Patrick M. Lynch

THE EFFECT OF CELECOXIB, A CYCLOOXYGENASE-2 INHIBITOR, IN FAMILIAL ADENOMATOUS POLYPOSIS

BACKGROUND Patients with familial adenomatous polyposis have a nearly 100 percent risk of colorectal cancer. In this disease, the chemopreventive effects of nonsteroidal antiinflammatory drugs may be related to their inhibition of cyclooxygenase-2. METHODS We studied the effect of celecoxib, a selective cyclooxygenase-2 inhibitor, on colorectal polyps in patients with familial adenomatous polyposis. In a double-blind, placebo-controlled study, we randomly assigned 77 patients to treatment with celecoxib (100 or 400 mg twice daily) or placebo for six months. Patients underwent endoscopy at the beginning and end of the study. We determined the number and size of polyps from photographs and videotapes; the response to treatment was expressed as the mean percent change from base line. RESULTS At base line, the mean (+/-SD) number of polyps in focal areas where polyps were counted was 15.5+/-13.4 in the 15 patients assigned to placebo, 11.5+/-8.5 in the 32 patients assigned to 100 mg of celecoxib twice a day, and 12.3+/-8.2 in the 30 patients assigned to 400 mg of celecoxib twice a day (P=0.66 for the comparison among groups). After six months, the patients receiving 400 mg of celecoxib twice a day had a 28.0 percent reduction in the mean number of colorectal polyps (P=0.003 for the comparison with placebo) and a 30.7 percent reduction in the polyp burden (the sum of polyp diameters) (P=0.001), as compared with reductions of 4.5 and 4.9 percent, respectively, in the placebo group. The improvement in the extent of colorectal polyposis in the group receiving 400 mg twice a day was confirmed by a panel of endoscopists who reviewed the videotapes. The reductions in the group receiving 100 mg of celecoxib twice a day were 11.9 percent (P=0.33 for the comparison with placebo) and 14.6 percent (P=0.09), respectively. The incidence of adverse events was similar among the groups. CONCLUSIONS In patients with familial adenomatous polyposis, six months of twice-daily treatment with 400 mg of celecoxib, a cyclooxygenase-2 inhibitor, leads to a significant reduction in the number of colorectal polyps.

Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications

More than one million patients will manifest colorectal cancer (CRC) this year of which, conservatively, approximately 3% (∼30,700 cases) will have Lynch syndrome (LS), the most common hereditary CRC predisposing syndrome. Each case belongs to a family with clinical needs that require genetic counseling, DNA testing for mismatch repair genes (most frequently MLH1 or MSH2) and screening for CRC. Colonoscopy is mandated, given CRCs proximal occurrence (70–80% proximal to the splenic flexure). Due to its early age of onset (average 45 years of age), colonoscopy needs to start by age 25, and because of its accelerated carcinogenesis, it should be repeated every 1 to 2 years through age 40 and then annually thereafter. Should CRC occur, subtotal colectomy may be necessary, given the marked frequency of synchronous and metachronous CRC. Because 40–60% of female patients will manifest endometrial cancer, tailored management is essential. Additional extracolonic cancers include ovary, stomach, small bowel, pancreas, hepatobiliary tract, upper uroepithelial tract, brain (Turcot variant) and sebaceous adenomas/carcinomas (Muir‐Torre variant). LS explains only 10–25% of familial CRC.

Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience

PURPOSE To evaluate the rates of tumor downstaging after preoperative chemoradiation for locally advanced rectal cancer. MATERIALS AND METHODS Preoperative chemoradiotherapy (CTX/XRT) that delivered 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2/day) was given to 117 patients. The pretreatment stage distribution, as determined by endorectal ultrasound (u), included uT2N0 in 2%, uT3N0 in 47%, uT3N1 in 49%, and uT4N0 in 2% of cases; endorectal ultrasound was not performed in 13% of cases (15 patients). Approximately 6 weeks after completion of CTX/XRT, surgery was performed. RESULTS The pathological tumor stages were Tis-2N0 in 26%, T2N1 in 5%, T3N0 in 21%, T3N1 in 15%, T4N0 in 5%, and T4NI in 1%; a complete response (CR) to preoperative CTX/XRT was pathologically confirmed in 32 (27%) of patients. Tumor downstaging occurred in 72 (62%) cases. Only 3% of cases had pathologic evidence of progressive disease. Pretreatment tumor size (< 5 cm vs. > or = 5 cm) was the only factor predictive of tumor downstaging (p < 0.04). A decrease of > 1 T-stage level was accomplished in 45% of those downstaged. Overall, a sphincter-saving (SP) procedure was possible in 59% of patients and an abdominoperineal resection (APR) was required in 41 % of cases. Factors predictive of SP included downstaging (p < 0.03), age > 40 years (p < 0.007), pretreatment tumor distance, 3 to 6 cm from the anal verge (p < 0.00001), tumor size <6 cm (p < 0.02), mobility (p < 0.004), tumor stage <T4 (p < 0.01), and uN negative (p < 0.008). SP was performed in 23 patients (72%) with a CR and in 48 (67%) of downstaged cases. Among the 69 tumors located < 6 cm from the anal verge, 29 (42%) were resected with a SP. The level of response was important for tumors located < 6 cm from the anal verge because a SP was performed in 9 of the 17 (53%) CRs in this group while only 20 of 52 patients (38%) had a SP when residual disease was present after CTX/XRT. For tumors located > 6 cm from the anal verge, SP was performed in 14 of the 15 (93%) patients with a CR and 32 of 33 (97%) of patients with residual disease (p < 0.00004). CONCLUSIONS Significant tumor downstaging results from preoperative chemoradiation allowing sphincter sparing surgery in over 40% of patients whose tumors were located < 6 cm from the anal verge and who otherwise would have required colostomy.

A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis

Background: Non-selective cyclooxygenase (COX) inhibitors (non-steroidal anti-inflammatory drugs) inhibit large bowel carcinogenesis in patients with familial adenomatous polyposis (FAP). Their role in the duodenum of these patients is less certain. The disease modifying activity of specific COX-2 inhibitors has not been explored in humans. Patients and methods: This was a randomised, double blind, placebo controlled study of celecoxib (100 mg twice daily (n=34) or 400 mg twice daily (n=32)) versus placebo (n=17), given orally twice daily for six months to patients with FAP. Efficacy was assessed qualitatively by blinded review of shuffled endoscopy videotapes comparing the extent of duodenal polyposis at entry and at six months and quantitatively by measurement of the percentage change in duodenal area covered by discrete and plaque-like adenomas from photographs of high and low density polyposis. Results: Shuffled and blinded video review showed a statistically significant effect of 400 mg twice daily celecoxib compared with placebo treatment (p=0.033) with all five independent observers scoring a beneficial effect. Overall, patients taking celecoxib 400 mg twice daily showed a 14.5% reduction in involved areas compared with a 1.4% for placebo (p=0.436). However, patients with clinically significant disease at baseline (greater than 5% covered by polyps) showed a 31% reduction in involved areas with celecoxib 400 mg twice daily compared with 8% on placebo (p=0.049). Conclusions: A panel of five endoscopists found a significant reduction in duodenal polyposis after six months of treatment with celecoxib 400 mg twice daily. COX-2 inhibition may help this otherwise untreatable condition.

Preoperative infusional chemoradiation therapy for Stage T3 rectal cancer

PURPOSE To evaluate preoperative infusional chemoradiation for patients with operable rectal cancer. METHODS AND MATERIALS Preoperative chemoradiation therapy using infusional 5-fluorouracil (5-FU), (300 mg/m2/day) together with daily irradiation (45 Gy/25 fractions/5 weeks) was administered to 77 patients with clinically Stage T3 rectal cancer. Endoscopic ultrasound confirmed the digital rectal exam in 63 patients. Surgery was performed approximately 6 weeks after the completion of chemoradiation therapy and included 25 abdominoperineal resections and 52 anal-sphincter-preserving procedures. RESULTS Posttreatment tumor stages were T1-2, N0 in 35%, T3 N0 in 25%, and T1-3, N1 in 11%; 29% had no evidence of tumor. Local tumor control after chemoradiation was seen in 96% (74 out of 77); 2 patients had recurrent disease at the anastomosis site and were treated successfully with abdominoperineal resection. Overall, pelvic control was obtained in 99% (76 out of 77). The survival after chemoradiation was higher in patients without node involvement than in those having node involvement (p = n.s.). More patients with pathologic complete responses or only microscopic foci survived than did patients who had gross residual tumor (p = 0.07). The actuarial survival rate was 83% at 3 years; the median follow-up was 27 months, with a range of 3 to 68 months. Acute, perioperative, and late complications were not more numerous or more severe with chemoradiation therapy than with traditional radiation therapy (XRT) alone. CONCLUSIONS Excellent treatment response allowed two-thirds of the patients to have an anal-sphincter-sparing procedure. Gross residual disease in the resected specimen indicates a poor prognosis, and therapies specifically targeting these patients may improve survival further.

