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Howard Hochster

Publications and source records attributed to Howard Hochster.

17 recordsLinked to original sources
PubMed2006

Phase II trial of nolatrexed dihydrochloride [Thymitaq, AG 337] in patients with advanced hepatocellular carcinoma.

BACKGROUND: To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma. PATIENTS AND METHODS: Forty-eight patients were entered onto this study. Nolatrexed was administered every 3 weeks as a 24-h continuous intravenous infusion of 725 mg/m(2)/day for 5 days. Doses were adjusted to maintain a dose level that produced > or = grade 2 toxicity. Response was assessed after every two cycles. Plasma pharmacokinetic samples were assayed using a validated high performance liquid chromatography ultraviolet method. RESULTS: Thirty-nine (81%) patients were evaluable for response. The mean number of cycles received was 2.8 (range 1-12). The mean dose intensity was 700 mg/m(2)/day (SD of 71). One patient had a partial response (2.6%) for 7 months. Eighteen (46%) patients had SD, 20 (51%) patients had progressive disease. The median duration of SD was 93 days. The median overall survival was 32 weeks [95% CI (22-37)]. The most frequent Grade 3 or 4 adverse events were stomatitis (25%), dehydration (23%) and asthenia (21%). There was no evidence of cumulative toxicity. The overall median plasma concentration (C (max)) was 14.20 microg/mL (range 1.41 to 119 microg /mL) with no accumulation observed between cycles 1-6. CONCLUSION: This phase II study of nolatrexed in advanced HCC patients, demonstrated minimal activity and significant stomatitis. Hence, it does not warrant further study as a single agent for this disease.

Adult↗
PubMed2005

Phase I study of combined pegylated liposomal doxorubicin with protracted daily topotecan for ovarian cancer.

PURPOSE: To determine the maximum tolerated dose and dose-limiting toxicity of Doxil with low-dose continuous infusion topotecan and subsequently with low-dose oral topotecan. Other specific aims were preliminary assessment of activity in advanced ovarian and tubal malignancies, pharmacokinetics of oral topotecan, and correlation of response with topoisomerase I and II expression in tumors. METHODS: Eligible patients had histopathologically documented advanced cancers beyond standard therapy, performance status <2, and adequate organ functions. Doxil (30-40 mg/m2 i.v.) was given on day 1, with topotecan either oral topotecan 0.4 mg/m2 bid for 14 days or continuous infusion topotecan (0.3-0.4 mg/m2/d) for 14 to 21 days, in 28-day cycles. Fifty-seven patients, 23 with epithelial ovarian or tubal cancers were enrolled. Plasma levels of lactone form of topotecan were determined on patients receiving oral topotecan. RESULTS: Grade 4 neutropenia and thrombocytopenia and grade 3 diarrhea were dose-limiting toxicities at the highest dose levels explored. Doxil (40 mg/m2/day 1) and continuous infusion topotecan at 0.4 mg/m2/days 1 to 14 could be safely given and is the recommended phase II dose. Oral topotecan was limited by low and erratic plasma topotecan levels and frequent gastrointestinal toxicity. Particularly long partial responses and stable disease were observed in patients with epithelial ovarian or tubal cancers. Clinical benefit (objective responses and stable diseases) correlated with elevated expression of both topoisomerases by immunohistochemistry in four of six epithelial ovarian or tubal cancer tumor samples. CONCLUSION: Doxil with 14-day topotecan infusion is a well-tolerated regimen and suitable for study in platinum-resistant or refractory ovarian or tubal cancers. Frequent gastrointestinal toxicity and/or erratic absorption complicate treatment with a longer topotecan infusion or with oral topotecan, respectively, and these combinations are not recommended.

Administration, Oral↗
PubMed2005

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.

Adenocarcinoma↗
PubMed2005

Assessment of infusional 5-fluorouracil schedule and dose intensity: a Southwest Oncology Group and Eastern Cooperative Oncology Group study.

