Postoperative intraperitoneal 5-fluoro-2'-deoxyuridine added to chemoradiation in patients curatively resected (R0) for locally advanced gastric and gastroesophageal junction adenocarcinoma.

PURPOSE: Chemoradiation after surgery for locally advanced gastric cancer improves overall and relapse-free survival compared with observation. However, locoregional recurrences remain high. Accordingly, we instituted this pilot/feasibility study, including intraperitoneal 5-fluoro-2'-deoxyuridine (IP FUDR) as part of the treatment. METHODS: Gastric/gastroesophageal junction adenocarcinoma stage Ib-IV (M0) patients who underwent R(0) resection were eligible and had IP catheters inserted at time of surgery. IP FUDR (3 g/dose/day) was given during study days 1-3 and 15-17 before combined 5-fluorouracil, leucovorin, and external beam radiation (45 Gy). Endpoints included toxicity, completion rate, locoregional recurrence, and survival. RESULTS: Twenty-eight patients (22 men) were enrolled from 2002-2006 at two institutions; their median age was 59.5 years. After R(0) resection, a median 22 (range, 8-102) lymph nodes were examined, and 22 patients had positive nodes. AJCC stages were IB (n = 8), II (n = 10), IIIA (n = 5), IIIB (n = 1), and IV (n = 4). Full-dose IP FUDR and chemoradiation treatment was completed in 20 and 25 patients, respectively. At nearly 4-year median follow-up, 11 patients were disease-free, 5 were alive with disease, 7 were dead of disease, and 1 was dead from other cause; 4 have been lost to follow-up. Recurrences were local in one, intra-abdominal in six, distant in two, multiple sites in two, and unknown in one. The median relapse-free survival is 65.3 months, and the median overall survival has not yet been reached. CONCLUSIONS: IP FUDR before chemoradiation after R(0) gastric cancer resection is well tolerated without compromising completion of postoperative adjuvant treatment. Larger randomized trials studying IP FUDR as part of gastric cancer multidisciplinary treatment are needed to prove efficacy in reducing regional recurrence and improving survival.

Neoadjuvant chemotherapy, surgery, and adjuvant intraperitoneal chemotherapy in patients with locally advanced gastric or gastroesophageal junction carcinoma: a phase II study.

A phase II trial, using neoadjuvant chemotherapy and intraperitoneal (IP) consolidation, was conducted in patients with locally advanced, potentially resectable gastric cancer or cancer of the gastroesophageal junction, both staged as T3N0, T4N0, or any TN1 or TN2 disease. Preoperative chemotherapy consisted of two cycles of irinotecan 75 mg/m(2) with cisplatin 25 mg/m(2)/week for 4 weeks followed by a 2-week break. Unless disease progression was encountered, surgery was performed and followed by two courses of adjuvant therapy with IP floxuridine 3 g x 3 days plus IP cisplatin 60 mg/m(2) on day 3. Of 32 evaluable patients, 29 (90.6%) underwent surgery, and 25 (86.2%) had R0 on resection. Evidence of primary-tumor downstaging was documented in at least one half of the patients. Toxicity of induction therapy was primarily grade 3/4 neutropenia (38.2%/8.8%), grade 3 diarrhea (20.6%), and grade 3 nausea/vomiting (14.7%). Except for three catheter complications, toxicities with IP therapy were infrequent. After a median follow-up of 28.0 months in 32 patients, 10 patients (31.3%) had no evidence of disease, 4 (12.5%) were alive with disease, 13 (40.6%) had died from disease, and 5 (15.6%) died from unrelated causes. Among 25 patients who underwent R0 resection, there were no local recurrences. Sites of first recurrences were outside the abdominal cavity in seven patients, in the liver in two, and in the abdominal cavity in four patients. Median overall survival for all 32 patients was 36.5 months from the start of treatment after median follow-up of 28 months, whereas median disease-specific survival had not been reached at the time of this analysis. For patients with R0 resection, median overall survival was 48 months after median follow-up of 35 months. The data suggest that an approach consisting of systemic induction therapy, curative surgery with high R0 resection rates, and IP adjuvant therapy has acceptable toxicity and encouraging survival outcomes.

Complications of gastrectomy following CPT-11-based neoadjuvant chemotherapy for gastric cancer.

