Annals of Oncology Advance Access originally published online on October 19, 2007
Annals of Oncology 2007 18(12):2006-2008; doi:10.1093/annonc/mdm357
© 2007 European Society for Medical Oncology
gastrointestinal tumors |
Systemic chemotherapy does not increase the risk of gastrointestinal perforation
Memorial Sloan Kettering Cancer Center, New York, USA
* Correspondence to: Dr Manish A. Shah, Memorial Sloan Kettering Cancer Center, Gastrointestinal Oncology, 1275 York Avenue, Howard 910, New York, NY, 10021, USA. Tel: +1–212–639–3113; Fax: +1–212–717–3342; E-mail: Shah1{at}mskcc.org.
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Abstract |
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Background: Gastrointestinal perforation is a rare complication of gastric cancer. Although there is the perception of chemotherapy aggravating the perforation risk, the rate of perforation in patients with gastric cancer receiving chemotherapy is unknown. This study describes the incidence and clinical course of patients with gastric or gastroesophageal junction (GEJ) carcinoma who experience a perforation while receiving chemotherapy.
Patients and methods: The records of patients with gastric or GEJ adenocarcinoma over a 6-year period who received chemotherapy for locally advanced or metastatic disease were reviewed. Extracted information included demographics, treatment received, and overall survival was calculated.
Results: 1032 patients at MSKCC received systemic cytotoxic chemotherapy for locally advanced or metastatic gastric or GEJ carcinoma; 11 patients experienced a perforation (1.1%, 95% CI 0.5–1.9%); 5/11 (45%) patients received further chemotherapy and had a median survival of 5.6 months.
Conclusions: The rate of perforation in patients with advanced GEJ/gastric adenocarcinoma receiving chemotherapy is 1.1%, which is the same rate as in surgical series of patients presenting with perforation. Chemotherapy does not significantly add to the risk of gastrointestinal perforation.
Key words: gastric /gastroesophageal adenocarcinoma, preoperative chemotherapy, perforation, surgery
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introduction |
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Gastrointestinal perforation from a primary gastric carcinoma is a rare but serious event associated with substantial morbidity and mortality. One concern regarding the strategy of preoperative chemotherapy for gastric cancer is a perceived increased risk of perforation related to chemotherapy. However, to our knowledge, the rate of perforation while receiving systemic chemotherapy is unknown. The current literature describes patients with gastric cancer who present with an acute gastrointestinal perforation, having an incidence of 0.4–4% [1–4]. Reports of gastric perforation while receiving systemic therapy have been confined to one case described by Sarela et al. [5] and the two cases reported by us [6]. The perforations in our study occurred while cytotoxic chemotherapy was administered with the angiogenesis inhibitor, bevacizumab, which is known to be associated with intestinal perforation in its own right, although the incidence appears to be low [7].
Since preoperative chemotherapy is being used more often, to a large extent because of the survival advantage reported in the MAGIC trial [8], we performed the current study to examine the incidence of perforation in patients with gastric/gastroesophageal junction (GEJ) adenocarcinoma receiving palliative systemic therapy and to describe their clinical course.
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methods |
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We reviewed the records of all patients with gastric/GEJ carcinoma referred to MSKCC between January 1, 2000 and October 1, 2006 and who developed a perforation while receiving chemotherapy. A waiver of authorization was obtained from the MSKCC institutional review board. We queried all MSKCC patients with a diagnosis of abdominal perforation, gastrointestinal hemorrhage, enteric fistula, as well as the location of the perforation, demographics, date of diagnosis, stage, pathologic diagnosis, medical and surgical therapy and date of death or last follow-up. Patients were excluded if they received bevacizumab.
The Kaplan–Meier method was used to estimate the overall survival (defined as the time from start of chemotherapy to death or last follow-up) and the time from perforation to death or last follow-up. Survival curves were compared using the permutation log-rank test [9]. P-values <0.05 were considered statistically significant. Exact 95% confidence intervals were provided for proportions. All statistical analyses were performed using SAS 9.1.
