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R Pazdur

Publications and source records attributed to R Pazdur.

At least 37 records · Page 2Linked to original sources
PubMed2000

Capecitabine, an oral fluoropyrimidine carbamate with substantial activity in advanced colorectal cancer: results of a randomized phase II study.

PURPOSE: To evaluate in patients with advanced colorectal cancer (CRC) three treatment regimens of oral capecitabine in order to select the most appropriate regimen for testing in phase III. PATIENTS AND METHODS: Three capecitabine schedules were evaluated in a randomized phase II design: arm A, 1,331 mg/m(2)/d bid continuously; arm B, 2,510 mg/m(2)/d bid intermittently (2 weeks on/1 week off); and arm C, 1,657 mg/m(2)/d plus oral leucovorin 60 mg/d bid intermittently (2 weeks on/1 week off). RESULTS: One hundred nine patients were randomized; 39 patients were assessable for efficacy in arm A, 34 in arm B, and 35 in arm C. Patient characteristics were balanced in the arms. Confirmed tumor responses (partial response [PR] + complete response [CR]) were reported for eight patients with two CRs (21%; 95% confidence interval [CI], 9% to 36%) in arm A, eight patients with one CR (24%; 95% CI, 11% to 41%) in arm B, and eight patients with two CRs (23%; 95% CI, 10% to 40%) in arm C. Median times to progression (TTP) in arms A, B, and C were 127, 230, and 165 days, respectively. Overall, more toxicity was seen with capecitabine plus leucovorin, particularly diarrhea and hand-foot syndrome. There was no grade 3 or 4 marrow toxicity. CONCLUSION: Capecitabine offers a new, effective treatment option as an oral single agent in advanced CRC. Promising overall response rates were reported for all three regimens. The addition of leucovorin to the intermittent regimen had no marked effect on tumor response or median TTP. The intermittent single-agent capecitabine schedule is proposed for phase III evaluation, based on considerations of toxicity, dose-intensity, response rate, and TTP.

Administration, Oral↗
PubMed2000

Pediatric oncology: regulatory initiatives.

The majority of children with cancer receive therapy as participants in clinical research protocols coordinated by national pediatric cooperative groups. One of the highest priorities of these groups is the development of novel therapies. Due to differences in the biology of pediatric and adult tumors and in physiology between adults and children, it is usually necessary to evaluate the safety and effectiveness of new drugs separately in adult and pediatric populations. To stimulate the development of new therapies for pediatric indications and encourage the submission of clinical data to support pediatric product labeling, the U.S. Food and Drug Administration has undertaken two initiatives. In 1998 the FDA issued a regulation (The 1998 Final Pediatric Rule) that mandated if a drug or biological is under review for a claim and the disease exists in both pediatric and adult populations, pediatric studies must be performed. Section 111 of the FDA Modernization Act of 1997 states that if a drug product has exclusivity based on a patent or marketing license, the exclusivity can be extended by six months for the submission of pediatric data to the FDA. The incentive applies to both approved drugs and those under development. These initiatives are intended to enhance access to new anticancer therapies and promote labeling for pediatric oncology indications.

Child↗
PubMed2000

Progress in colorectal cancer chemotherapy: how far have we come, how far to go?

Fluorouracil has been the mainstay of treatment for colorectal cancer (CRC) for almost 40 years. Various schedules and biochemical modulators have been investigated in an attempt to improve the therapeutic efficacy of fluorouracil. To date, fluorouracil plus folinic acid represents the standard therapy in CRC for the adjuvant treatment of patients at high risk for relapse and for the first-line treatment of metastatic disease. To gain clinical acceptance, however, oral fluoropyrimidines must confer at least the same survival advantages associated with the optimal intravenous fluorouracil regimens. Irinotecan and oxaliplatin are 2 other novel agents that have mechanisms of action that are uniquely different from those of fluorouracil, with demonstrated activity in patients with fluorouracil-refractory disease. Recent randomised trials comparing fluorouracil plus folinic acid with combinations of either irinotecan or oxaliplatin and fluorouracil plus folinic acid have shown that response rates are improved and time to progression is increased in patients receiving the combination regimens. These regimens are being rapidly introduced in the adjuvant setting, and the role and acceptance of these combination regimens as first-line therapy needs to be defined. Other novel agents being evaluated in the treatment of patients with advanced CRC include oral edrecolomab (monoclonal antibody 17-1A) and tumour vaccines. Future research is focused on enabling clinicians to individualise treatment strategies in patients with CRC, so as to improve clinical outcomes and reduce drug toxicity.