Potential benefits of neoadjuvant therapy for locally advanced gastric cancer include tumor downstaging and an increased R0 resection rate. Potential disadvantages include increased surgical complications. This study assesses postoperative morbidity and mortality by comparing patients undergoing gastrectomy with and without neoadjuvant chemotherapy. From October 1998 to July 2002, a total of 34 patients with locally advanced gastric cancer were placed on a phase II neoadjuvant chemotherapy protocol consisting of two cycles of CPT-11 (75 mg/m(2)) with cisplatin (25 mg/m(2)). Demographic, clinical, morbidity, and mortality data were compared for these patients (CHEMO) versus 85 patients undergoing gastrectomy without neoadjuvant chemotherapy (SURG). The CHEMO patients were more likely to be less than 70 years of age (P< or =0.01), have proximal tumors (P< or =0.01), and undergo proximal gastrectomy (P< or =0.025). Fifty-two percent of SURG patients had T3/T4 tumors compared to 19% of CHEMO patients, consistent with tumor downstaging. The R0 resection rate was similar (80%). Morbidity was 41% in CHEMO patients and 39% in SURG patients. There were five postoperative deaths (4.4%), two in the CHEMO group and three in the SURG group (P=NS). It was concluded that neoadjuvant chemotherapy with CPT-11 and cisplatin is not associated with increased postoperative morbidity compared to surgery alone. CPT-11-based neoadjuvant chemotherapy should be tested further in combined-modality treatment of gastric cancer.

Phase I and pharmacologic study of i.p. 9-aminocamptothecin given as six fractions over 14 days.

We sought to define the tolerance of 9-amino-20(S)-camptothecin (9-AC) when given by the i.p. route to patients with cancer in the peritoneal cavity consisting of nodules that did not exceed 1 cm in maximum diameter. 9-AC was given in six fractions over 12 days, at doses ranging from 1.25 to 13.5 mg/m(2) in cycles repeated every 28 days. Dose escalations after the first two dose levels took place in cohorts of three patients, with expansion of the dose level once a dose-limiting toxicity (DLT) was encountered. All patients had blood and i.p. pharmacokinetic (PK) analysis during cycle 1 of each dose level. Topoisomerase (Topo) I signal was serially measured in peripheral blood mononuclear cells (PBMCs) in blood and cells collected in i.p. cytologic washings. Twelve patients received 31 cycles of 9-AC. Tolerance to repeated i.p. drug administration was generally excellent. The DLT was neutropenia encountered at the highest dose level in two patients, whereas the dose of 9 mg/m(2) was well tolerated. The DLTs were associated with peak plasma levels ranging from 47 to 81 ng/ml and also depletion of Topo I in PBMCs. The i.p.:plasma AUC ratio (+/-SD) was 11.5 (+/-3.8). Two patients had objective evidence of clinical benefit and only one of seven patients deemed evaluable for response had progressive disease. We conclude that i.p. 9-AC demonstrates excellent local tolerance at a dose and schedule associated with evidence of systemic effects. A dose of 9 mg/m(2)/cycle administered in a schedule of six divided fractions is suitable for further evaluation against tumors involving primarily the peritoneal cavity.

Neoadjuvant chemotherapy with CPT-11 and cisplatin downstages locally advanced gastric cancer.

We examined the role of neoadjuvant therapy in downstaging locally advanced gastric cancer. Preoperative staging was performed with a combination of CT scans, endoscopic ultrasonography and/or laparoscopy, and laparoscopic ultrasonography. Patients with T > or =3 tumors and/or node-positive disease by preoperative clinical staging were eligible for entry. Neoadjuvant therapy consisted of two cycles of CPT-11 (75 mg/m(2)) with cisplatin (25 mg/m(2)) weekly four times every 6 weeks. This was followed by resection with D2 lymph node dissection and two cycles of intraperitoneal chemotherapy with floxuridine and cisplatin. Twenty-two patients were entered into the study (4 with T3N0 disease and 18 with T3N1 disease). Induction chemotherapy was well tolerated with major toxicities being neutropenia and diarrhea. A median of 78%/75% of the planned dosage of CPT-11/cisplatin was delivered. Two patients withdrew consent during the first cycle and were lost to follow-up. One patient progressed to stage IV disease during induction chemotherapy and did not undergo surgery. Nineteen patients underwent surgery. One patient had undetected stage IV disease (liver) and underwent a palliative R2 resection. Of the 18 remaining patients, 17 had curative R0 resections and one had a palliative R1 resection. A median of 21 lymph nodes (range 1 to 121) were examined histologically. There was one postoperative death. Surgical morbidity did not appear to increase after the neoadjuvant regimen. The median postoperative length of hospital stay was 9 days (range 3 to 75 days). Postoperative pathologic staging yielded 16% T3 lesions compared to 85% before treatment based on clinical staging; postoperative American Joint Committee on Cancer staging yielded 37% stage IIIA disease compared to 70% stage IIIA before treatment. With a median follow-up of 15 months, median survival has not yet been reached. We conclude that CPT-11-based neoadjuvant therapy downstages locally advanced gastric cancer. Further follow-up is necessary to determine the ultimate impact of this combination therapy on recurrence and survival.