BACKGROUND: Building on results from Southwest Oncology Group trial 8905, this trial was designed to compare low-dose continuous infusion (LDCI) of 5-fluorouracil (5-FU) versus intermittent high-dose infusion (HDI) of 5-FU in disseminated colorectal cancer (CRC) for evidence of survival advantage based on dose intensity. A companion trial was funded to assess molecular parameters associated with fluoropyrimidine response or resistance and toxicity from these treatments. PATIENTS AND METHODS: Eligibility included histologic diagnosis of disseminated CRC, measurable or evaluable disease, no previous therapy for metastatic disease, performance status of 0-2, and adequate renal, hepatic, cardiac, and hematologic function. Stratification factors were measurable versus evaluable disease, performance status of 0/1 versus 2, presence versus absence of adjuvant therapy, and presence versus absence of previous surgery and enrollment on the companion trial. Patients were randomized to receive (1) LDCI 5-FU 300 mg/m(2) per day for 28 days every 5 weeks or (2) HDI 5-FU 2,600 mg/m(2) for 24 hours each week. RESULTS: Between April 1995 and May 1999, 730 patients were accrued (LDCI arm, n = 360; HDI arm, n = 370). Of these, 708 eligible patients were assessable for survival and 690 for toxicity. Median survival for both groups was 13 months. Toxicity was mild; < 10% of patients in both arms had grade > 4 events. There were 8 study-related deaths (1%). Less than 10% of patients were enrolled in the companion trial. CONCLUSIONS: Increasing 5-FU dose intensity yields no survival advantage beyond that achieved with LDCI 5-FU. This study confirms the favorable toxicity profile of infusional 5-FU. Because no preferential benefit was observed for either infusion schedule, the more convenient weekly schedule should be considered for 5-FU-based combination regimens for disseminated CRC.

Adolescent↗
PubMed2005

Phase I/II dose-escalation study of pemetrexed plus irinotecan in patients with advanced colorectal cancer.

BACKGROUND: Pemetrexed and irinotecan have demonstrated antitumor activity as single agents in lung, pancreatic, breast, and colorectal cancer (CRC). The distinct mechanisms of action and patterns of resistance displayed by pemetrexed and irinotecan make them attractive agents for combination therapy. PATIENTS AND METHODS: This phase I/II, nonrandomized, open-labeled, single-arm study was composed of 3 segments. The initial phase II portion of the study enrolled 23 patients with advanced CRC who had received 1 previous dose of 5-fluorouracil (5-FU)-based chemotherapy for advanced disease. Because of poorer than anticipated efficacy, a phase I dose-escalation study using vitamin supplementation (n = 12) was added to the original protocol. The phase II dose-escalation portion of the study enrolled 36 patients (64% with previous oxaliplatin-based therapy) who received pemetrexed 500 mg/m2 followed by irinotecan 300 mg/m2 on day 1, every 21 days. RESULTS: For the 35 evaluable patients in the phase II dose-escalation study, the objective response rate was 11.4% (95% confidence interval, 3.2%-26.7%); there was 1 patient with a complete response, 3 with partial responses, and 17 with stable disease. Three of four responders had received previous oxaliplatin-based combination therapy. Grade 3/4 hematologic toxicities included leukopenia (5.6%), anemia (2.8%), and thrombocytopenia (2.8%). Grade 3/4 nonhematologic toxicities included diarrhea (11.1%), increased aminotransferase levels (8.3%), nausea (8.3%), febrile neutropenia (5.6%), vomiting (5.6%), and reduced creatinine clearance (2.8%). CONCLUSION: Pemetrexed plus irinotecan appears to be at least as active as FOLFIRI (leucovorin/5-FU/irinotecan) for second-line therapy of CRC following 5-FU-based combination chemotherapy. Further studies are warranted.

Adult↗
PubMed2004

Randomized multicenter phase II trial of bolus plus infusional fluorouracil/leucovorin compared with fluorouracil/leucovorin plus oxaliplatin as third-line treatment of patients with advanced colorectal cancer.