Camptothecin↗
PubMed2000

A phase I study. Preoperative UFT/leucovorin and radiation therapy in rectal cancer.

The use of combined modality regimens has been well established in the treatment of stages II and III rectal cancer. The most common chemotherapy regimens used include continuous-infusion 5-FU delivered with the help of a central venous catheter and the use of portable pumps. These regimens are expensive and can potentially develop line problems. The availability of the oral agent UFT in combination with oral leucovorin prompted the development of an all-oral chemotherapy regimen that could be combined with radiotherapy. At The University of Texas M. D. Anderson Cancer Center, we routinely use combined chemotherapy and radiotherapy preoperatively for the treatment of rectal cancers, and decided to conduct a phase I trial in which UFT and leucovorin was used instead of the conventional 5-FU. The preliminary results are encouraging and seem to demonstrate the feasibility of this approach.

Administration, Oral↗
PubMed2000

Phase I study of irinotecan and concurrent radiation therapy for upper GI tumors.

Irinotecan (Camptosar) is an active chemotherapeutic agent for lung, gastric, esophageal, and colorectal cancers and a potent radiosensitizer. This phase I study was designed to assess the maximum tolerated dose of weekly irinotecan combined with concurrent radiotherapy for patients with locally advanced, unresectable gastric, gastroesophageal junction, or esophageal cancer. Patients who received previous chemotherapy (excluding irinotecan) or who experienced recurrent cancer after surgery were eligible for this protocol. The total dose of radiation did not exceed 50.4 Gy (28 fractions of 1.8 Gy each). The starting dose level of irinotecan was 30 mg/m2 infused over 90 minutes given weekly for 5 weeks. Subsequent dose levels were increased in 10 mg/m2 increments to 40, 50, 60, and 70 mg/m2. Of 15 patients who have been enrolled to date, all are evaluable for toxicities and 12 for response. Major hematologic toxicities (grade 3/4) were neutropenia, chills, hemorrhage, and anemia. Grade 3/4 gastrointestinal toxicities included nausea, vomiting, dehydration, anorexia, and constipation. Other severe nonhematologic toxicities included fatigue, hypotension, and hypothermia, as well as cardiovascular toxicities. There was no severe diarrhea and no treatment-related deaths. Of the 12 evaluable patients, 7 (58%) responded, including 2 complete responses; 4 (30%) had no change and 1 had progressive disease. Survival ranged from 1 month to 15 months, with a median survival of 8 months. When the total dose of irinotecan given concurrently with radiotherapy was higher than 250 mg/m2, patients experienced significantly more severe grade 3/4 toxicities than with lower doses (P = .04), with no improvement in response rate. It was concluded that weekly doses of irinotecan of up to 60 mg/m2 with concurrent radiotherapy given over 5 weeks was feasible and demonstrated good response. This regimen did not cause severe diarrhea or pneumonitis, but neutropenia and fatigue were major toxicities. The study continues to accrue.

Adolescent↗
PubMed2000

Colorectal cancer: chemotherapy treatment overview.

Fluorouracil (5-FU) has remained the standard therapy for the treatment of advanced colorectal cancer for over 40 years. Unfortunately, only a minority of patients experience objective clinical response. Discussed herein are attempts to improve on the activity of 5-FU by biochemically modulating its action. In addition, novel agents for the treatment of advanced colorectal cancer (oral fluoropyrimidines, oxaliplatin, and irinotecan) are discussed. Oral fluoropyrimidines (UFT plus leucovorin, capecitabine, eniluracil plus oral 5-FU) provide the convenience of oral delivery with a marked reduction in febrile neutropenia and mucositis. Recent randomized trials with these agents have demonstrated therapeutic activity that is comparable with intravenous schedules of 5-FU plus leucovorin. Compared to 5-FU, both oxaliplatin and irinotecan have uniquely different mechanisms of action and have demonstrated clinical activity in patients whose disease has progressed with 5-FU treatment. Combinations of either irinotecan or oxaliplatin plus 5-FU/leucovorin have demonstrated that the addition of these agents to 5-FU/leucovorin improves response rates and time to progression compared to 5-FU/leucovorin alone. Combination chemotherapy regimens with these novel agents are rapidly being introduced into the adjuvant setting.

Administration, Oral↗
PubMed1999

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 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.

Adult↗
PubMed1999

A multicenter, phase II trial of weekly irinotecan (CPT-11) in patients with previously treated colorectal carcinoma.

