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10.1245/s10434-006-9069-x
Annals of Surgical Oncology 13:1372-1378 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Bleeding, Obstruction, and Perforation in a Series of Patients With Aggressive Gastric Lymphoma Treated With Primary Chemotherapy

Galia Spectre, MD1, Diana Libster, MD1, Sigal Grisariu, MD1, Nael Da’as, MD4, Dina Ben Yehuda, MD1, Zvi Gimmon, MD2 and Ora Paltiel, MDCM1,3

1 Department of Hematology, Hadassah Hebrew University Medical Center, P.O. Box 12000, Jerusalem, Israel 91120
2 Department of Surgery, Hadassah Hebrew University Medical Center, P.O. Box 12000, Jerusalem, Israel 91120
3 School of Public Health, Hadassah Hebrew University Medical Center, P.O. Box 12000, Jerusalem, Israel 91120
4 Department of Internal Medicine, Hematology Unit, Bikur Cholim Hospital, Jerusalem, Israel

Correspondence: Address correspondence and reprint requests to: Galia Spectre, MD; E-mail: galia.spectre{at}gmail.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The management of patients with gastric lymphoma has evolved, with a shift toward nonsurgical treatment. The rates of surgical complications in patients receiving chemotherapy have been insufficiently studied. The objective of this study was to assess the frequency of bleeding, perforation, and gastric outlet obstruction in patients who received chemotherapy as primary treatment for gastric diffuse large B cell lymphoma (DLBCL).

Methods: We reviewed files of all patients with gastric DLBCL who were diagnosed and treated primarily with chemotherapy in our hospital between 1990 and 2005.

Results: Eighteen (25%) of 73 patients experienced surgical complications, of whom 6 (8%) underwent surgery. Eight patients (11%), six with active lymphoma, experienced gastric bleeding; one required gastrectomy. Eight patients (11%) developed gastric outlet obstruction, of whom three were treated conservatively, three required surgery, one stopped treatment, and one received further chemotherapy. Six of the eight patients had no evidence of active lymphoma at the time of obstruction. Two additional patients underwent gastrectomy due to resistant or relapsed disease. Gastric perforation was not observed. Median survival was 90 months for the entire series, 94 months for patients with gastric outlet obstruction, and 11.5 months for patients with gastric bleeding.

Conclusions: Given the rate of surgical complications, especially gastric bleeding and gastric outlet obstruction, there is still an important role for the surgical consultant in the treatment of patients with gastric DLBCL receiving chemotherapy. Gastric perforation, although frequently cited as a complication, is in fact rarely observed.

Key Words: Gastric • Diffuse large B cell lymphoma • Chemotherapy • Surgical complications


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The stomach is the most common extranodal site for lymphoma.1 Diffuse large B cell lymphoma (DLBCL) may arise from mucosa associated lymphoid tissues (MALT) lymphoma or as a primary tumor and is the most common histological subtype.2 The presence of reactive lymphoid follicles and lymphoepithelial lesions is suggestive of transformation of MALT lymphoma to DLBCL. However, in the absence of these lesions, the tumor may be histologically and cytologically indistinguishable from DLBCL arising at nodal sites.3

Controversy in the literature remains regarding the optimal treatment for early stages of gastric lymphoma. Historically, surgery was the initial and sole therapy for these tumors. Despite increasing evidence supporting treatment that is based on systemic multiagent chemotherapy,4–7 some centers continue to operate in early-stage gastric lymphoma.8–11 Complications of gastrectomy are both short- and long-term and include early satiety, abdominal discomfort, afferent loop syndrome, malabsorption, and dumping syndrome.12–14

However, surgical complications also occur in patients receiving chemotherapy. The rate of these complications is underreported in the literature. In the era of evidence-based medicine, treatment decisions should be made on the basis of the best available evidence. Recently a large prospective randomized controlled clinical trial established that chemotherapy is essential in the treatment of the early stages of the disease, and not only in advanced stages, because patients who did not receive chemotherapy had a far lower event-free survival and overall survival compared with those who did receive chemotherapy.14 In that study, only fatal complications were reported. The aim of the current study was to assess the frequency of bleeding, perforation, and gastric outlet obstruction in patients with gastric DLBCL who received chemotherapy as the primary treatment for their disease.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
We retrospectively analyzed files of all patients with gastric lymphoma who were treated in our hospital from 1990 to 2005. Only patients with DLBCL (World Health Organization classification) or transformed lymphoma were included. We included all patients with stage I to IV disease.15 Computed tomographic scan, gallium or positron emission tomography (PET) scans, bone marrow examinations, and, for some cases, endoscopic ultrasound were used for staging. Patients with primary gastric lymphoma, recurrent disease, or transformed lymphoma were included in the study.

Surgical complications were defined as bleeding (melena or hematemesis that occurred during chemotherapy treatment and required hospital monitoring and blood transfusions); gastric perforation; and gastric outlet obstruction resulting in symptoms of early satiety, eating difficulty, or vomiting, and proven by endoscopy and upper gastrointestinal imaging.