PURPOSE: The addition of oxaliplatin to fluorouracil (FU) and leucovorin (LV) improves the outcome of patients with colorectal cancer (CRC). This multicenter study evaluated FU/LV with or without oxaliplatin in patients with metastatic CRC after disease progression on sequential fluoropyrimidine and irinotecan. PATIENTS AND METHODS: Two hundred fourteen patients were randomly assigned to receive LV 200 mg/m2 intravenously (IV) and FU 400 mg/m2 IV bolus, followed by FU 600 mg/m2 IV over 22 hours on days 1 and 2, every 2 weeks (LV5FU2); or LV and FU as described, plus oxaliplatin 85 mg/m2 IV over 2 hours on day 1 of the schedule (FOLFOX4). The primary end point was overall response. RESULTS: Baseline characteristics were similar in the two treatment arms. Objective response (complete + partial) rates for LV5FU2 versus FOLFOX4 were 2% v 13% (P = .0027), respectively. Median time to disease progression was 2.4 v 4.8 months (P < .0001), and median survival was 11.4 v 9.9 months (P = .20) for LV5FU2 and FOLFOX4, respectively. Among the 72 patients who crossed over from LV5FU2 to FOLFOX4, 6% responded. Symptomatic improvement was significantly better for patients in the FOLFOX4 arm (32% v 18% for LV5FU2, P = .05). Grade 3/4 toxicities for LV5FU2 and FOLFOX4 were neutropenia (13% and 42%, respectively), diarrhea (6% and 16%, respectively), and overall neuropathy (0% and 6%, respectively). CONCLUSION: In patients with metastatic CRC, the FOLFOX4 regimen was superior to LV5FU2 with a higher response rate and time to disease progression. FOLFOX4 is an effective regimen even after disease progression on two previous chemotherapy regimens with fluoropyrimidines and irinotecan.

Adenocarcinoma↗
PubMed2004

Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors.

PURPOSE: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550. RESULTS: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m(2). At 50 mg/m(2), 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m(2) (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3-4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m(2), the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1-2 neuropathy was observed in all patients enrolled and treated at 40 mg/m(2). Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naïve breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively). The mean pharmacokinetic parameter values during course 1 for clearance, volume of distribution, and apparent terminal elimination half-life at the 40 mg/m(2) (recommended Phase II dose) dose level were 21 liters/h/m(2), 826 liters/m(2), and 35 h (excluding one outlier of 516 h), respectively. Values during course 1 and course 2 were similar. CONCLUSIONS: The recommended dose for Phase II evaluation of BMS-247550 is 40 mg/m(2), although more long-term observations are needed. BMS-247550 has advantages over taxanes in relation to drug resistance and warrants further study.

Adult↗
PubMed2004

Biweekly 72-hour 9-aminocamptothecin infusion as second-line therapy for ovarian carcinoma: phase II study of the New York Gynecologic Oncology Group and the Eastern Cooperative Oncology Group.

PURPOSE: To determine the antitumor activity of the novel topoisomerase I inhibitor 9-aminocamptothecin (9-AC) given over 72 hours every 2 weeks in patients with ovarian carcinoma previously treated with one platinum-containing regimen. PATIENTS AND METHODS: Patients with ovarian carcinoma who received one prior platinum-containing regimen were eligible. Patients were stratified based on whether their disease was measurable, or nonmeasurable but assessable. 9-AC 35 microg/m(2)/h was administered by continuous infusion for 72 hours every 2 weeks via ambulatory pump. RESULTS: Sixty patients were entered, 32 with measurable and 28 with nonmeasurable but assessable disease. Ten (16.7%) of 60 patients responded (95% CI, 7.2% to 26.1%), with four complete responses and six partial remissions. The response rate for patients with measurable and nonmeasurable but assessable disease was 22% (95% CI, 7.6% to 36.2%) and 10.7% (95% CI, 2.3% to 28.2%), respectively. None of the responders were platinum-resistant. Nineteen patients (32%) had stable disease. The major toxicities were hematologic, with 25% of patients having grade 3 and 35% having grade 4 neutropenia, including five episodes of febrile neutropenia, 17% having grade 3 to 4 thrombocytopenia, and 27% having grade 3 to 4 anemia. Nonhematologic toxicity included grade 3 to 4 nausea (27%) and grade 3 to 4 vomiting (12%). CONCLUSION: This phase II multicenter trial of biweekly 72 hour 9-AC infusion as second-line therapy for ovarian cancer demonstrates comparable activity to standard approved agents in patients with both measurable and nonmeasurable but assessable disease. Toxicity consists mainly of moderate but controllable myelosuppression. Further studies combining 9-AC with other agents active in ovarian cancer for use as second-line therapy are warranted.

Adult↗
PubMed2004

A phase I and pharmacokinetic study of docetaxel combined with Doxil (pegylated liposomal doxorubicin) without and with granulocyte colony stimulating factor.