BACKGROUND: This multicenter, Phase II trial was performed to evaluate the antitumor activity and toxicity of irinotecan (CPT-11) in patients with metastatic colorectal carcinoma that had recurred or progressed after 5-fluorouracil (5-FU)-based chemotherapy. METHODS: CPT-11 was given as a 90-minute intravenous infusion in repeated 6-week (42-day) courses comprising weekly treatment for 4 consecutive weeks followed by a 2-week rest. Tumor measurements were obtained after every second course of therapy. Toxicity was assessed weekly using the National Cancer Institute Common Toxicity Criteria. RESULTS: A total of 166 patients were entered into the trial. The first 64 patients received a starting dose of 125 mg/m2. An additional 102 patients were enrolled at a starting dose of 100 mg/m2 to determine whether a reduction in the starting dose would result in lower toxicity without sacrificing efficacy. Objective responses to CPT-11 were observed in 18 patients (1 complete response and 17 partial responses) (response rate [RR] = 10.8%; 95% confidence interval [CI], 6.1-15.6%). An additional 67 patients (40.4%) had stable disease as their best response. At the 125 mg/m2 starting dose, the RR was 14.1% (9 of 64 patients; 95% CI, 5.5-22.6%). Among patients given a starting dose of 100 mg/m2, the RR was 8.8% (9 of 102 patients; 95% CI, 3.3-14.3%). The overall median survival was 9.9 months (range, 0.3-36.8 months). The most frequently observed Grade 3/4 toxicities were gastrointestinal events (i.e., diarrhea [27.1%], nausea [15.1%], emesis [9.6%], abdominal cramping [22.2%], and neutropenia [19.9%]). There were no significant differences in the frequencies of Grade 3/4 toxicities between the 125 mg/m2 and 100 mg/m2 starting dose levels except for Grade 3/4 emesis (21.9% vs. 2%; P < 0.001). Patients age > or = 65 years were twice as likely (38.6% vs. 18.8%; P < 0.008) to develop Grade 3/4 diarrhea compared with younger patients when all courses of therapy were evaluated. However, older age did not significantly predict for a higher incidence of first-course diarrhea (25.0% vs. 14.7%; P = 0.106). CONCLUSIONS: CPT-11 can induce tumor regression in patients with metastatic colorectal carcinoma that has progressed during or shortly after 5-FU-based chemotherapy. Gastrointestinal events and neutropenia were the most common serious toxicities. Given the trend toward a higher response rate without substantially greater toxicity, 125 mg/m2 has been selected as the preferred starting dose for further studies. Careful attention to appropriate CPT-11 dose modification and early intervention with loperamide may be especially important in elderly patients.

Adult↗
PubMed1999

Prognostic implications of response to preoperative infusional chemoradiation in locally advanced rectal cancer.

BACKGROUND AND PURPOSE: To evaluate the influence of response to preoperative infusional chemoradiation on outcome parameters among patients with locally advanced rectal cancer. MATERIALS AND METHODS: Preoperative chemoradiotherapy, 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2 per day), was given to 117 patients. As determined by pretreatment endorectal ultrasound (EUS), 96% of cases were Stage T3, and 51% had EUS evidence of perirectal adenopathy. Surgery was performed approximately 6 weeks after chemoradiation therapy. Postoperatively adjuvant systemic therapy, consisting of 400-425 mg/m2 of 5-fluorouracil plus 20 mg/m2 leucovorin for 5 days, was administered every 28 days for six cycles. Outcome parameters of local control (LC), freedom from distant metastases (DMC), disease-free survival (DFS) and cancer specific survival (CSS) were evaluated relative to primary tumor characteristics. RESULTS: The final post-treatment pathological tumor stages were complete response in 27%, Tis-2 N0 in 26%, T2 N1 in 5%, T3 N0 in 21%, T3 N1 in 15%, T4 N0 in 5% and T4 N1 in 1%. Down-staging occurred in 61% of cases. The pretreatment primary tumor size only influenced rates of local control (P < 0.03) and had no other influence on outcome parameters. Pretreatment evidence of perirectal lymph node involvement had no impact on outcome parameters. Pathologic evidence of nodal involvement did affect DMC (P < 0.002) and DFS (P < 0.003). Pathologic evidence of response did influence freedom from the development of distant metastases (P < 0.004). On pairwise analysis this relationship held only when responders were compared to non-responders. No difference was observed based on the level of downstaging at the primary tumor. Correspondingly, DFS was improved when non-responders were compared to downstaged patients (P < 0.01). Response to preoperative chemoradiation failed to affect rates of LC or CSS. For the group as a whole, adjuvant chemotherapy improved only CSS (P < 0.03). Adjuvant chemotherapy was given to 74 patients, 36 of whom had responded to preoperative chemoradiation. Improvements were only seen in DFS (P < 0.03) when down-staged patients were compared to the non-responders who received adjuvant chemotherapy. In addition, the DFS rates were lower in the non-responder group who received adjuvant chemotherapy even when they were compared to down-staged patients who did not receive adjuvant chemotherapy (P < 0.04). CONCLUSION: Consistent with other reports, disease free survival and subsequent development of distant metastases is reduced in the more than 60% of patients who respond to preoperative infusional chemoradiation. Evidence of response appears more significant than the degree of response. At present, no impact is seen on cancer specific survival rates. Consideration should be given for strategies that base selection of subsequent adjuvant chemotherapy on response to preoperative chemoradiation.