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results |
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patient characteristics
A total of 2053 cases of gastric and GEJ cancers (1918 adenocarcinoma, 132 squamous cell, and three neuroendocrine carcinomas) were referred to MSKCC from January 1, 2000 to October 31, 2006, of whom 1032 patients received systemic cytotoxic chemotherapy at MSKCC for locally advanced or metastatic disease (Table 1). Eleven patients developed a gastrointestinal perforation while receiving chemotherapy (1.1%, 95% CI 0.5–1.9%). The median time from start of chemotherapy to perforation was 3.4 months (range 0.03– 19.6 months), and the median survival following perforation was 2.8 months (95% CI 0.8–9.4 months). The majority of patients with perforation had poorly differentiated adenocarcinoma (Table 2). Six patients (54%) received cisplatin/irinotecan, three patients received a docetaxel-containing regimen, one patient each received a mitomycin- or capecitabine-based therapy at the time of perforation.
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management
The primary tumor (e.g. stomach or GEJ) was the site of perforation in five patients, the small or large bowel in four patients, and was not established in two patients. Four of the five patients who developed a perforation at the primary tumor underwent a total or subtotal gastrectomy to resect the tumor and correct the perforation. The remaining patients were managed with supportive measures: diversion (n = 2), palliative drainage (n = 3), and IV fluids and antibiotics (n = 2). We describe three colonic perforations. In one case (#11), the perforation was associated with peritoneal disease identified at exploration. In the other two cases, the perforation occurred within 2 months of chemotherapy, following resection for locally advanced disease. The etiology was not established, although it was felt not to be related to the recent surgery.
Five patients (45%) received further chemotherapy following the perforation, beginning at 1.4 months (range 1.3–3.6 months). For this group, median survival was 5.6 months (95% CI 2.73–not reached), whereas the median survival for those patients who did not receive further systemic therapy was 1.7 months (95% CI 0.7–2.8 months, permutation log-rank test P = 0.2).
discussion
Gastrointestinal perforation is a rare but serious adverse event for any patient, and is particularly worrisome for patients with cancer receiving immunosuppressive cytotoxic therapy. The risk of presenting with a perforation for patients with gastric/GEJ carcinoma is low, estimated at 0.4%–4% [1–3]. In this retrospective analysis, we report that the risk of developing a gastrointestinal perforation while on chemotherapy is equally low at 1.1% (95% CI 0.5–1.9%).
Perforation rates were not reported in several recent, large random assignment studies [8,10,11], either because they did not occur or because their incidence was below reporting threshold. In both recent random assignment studies evaluating docetaxel-based combination therapies for advanced gastric and GEJ carcinoma, although no perforations were reported, the authors did report a 10% rate of death within 30 days of chemotherapy [10,11]. The majority of these deaths were not attributed to chemotherapy. In the recent MAGIC study evaluating pre- and postoperative chemotherapy for localized gastric cancer, no perforations were reported [8] because none were observed (personal communication, David Cunningham). These data would suggest that the true rate of perforation with chemotherapy is indeed exceedingly low, thus supporting our own findings of a rate of 1.1%. However, we note that our observed rate may be an underestimation of the true incidence in this population because it reflects a retrospective analysis of patients who presented to a single large, comprehensive cancer center and who continued to receive their care at that center.
In this retrospective analysis, we demonstrate that gastrointestinal perforation during palliative chemotherapy occurs at the same rate as in surgical series of patients who did not receive chemotherapy prior to presenting with perforation. Thus, it is unlikely that cytotoxic chemotherapy adds significantly to the risk of perforation. Two of the perforations of the colon were not clearly associated with malignancy or with treatment. The occurrence of colonic perforation has been previously reported during chemotherapy or during corticosteroid use, due to possible impaired reparative activity within the bowel wall [12]. There is an established 1–2% rate of intestinal perforation with the use of bevacizumab; however, it is not clear that bevacizumab increases the rate of gastric perforation. Additional patient data, or a random assignment study, will be required to conclusively establish the potential increase in risk of perforation with angiogenesis inhibition in this population. These results further support a strategy of systemic neoadjuvant chemotherapy prior to surgery for localized gastric cancer, as the risk of perforation does not appear to increase with chemotherapy.
Received for publication May 15, 2007. Revision received June 8, 2007. Revision received June 12, 2007. Accepted for publication June 13, 2007.
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References |
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