The purpose of this study was (i) to determine the maximum tolerated dose (MTD) of docetaxel that can be administered in combination with Doxil, given without and with granulocyte colony stimulating factor (G-CSF), (ii) to define the pharmacokinetics (PK) of docetaxel when used in combination with Doxil, and (iii) to make preliminary observations on the anti-tumor activity of this combination in patients with metastatic solid tumors. Thirty-seven patients with metastatic cancer were enrolled. Courses were repeated every 3 weeks. Patients received a fixed dose of Doxil 30 mg/m(2) in combination with escalating doses of docetaxel ranging from 40 to 100 mg/m(2). After encountering dose-limiting febrile neutropenia, subsequent escalation was accomplished with G-CSF support. Selected patients at the recommended phase II dose underwent PK evaluation. The most common toxicity observed was neutropenia. Dose-limiting toxicity (30 mg/m(2) Doxil + 80 mg/m(2) docetaxel) was febrile neutropenia in three of six patients treated without G-CSF. Major non-hematological toxicities included alopecia, mucositis and hand-foot syndrome, and were observed after cumulative doses of chemotherapy. Objective responses (complete/partial) were documented in eight of 37 patients (four with breast cancer) and stable disease was seen in 17 patients. PK studies showed an increased tissue retention (decreased clearance) of docetaxel when given with Doxil. The recommended phase II dose of Doxil/docetaxel is 30/60 mg/m(2), q3 weeks, without G-CSF. Further dose escalation to 30/80 mg/m(2) is safe with G-CSF support. Anti-tumor activity, particularly against breast cancer, was observed at various dose levels. Our observations should provide evidence for phase II studies of this combination in patients with breast cancer and other anthracycline/taxane-sensitive cancers.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Oxaliplatin: practical guidelines for administration.

Colorectal cancer (CRC) accounts for about 11% of all new cancers in the United States and kills approximately 56,000 people each year. Although the use of antineoplastic agents has demonstrated palliation of symptoms, increased survival, and improved quality of life when compared with best supportive care, improved therapies still are needed. Oxaliplatin, released in August 2002, offers an effective expansion of the CRC treatment armamentarium. Proper dosage and administration of oxaliplatin are vital to maximizing its efficacy and safety. This article reviews administration guidelines, adverse events, side effects, and key areas for patient education.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2003

Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma.

PURPOSE: To conduct a randomized phase II trial of dose-intense gemcitabine using a standard 30-minute infusion or the fixed dose rate (FDR) infusion (10 mg/m2/min) in patients with pancreatic adenocarcinoma. PATIENTS AND METHODS: In this prospective trial, patients with locally advanced and metastatic pancreatic adenocarcinoma were treated with 2,200 mg/m2 gemcitabine over 30 minutes (standard arm) or 1,500 mg/m2 gemcitabine over 150 minutes (FDR arm) on days 1, 8, and 15 of every 4-week cycle. The primary end point of this trial was time to treatment failure. Secondary end points included time to progression, median survival, safety, and pharmacokinetic studies of gemcitabine. RESULTS: Ninety-two patients were enrolled onto this study; 91% of the patients had metastatic disease. Time to treatment failure was comparable in both treatment groups; however, the median survival for all patients was 5.0 months in the standard arm and 8.0 months in the FDR arm (P =.013). For patients with metastases, the median survival was 4.9 months in the standard arm and 7.3 months in FDR arm (P =.094). The 1- and 2-year survival rates for all patients were 9% (standard arm) versus 28.8% (FDR; P =.014) and 2.2% (standard arm) versus 18.3% (FDR; P =.007), respectively. Patients in the FDR infusion arm experienced consistently more hematologic toxicity. Pharmacokinetic analyses demonstrated a two-fold increase in intracellular gemcitabine triphosphate concentration in the FDR arm (P =.046). CONCLUSION: Pharmacokinetic and clinical data in this trial supports the continued evaluation of the FDR infusion strategy with gemcitabine.

Adenocarcinoma↗
PubMed2003

Oxaliplatin with weekly bolus fluorouracil and low-dose leucovorin as first-line therapy for patients with colorectal cancer.