Adult↗
PubMed1999

Effects of age on balance assessment using voluntary and involuntary step tasks.

BACKGROUND: Taking a step while standing and modifying a step while walking are two strategies often used to maintain balance when balance disturbances are encountered during activities of daily living. This study investigated whether performance on an involuntary step task, which is assumed to be a surrogate for fall recovery abilities, was comparable to performance on a voluntary step task. METHODS: The performance of a voluntary and an involuntary step task was measured in healthy young adult (mean age 21 years) and healthy elderly adult (mean age 68 years) female subjects. Subjects stepped as fast as possible in the direction of a minimally destabilizing lateral waist pull (voluntary step task), or they responded naturally to a large destabilizing lateral waist pull (involuntary step task). The effects of age, task, and their interaction on the primary outcome variables of step foot liftoff time, landing time, step length, and step height were examined. RESULTS: In the voluntary step task, the older adults, compared to the young, required significantly more time to lift their foot (Young: 307 msec; Elderly: 424 msec). In the involuntary step task, the elderly were as quick as the young in lifting their foot (Young: 322 msec; Elderly: 335 msec). The young lifted their foot at about the same time for the two tasks. The elders, on the other hand, lifted their foot significantly earlier in the involuntary step task, compared to the voluntary step task (Vol: 424 msec; Invol: 335 msec). CONCLUSIONS: A voluntary step task underestimates the ability of healthy elderly adults to respond quickly when large destabilizing balance disturbances are encountered.

Accidental Falls↗
PubMed1999

Phase II trial of docetaxel for cholangiocarcinoma.

The authors evaluated the activity and toxicity of docetaxel given as a 1-hour infusion every 21 days in patients with unresectable cholangiocarcinoma. Seventeen patients with cytologically or histologically confirmed cholangiocarcinoma received intravenous docetaxel over 1 hour, repeated every 21 days. The initial dose of docetaxel was 100 mg/m2, with a subsequent 25% dose reduction for patients experiencing grade 3 or 4 toxicities. Treatment was continued until disease progression or occurrence of intolerable side effects. All patients received premedication with dexamethasone 8 mg by mouth twice daily for 5 days, starting 1 day before docetaxel infusion. Sixteen of the 17 patients were assessable for response and toxicity; one patient was removed from the trial for intercurrent illness. Thirty-eight cycles of docetaxel were delivered (median, two cycles). No complete or partial responses were noted. Fourteen patients had progressive disease, one patient had stable disease, and one patient died of septic shock shortly after starting treatment. Granulocytopenia was the dose-limiting toxicity. Thirteen patients had grade 4 granulocytopenia, 11 of whom required antibiotics for neutropenic fever. Granulocytopenia was the only grade 4 toxicity observed. Grade 3 toxicities included stomatitis, anemia, fatigue, vomiting, and hypotension. Grade 1 or 2 toxicities included alopecia, diarrhea, peripheral edema, myalgias, and anorexia. Administered on this dose and schedule, docetaxel lacked activity in patients with cholangiocarcinoma. The toxicity profile, including dose-limiting granulocytopenia, has been previously described in patients receiving docetaxel.

Adult↗
PubMed1999

Response to neoadjuvant chemotherapy best predicts survival after curative resection of gastric cancer.