Multi-Institutional Trial of Preoperative Chemoradiotherapy in Patients With Potentially Resectable Gastric Carcinoma

PURPOSE In the West, curative (R0) resection is achieved in approximately 50% of patients with localized gastric carcinoma, and more than 60% die of cancer following an R0 resection. A multi-institutional study of preoperative chemoradiotherapy was done to assess the R0 resection rate, pathologic complete response (pathCR) rate, safety, and survival in patients with resectable gastric carcinoma. PATIENTS AND METHODS Operable patients with localized gastric adenocarcinoma were eligible. Staging also included a laparoscopy and endoscopic ultrasonography (EUS). Patients received up to two 28-day cycles of induction chemotherapy of fluorouracil, leucovorin, and cisplatin, followed by 45 Gy of radiation plus concurrent fluorouracil. Patients were then staged and surgery was attempted. RESULTS Thirty-four patients were registered at three institutions. One ineligible patient was excluded. Most patients had a promixal cancer and EUST3N1 designation. Twenty-eight (85%) of 33 patients underwent surgery. The R0 resection rate was 70% and pathCR rate was 30%. A pathologic partial response (< 10% residual carcinoma in the primary) occurred in eight patients (24%). EUS T plus N and postsurgery T plus N correlation showed significant downstaging (P = <.01). The median survival time for 33 patients was 33.7 months. Patients achieving a pathCR or pathPR had a significantly longer median survival time (63.9 months) than those achieving less than pathPR (12.6 months; P =.03). There were two treatment-related deaths. CONCLUSION Our data suggest that the three-step strategy of preoperative induction chemotherapy followed by chemoradiotherapy resulted in substantial pathologic response that resulted in durable survival time. This strategy is worthy of a direct comparison with postoperative adjuvant chemoradiotherapy.

Improved overall survival among responders to preoperative chemoradiation for locally advanced rectal cancer

The aim of this study was to determine if the response to preoperative radiation and chemotherapy with continuous infusion 5-fluorouracil (5-FU) was predictive for survival among patients with locally advanced rectal cancer. Preoperative chemoradiation (CTX/XRT) that delivered 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-FU (300 mg/m2/day) was given to 117 patients. The pretreatment stage distribution, as determined by endorectal ultrasound (u), included uT2N0 in 2%, uT3N0 in 47%, uT3N1 in 49%, and uT4N0 in 2% of cases; endorectal ultrasound was not performed in 13% of cases (15 patients). Approximately 6 weeks after completion of CTX/XRT, surgery was performed. Adjuvant chemotherapy, consisting of 400 to 425 mg/m2 of 5-FU plus 20 mg/m2 leucovorin for 5 days, was administered every 28 days for 4 to 6 cycles after surgical resection. Among the 74 patients treated with adjuvant chemotherapy, the preoperative stage of disease was 31 with T3N0 and 43 T3N1. Median follow-up was 46 months (range 2 to 89 months). The pathologic tumor stages were Tis-2N0 in 26%, T2N1 in 5%, T3N0 in 21%, T3N1 in 15%, T4N0 in 5%, and T4N1 in 1%; a complete response (CR) to preoperative CTX/XRT was pathologically confirmed in 32 (27%) of patients. Tumor down-staging occurred in 72 (62%) cases. A sphincter-saving procedure (SP) was possible in 59% of patients. The median DFS and overall survival rates for responders were 46 months and 47 months, respectively; for non-responders these outcome measures were 38 months and 41 months, respectively. Log-rank analysis showed that the distant metastatic-free survival rates improved with any response to CTX/XRT (p < 0.00001), CR to CTX/XRT (p < 0.009) and SP (p < 0.012). Likewise, these parameters also significantly influenced DFS rates (CTX/XRT p < 0.00001; CR p < 0.006; and SP p < 0.008). Control of pelvic disease was influenced by clinical size (p < 0.002) and SP (p < 0.016) on univariate analysis. On multivariate analysis only clinical size (p < 0.002) continued to be a significant factor for local control. Factors on multivariate analysis that resulted in significant improvements in cancer-specific survival included any response to preoperative CTX/XRT (p < 0.017) and administration of adjuvant chemotherapy (p < 0.034). Any response to preoperative CTX/XRT improved distant metastatic-free and disease-free survival rates. Multivariate analysis confirmed that a response to preoperative CTX/XRT predicted for improvements in overall survival among patients with locally advanced rectal cancer. Patients who fail to respond to preoperative 5-FU based chemotherapy given concomitantly with radiation have higher rates of distant metastases with adjuvant 5-FU therapy.