PURPOSE: To determine the activity of biweekly oxaliplatin, combined with weekly bolus fluorouracil (FU) and low-dose leucovorin (LV) chemotherapy (bFOL), as first-line therapy for patients with metastatic colorectal cancer. PATIENTS AND METHODS: Patients with measurable metastatic colorectal cancer; no previous therapy for advanced disease (adjuvant therapy allowed if >6 months since completion); and performance status 0, 1, or 2 were eligible and were treated with oxaliplatin 85 mg/m2 days 1 and 15 plus LV 20 mg/m2 over 10 to 20 minutes, followed by a 500 mg/m2 bolus dose of FU on days 1, 8, and 15 every 28 days. Patients underwent response evaluation by computed tomographic scan every 2 months. RESULTS: Forty-two patients were entered, and 41 patients were treated, including 20 men and 22 women, nine with previous adjuvant chemotherapy and four with radiation therapy. Three patients achieved complete response, and 23 patients achieved partial response, for a response rate of 63% (95% CI, 49% to 78%). Major toxicities included cumulative neuropathy grade 2 (24%) and grade 3 (12%; requiring discontinuation of oxaliplatin), diarrhea grade 3 to 4 (29%) and grade 3 to 4 hematologic toxicity (10%). Median time to progression was 9.0 months (95% confidence interval, 7.1 to 10.8 months) with median survival of 15.9 months (95% confidence interval, 11.4 to 19.7 months). CONCLUSION: The bFOL regimen seems to have activity comparable to be infusional programs of FU combined with oxaliplatin. Prospective trials are warranted to determine the relative merits of this schedule compared with the currently indicated schedules.

Adenocarcinoma↗
PubMed2003

Phase I study of amifostine as a cytoprotector of the gemcitabine/cisplatin combination in patients with advanced solid malignancies.

Our objective was to evaluate the role of amifostine as a cytoprotector in patients with solid tumors receiving the myelosuppressive regimen of gemcitabine/cisplatin combination. Patients with advanced solid tumors were randomized to gemcitabine-amifostine-cisplatin (GAP) or gemcitabine-cisplatin (GP) in Cycle 1 (C1) and then were crossed over to the other treatment in Cycle 2 (C2). Amifostine at 740 mg/m2, followed by gemcitabine and cisplatin, were given for 2 consecutive weeks, every 4 weeks. Two GP combinations were studied: G 1000 mg/m2 and P 40 mg/m2 days 1, 8 (high dose), and G 800 mg/m2 and P 30 mg/m2 days 1, 8 (low dose). Forty patients were enrolled. Of the 19 patients treated with high-dose GP, 11 (nine patients GP in C1 and GAP in C2, two patients GAP in C1 and GP in C2) completed 2 cycles of therapy. Of the eight non-evaluable patients, five patients dropped out due to toxicity or refusal after treatment with amifostine in C1. Of the 21 patients treated with low-dose GP, 15 (eight patients GP in C1 and GAP in C2, seven patients GAP in C1 and GP in C2) were likewise evaluable. The incidence of grade 3 or 4 hematologic toxicities was similar for GP and GAP during the first 2 cycles of treatment, and there were no statistically significant differences in mean absolute neutrophil count, hemoglobin level and platelet levels between the cycles in each arm. We conclude that amifostine, at 740 mg/m2, does not lead to less myelosuppression when combined with gemcitabine/cisplatin chemotherapy regimens and may possibly contribute to subjective intolerance.

Adult↗
PubMed2002

The role of pemetrexed in the treatment of colorectal cancer.

Advanced colorectal cancer is a leading cause of cancer-related morbidity and mortality. Chemotherapeutic options, however, have recently expanded with concomitant improvements in survival. Through the 1980s and early 1990s research focused mainly on the major fluoropyrimidine, 5-fluorouracil, a thymidylate synthase inhibitor, and methods to enhance its activity through scheduling changes or by biochemical modulation. Pemetrexed is a novel antifolate that inhibits several folate-dependent enzymes in addition to thymidylate synthase. This agent has theoretical and preclinical advantages over fluoropyrimidines and specifically acting antifolates. Phase II studies have shown a broad spectrum of activity in solid tumors, including colorectal cancer. Further studies at higher doses with the use of vitamin supplementation may be desirable. Combinations of pemetrexed with irinotecan and oxaliplatin have also proven feasible. Pemetrexed is a promising new drug for the treatment of colorectal cancer.

Antimetabolites, Antineoplastic↗
PubMed2002

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.

Adult↗
PubMedDate not supplied

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.

Adenocarcinoma↗