Response to therapy was assessed with diagnostic procedures such as computed tomography, endos-copy with biopsies, and gallium and PET scans. If a residual mass was noted but biopsy findings were negative, and gallium or PET scans were also negative, the patient was considered to be in remission.

We compared the frequencies of categorical variables for patients with and without surgical complications by {chi}2 test, or by Fisher’s exact test when expected cell size was <5 observations. Overall survival for the whole group and subgroups with complications were compared by the Kaplan-Meier method. All analyses were performed by SAS software, version 9.1 (SAS Institute, Cary, NC).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
During the study period, 87 patients were diagnosed with gastric DLBCL, of whom 73 were initially treated with chemotherapy and were eligible for evaluation of surgical complications. The remaining 14 patients underwent gastrectomy or irradiation, or died before treatment could be initiated.

Characteristics of the 73 patients are listed in Table 1Go. There was a male predominance. The most frequent presenting symptoms were abdominal pain, weight loss, and bleeding. The majority of patients presented with stage I or II disease and low or low-intermediate International Prognostic Index.16 The majority, 66 (90%), had primary DLBCL or DLBCL arising in a MALT background.


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  		TABLE 1. Patient characteristics
 
Chemotherapy regimens used were mainly CHOP (cyclophosphamide, Adriamycin, vincristine and prednisone) or CHOP-like regimens with the addition of rituximab in patients treated since 2002.

Treatment Outcome
Complete remission (CR) was achieved in 45 (62%) of 73 patients, 5 of whom experienced relapse between 8 months and 5 years after diagnosis (median, 3 years). Eight patients (11%) achieved only partial response with chemotherapy, four of them attained CR after salvage chemotherapy, autologous bone marrow transplantation, and/or radiation therapy, and four died. Disease progression or failure to respond to treatment was observed in 15 patients (20%); 14 of these patients died, and only 1 patient who underwent gastrectomy and completed the chemotherapy after surgery is alive and free of disease 3 years after diagnosis. In five patients, data regarding response to treatment are missing, or the response could not be determined as a result of early death or stopping the treatment.

Overall survival was 62% with median time of follow-up of 3 years (range; 5–11 years). Median survival for all patients was 90 months (95% confidence interval [95% CI], 21–120 months). Treatment-related mortality was 1% (one patient, an 80-year-old woman who died of neutropenia and respiratory failure after her first course of chemotherapy).

Surgical Complications
Surgical complications occurred in 18 (25%) of 73 patients during the course of their treatment.

Gastric Bleeding
Eight patients developed gastric bleeding during chemotherapy treatment; in six patients, bleeding was already present before chemotherapy was initiated as a presenting symptom of their disease (Table 2Go). Two patients were treated conservatively with blood transfusions and continued chemotherapy, and they stopped bleeding. One patient continued irradiation and experienced further bleeding. Two patients did not respond to conservative treatment; one underwent angiography with embolization, and the other underwent a subtotal gastrectomy. Pathology of the stomach confirmed the presence of active DLBCL (CD20 positive), which penetrated the gastric wall and reached to the surrounding fat. In three patients, treatment was stopped as a result of bleeding, evidence of active disease, and poor performance status. Six of eight patients had clear evidence of active lymphoma at the time of bleeding. Of these eight patients, five have died from active disease.


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  		TABLE 2. Patients with gastric bleeding
 
The two patients who were treated invasively by angiography or gastrectomy are alive and free of disease 2 and 4 years after diagnosis, respectively. The eighth patient experienced a late relapse (5 years) of lymphoma in the adrenal and underwent autologous stem cell transplantation but failed to achieve complete remission. Factors associated with developing gastric bleeding during chemotherapy were evidence of bleeding before treatment (P = .01) and hemoglobin levels less than 12 g/dL at admission (P = .004). Age, sex, International Prognostic Index, stage, lactate dehydrogenase (LDH), or the years of presentation were not associated with increased risk of bleeding. Median survival of patients with gastric bleeding was 11.5 months (95% CI, 5–{infty}).

Gastric Outlet Obstruction
Eight patients had gastric outlet obstruction (Table 3Go). Six of these patients had antral involvement at the time of diagnosis. Gastric outlet obstruction occurred between the second and eighth course of chemotherapy treatment (median, fourth treatment). Three patients were treated conservatively with nasogastric tube drainage and total parenteral nutrition. Three patients required surgery after conservative treatment failed; of these, two underwent total gastrectomy between chemotherapy courses and had a long delay of 3 months in chemotherapy treatment. The third underwent gastrojejunostomy 3 years after completion of treatment. All three patients who underwent surgery had no evidence of active lym-phoma in the pathology specimens, but rather tumor necrosis, inflammation, and fibrous reaction. One was treated with irradiation and further chemotherapy, and one stopped treatment. Six of eight patients had no evidence of active lymphoma at the time of gastric outlet obstruction.


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  		TABLE 3. Patients with gastric outlet obstruction
 
Five of eight patients with gastric outlet obstruction are in CR between 1.5 and 6 years after the diagnosis of lymphoma. Two patients with evidence of active lymphoma at the time of obstruction died from active disease, and one other patient died from obstructive jaundice and sepsis while in CR 8 years after diagnosis. (Of note, during the study period, an additional patient, who was not included in the series, was referred to our hospital for an operation because of gastric outlet obstruction after four courses of CHOP. Analysis of gastric biopsy samples showed fibrosis with no evidence of active lymphoma, and she was successfully treated with recurrent pneumatic dilatation).