Gynecologic cancer as a sentinel cancer for women with hereditary nonpolyposis colorectal cancer syndrome

OBJECTIVE: Women with hereditary nonpolyposis colorectal cancer syndrome have a 40–60% lifetime risk for colon cancer, a 40–60% lifetime risk for endometrial cancer, and a 12% lifetime risk for ovarian cancer. A number of women with hereditary nonpolyposis colorectal cancer syndrome will have more than one cancer in their lifetime. The purpose of this study was to estimate whether women with hereditary nonpolyposis colorectal cancer syndrome who develop 2 primary cancers present with gynecologic or colon cancer as their “sentinel cancer.” METHODS: Women whose families fulfilled Amsterdam criteria for hereditary nonpolyposis colorectal cancer syndrome and who developed 2 primary colorectal/gynecologic cancers in their lifetime were identified from 5 large hereditary nonpolyposis colorectal cancer syndrome registries. Information on age at cancer diagnoses and which cancer (colon cancer or endometrial cancer/ovarian cancer) developed first was obtained. RESULTS: A total of 117 women with dual primary cancers from 223 Amsterdam families were identified. In 16 women, colon cancer and endometrial cancer/ovarian cancer were diagnosed simultaneously. Of the remaining 101 women, 52 (51%) women had an endometrial or ovarian cancer diagnosed first. Forty-nine (49%) women had a colon cancer diagnosed first. For women who developed endometrial cancer/ovarian cancer first, mean age at diagnosis of endometrial cancer/ovarian cancer was 44. For women who developed colon cancer first, the mean age at diagnosis of colon cancer was 40. CONCLUSION: In this large series of women with hereditary nonpolyposis colorectal cancer syndrome who developed 2 primary colorectal/gynecologic cancers, endometrial cancer/ovarian cancer was the “sentinel cancer,” preceding the development of colon cancer, in half of the cases. Therefore, gynecologists and gynecologic oncologists play a pivotal role in the identification of women with hereditary nonpolyposis colorectal cancer syndrome. LEVEL OF EVIDENCE: II-3

Antibiotic Treatment of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue: An Uncontrolled Trial