OBJECTIVE: In Western populations, long-term survival rates after curative resection of gastric cancer remain extremely poor. The lack of effective adjuvant therapy has prompted the evaluation of neoadjuvant approaches. Since 1988, we have conducted three separate phase II trials using neoadjuvant chemotherapy to treat patients with potentially resectable gastric cancer. The present study was conducted to evaluate whether response to neoadjuvant chemotherapy is predictive of survival in patients with resectable gastric cancer. METHODS: Eighty-three patients with pathologically confirmed gastric adenocarcinoma were treated with neoadjuvant chemotherapy before planned surgical resection. Response was assessed by upper gastrointestinal series, endoscopy, computed tomography scan, and pathologic examination. RESULTS: For the three phase II trials, clinical response rates ranged from 24% to 38%. Three patients (4%) had a complete pathologic response. Sixty-one patients (73%) underwent a curative resection. Median follow-up was 26 months. Univariate analysis revealed T stage, number of positive nodes, and response to chemotherapy to be significant predictors of overall survival. However, on multivariate analysis, response to chemotherapy was found to be the only independent prognostic factor. CONCLUSIONS: Response to neoadjuvant chemotherapy is the single most important predictor of overall survival after neoadjuvant chemotherapy for gastric cancer. These findings support further evaluation of neoadjuvant approaches in the treatment of this disease.

Adenocarcinoma↗
PubMed1999

Novel chemotherapeutic agents for gastrointestinal cancers.

Although 5-fluorouracil has been the most commonly prescribed chemotherapy agent in the treatment of patients with gastrointestinal malignancies, new agents discussed herein provide options for the treatment of patients with colorectal, gastric, and pancreas cancer. Irinotecan was recently approved for the treatment of patients with colorectal cancer refractory to 5-fluorouracil. It has also been evaluated in chemotherapy-naïve patients both alone and in combination with 5-fluorouracil plus leucovorin or with oxaliplatin. Evaluated primarily in patients with colorectal cancer, oxaliplatin, a novel platinum compound, is an active agent. In combination with 5-fluorouracil and leucovorin, oxaliplatin provides a higher response rate than 5-fluorouracil and leucovorin alone. Furthermore, when oxaliplatin was added to the same 5-fluorouracil-based regimen in which patients had disease progression, clinical activity was observed. Other agents discussed herein are raltitrexed and the oral fluorinated pyrimidines, including uracil:tegafur plus leucovorin, capecitabine, eniluracil plus oral 5-fluorouracil, and S-1. Gemcitabine has been demonstrated to be more effective than 5-fluorouracil in the alleviation of disease-specific symptoms in patients with advanced pancreatic cancer. Gemcitabine also confers a modest survival advantage. Combinations of these novel compounds are evaluated in gastrointestinal malignancies in the advanced disease setting and in adjuvant therapy programs.

Antineoplastic Agents↗
PubMed1999

Phase II trial of 5-fluorouracil, folinic acid and recombinant alpha-2a-interferon in patients with advanced colorectal cancer.

A clinical trial regimen modulating 5-fluorouracil (5-FU) with both folinic acid (FA) and recombinant alpha-2a-interferon (ralpha-2a-IFN) was noted to have a response rate of 54% and median survival of 16.3 months (Grem et al., J Clin Oncol 1993, 11: 1737-45). Reported herein is a phase II trial performed to further examine this regimen in metastatic colorectal cancer. Fifty-one patients with histologically proven, measurable advanced colorectal cancer with no prior therapy for metastatic disease were enrolled. ralpha-2a-IFN, 5 MIU/m2/day was given s.c. on days 1-7. FA, 500 mg/m2/day, and 5-FU, 370 mg/m2/day, were given i.v. on days 2-6. Cycles were repeated at 3 week intervals. Three complete and 12 partial responses were observed for an overall response rate of 29% (95% confidence interval: 18-45%). The median time to treatment failure and median survival were 4.6 and 15.5 months, respectively. Dose-limiting toxicities encountered were gastrointestinal, and included diarrhea, stomatitis, nausea and vomiting. These results do not support the concept of using concurrent ralpha-2a-IFN and FA as biochemical modulators of 5-FU. We observed increased toxicity and similar efficacy compared to using either modulator separately with 5-FU.

Adult↗
PubMed1999

Phase I trial of intoplicine (RP 60475) administered as a 72 h infusion every 3 weeks in patients with solid tumors.

