of the EUS findings are listed in Table 3. Five patients (38%) had a T3N1 lesion, three (23%) had a T3N0 lesion, two (15%) had a T2N0 lesion, and four (31%) had a T1N0 lesion. Thus only 62% of patients had at least T3 or N1 lesion.

Correlation between baseline and preoperative EUS. Both studies were attempted in 10 patients but were technically feasible in only eight patients. The results are listed in Table 3. There was no change in three patients, there was an upward stage migration (T2N1 to T3N1 in a patient with no clinical response) in one patient, and downstage migration was noted in four patients. However, the numbers are too small to make any definitive conclusions.

Surgery Results and Surgical Pathology
The physical condition of one patient (3%) deteriorated after three courses of preoperative chemotherapy; this patient was considered inoperable but is included in the toxicity and survival analyses. In the other 29 (97%) patients, resection was attempted. Surgical and pathologic results are listed in Table 2. Twenty-five (83%) of the 30 study subjects or 25 (86%) of 29 who underwent surgery had an R0 resection. Four operable patients had an unresectable carcinoma (R2M1 in two and R1 in two). Liver metastases were uncovered at surgery in one patient, gross peritoneal disease in one patient, and positive resection margins in two patients.

Two patients (7%) had no evidence of carcinoma in the surgical specimen (one patient had CCR, but the tumor was determined to be T3N0 on preoperative EUS staging, and one patient had a clinical minor response). Three patients had only microscopic residual carcinoma in the resected specimen. In 13 (48%) of 27 surgical specimens, lymph node metastases were present. Twelve specimens (44%) revealed a T3 carcinoma, seven (26%) revealed a T2 carcinoma, two revealed a T4 carcinoma, and one revealed a T1 carcinoma.

Correlation between CCR and surgical pathology. One of the five patients with CCR had no residual carcinoma (T0N0M0), one had only microscopic carcinoma ( 90% necrosis), and one had nodal metastases in the surgical specimen (also microscopic carcinoma).

Correlation between preoperative EUS and surgical pathology. In 13 patients, preoperative EUS could be correlated with surgical staging. Preoperative EUS accurately predicted final staging in only three instances, overpredicted the final stage in two instances, and underpredicted the final stage of the carcinoma in eight instances.

Survival and Patterns of Failure
The median duration of follow-up was 30 months (range, 5 to 65+ months) for this study. The median duration of follow-up for the 10 patients who survived was 50+ months (range, 36+ to 65+ months). The median survival time for all 30 patients, calculated by the Kaplan-Meier method, was 30 months (range, 5 to 65+ months) (Fig 1). Nineteen patients died of progressive carcinoma, and one patient who was without any evidence of carcinoma at the 20-month follow-up appointment died of unknown cause.

View larger version (9K): [in this window] [in a new window]   Fig 1. A plot of overall actuarial survival of all 30 patients calculated by the Kaplan-Meier method.

Ten patients (33%) remain alive, and nine remain free of disease at a median follow-up time of 50+ months (range, 36+ to 65+ months). Median survival duration for the 25 patients who had R0 resections was 40 months (range, 11 to 65+ months). Survival durations for the two patients who had R1 resections were 21 months and 31.5 months; however, the two patients with R2 resections had the worst survival duration (4.6 months and 5 months). One patient became inoperable (Table 2, patient no. 25; survival, 8 months). Comparative survival durations for patients with R0, R1, and R2 resections are shown in Fig 2.

View larger version (12K): [in this window] [in a new window]   Fig 2. A plot of overall actuarial survival of all 30 patients according to the type of resection performed and calculated by the Kaplan-Meier method.

To date, recurrences have been observed in 19 (65.5%) of 29 patients in whom resection was attempted. Initial sites of failure or persistent carcinoma are listed in Table 2.

Among the 13 patients whose carcinoma relapsed after R0 resection, 16 initial failure sites have been identified (Table 2), including nodal metastasis (local recurrence only) in 31% of patients, nodal plus distant metastasis in 23% of patients, peritoneum metastasis alone in 23% of patients, and distant metastasis only (liver, lung, and bone in 23% of patients).

Toxic Effects
There were no deaths associated with chemotherapy or surgery in this study.

Toxic effects from chemotherapy. Chemotherapy induced only modest myelosuppression in patients. The median nadir absolute granulocyte count was 17,500/µL (range, 100 to 15,500/µL). The median duration of myelosuppression was 9 days. The median nadir platelet count was 148,000/µL (range, 32,000 to 306,000/µL). Nonhematologic toxic effects are listed in Table 4. There were no cases of grade 4 toxicity. Major categories included nausea (grade 3 in one patient) and vomiting (grade 3 in three patients), fatigue (grade 3 in two patients), and diarrhea (grade 3 in two patients). Interferon-induced constitutional symptoms were frequent.

Surgical complications. Major surgical complications were observed in seven patients. Severe reflux esophagitis occurred in one patient. Intra-abdominal abscesses that required a drainage procedure occurred in two patients. Acute reversible tubular necrosis attributable to postoperative sepsis occurred in one patient. Reversible acute respiratory distress syndrome occurred in one patient, and postoperative pneumonia developed in one patient. One patient required re-exploration of the abdominal incision for suspected abscess formation.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The patient care study by the American College of Surgeons was revealing.⁴ In this retrospective review of the medical records of several thousand patients, it was demonstrated that 1,100 patients who had stage II carcinoma had a 5-year survival rate of 29%. Additionally, approximately 2,300 patients with stage III carcinoma had a 5-year survival rate of 13%. Among 13,295 patients examined, only 3,044 had an R0 resection (29%). Obviously, this is a biased figure and might have resulted from minimal or no clinical staging as well as the previously common practice of surgical palliation in clearly unresectable situations. The high rate of local-regional relapse (41%) in patients who underwent R0 resection deserves mention. These statistics support a consideration for an alternate strategy in patients with local-regional gastric carcinoma.