Gastric low-grade B-cell lymphoma is related to Helicobacter pylori infection according to histopathologic, epidemiologic, and clinical characteristics. Although normal gastric mucosa does not contain organized lymphoid tissue, lymphoid follicles develop with H. pylori infection (1) and with autoimmune diseases, such as the Sjgren syndrome (2). Low-grade B-cell lymphoma has been postulated to arise within this mucosa-associated lymphoid tissue (MALT) and is often called low-grade MALT lymphoma (3, 4). The incidence of gastric low- and high-grade MALT lymphoma is increased in populations with a high prevalence of H. pylori infection, and H. pylori infection has been reported in up to 90% of patients with low-grade MALT lymphoma (4-6). In addition, investigators have shown that growth of this tumor may depend on antigenic stimulation by H. pylori: They demonstrated that the proliferation of lymphoma B cells in cell culture can be stimulated by H. pylori-specific T cells and related cytokines in the presence of H. pylori (7). On the basis of these findings, trials of antibiotic treatment of gastric low-grade MALT lymphoma have been initiated, and the regression of lymphoma after cure of H. pylori infection has been reported in a high proportion of patients with low tumor burden (8-13). Data on patients with significant tumor infiltration are still forthcoming (13, 14). Because MALT lymphoma has only recently been approached as a distinct clinicopathologic entity (15, 16), its natural history and clinical course are not fully defined. Current data suggest that it is often an indolent tumor with long periods of mild activity and confinement to the stomach. Patients often present with nonspecific upper intestinal discomfort, ulcer-associated symptoms, or gastric bleeding. The endoscopic appearance may suggest benign gastritis, and extensive biopsies may be required for diagnosis. Progression to significant tumor mass, dissemination, or transformation to high-grade, aggressive lymphoma occur in an undefined subset of patients, who may present with early satiety or weight loss. Spontaneous remissions are rare (17-20). Because low-grade MALT lymphoma is an uncommon, often indolent form of cancer with few clinical findings and because the risk for progression to high-grade MALT lymphoma is still unknown (15, 16), definitive data on cure require long-term follow-up of large cohorts from standardized clinical trials. This report presents an interim analysis of an ongoing trial designed to determine the long-term response of low-grade gastric MALT lymphoma to antibiotic treatment and to define criteria for treatment and follow-up. Methods Patients Patients with gastric MALT lymphoma restricted to the stomach and perigastric lymph nodes (modified Ann Arbor stage I and II N1) were eligible for the study. The University of Texas, M.D. Anderson Cancer Center (MDACC), Internal Review Board approved the study, and all patients provided written informed consent. The National Cancer Institute and the institutional review boards of participating institutions approved the multi-institutional protocol. To enable a follow-up period of at least 18 months, only patients treated before May 1997 were included in this analysis. Study Design and Treatment The interim data are derived from an ongoing, prospective, uncontrolled treatment trial with third-party patient registry. Patients were studied at four participating centers. Pathologic diagnosis and resolution of MALT lymphoma were confirmed at MDACC, and all but one patient were examined endoscopically at MDACC. Study design included 1) tumor staging with bilateral bone marrow biopsies and aspirates and computed tomography of the abdomen and pelvis done at baseline and yearly; 2) endoscopy at baseline, at weeks 6 to 8, at 3- to 4-month intervals thereafter until resolution of MALT lymphoma was seen on two consecutive endoscopies, at 6-month intervals thereafter for 2 years, and then yearly thereafter; and 3) endoscopic ultrasonography at baseline and at each endoscopy until resolution of masses or infiltration of the muscularis propria, if present (defined as thickness>2 mm or obliteration of wall architecture), and then at 6- to 12-month intervals. The treatment protocol consisted of two of the following three oral antibiotic regimens1] amoxicillin, 750 mg three times daily, and clarithromycin, 500 mg three times daily; 2) tetracycline, 500 mg four times daily, and clarithromycin, 500 mg three times daily; or 3) tetracycline, 500 mg four times daily, and metronidazole, 500 mg three times dailyadministered sequentially for 21 days at baseline and at 8 weeks along with a proton-pump inhibitor (lansoprazole, 30 mg twice daily [n=29], or omeprazole, 20 mg twice daily [n=5]), and bismuth subsalicylate, two tablets four times daily. Patients who were allergic to penicillin received the tetracycline-based regimens. Tumor Staging Tumors were staged endoscopically to separate superficial gastritis from significant ulcers and infiltration and from mass lesions. A modified Ann Arbor staging system that incorporated changes proposed by Blackledge, Musshoff, and Rohatiner and their coworkers was used initially (21-23). The TNM (tumor, node, metastasis) classification of the American Joint Committee on Cancer and Union Internationale Contre le Cancer (24, 25), which corresponds to the modified Ann Arbor staging, was subsequently adapted and applied (Table 1). The extent of tumor (T) infiltration through the stomach wall and to adjacent organs corresponds to T staging of gastric cancer. Modified Ann Arbor stage I corresponds to stage I T1-4 N0 M0. Modified Ann Arbor stage II1 (22) (involvement of perigastric lymph nodes) corresponds to stage II T1-4 N1 M0. Modified Ann Arbor stage II2 (22) (involvement of distant lymph nodes caudal to the diaphragm, including para-aortic and retroperitoneal lymph nodes) corresponds to stage II T1-4 N2 M0. Ann Arbor stage III (lymph node involvement on both sides of the diaphragm) is designated by stage III T1-4 N3 M0. Ann Arbor stage IV (organ metastasis or involvement of a second extranodal site) is designated by stage IV T1-4 N0-3 M1. Table 1. Staging of Gastric Lymphoma of Mucosa-Associated Lymphoid Tissue Criteria for Response Response to treatment was evaluated at 3- to 4-month intervals beginning with the fifth month after treatment. Treatment was considered to have failed if patients did not meet criteria for improvement; these patients were removed from the study. In stage I T2, I T3, and II N1 tumors, improvement was defined as regression to a lower stage, 30% reduction in abnormal wall thickness, or 30% reduction in the size of the tumor mass (product of the greatest diameters). These patients remained in the study if sequential improvement was evident at each 3-month interval. Patients with persistent mucosal disease (stage I T1) documented by histopathology were formally reviewed at 12-month intervals; a consensus on withdrawal from or continuation in the study was based on clinical considerations, current knowledge, and patient preference. Initially, patients with persistent stage I T1 disease were withdrawn from the study at 12 months (n=2). Subsequently, patients with persistent stage I T1 disease were observed for more than 36 months if improvement was documented at 12-month intervals. Criteria for improvement in stage I T1 disease included reduction in the number of affected gastric sites or affected biopsy specimens or improved histologic score (8), endoscopic appearance of progressive atrophy and scarring, or resolution of abnormal wall thickness on endoscopic ultrasonography. Complete remission was defined as the absence of histopathologic evidence of lymphoma and an endoscopic appearance of gastritis or better. Partial remission was defined as a reduction in endoscopic stage in stage I T2 disease or at least 50% reduction in the size of the mass lesions in stage I T3 or II T3 N1 disease. In stage I T1 disease, partial remission was defined as at least 75% reduction in the number of gastric sites or biopsy specimens showing lymphoma. Treatment was considered to have failed in patients who met criteria for failure or who were withdrawn from the study before complete remission occurred. Endoscopy and Biopsies The gastric mapping protocol included 2 or more maximum-capacity biopsies from each of 7 to 12 areas of the gastric map (26) and at least 6 biopsies from 2 or more of the most abnormal areas. The more extensive mapping was done at baseline and at clinically relevant time points. Studies, done at defined intervals, included routine histopathology, H. pylori testing by Genta stain, rapid urease test (CLO-test, Delta West, Bentley, Australia) or serology, Southern blot or polymerase chain reaction (PCR) for immunoglobulin gene rearrangement analysis, and immunoglobulin light-chain immunocytochemistry. Diagnostic Criteria Low-grade B-cell MALT lymphoma was diagnosed by established histologic criteria [15, 27], including 1) a dense diffuse infiltrate of marginal-zone centrocyte-like B cells with round to slightly irregular nuclear contours, often with abundant pale cytoplasm; 2) presence of lymphoepithelial lesions, characterized by infiltration and disruption of gastric glands or crypts by groups of neoplastic lymphoid cells; and 3) absence of any areas where large cells predominate. Minor criteria supporting but not essential for diagnosis included presence of immunoglobulin light-chain restriction; presence of residual secondary follicle centers with or without intact mantles; and presence of follicular colonization, defined as replacement of follicle centers by neoplastic lymphoid cells. Immunophenotypic expression of pan-B-cell antigens, such as CD20, and lack of expression of CD5 or CD10 supported the diagnosis. Patients with foci of large-cell transformation were excluded from the study. Southern Blot and Polymerase Chain Reaction High-molec