Intoplicine (RP 60475) was selected for a phase I evaluation because it inhibits topoisomerase I and II, and has exhibited antitumor activity against a variety of preclinical solid tumor models. Intoplicine is a 7H-benzo[e]pyrido[4,3-b]indole that inhibits DNA nicking and closing reactions by stabilizing the cleavable complex, a transient intermediate in the religation reaction involving topoisomerase I and II and DNA. Twenty-eight patients with refractory advanced malignancies who met standard phase I eligibility criteria were enrolled in a dose-escalation study of intoplicine, ranging from 7 to 420 mg/m2/day administered as a continuous 72 h i.v. infusion. Fifty-three courses were administered and evaluated. Myelosuppression (four patients, grade 3; two patients, grade 4) and hepatic toxicity (one patient, grade 3) were dose limiting at 336 mg/m2/day. No objective antitumor responses were observed. The pharmacokinetic parameters of intoplicine were investigated in 11 patients at dose levels of 112 (n=1), 224 (n=3), 336 (n=6) and 420 (n=1) mg/m2/day. Both the area under the plasma concentration versus time curves and the maximum plasma concentrations increased linearly within the dose range studied. Intoplicine content measured in whole blood exceeded that found in plasma by 3- to 7-fold, indicating that red blood cells may serve as a drug reservoir. Preclinical cytotoxic concentrations were not achieved at the dose levels studied.

Adult↗
PubMed1999

Fluoropyrimidines: a critical evaluation.

After nearly four decades of clinical experience with the fluoropyrimidines, 5-fluorouracil (5-FU) remains an integral part of chemotherapy for colorectal cancer. A range of 5-FU treatment regimens with or without biochemical modulation are currently used and toxicity appears to be schedule dependent. The use of oral 5-FU was abandoned because of erratic absorption caused by varying levels of dihydropyrimidine dehydrogenase (DPD) found in the gastrointestinal tract. This effect may be overcome by administering agents that are converted to 5-FU or by inhibiting or inactivating DPD. Xeloda((R)) (capecitabine) was designed as an orally administered, selectively tumoractivated(TM) cytotoxic agent which achieves higher levels of 5-FU in the primary tumor than in plasma or other tissues. The United States Food and Drug Administration (FDA) has approved Xeloda for use in patients with metastatic breast cancer resistant to paclitaxel and in whom further anthracycline therapy is contraindicated. Xeloda is also registered in Canada, Switzerland, Thailand and Argentina. In phase II clinical trials in colorectal cancer, Xeloda produced response rates of 21-24% and median time to disease progression of 127-230 days. Other oral agents in development for the treatment of colorectal cancer include tegafur/uracil plus oral leucovorin, S-1 and eniluracil plus oral 5-FU.

Administration, Oral↗
PubMed1999

Sequential biochemical modulation of fluorouracil with folinic acid, N-phosphonacetyl-L-aspartic acid, and interferon alfa-2a in advanced colorectal cancer.

PURPOSE: Several agents have been evaluated for their effect as biochemical modulators of fluorouracil (5-FU) in the treatment of metastatic colorectal carcinoma. In this study, we used folinic acid (FA), N-phosphonacetyl-L-aspartic acid (PALA), and recombinant interferon alfa-2a (IFNalpha-2a) in a sequential order to assess the efficacy of this approach in patients with metastatic colorectal carcinoma. PATIENTS AND METHODS: Forty-four patients with metastatic colorectal carcinoma were enrolled onto the study. The treatment course consisted of three cycles: (cycle 1) FA 20 mg/m(2) followed by 5-FU 425 mg/m(2) on days 1 to 5; (cycle 2) PALA 250 mg/m(2) on days 29, 36, 43, and 50 and 5-FU 2,600 mg/m(2) as a 24-hour infusion on days 30, 37, 44, and 51; and (cycle 3) IFNalpha-2a 9 million units (MU) three times a week for 5 weeks beginning on day 57, with a continuous infusion of 5-FU 750 mg/m(2) on days 57 to 61, and then weekly bolus of 5-FU 750 mg/m(2)/wk on days 71, 78, and 85. Response was determined after cycle 3. RESULTS: All patients had a Zubrod performance status >/= 2, measurable disease, and had received no prior chemotherapy for their metastatic disease. A total of 212 cycles were given. Thirty-six patients were assessable for response. No complete responses were seen. Seven patients had a partial response, eight had stable disease, and 15 had progressive disease. The median duration of response was 25 weeks, and the median survival was 53 weeks. Grade 3 and 4 toxic effects included granulocytopenia, stomatitis, diarrhea, rash, nausea, and fatigue. CONCLUSION: This trial provided no evidence that sequential biochemical modulation of 5-FU in patients with metastatic colorectal carcinoma had any therapeutic advantage over conventional treatment regimens of 5-FU plus FA.

Adult↗