Additional staging of gastric carcinoma with laparoscopy is being widely considered as a useful tool for peritoneal staging. At our institution, all operable patients with local-regional gastric carcinoma undergo a laparoscopic evaluation before laparotomy. This approach permits better selection of patients. Laparoscopy may be more justifiable in the group of patients who participate in the preoperative therapy studies; however, its routine use and the costs involved need further discussion. EUS helps in defining T and N stages, but it is not the standard of care and does not yet help in the therapeutic decision-making process. However, the usefulness of EUS in proper selection of patients in preoperative therapy studies cannot be denied. In our study, 90% of patients who had an EUS performed before therapy had either a T3 or N1 carcinoma. Intriguingly, EUS was able to assess downstaging after preoperative chemotherapy; only 57% of patients had either a T3 or N1 carcinoma. However, the correlation between preoperative EUS and surgical pathology was disappointing; surgical pathology was accurately predicted in only three (13%) of 13 instances. In eight of 13 instances, EUS underpredicted the final stage of the carcinoma. Kelsen et al²³ have reported similar results. Our hypothesis is that physical distortion in the bowel wall caused by carcinoma is not restored despite treatment-induced death and resorption of carcinoma, thus resulting in discordance. We are conducting additional studies to further clarify this type of correlation.

Tolerance to preoperative chemotherapy was excellent in our study; dose reductions were required in only 5.5% of 108 courses. In our first study,¹⁶ six of 19 patients either refused or were intolerant to postoperative chemotherapy. In our second study,¹⁷ 77% of patients required dose reduction for postoperative therapy, and six patients either refused or were intolerant to postoperative chemotherapy. Thus we believe that administering all intended therapy preoperatively is a feasible strategy and may even be a desirable approach, because dose reductions and poor tolerance are common after surgery. We documented five CCRs, and among these, one patient had a pathCR and two additional patients had a pathologic partial response ( 90% necrosis). Our numbers here are small, but our next study²⁴ is likely to provide a larger number of patients for further examination of this issue. In the current study, the R0 resection rate was achieved in 83% of patients, and the median duration of survival for all 30 patients was 30 months. These numbers are higher than we have ever reported. We attribute this to better patient selection as a result of enhanced staging. Any contribution of prolonged preoperative therapy would be speculative because of the phase II nature of the current trial. At present, we are uncertain of the value of CCR in this group of patients; however, all five patients who achieved CCR received five courses of preoperative chemotherapy; seven of 10 patients who are still alive received five courses of preoperative chemotherapy, and the median survival duration for the 14 patients who received five courses of preoperative chemotherapy was 36+ months (range, 14 to 65+ months). In an analysis of outcome in 83 patients from our institution, the degree of response correlated with survival.²⁵

One major goal of preoperative therapy in patients with local-regional gastric carcinoma is to substantially improve the R0 resection rate. The current strategy allowed 83% of patients to have an R0 resection. The median survival duration for this group was 40 months. We acknowledge, however, that only properly designed randomized controlled trials can demonstrate the value of preoperative therapy in patients with gastric carcinoma. Two suboptimally designed randomized studies have been reported,^26,27 and another study is currently underway in Europe.

Preoperative strategies have not only emphasized attempts to reduce the bulk of the primary tumor to achieve a higher R0 resection rate, but also have attempted to address the treatment of carcinoma noted in the failure patterns.^23,24,28 In the current study, at a median follow-up of more than 30 months, initial local/nodal-only failure occurred in 31% of patients and peritoneal-only failure occurred in 23% of patients. Thus we have already launched a multi-institutional trial using preoperative chemoradiotherapy in this group of patients with the hope of reducing the incidence of local/nodal-only relapses.²⁴

The strategy of preoperative chemotherapy combined with adjuvant intraperitoneal fluoropyrimidine plus cisplatin has been emphasized by two groups.^23,28 In one study,²⁸ 38 patients received two courses of preoperative chemotherapy followed by surgery. Patients who had an R0 resection received intraperitoneal chemotherapy. Enhanced staging was not used in this study; however, similar to the current study, three patients (8%) had a pathCR. In another study,²³ 56 patients received three courses of preoperative chemotherapy followed by surgery. Patients who had an R0 resection received intraperitoneal chemotherapy. Although laparoscopy was not used for patient selection in this study, EUS performed at various times during therapy was reported in 22 patients. Similar to our results, poor concordance between preoperative EUS and surgical pathology was reported. The authors also felt that the intraperitoneal approach was useful and needed to be pursued further. This strategy of preoperative chemotherapy followed by intraperitoneal therapy is now being pursued further in a multi-institutional setting.

A logical multimodality treatment approach for patients with local-regional gastric carcinoma could easily fail because of ineffective and sometimes toxic components. In this regard, highly effective combination chemotherapy for gastric carcinoma is yet to be defined. Many new agents used alone and in various combinations in early trials have shown promise²⁹; however, these drugs need investigation in the preoperative setting and also in combination with radiotherapy. Thus preoperative or postoperative adjuvant therapy has no proven value and remains a subject of active investigation.

	ACKNOWLEDGMENTS

 
Supported in part by a grant from Schering-Plough Corporation, NJ, and the Caporella Family Fund

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Submitted December 28, 1998; accepted April 9, 1999.

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