Paclitaxel-Based Chemoradiotherapy in Localized Gastric Carcinoma: Degree of Pathologic Response and Not Clinical Parameters Dictated Patient Outcome

PURPOSE Preoperative chemoradiotherapy may increase the R0 (curative) resection rate, overall survival (OS) duration, and disease-free survival (DFS) duration. We evaluated paclitaxel-based induction chemotherapy and chemoradiotherapy in patients with localized gastric or gastroesophageal adenocarcinoma to determine its feasibility, impact on the R0 resection rate, type of pathologic response, OS, and DFS. PATIENTS AND METHODS Patients with operable, localized gastric, or gastroesophageal adenocarcinoma were eligible. Staging included endoscopic ultrasonography (EUS) and laparoscopy. Patients received two 28-day cycles of induction chemotherapy of fluorouracil, paclitaxel, and cisplatin followed by 45 Gy of radiation and concurrent fluorouracil plus paclitaxel. The cancer was restaged and surgery was attempted. Postsurgery pathologic findings and R0 resection were correlated with OS and DFS. RESULTS Forty-one patients were enrolled. Most carcinomas were proximal (83%) and pretreatment stage EUST3 (85%). Forty patients (98%) underwent surgery, and 78% had an R0 resection. We observed a pathologic complete response (pathCR) rate of 20% and a pathologic partial response (pathPR) rate of 15% (< 10% residual cancer cells in the resected specimen). No pretreatment parameter (sex, cancer location, baseline T stage, or baseline N stage) predicted the type of postsurgery pathologic response, OS, or DFS. However, pathCR (P = .02), pathCR + pathPR (P = .006), R0 resection (P < .001), and postsurgery T and N stages (P = .01 and P < .001, respectively) were associated with OS. Same parameters were significantly correlated with DFS. Toxicity was manageable. CONCLUSION The type of pathologic response but not pretreatment parameters was associated with OS and DFS. Efforts to increase the rate of pathologic response and better systemic cancer control are warranted.