Morbidity in patients who developed gastric outlet obstruction was marked. Patients were hospitalized for periods of weeks with a nasogastric tube. One patient experienced recurrent vomiting and weight loss for 3 years after treatment for lymphoma until a gastroenterostomy was performed. One of three patients in whom conservative treatment was successful still has a partial obstruction.

None of the baseline variables (age, sex, International Prognostic Index, stage, hemoglobin, prior bleeding, LDH, year of presentation, or antral disease) was associated with increased risk for developing gastric outlet obstruction in our patients. The median survival of patients with gastric outlet obstruction was 94 months (95% CI, 14–94 months), similar to the survival of the entire series.

Other Surgical Complications
Two additional patients underwent gastrectomy, one for resistant disease and one for relapsed disease. Gastric perforation was not observed in any of the patients. Overall, 6 (8%) of 73 patients eventually required gastric surgery, of whom 3 are alive and free of disease, 1 died of lymphoma, and 2 died from other causes while in remission from lymphoma.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
In the past 15 years, most patients with primary gastric DLBCL treated at our institution were primarily treated by chemotherapy. We noticed that a number of patients develop gastric bleeding or obstruction during or after chemotherapy treatment. The data in the literature regarding these types of complications are few. Series reporting complications are often small or combine different histologies.5,17–19 Some large series did not report complications in detail, or reported only fatal complications.7,14,17 Notably, the recently published large clinical trial of patients with gastric lymphoma by Aviles et al.14 has been criticized for not reporting data regarding the frequencies of acute toxicities and surgical complications in patients who received chemotherapy.20

Surprisingly, gastric outlet obstruction as a result of chemotherapy treatment was not reported in any of the studies to date. A summary of the data found in the literature regarding the rate of bleeding, perforation, and gastric outlet obstruction in patients with large cell gastric lymphoma primarily treated with chemotherapy is listed in Table 4Go. Only studies that reported more than 20 patients were included.


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  		TABLE 4. Summary of studies reporting surgical complications in patients with large cell gastric lymphoma receiving chemotherapya
 
In the current study, a careful retrospective analysis of data of 73 patients with large cell lymphoma treated primarily with chemotherapy reveals a rate of 25% of surgical complications during or after chemotherapy treatment. The patient characteristics (Table 1Go) resemble those of a larger series and therefore may be considered representative of patients with gastric lymphoma.2

Gastric perforation did not occur in our patients. We thus conclude that this is a rare complication in practice in patients receiving chemotherapy, although it is frequently cited as a caveat in the treatment of these patients.21,22 This observation is in agreement with previous reports in the literature (Table 4Go).

Bleeding and gastric outlet obstruction, however, were observed much more frequently (each occurring in 11% of the patients). In most cases with surgical complications, the hematologists requested the assistance of the surgical consultants regarding the management of these patients. Indeed, 31% f patients with surgical complications eventually required an invasive intervention (surgery or angiography), whereas the others were managed without surgery.

Most of the patients who bled during chemotherapy had also bled as a presenting symptom of their disease. Bleeding occurred relatively early in the chemotherapy course or at the time of disease progression. Bleeding was usually indicative of active lymphoma or an adverse response to chemotherapy. Thus, the prognosis of this group of patients was usually poor, and gastric bleeding during treatment may be considered a risk factor for poor prognosis in DLBCL.

In contrast, most of the patients with gastric outlet obstruction had no evidence of active lymphoma at the time of obstruction. Gastric outlet obstruction occurred relatively late during chemotherapy (median, four courses) usually as a result of healing, scarring, and fibrosis at the site of the initial tumor, as can be seen in some of the pathology reports (Table 3Go). Survival in patients experiencing gastric outlet obstruction was equal to patients without surgical complications, and marginally better compared with patients with gastric bleeding (Fig. 1Go). The P value shows borderline significance (P = .09), but in a small study such as ours with a high probability of a type II error, trends may provide preliminary clues to true differences. Gastric outlet obstruction was associated with marked adverse impact on quality of life, often for the long term. Surprisingly, reports of gastric outlet obstruction are lacking from the studies reporting surgical complications (Table 4Go).


Figure 1
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  		FIG. 1. Overall survival for patients with and without surgical complications. Dx, diagnosis; LFU, lost to follow-up. *Comparison of 3 curves, log rank P value = .09.

 
Although chemotherapy is a primary mode of treatment for aggressive lymphomas, there is still a major role for the surgical consultant in the treatment of these patients. Gastric bleeding portends active disease. Gastric perforation is a rare complication, but gastric outlet obstruction is not an uncommon outcome in this patient population and is observed in patients whose disease responds to chemotherapy. The latter finding necessitates further attention and cooperation between hematologists and medical oncologists, and their surgical colleagues.

Received for publication June 27, 2006. Accepted for publication June 28, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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